WO2002072599A1

WO2002072599A1 - Anti-apoptosis agents or regeneration promoters comprising ginsenosides

Info

Publication number: WO2002072599A1
Application number: PCT/JP2002/000369
Authority: WO
Inventors: Masahiro Sakanaka; Junya Tanaka; Kimihiko Nakata; Hidemitsu Uno; Makoto Kuramoto
Original assignee: Japan Science And Technology Corporation
Priority date: 2001-02-21
Filing date: 2002-01-21
Publication date: 2002-09-19
Also published as: JP2002249498A

Abstract

Efficacious intravenous preparations, skin preparations for external use, mucosal preparations for external use or cosmetics comprising novel ginsenoside derivatives (in particular, dihydroxyginsenoside Rb1 or epoxyginsenoside Rb1) which are useful as anti-apoptosis agents, skin tissue regeneration/reconstruction promoters or wound healing promoters are provided. Also, fertilizer compositions comprising ginsenoside derivatives (in particular, dihydroxyginsenoside Rb1 or epoxyginsenoside Rb1) which are useful as plant tissue generation/regeneration promoters are provided. Namely, intravenous preparations, skin preparations for external use, mucosal preparations for external use or cosmetics comprising ginsenoside derivatives (in particular, dihydroxyginsenoside Rb1 or epoxyginsenoside Rb1) which are particularly useful in promoting the regeneration/reconstruction of tissues suffering from mucosal or skin aging, section wound, open wound, bite or defect, promoting wound heating or preventing, treating or remedying diseases causing cell death. Also, fertilizer compositions comprising ginsenoside derivatives (in particular, dihydroxyginsenoside Rb1 or epoxyginsenoside Rb1) which are particularly useful in aquaculture and growth of agricultural crops.

Description

Description Anti-apoptotic agent or regeneration promoter consisting of ginsenoside derivatives

The present invention is represented by the following general formula (I) (wherein R ¹ and R ² represent a hydroxyl group, or R ¹ and R ² together represent an oxygen atom and form an oxysilane ring together with an adjacent carbon atom). Dihydroxidine senoside R bi or epoxy ginsenoside R bi or a metabolite thereof or a salt thereof, a pharmaceutical composition comprising these compounds, a composition for external skin or mucosa, and growth Regarding the composition for adjustment

More specifically, the present invention relates to a pharmaceutical composition for inhibiting apoptosis or apoptosis-like cell death of cells, particularly brain and nerve cells. More specifically, the present invention relates to a dihydroxidine senoside Rb or an epoxy ginsenoside Rbi useful for prevention, treatment or treatment of a disease or pathological condition which causes cell apoptosis or apoptosis-like cell death. A pharmaceutical composition comprising: In the present invention, a disease state includes a disease state. Further, the present invention relates to the ginseng syrup described in PCT / JP00 / 04102, PCT / JP00 / 05555 and Japanese Patent Application No. 2000-248485. As well as the effects, indications, and uses of Rb ゃヒドロドロジンジン bi bi 脳優れ優れ脳脳脳脳脳脳脳脳脳脳脳脳同様同様Or a metabolite thereof or a salt thereof. In addition, the present invention provides a composition for external use on the skin (cosmetic composition, hair growth and hair growth) similar to ginsenoside R bi ゃ dihydrozincenoside R bi described in Japanese Patent Application No. 2000-248458. A composition, a composition for chemical peeling), a dihydroxidine senoside R bi or an epoxy ginsenoside R b useful as an external mucosal composition or a composition for regulating growth. Landscape technology

In WO 00/3784 81 and WO 0/46806, the present inventors (Sakanaka, Tanaka) have the following structural formula

Ginsenoside R bt (60 ^ g / day, 12 days or 6 / Z g / day) indicated in the middle cerebral artery cortical branch (MCA) permanent occlusion rat (weight of about 30 0 g) of cerebral cortical infarct area is reduced to less than one-half that of MCA permanently occluded rats receiving vehicle, and improved paraplegia in bedridden spinal cord injured rats And invented to raise the animal. Ginsenoside Rb inhibits apoptosis or apoptosis-like cell death of all cells including neurons in the optimal extracellular solution concentration range of 1 to 100 μg / m1. Are disclosed in WO 00 Z 37481. That is, it is disclosed in WO 00/374781 that ginsenoside Rb is a pharmaceutical composition for preventing, treating, and treating diseases that cause apoptosis or apoptotic cell death.

Therefore, the therapeutic effects of low doses of low concentrations of ginsenoside Rb on the treatment of cerebral infarction and spinal cord injury were far superior to those of the past. 〇 In the issue of 0 0/4 8 6 08, the present inventors (Sakanaka, Tanaka) It can be said that it was found earlier. Therefore, the present inventors have determined that ginsenoside Rb! Can be newly developed as a lead compound, a compound for treating cerebral infarction, a compound for treating nerve trauma, or a nerve cell protective agent can be developed, as described in WO 00/486680. I have. But ginsenoside R b! No specific examples of compounds that can be prepared by utilizing the compound as a lead compound are disclosed in WO 00/48608.

In addition, ginsenoside Rbi itself is a natural compound for which no synthetic method has been established at the present time, so ginsenoside Rbi is a lead compound, a novel compound for treating neurological trauma, cerebral infarction or brain / neural cells. It was thought by those skilled in the art that it was impossible to make a protective agent. Furthermore, even if ginsenoside Rb is chemically modified to produce a ginsenoside derivative, if any part of the chemical structure of ginsenoside Rb is modified, it is equivalent to or equal to ginsenoside Rbi. At first, the present inventors were completely unpredictable as to whether a better novel compound for treating neurological trauma, a compound for treating cerebral infarction or a brain / neuron protective agent could be prepared. Specific examples of ginsenosides and ginsenoside derivatives will be described later.

However, in P CTZJ P 0 0 Z 0 4 10 2 and Japanese Patent Application No. 2000-0—2484 58, the present inventors (Sakanaka, Tanaka) unexpectedly thought that the following structural formula The dihydrozincenoside R bi represented by

Excellent in extracellular concentration range (0.01 fg / m1 to 1 ng / m1) wider than ginsenoside Rbi, which is superior to ginsenoside Rbi for protecting brain and nerve cells A pharmaceutical composition, a pharmaceutical composition for treating an organic disease, a pharmaceutical composition for promoting biological tissue regeneration, a pharmaceutical composition for promoting wound healing, an external skin composition, an external mucosal composition, and a composition for regulating growth. I found it. In other words, an excellent pharmaceutical agent can be obtained by chemically modifying the double bond of the side chain (force-punch chain) bonded to the steroid-like skeleton (damaran skeleton) of ginsenosides such as ginsenoside Rbi. The present inventors have found that a composition, a composition for external use on the skin (including a composition for cosmetics, a composition for chemical peeling, and a composition for hair growth and hair growth), a composition for external use on mucous membranes, and a composition for regulating growth can be prepared. It came before the world.

The present inventors have the following general formula (I)

(In the formula, RR ² is a hydroxyl group, or R ¹ and R ² represent an oxygen atom together with an adjacent carbon atom to form an oxysilane ring.)

In the optimal extracellular solution concentration range (1 fg / m1 to 100 ng / m1) that is wider than ginsenoside Rbi. The present inventors have found that apoptosis or apoptosis-like nerve cell death of nerve cells is inhibited and completed the present invention. That is, dihydroxy ginsenoside R b or epoxy ginsenoside R bt or a metabolite thereof or a salt thereof is PCT / JP 0 0 0 4 0 102, PCT / JP 0 0/0 55 5 No. 4 if No. Each time 2 0 0 0 - 2 4 8 4 5 similarly to the effectiveness and efficacy * application of the described Jinsenosai de R b [Yaji hydro ginsenosides Sai de R b _t in No. 8, excellent Pharmaceutical composition for protecting brain and nerve cells, pharmaceutical composition for treating brain and neurological diseases, pharmaceutical composition for treating organic diseases, pharmaceutical composition for promoting biological tissue regeneration, pharmaceutical composition for promoting wound healing, and external skin composition object, It has been found that it is a composition for external mucosa and a composition for regulating growth. Disclosure of the invention

An object of the present invention is to provide a pharmaceutical composition for inhibiting apoptosis or apoptosis-like cell death of cells, particularly brain and nerve cells. More specifically, the present invention relates to a pharmaceutical composition comprising dihydroxy ginsenoside R bi or epoxy ginsenoside R bi, which is useful for the prevention, treatment or treatment of diseases or conditions that cause cell apoptosis or apoptosis-like cell death. It provides things. Further, the present invention relates to the ginsenoside R described in PCT / JPOO / 04102, PCTZ JP0000Z055554 and Japanese Patent Application No. 2000-0248584. Bi-dihydrodinsenoside R Bi has the same effects as its efficacy, efficacy, and uses, as well as excellent brain and nerve cell protective effects, therapeutic effects on cranial nerve diseases, therapeutic effects on organic diseases, promoting tissue regeneration, and promoting wound healing. The present invention provides the compound, a metabolite thereof, or a salt thereof. In addition, the present invention relates to ginsenoside R b ゃ dihydroginsenoside R bi described in PCT / JP 00 / 55,554 and Japanese Patent Application No. 2000-248,584. Similarly, dihydroxy ginsenoside R bi, which is useful as a composition for external use on skin (cosmetic composition, composition for hair growth and growth, composition for chemical ruby ring), composition for external mucous membrane or composition for growth regulation It provides an epoxy ginsenoside R b. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a ΔR chart of dihydroxyginsenoside R bi (code name: S2821).

The upper part of Fig. 2 shows the dihydroxy ginsenoside Rb (code name: S2821) against apoptosis or apoptosis-like neuronal cell death of cultured neurons by SNP (sodium nitroprusside). This is a photograph of MAP 2 (microtubule-associated protein2) immublot instead of the drawing. The lower part of FIG. 2 is a graph obtained by densitometric analysis of the data of the MAP2 membrane knob. Figure 3 shows the NMR chart of the epoxy ginsenoside R bi (code name: S2822).

The upper part of Fig. 4 shows the protective effect of epoxy ginsenoside R bi (code name: S2822) on apoptosis or apoptosis-like neuronal cell death of cultured neurons by SNP. It is a picture of a MA P 2 imno plot. The lower part of FIG. 4 is a graph obtained by densitometric analysis of MAP2 immunoblot data.

FIG. 5 is a diagram showing a part of chemical derivatives that can be prepared by using ginsenoside Rb as a lead compound.

FIG. 6 is a light micrograph instead of a drawing showing the effect of intravenous administration of ginsenoside R b on incision wounds. A is a case of ginsenoside Rbt administration, and B is a case of physiological saline administration.

Fig. 7 shows ginsenoside R b! 4 is an optical micrograph as a substitute for a drawing showing the therapeutic effect of intravenous administration. A is a case of ginsenoside Rbt administration, and B is a case of physiological saline administration.

FIG. 8 is an optical micrograph instead of a drawing showing the effect of intravenous pre-administration of ginsenoside Rbi on open wounds. A is a case of ginsenoside Rb administration, and B is a case of physiological saline administration.

FIG. 9 is a photograph instead of a drawing showing the slight therapeutic effect of topical administration of ginsenoside R b 丄 at a low concentration (0.001% by weight) on open wounds.

Fig. 10 shows the skin of ginsenoside R bi at lower concentrations (0.0001% by weight, 0.00001% by weight, 0.00001% by weight) on open wounds. 4 is a photograph replacing a drawing showing the effect of topical administration.

First FIG. 1 is a photograph as a drawing which shows the effect of mucosal topical application of 1 0 ⁵ wt% of Jinsenosai de R bi for Hitoro腔粘film bites.

FIG. 12 is a photograph instead of a drawing showing the effect of applying 10 to ⁵ % by weight of ginsenoside Rbi to the mucosa of human oral mucosa.

FIG. 13 is a photograph instead of a drawing showing the effect of ginsenoside R bi (100 fg / m 1) on the day 13 of pothos root regeneration and regeneration and rooting. Fig. 14 shows ginsenoside R b! (100 fg / m 1) is a photograph replacing a drawing showing the effect of the second day.

The first 5 figures of 1 0 ⁴ -1 0 ^8% by weight with respect to open wounds in rats Jinsenosai de R b! 4 is a photograph in place of a drawing showing the effect of topical administration.

The first 6 is a graph showing the effect of topical administration of 1 0 ⁴ -1 0 ^8% by weight of Jinsenosai de R bt for open wounds in rats.

The first 7 is a photograph as a drawing which shows the effect of topical administration of 1 0 ⁴ -1 0 ^7% by weight of Jihidorojinse Nosai de R b for open wounds of rats.

The first 8 is a graph showing the effect of topical administration of 1 0 ⁴ -1 0 ^7% by weight of Jihidorojinse Nosai de R bi for open wounds of rats Bok.

FIG. 19 is a photograph of a MAP2 immunoblot instead of a drawing, showing the protective effect of dihydroginsenoside Rb on apoptosis or apoptosis-like neuronal cell death of cultured neurons by SNP.

Fig. 20 is a graph showing the protective effect of dihydroginsenoside Rb on apoptosis of cultured neurons or death of apoptotic neurons by SNP.

FIG. 21 shows an NMR chart of dihydroginsenoside R bi.

FIG. 22 is a photograph, instead of a drawing, showing the results of TTC staining of rat brains (two cases) to which saline was intravenously administered after MCA permanent occlusion (ie, after the onset of cerebral infarction).

Fig. 23 shows TTC staining of rat brains (2 cases) to which dihydroginsenoside Rbi (6; Cig / day) was intravenously administered after MCA permanent occlusion (ie, after onset of cerebral infarction). This is a photograph that shows the result and replaces the drawing.

FIG. 24 is a graph showing the effect of intravenous administration of dihydroginsenoside Rbi (6 g / day) on rats with cerebral infarction.

FIG. 25 is a photograph replacing a drawing showing a rat 2 days after spinal cord injury. The photograph on the left shows an example of administration of physiological saline, and the photograph on the right shows an example of administration of dihydroginsenoside Rbi.

FIG. 26 is a photograph replacing a drawing showing another rat on the second day after spinal cord injury. The photograph on the left is an example of saline administration, and the photograph on the right is an example of dihydroginsenoside Rbt administration.

Figure 27 is a photograph replacing the drawing showing the evening nago immediately after the creation of the open wound.

Figure 28 is a photograph replacing a drawing showing freshwater reared locusts (5) on the eighth day after creation of the open wound.

Fig. 29 is a drawing showing seven evening nagos reared in freshwater containing ginsenoside R b, (100 fg / m 1), which survived on the eighth day after the creation of the open wound. This is an alternative photo. BEST MODE FOR CARRYING OUT THE INVENTION

The present invention provides a compound represented by the following general formula (I):

A dihydroxy or epoxyzincenoside R bt or a metabolite thereof Or a salt thereof, and a pharmaceutical composition comprising these compounds, preferably a pharmaceutical composition comprising these compounds, and a pharmaceutically acceptable carrier.

More specifically, the present invention relates to a pharmaceutical composition for inhibiting apoptosis or apoptosis-like cell death of cells, particularly brain and nerve cells. More specifically, the present invention relates to a dihydroxidine zenoside R bi or an epoxy ginsenoside R bi which is useful for prevention, treatment or treatment of diseases or pathologies that cause cell apoptosis or apoptosis-like cell death. A pharmaceutical composition comprising: Further, the present invention relates to PCT / JP0Z04102, PCT / JP0 / 055554, and Japanese Patent Application No. 2000-248.

The effect, efficacy and use of ginsenoside R bi ゃ dihydrozinenoside R bi described in No. 458, as well as excellent brain and nerve cell protection effects, brain and neurological treatment effects, organic disease treatment effects, The present invention relates to the compound, a metabolite thereof, or a salt thereof, which has a biological tissue regeneration promoting effect or a wound healing promoting effect.

Also, the present invention relates to Japanese Patent Application No. 2000-248485 and PCT / JP00 / 05.

Similar to ginsenoside R bi ゃ dihydrozin genoside R bi described in No. 554, a composition for external use on the skin (cosmetic composition, composition for hair growth and hair growth, composition for chemical peeling), composition for external mucosa The present invention relates to dihydroxidine senoside R bi or epoxy ginsenoside R bi useful as a product or a composition for regulating growth.

The dihydroxyzine senoside R bi and the epoxy ginsenoside R bt of the present invention are typical examples of ginsenoside derivatives, and the natural ginsenosides and ginsenoside derivatives will be specifically described below. Ginsenoside R is used as “natural ginsenosides” or naturally occurring ginsenoside. (Gin senoside Ro; Chikusessa Nin V; chikuset susaponin V '· saponin A; saponi n A), Jinsenosai de R ai (ginsenoside Ra 1), Jinsenosai de _{_{R a 2 (gin senoside Ra 2}} ), Jinsenosai de R bi (ginsenos ide Rb 1; saponin D (sapon in D), Jinsenosai de R b 2 (ginsenoside Rb 2) , Jinsenosai de _{_{R b 3 (gi nsenoside Rb 3}} ), Jinsenosai de R c (ginsenoside Rc), Jinsenosai de R d (ginsenoside Rd), Jinsenosai de R e (ginsenoside Re); Jinsenosai de _{R a 3 (ginsenos ide Ra 3} ); Bruno Bok Jinsenosai de R 4 (notoginsenos ide R4); Kinkenosai (kinkenoside Ri); Jinsenosai de R si (ginsenoside Rs i); Jinsenosai de _{_{R s 2 (ginsenoside Rs 2)}} ; (2 0 S) - Jinsenosai de R g 3 (20s - ginsenoside Rg 3); 2 0- Darko Ginsenoside R f (20-glucogins enoside Rf); notoginsenoside R l (notoginsenoside R 1); ginsenoside R f (ginsenoside Rf); (2 OR) — ginsenoside R g ₂ (20R-ginsenos i de Rg ₂ ); (2 OR) — ginsenoside R hi (20R-ginsenoside Rhi); ginsenoside R f (ginsenoside Rf); ginsenoside R gi (ginsenoside Rgi); ginsenoside R g 2 (ginsenoside Rg ₂ ) Chikusetsusa ponin I; ginsenoside R g ₃ (ginsenos i de Rg ₃ ); ginsenoside Rh i

(ginsenoside Rhi); Jinsenosai de _{_{R h 2 (ginsenoside Rh 2)}} ; Maronirujin Senosai de R bi (maronylginsenoside Rb; Malo Elgin Seno Sai de R b ₂

(maronylginsenos ide R ₂ ); maronylginsenoside Rc; maronylginsenos i de Rc; malonylginsenoside Rd; maronylginsenoside Rd; chicusesusaponin la; chiksesaponlb Chikusetsusaponin III); chikusetsusaponin IV; c hikusetsusaponin IV; saponin B (saponin B); chixsetsusaponin IVa; saponin C (saponin C); protopanaxadiol), D ton ヽ. Protopanaxatriol, oleanolic acid, and the stereoisomers of these compounds are mentioned. These ginsenosides are considered to have a common effect, efficacy, and application because they have similar chemical structures. Note that naturally occurring ginsenoside compounds or ginsenosides are also described in PCTZ JP 00/04102 and PCT / JP 0 Z05554.

In addition, as a compound derived by chemically modifying ginsenoside compounds such as naturally occurring ginsenoside Rb by chemical means, the chemical structure of the natural ginsenosides described above is modified in the following manner. (Hereinafter, these compounds are referred to as “ginsenoside derivatives” in the present specification.)

That is, (1) a product obtained by reducing the double bond of the side chain (carbon chain) bonded to the steroid-like skeleton (damaran skeleton) of ginsenosides (the so-called dihydrogen group). (Drosincenosides) or those obtained by acylation or acetylation; (2) Ginsenosides obtained by acylation or acetylation of hydroxyl groups; (3) Side chain (carbon chain) in addition to acylation or acetylation (1) a double bond having a single bond and an arbitrary functional group (for example, one or more hydroxyl groups) bonded to the same bond, or a bimolecular hydroxyl group dehydrated and epoxidized; In addition to acylation or acetylation, the double bond in the side chain is cleaved to give an aldehyde group at the end,

(5) In addition to the acylation or acetylation, an arbitrary functional group such as an alkyl group or a aryl group is bonded to the end of the side chain. (6) The double bond of the side chain in addition to the acylation or acetylation. (7) A double bond in the side chain is cut to bond a lipoxyl group or an aldehyde group, (8) One of the two A methyl group substituted with a hydrogen atom and the other methyl group substituted with an arbitrary functional group such as an alkyl group or a aryl group. (9) A double bond in the side chain is converted into a single bond, and A group in which one or more hydroxyl groups are bonded, or a hydroxyl group of a dimer is dehydrated and epoxidized, and (10) a diene compound such as cyclopentadiene is used for a double bond in a side chain. ie 1 s-A 1 der reaction, (1 1) Protopanaxadi Or any compound having, as a basic skeleton, a phenol, protopanaxatriol, damarane, oleanolic acid or a reduced form thereof. The derivatives of the ginsenosides (particularly, protopanaxadiol-based saponins and protopanaxatriol-based saponins) are described in PCT / JP00 / 04102 (a brain cell consisting of ginseng). And PCTZJP 0/05554 (a skin tissue regeneration promoting agent comprising ginsenoside R bi). Further, in PC TZ JP 00/004 102 and PCT / JP 00/0555 54, the neuroprotection of dihydrozincenoside Rb, which is one of the above ginsenoside derivatives, is described. The method describes how to create an action and a skin tissue regeneration promoting action, as well as NMR charts and the like.

Among ginsenosides, oleanolic acid having a slightly different chemical structure, for example, ginsenoside Ro (chixessaponin V), may be chemically modified in the following manner. In other words, (1) the steroid-like skeleton of ginsenosides (oleanolic acid) or the double structure existing in the chemical structure of aglycone (2) those in which the hydrogen atom at the reduction site in (1) is replaced with an arbitrary functional group (for example, hydroxyl group, alkyl group, aryl group, etc.); Esterified carboxyl groups; (4) acylated or acetylated hydroxyl groups; (5) and (1) a combination of two or more of the modifications (1) to (4). The above-described ginsenoside derivatives and their stereoisomers are considered to have common effects and effects because they have similar chemical structures to each other, and can be used alone or in some cases. Alternatively, they can be used simultaneously in combination with a plurality of different ginsenoside derivatives or ginsenosides. In the present invention, among the above-mentioned ginsenoside derivatives, dihydroxyzine senoside R bi and epoxy ginsenoside R bi are described below. This also applies to the derivatives of the dos.

The metabolites of the ginsenoside derivatives of the present invention, in particular, dihydroxyzinenoside R bi and epoxy ginsenoside R bt include compounds produced as a result of metabolizing the ginsenosides of the present invention in vivo. Particularly, the sugar chain is cleaved, and the active ingredient of the present invention is not limited to the above-mentioned ginsenosides, but is a metabolite of these in vivo and achieves the object of the present invention. It is a compound that can be produced.

The pharmaceutical composition of the present invention comprising dihydroxyxenosenoside Rb or epoxyzinsenoside Rbi is a novel compound to the knowledge of the present inventors. The pharmaceutical composition comprising dihydroxyxenosenoside R b or epoxyzine senoside R bi of the present invention comprises dihydroxyxenosenoside R bi or epoxy ginsenoside R bi or a metabolite thereof, or a metabolite thereof. It is preferable to use a low concentration of the above-mentioned salt. In addition, these pharmaceutical compositions of the present invention can be administered intravenously or mucosally in the same manner as ginsenoside R bi disclosed in WO 00/37841 and WO 00/46808. Parenteral administration forms such as are preferred. More specifically, these pharmaceutical compositions of the present invention contain a parenteral composition comprising dihydroxyxenosenoside Rb or epoxyzinenoside Rbi or a metabolite thereof or a salt thereof at a low concentration. Administration formulations are preferred. In addition, the present invention provides a method for preventing cranial nerve disease or any disease involving cell death, which preferably contains dihydroxy ginsenoside R bi or epoxy ginsenoside R b or a metabolite thereof or a salt thereof at a low concentration. The present invention relates to a preparation for parenteral administration for treatment or therapy, preferably an intravenous preparation, an external preparation for skin, and an external preparation for mucosa similar to those for ginsenoside Rbi.

These pharmaceutical compositions of the present invention are preferably intravenous preparations, skin external preparations, and mucosal external preparations, but are preferably topical external preparations for lesions, local injections for lesions, oral preparations, nasal drops, eye drops, and intraarticular administration. Formulation, intrathecal formulation, intraarterial formulation, ophthalmic ointment, ear drops, suppositories (including vaginal suppositories), subcutaneous injections, intradermal injections, intramuscular injections, inhalants, sublinguals, transdermal Any or known route of administration, such as an absorbent, can be selected.

The present invention also relates to a long-term therapeutic, preventive, or therapeutic agent for cerebral and neurological diseases, or an agent for protecting brain cells or neuronal cells, comprising the above-mentioned preparation for intravenous administration or topical preparation for lesions.

Further, the present inventors have Jinsenosai de R b ^ dihydroxy obtained newly by chemically modifying ginsenosides Sai de R b _t or epoxy ginsenosides Sai de R bt, metabolites thereof or salts thereof Have an excellent anti-apoptosis or apoptosis-like cell death-suppressing action. It demonstrates that it can be used as a lead compound to search for other active ingredients for prevention, treatment or treatment of cerebral and neurological diseases such as diseases or stroke. Alternatively, after modifying a part of the chemical structure of dihydroxy ginsenoside Rb or epoxy ginsenoside R bi to produce a prodrug, any or a known administration route can be selected. It is.

The dihydroxy ginsenoside R b or the epoxy ginsenoside R b of the present invention is represented by the above structural formula, and the dihydroxy ginsenoside R bi or the epoxy ginsenoside R bi is owned by the present inventors. It can be produced by chemically modifying high-purity ginsenoside R bi by the method described below.

The dihydroxyxenosenoside R bi or epoxyzinsenoside R b of the present invention can be used in free form, but it can also be used with an appropriate salt. You. They can also be used as solvates such as hydrates thereof.

The concentration of the dihydroxyxenosenoside R bi or the epoxy ginsenoside R bi of the present invention is preferably low, more specifically, the extracellular solution concentration is preferably 100 g / m 1 or less, more preferably The concentration is 100 ng / ml or less, more preferably 1 ng / m 1 or less, and even more preferably 100 og / ml or less. When the dihydroxycinnoside R bi or epoxy ginsenoside R bi of the present invention is used as an intravenous preparation, an external preparation for skin, or an external preparation for mucous membrane as in the case of ginsenoside R bi, the affected area of the patient is also affected. It is preferable to adjust the preparation so that the extracellular fluid concentration in the tissue becomes the above-mentioned concentration. The pharmaceutical composition and preparation of the present invention can provide a sufficient effect even when the concentration of extracellular fluid in the affected tissue is about 0.01 to 100 μg / m 1.

The preparation for intravenous administration of the dihydroxy ginsenoside Rb or the epoxy ginsenoside R bi or a salt thereof according to the present invention can be administered directly into a blood vessel, preferably into a vein similarly to ginsenoside Rbt. Once dissolved in a known biologically, pharmaceutically or pharmaceutically acceptable carrier such as physiological saline, distilled water, phosphate buffer, glucose solution, ribosome, fat emulsion, etc. It can be used as a formulation for intravenous infusion or a formulation for continuous intravenous administration. It may also be a dosage form that can be used by adding to an intravenous preparation such as a composition for infusion. Also, dihydroxy ginsenoside R b! Alternatively, a part of the chemical structure of the epoxyginsenoside Rbi can be modified to form a prodrug, and any or known administration route and administration method can be selected. For example, esterification of the hydroxyl group of dihydroxy ginsenoside Rb or epoxy ginsenoside Rb: produces a prodrug, which is passed through the blood-brain barrier and then hydrolyzed by endogenous esterase to produce a drug in the brain. It is also possible to increase the amount of transfer of dihydroxy ginsenoside R or epoxy ginsenoside R b to the surface.

The dihydroxy ginsenoside R bi or the epoxy ginsenoside R bi of the present invention is described in WO 00Z3748.1, WO0Z4868, PCT / JP 00/041. Similarly to ginsenoside Rb and dihydroginsenoside Rbi described in No. 02, intravenous administration is thought to reduce the volume of cerebral infarction lesions to about 1/4 of the non-administration group. Acute and chronic cerebral infarction (cerebral thrombosis and cerebral embolism) as well as cerebral hemorrhage and acute or chronic stage of subarachnoid hemorrhage or transient ischemic attack However, it can be used as a neuroprotective agent. In other words, dihydroxidine genoside Rbi or epoxy ginsenoside Rbi is considered to be a drug that allows intravenous infusion in an ambulance for patients with suspected stroke. In addition, the administration of dihydroxyxenosenoside Rt or epoxyzinosenoside Rbt to cerebral infarction patients before the administration of thrombolytic therapy improves the prognosis of the patients. Needless to say, the pharmaceutical composition of the present invention is useful for prevention, treatment or treatment of any disease or condition that causes impaired blood flow, like ginsenoside Rbi.

In the present invention, dihydroxyxenosenoside Rb or epoxyzinsenoseide Rbi is described in WO 00/37484, WO 00Z46806 and PCT / JP00 / Similarly to ginsenoside R b L ゃ dihydrozinsenoside R bi described in No. 0 4 102, it suppresses apoptotic neuron death in the ischemic foci periphery (ischemicpen um bra), and in addition, glial cells, It is thought to inhibit apoptosis or apoptosis-like cell death of all cells including vascular endothelial cells. That is, it can be said that dihydroxyzine senoside R b or epoxy ginsenoside R b has almost the same pharmacological action as ginsenoside R b ゃ dihydroxy ginsenoside R bi. More specifically, WO 00/37848 (a brain cell or nerve cell protective agent comprising ginsenoside R b), WO 00/46806 (a ginsenoside R bi comprising Cerebral blood vessel regeneration / remodeling promoter and inhibitor for secondary degeneration of nerve tissue) PCT / JP 00/04101 (protective agent for brain cells or nerve cells consisting of ginseng) or Japanese patent application 20 The present inventors (Sakanaka, Tanaka, Nakada) found in 0 0 — 2 4 8 4 5 8 and PCT / JP 0 0Z0 5 5 5 4 (skin tissue regeneration promoter comprising ginsenoside R bi). All effects of ginsenoside Rbt or dihydrogensenoside Rbi or its metabolites, efficacy, uses, and effects are all dihydroxyzinenosides Rbi or epoxy ginsenosides Rbi or their metabolites or salts thereof. Is considered to have both. More specifically, a pharmaceutical composition comprising dihydroxyxenosenoside R bi or epoxy ginsenoside R bi or a metabolite thereof or a salt thereof has an anti-apoptotic effect, apoptosis-like cell death inhibition Effect, cerebral nerve cell protection effect, cerebral infarction · stroke treatment effect, spinal cord injury · nerve trauma · head injury treatment effect, nervous tissue secondary degeneration deterrent effect, cerebrovascular revascularization It is considered to have the effect of promoting bio-reconstruction, protecting cardiomyocytes, treating pressure sores, improving cerebral edema, regenerating biological tissue, promoting remodeling, treating organic diseases, and promoting wound healing. In addition, dihydroxy ginsenoside R b! Or epoxy ginsenoside R bi or a metabolite thereof or a salt thereof is disclosed in Japanese Patent Application No. 2000-248484 and PCT / JP 00/0. Similar to ginsenoside Rb or dihydroginsenoside Rbi described in No. 5.55, it is an excellent cosmetic composition, a composition for hair growth and growth, a composition for chemical peeling, and an external mucous membrane It would be a composition, a plant growth regulating composition, an animal growth regulating composition. The composition comprising a ginsenoside derivative such as dihydroxy ginsenoside R b or epoxy ginsenoside R b is 1% by weight or less, preferably 0.01% by weight or less, more preferably 0% by weight or less. Although it can be used at a concentration of 0.001% by weight or less, it is especially useful for controlling, improving, and treating aging symptoms of the skin and mucous membranes.

In particular, a pharmaceutical composition comprising dihydroxy ginsenoside R bt or epoxy ginsenoside R b or a metabolite thereof or a salt thereof inhibits apoptosis-like neuronal death, apoptosis of brain and nerve cells, and apoptosis of glial cells. Suppress all neurodegenerative diseases (Alzheimer's disease, Pick's disease, spinocerebellar degeneration, Parkinson's disease, chorea, polyglutamine disease, amyotrophic lateral sclerosis, etc.) ゃ Demyelinating disease (leukoencephalitis, It is also effective for Binswanger's disease, chronic hypoperfusion injury of the brain, multiple sclerosis, etc., and slows the progression of higher nervous dysfunction caused by these diseases, and the quality of life (QOL) of patients Can be increased. That is, dihydroxyginsenoside R bi or epoxy ginsenoside R b is a disease that causes cell death described in PCT / JPOO / 04102 (a brain cell or nerve cell protective agent composed of ginseng). · Valid for all conditions.

By the way, as described in WO 00Z37481 (a brain cell or nerve cell protective agent comprising ginsenoside R b), ginsenoside R bi is a permanent occlusion rat of the middle cerebral artery cortex (MCA) (about body weight). In the case of 300 g), daily dose and continuous intravenous administration of 60 g significantly reduce cerebral infarction lesions and improve location learning disorder (cerebrovascular dementia). Furthermore, in WO 00/37841, apoptosis of neurons or ginsenoside R bl to 100 igZml in the optimal extracellular fluid concentration range is described. Disclose inhibiting apoptosis-like cell death. The dose of the dihydroxycinenoside R bi or epoxy ginsenoside R b of the present invention to be continuously infused into the vein of a cerebral infarction rat (body weight: about 300 g) was determined based on the results of culture experiments described below. It is considered to be equal to or greater than the ginsenoside R bi.

Based on the above assumptions, the optimal intravenous dose of dihydroxyginsenoside Rb or epoxyginsenoside Rb for a 60 kg human stroke patient is Calculate from 1.2 mg to 12 mg or more per day. Therefore, the daily dose of the pharmaceutical composition of the present invention for a human stroke patient depends on the individual differences and the medical condition of the patient, but is 0.1 mg or more, preferably 1 mg or more, more preferably 1 mg or more. 0 mg or more. However, since the required drug dose per body weight generally decreases as the weight of the animal increases, less than 1/20 of this dose may be sufficient in humans. Conversely, cranial nerve disorders with a minimal degree of blood-brain barrier failure (eg, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, polyglutamine disease, demyelinating diseases, nerve trauma, When administering dihydroxyzine cenoside Rt or epoxyzine senoside Rbi for transient cerebral ischemic attack, spinal cord injury, or head trauma, the same dose as described above or 5-1 It may be necessary to increase the dose about 0-fold. Also, dihydroxy ginsenoside R b! Or, when using epoxy ginsenoside Rb for the prevention, treatment, or treatment of diseases other than cranial nerve disease, administer the same dose as described above, or a dose of about 1/10 to 1/10000 It is preferred to choose the amount. The pharmaceutical composition of the present invention has few side effects, and the upper limit of the systemic dose for the prevention, treatment or treatment of the above-mentioned diseases can be considerably large, but is preferably 10 g or less per day, preferably It is less than lg per day, more preferably less than 0.1 lg per day. The lower limit of the systemic administration dose of the pharmaceutical composition of the present invention is considered to be 1 fg / day, judging from the effective extracellular fluid concentration. When the pharmaceutical composition of the present invention is locally administered to a lesion site, for example, as an external preparation for skin or mucous membrane, the upper limit of the dosage is 10 Omg or less per day, preferably 1 Omg, and the lower limit is 0.1. It is considered to be about fg. However, in practice, it is preferable to appropriately adjust the dose while using the extracellular solution concentration (0.01 fg / ml to 100 βg / m 1) of the affected tissue as a guide. As a systemic administration method of the pharmaceutical composition of the present invention, intravascular administration, particularly intravenous administration is preferable, and the above-mentioned dose can be administered intermittently or continuously. Dihydroxy ginsenoside Rb or epoxy ginsenoside R, which is an active ingredient of the present invention, can be formulated by a usual method. For example, the water-soluble pharmaceutical composition of the present invention is obtained by dissolving freeze-dried crystals in a known biologically or pharmaceutically acceptable carrier such as physiological saline, distilled water, phosphate buffer, glucose solution, and the like. Can be used as a preparation for intravenous administration. It can also be used as a fat emulsion and ribosome preparation. The concentration of the preparation for intravenous administration can be adjusted to any concentration as long as it is not very high. For example, 0.001 to 10 mg Zm1, preferably 0:! The dose can be about mg / m1.

Next, the ginsenoside derivatives of the present invention can be used as excellent pharmaceutical compositions for protecting brain and nerve cells, pharmaceutical compositions for treating cranial nerve diseases, pharmaceutical compositions for treating organic diseases, medical compositions for promoting biological tissue regeneration, and wounds. Healing promotion pharmaceutical composition, cell protection pharmaceutical composition, skin external composition (hair growth and hair growth composition, cosmetic composition, chemical peeling composition), mucosal external composition, and growth preparation composition This will be described in detail based on a specific example. In the present invention, compositions used for skin peeling such as chemical peeling and physical peeling are collectively referred to as a composition for chemical peeling. Therefore, as examples of ginsenoside derivatives, the results of experiments conducted by newly preparing dihydroxy ginsenoside Rb and epoxy ginsenoside Rb, and dihydroginsenoside Rbi or ginsenoside Rtw The following describes mainly the experimental results used.

First, the present inventor prepared the dihydroxy ginsenoside R bi of the present invention by the following method.

(1) acetylation

Add ginsenoside Rtl 0.0 mg into an eggplant-shaped flask, add 1 ml of pyridine to dissolve, add 0.5 ml of acetic anhydride, and stir overnight. Water was added, stirred and 3 ml and extracted three times with CHC 1 _{3 (3} ml). Concentrate the organic layer to obtain crystals. All the reactions were performed at room temperature.

(2) Osmium oxidation The Asechiru body obtained above, NMO 0. 5 mg, acetone, and dissolved by adding water each lml, added O s tertiary heptyl alcohol (tertiary buthanol) of O ₄ solution 0. 0 3 ml, 5 Stirred for hours. Then, the addition of N a _₂ S ₂ 〇 _4, quenched and filtered. The filtrate is extracted three times with CHC 1 (3 × 3 m 1), washed with water, and the organic layer is concentrated to obtain crystals. These reactions were also performed at room temperature.

(3) Hydrolysis

To § cell ^ le of diols of the, and stirred for 5 hours 3. added K ₂ C_〇 ₃ while keeping at 0 was added a main evening Nord 5 m 1. The solution was directly concentrated and isolated on a column. A column filled with 〇DS resin filled with methanol was used. After charging the column with water, a sample dissolved in water was placed on the column. As a solvent, first, only water was flowed, and then methanol was flown. Concentration of methanol yielded 9.4 mg of white crystals (yield 95.2%). The melting point is 160.2-163.4 ° C. Incidentally, the melting point of ginsenoside R b is 197 to 198 ° C (literature value). In Figure 1, NMR chart (4 0 0 MH Z, CD 3 0 D) be shown.

Next, the present inventors consider that the dihydroxy ginsenoside R b! (Code name: S 2 8 2 1) is WO 0 0 Z 3 7 4 8 1, PCT / JP 0 0/0 5 5 5 4 or Japanese Patent Application 2 0 0 0 -2 4 8 4 5 8 Similar to the ginsenoside Rb and dihydroginsenoside Rb described in (1), it was examined whether they inhibit apoptosis or apoptosis-like cell death of nerve cells.

The present inventors (Sakanaka, Tanaka) and colleagues reported that short-term exposure of cultured neurons to the nitric oxide donor, sodium nitroprusside (SNP), resulted in neuronal apoptosis or apoptotic neuronal death. Et al., J. Neurosci. Res., 53, 415, 1998). Using this culture experiment system, the present inventors have already inhibited ginsenoside Rbi from inhibiting neuronal apoptosis or apoptotic neuronal death in the optimal extracellular solution concentration range of 1 to 100 μg / m1. (WO 0 Z 3 7 4 8 1). Therefore, using a similar experimental system, the neuroprotective effect of dihydroxydine cenoside Rb was examined.

Neurons from the fetal cerebral cortex of a 17-day-old rat using trypsin EDTA The cells were separated and plated on a poly-L-lysine-coated 24-well plate. After culturing for 16 hours in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum, the culture was replaced with a serum-free medium for nerve cell culture containing insulin, transferrin, etc. Cultured for 3-4 days. On day 3 or 4 of culture, sodium nitroprusside (SNP) was added at a concentration of 300 M and incubated for 10 minutes. Thereafter, the culture medium was replaced with Eagle's minimum essential medium (EMEM) containing dihydroxydincenoside Rt (0 to 100 ng / ml) and bovine serum albumin. Sixteen hours after SNP loading, neurons were lysed using a Laemm1i electrophoresis sample buffer, polyacrylamide gel electrophoresis was performed, and the electrophoretic proteins were transferred to a ditrocellulose membrane. The immunoblotting was performed using an antibody against the neuron specific protein MAP2. The results are shown in FIG. The details of the experimental procedure for the MAP2 immunbotlot are described in published papers by the present inventors (Sakanaka and Tanaka) (Wen, T- et al., J. Exp. Med., 188, 635-649, 1998). The upper part of FIG. 2 is a photograph in place of a drawing showing the result of the immunoblot of microtuble-associated protein 2 (MAP 2). The first lane from the left is a control cultured neuron, in which a clear MAP 2 band (ie, a band for a neuronal marker) was observed. SNP treatment caused many neurons to undergo apoptosis or apoptosis-like neuronal death, so the MAP2 band was clearly weakened, as in the second lane from the left. Dihydroxidine senoside Rbi was added to the culture medium at a concentration of 0.001 fg / ml (lane 4) to 100 ηg / ml (lane 10), Apoptosis or apoptosis-like neuronal cell death was clearly suppressed, and as a result, a strong band of MAP2, which is an indicator of neuronal cell survival and / or process elongation, was observed. Therefore, ginsenoside derivatives such as dihydroxy ginsenoside R b can inhibit apoptosis or apoptosis-like cell death of cells, particularly nerve cells, in an optimal extracellular solution concentration range wider than that of ginsenoside R b. It is thought to exert an excellent cytoprotective effect. That is, ginsenoside derivatives such as dihydroxy ginsenoside Rb are described in PCTZ JP 0 0 Z 04 10 2. It is invented to be a pharmaceutical composition for preventing / treating or treating any disease or condition that causes cell death, like the ginsenoside Rbt described above. The lower part of FIG. 2 shows the densitometric analysis of the intensity of the MAP2 band by repeating the above-mentioned immnobolot experiment. Dihydroxy ginsenosides side R b indicates a significant effect at concentrations of ^{1~ 1 0 8 ί g / m} 1. However, it is considered that significant effects can be found by adding the number of cases even at lower concentrations.

Next, the present inventors prepared the epoxyzincenoside Rb of the present invention by the following method.

(1) acetylation

To 4.2 g of ginsenoside RbL1 was added 2 ml of pyridine and dissolved, and 1 ml of acetic anhydride was slowly added dropwise. The mixture was stirred overnight at room temperature (18 hours). The next day, a large amount of water was added to quench the reaction. CHC 1 ₃ and extracted with (3m l X 5), concentrated and washed. The organic layer was washed with water.

(2) Epoxidation

The Asechiru of the CHC 1 ₃ was dissolved in 3m l (which was dissolved in _{C HC 1 3) mC P BA} 2 0. 6 mg 1. was stirred for 5 hours. TL C was quenched reaction by adding N a ₂ C_〇 ₃ After confirming epoxidation reaction (thin layer chromatogram rough). The reaction was extracted with CHC13 (3 ml x 5), washed with water, and the organic layer was concentrated. The obtained crystals were purified by applying to a column and concentrated again to obtain crystals.

(3) Deacetylation

M e OH 3 m 1 to the reaction product of the, water 3m I, and the mixture was stirred for 2 hours at K ₂ C0 ₃ was added 0 ° C. After removing the solvent by temporarily concentrating the reaction product, it was dissolved in water and desalted with a column. Thereafter, it was freeze-dried to obtain 13.5 mg of a white powder (yield: 91.8%). The melting point is 157.8-8-161.2. Incidentally melting point of Jinsenosai de R bi is 1 9 7~ 1 9 8 ° C ( literature value), in Figure 3, shows the NMR chart _{(4 0 0 MHZ, CD 3} 0 D).

Next, the present inventors have found that the epoxy ginsenoside R bi (code name: S2822) obtained by the above-mentioned method is referred to as WO 00/37481, PCT / JP0. Ginsenoside R b 丄ゃ described in 0Z0 5 5 5 4 or Japanese Patent Application No. 2 00 00-24 8 4 58 Similar to dihydroginsenoside Rbt, it was examined whether it inhibits apoptosis or apoptosis-like cell death of nerve cells.

As described above, the present inventors (Sakanaka, Tanaka) and colleagues report that short-term exposure of cultured neurons to the nitric oxide donor, nitroprusside sodium (SNP), results in neuronal apoptosis or apoptotic neuronal death. Is reported to be induced (Toku K. et al., J. Neurosci. Res., 53, 415, 1998). Using this culture experimental system, the present inventors have already found that ginsenoside Rbi has apoptosis or apoptosis-like neurons in neurons in the optimal extracellular solution concentration range of 1 to 100 μg / m 1. It has been found that death can be suppressed (WO 00/3784 81). Thus, using a similar experimental system, the neuroprotective effect of epoxyzine cenoside Rb: was examined.

Nerve cells were isolated from the fetal cerebral cortex of a 17-day-old rat using trypsin EDTA, and plated on a polyerysine-coated 24-well plate. After culturing for 16 hours in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum, the culture is cultured for neurons containing insulin, transferrin, etc. The medium was replaced with a serum-free medium and cultured for 3 to 4 days. On the third or fourth day of culture, sodium nitroprusside (SNP) was added at a concentration of 300 M and incubated for 10 minutes. Thereafter, the culture solution was replaced with Eagle's minimum essential medium (EMEM) containing epoxyzincenoside Rb! (0 to 100 ng / ml) and bovine serum albumin. 16 hours after SNP loading, lyse neurons using Laemm 1 i sample buffer for electrophoresis, perform polyacrylamide gel electrophoresis, transfer electrophoretic proteins to nitrocellulose membrane, and specify neurons Immunoblotting was performed using an antibody against the protein MAP2. The results are shown in FIG. The details of the experimental procedure of the MAP2 immnoplot are described in the published papers of the present inventors (Sakanaka and Tanaka) (Wen, T- et al., J. Exp. Med. , 188, 635-649, 1998).

The upper part of FIG. 4 is a photograph instead of a drawing showing the result of the immublot of microtuble-associated protein 2 (MAP2). The first lane from the left is a control cultured neuron, and a clear MAP2 band.

(Ie, a marker band of nerve cells). With SNP processing, Because many nerve cells fall into apoptosis or apoptosis-like nerve cell death,

The MAP 2 band was clearly weaker, as in the second lane from the left. Epoki shiginsenoside R b! Was added to the culture medium at a concentration of 1 fg / m 1 (lane 6) to lng / ml (lane 9), apoptosis or apoptosis-like neuronal death of neurons by SNP was clearly suppressed, As a result, a strong band of MAP2, which is an indicator of survival and / or process elongation of nerve cells, was observed. Therefore, epoxy ginsenoside R b! Ginsenoside derivatives, such as ginsenoside Rbi, provide superior cytoprotection by inhibiting apoptosis or apoptosis-like cell death of cells, especially neurons, in a wider range of optimal extracellular fluid concentrations than ginsenoside Rbi. It is thought to exert an effect. That is, ginsenoside derivatives such as epoxy ginsenoside R bi can be used in any disease causing cell death, similar to ginsenoside R or dihydrozin genoside R bi described in PCT / JP00 / 04102. It has been invented to be a pharmaceutical composition for preventing, treating or treating pathological conditions. The lower part of Fig. 4 shows the densitometric analysis of the intensity of the MAP2 band by repeating the above-mentioned immnobolot experiment. Epoxy ginsenosides Sai de R b: indicates a significant effect at a concentration of ^{^{1 0 2 ~ 1 0 6 fg}} / m 1. However, it is thought that a significant effect can be found by adding the number of cases even before and after this concentration.

From the above, ginsenoside derivatives such as dihydroxyxenosenoside Rb and epoxyzinsenoseside Rb have an extracellular solution concentration of the affected tissue of 100 g / m1 or less, preferably 10 g / m1 or less. 0 ng / m 1 or less, more preferably I ng / m 1 or less, and even more preferably 100 fg / m 1 or less, it has excellent cytoprotective, anti-apoptotic or apoptotic-like cell death inhibitory action. It can be said that. That is, a ginsenoside derivative such as dihydroxyzine senoside R bi or epoxy ginsenoside R b is preferably a medicament for preventing, treating or treating any disease which causes cell death at a low dose and a low concentration. It can be said that it has been invented to be a composition or a veterinary composition. Diseases and conditions that are expected to be indicated for ginsenoside derivatives such as dihydroxyzine senoside R b! Or epoxy ginsenoside R are described in the following books (Today's Therapeutic Guidelines 2000; General Editor, Taga The organic diseases and conditions described in Sachio Suzuki, Ogata Etsuro; Medical Shoin; 2000) are considered. The ginseng rhinoceros of the present invention Naturally, a pharmaceutical composition comprising a derivative of a parasite derivative can be administered not only to humans but also to vertebrate animals such as livestock, pets (including fish) or other invertebrates, and therefore, as a veterinary pharmaceutical composition. Can also be used. Thus, the expression pharmaceutical composition herein is intended to include veterinary pharmaceutical compositions.

By the way, as diseases and conditions for which ginsenoside derivatives such as dihydroxyxenosenoside Rb or epoxy ginsenoside Rbi are expected to be applied, any disease or condition that causes apoptosis or apoptosis-like cell death is considered. Although the pathological condition may be considered, the concentration of extracellular fluid in the affected tissue is preferably at most 100 / g / ml (90 βΜ), preferably at most 100 ng / m 1 (about 90 nM), more preferably Is less than 1 ng / m 1 (approximately 0.9 nM), more preferably low for skin and mucosal diseases that can be easily maintained at 100 fg / m 1 (90 fM) or less. · Low concentration of ginsenoside derivative has excellent effect · It can be said that it exerts its efficacy. Examples of skin and mucous membrane diseases and pathologies that cause such cell death are as follows. Wounds on skin tissue, burns, radiation damage, frost damage, UV damage, electric shock, trauma, skin ulcer, pressure sore, various wounds after surgical operation, electric shock, contact dermatitis, vesicular dermatitis, atopic Dermatitis, Depressive dermatitis, Xeroderma, Sebum deficiency, Diabetic skin ulcer, Self-sensitizing dermatitis, Erythroderma, Exfoliative dermatitis, Epidermolysis bullosa, Photosensitivity, Chronic pigmented purpura ( Schaumburg disease), strofluus, hay fever, insect bites, prurigo, erythema multiforme, erythema multiforme, erythema nodosum, pemphigus, pemphigus, herpetic dermatitis, palmar pustulosis, psoriasis, psoriasis Lichen, fish ichthyosis, lichen pilaris, Steven Johnson Syndrome xanthomatosis, cutaneous amyloidosis, herpes simplex, viral warts, infectious molluscum, pyoderma, cutaneous tuberculosis Atypical mycobacteriosis, Rash, skin, oral candidiasis, scabies, hair loss, syphilis, keloids, hypertrophic scars, hemangiomas, lymphomas, nevus, vitiligo vulgaris, egg spots, liver spots, melasma, sweat blisters, Rash, acne, rosacea, rosacea-like dermatitis, damage to oral mucosa, stomatitis, peri-dermatitis, aging symptoms of the skin (eg. Atrophy of the skin, susceptibility to infectious diseases, Sagging, dandruff, hair loss, gray hair, itching, shaving, sebum deficiency, keratinocyte detachment, horny layer detachment, cracks, irritations, spots, wrinkles, freckles, poor reproduction, pigmentation, dryness, etc.), alopecia, nails Surrounding flames, fitting claws and the like. In addition, damage to mucous tissues such as oral mucosa, rectal mucosa, vaginal mucosa, ocular mucosa, bites, wounds, heat It includes any disease or condition that causes histopathological changes in mucosal tissue, such as a disease caused by a wound, trauma or defect, such as caries, pulpitis, marginal periodontitis, stomatitis, glossitis, Recurrent Aphtha, Oral Aphtha, Bad breath, Oral abnormal sensation, Dental infection, Oral mucosa bite, Tongue bite, Oral mucosal burn, Tongue burn, Tongue damage, Oral mucosal damage, Gingivitis, Alveolar pus Leak, catal stomatitis, gangrene stomatitis, wansan stomatitis, aphthous stomatitis, acute herpetic gingivitis, herpangina, shingles, oral mucosal erosion, vaginal mucosal erosion, vaginal mucosal ulcer, oral mucosal ulcer, pressure ulcer , Radiation stomatitis, pemphigus, oral candidiasis, lichen planus, Riga-Fede disease, smooth tongue, erythema tongue, tongue pain, mucosal ulcer, mucosal erosion, cataract, dry eye, erosion of the bulbar conjunctiva, corneal erosion I or ulcers, erosions or ulcers of digestive tract mucosa, Shiedaren syndrome, mucous membranes, especially the aging symptoms of the oral mucosa (e.g., atrophy, mucosal excision, cracking, epithelial peeling, aplastic, dried) and the like.

Note that dihydroxyzine Senoside Rb or epoxyzine Senosai HR! As described later, ginsenoside derivatives such as ginsenoside Rb! Described in PCTZ JP 00/05554 and Japanese Patent Application No. 2000-248584 are described below.ゃ Similar to dihydroginsenoside Rb, it is thought to exert a tissue regeneration promoting action at a low concentration and at a low dose. It is thought to show the effect through the action. An external preparation for skin or mucous membrane for preventing, treating, or treating the above-mentioned diseases, which comprises a derivative of a dixenoside derivative such as dihydroxy ginsenoside R b or epoxy ginsenoside R bt, is a known or arbitrary base. Ginsenoside derivatives such as dihydroxy ginsenoside Rbi or epoxy ginsenoside Rb are preferably used in water-soluble bases, emulsion bases, compounding bases or fat-soluble bases (ointment bases). At a concentration of 1% by weight or less, preferably 0.1% by weight or less, more preferably 0.001% by weight or less, and still more preferably 0.001% by weight or less. . Similarly, low-concentration ginsenoside derivatives may be mixed into a preparation which adheres to mucous membranes such as aftatsu. Specifically, a water-soluble base (cream, etc.), an emulsion base, a compounding agent or an ointment base (fat-soluble base) For example, per 100 g of ophthalmic white cellulose (prototype), dihydroxyzine Senoside R bi or Epoki 1 g (1% by weight) or less, preferably 100 mg (0.1% by weight) or less, more preferably 1 mg (0.001% by weight) or less of ginsenoside derivatives such as ciginsenoside Rbt. It can be used as an external preparation for skin or mucous membrane for prevention, treatment or treatment of the above-mentioned diseases, after being mixed so as to be preferably at most 0.01 mg (0.00001% by weight).

Of course, in the above-mentioned external preparation for skin or mucosa, any pharmaceutical composition, carrier, base or substance (for example, glucose, antibiotics, vitamin E, vitamin E derivative, etc.) besides the ginsenoside derivative Vitamin D, vitamin D derivatives, vitamins, antivirals, immunosuppressants, antiallergic agents, steroids, ginseng components, natural ingredients, etc.).

Other diseases and conditions that lead to apoptosis or apoptosis-like cell death, for which ginsenoside derivatives are expected to be applied, include the following: Therapeutics (Today's Therapeutic Guidelines; Comprehensive Compendium; Yukio Taga, Etsuro Ogata; Medical Shoin, 2 All of the diseases and conditions described in (0) are considered, and representative examples thereof will be described below. That is, primary and secondary neurodegenerative diseases with apoptosis-like neuronal death or apoptosis (Alzheimer's disease, Pick's disease, spinocerebellar degeneration, Parkinson's disease, demyelinating disease, polyglutamine disease including chorea disease) , Amyotrophic lateral sclerosis, glaucoma, senile macular degeneration, diabetic retinopathy, central retinal arteriovenous obstruction, retinal detachment, retinitis pigmentosa, AIDS encephalopathy, hepatic encephalopathy, encephalitis, cerebral palsy, Head trauma, spinal cord injury, carbon monoxide poisoning, neonatal asphyxia, peripheral neuropathy, spastic paraplegia, brain tumor, encephalitis, alcoholism, toxic neuropathy, sphingolipidosis, progressive supranuclear palsy, spinal vascular Disorders, mitochondrial encephalomyopathy, meningitis, etc.) and stroke, nerve trauma, head trauma, transient cerebral ischemic attacks, spinal cord injury, myocardium, liver, kidney illness Blood reperfusion injury, cardiomyopathy, heart failure, myocardial infarction, angina pectoris, peripheral circulatory failure, skin ulcer, pressure sore, wound, autoimmune disease, immunodeficiency disease, rejection after organ transplantation, muscular dystrophy, corneal injury , Radiation damage, ultraviolet light damage, infectious disease, collagen disease, aortitis syndrome, acute arterial occlusion, obstructive thromboangiitis, obstructive arteriosclerosis, Reino's disease, diabetes, AIDS, Reino's syndrome, thrombotic Phlebitis, Tengitis, Hepatitis, Nephritis, Diabetic Nephropathy, Diabetic Cardiomyopathy, Tongue Pain, Aorticitis Syndrome, Collagen Disease, Acute Peripheral Artery Occlusion, Obstructive Thromboangitis, Obstructive Arteriosclerosis, Thrombus Phlebitis, sugar Uremic retinopathy, diabetic nephropathy, central retinal arteriovenous obstruction, acute peripheral circulatory insufficiency, shock, Reino's disease, Reino's syndrome, hemorrhoids, osteoporosis, knee osteoarthritis, anemia, myocardial infarction, Examples include, but are not limited to, pressure sores, peripheral circulatory insufficiency, angina pectoris, hepatic / renal / cardiac ischemia / reperfusion injury.

A pharmaceutical composition or veterinary pharmaceutical composition for the prevention, treatment, or treatment of the above-mentioned diseases, which comprises a dixenoside derivative such as dihydroxyxenosenoside R bi or epoxy ginsenoside R bi, may be a mucosal external preparation, External preparations for the skin or external application for the skin and external spraying are preferred, but if the extracellular fluid concentration in the affected tissue can be maintained at a low level as described above, as in the case of ginsenoside R bi and dihydrozincenoside R b (PC TZ JP 0 0/04 1 102, PCTZ JP 0 0Z 0 5 5 54) Formulation for intravenous administration, topical external preparation for lesions, local injection for lesions, oral administration preparation, nasal drops, ear drops, eye drops Well-known administration such as drugs, eye ointments, suppositories (including vaginal suppositories), subcutaneous injections, intradermal injections, intramuscular injections, inhalants, sublinguals, artificial saliva, intraarticular administration, transdermal absorption drugs, etc. The road can be selected. It may be used as a sustained release agent.

For oral administration, the preparation can be a solid or liquid preparation. Solid preparations include, for example, tablets, pills, powders or granules. In such solid preparations, the active substance is mixed with a pharmaceutically acceptable carrier such as sodium bicarbonate, calcium carbonate, potato starch, sucrose, mannitol, carboxymethyl cellulose and the like. The preparation operation is carried out according to a conventional method, and may contain additives other than the above-mentioned carriers for preparation, for example, lubricants such as calcium stearate and magnesium stearate.

The solid preparations described above include, for example, enteric substances such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol phthalate, styrene maleic anhydride copolymer or methacrylic acid, methyl methacrylate copolymer. An enteric coating can be obtained by spraying a solution or an aqueous solution with an organic solvent and applying an enteric coating. Solid preparations such as powders and granules can be packaged in enteric coated capsules.

Liquid preparations for oral administration include, for example, emulsions, solutions, suspensions, syrups or elixirs. These preparations are commonly used pharmaceutically acceptable Carrier, for example, water or liquid paraffin. Oil carriers such as coconut oil, fractionated coconut oil, soybean oil, and corn oil can also be used as carriers. Pharmaceutically acceptable carriers include other adjuvants, flavoring agents, stabilizing agents, or preservatives that are commonly used, as needed. Liquid preparations may also be administered in capsules made of a substance that is absorbed, such as gelatin. Solid preparations for vaginal or rectal administration include suppositories containing the active substance and produced by known methods.

Preparations for parenteral administration are administered as sterile aqueous or non-aqueous solutions, suspensions or emulsions. Non-aqueous solutions or suspensions are pharmaceutically acceptable, for example, propyl glycol, polyethylene glycol, vegetable oils such as olive oil or soybean oil, and injectable organic esters such as ethyl oleate. Carrier to be obtained. Such formulations may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, and stabilizing agents. These solutions, suspensions, and emulsions can be sterilized by, for example, filtration through a bacteria retention filter, heating, blending of a bactericide, or irradiation with ultraviolet light as appropriate. Alternatively, a sterile solid preparation can be manufactured and dissolved in sterile water or a sterile solvent for injection immediately before use. Water is added to a homogeneous solution of a vegetable oil such as soybean oil, a phospholipid such as styrene, and a ginsenoside derivative used in the present invention, for example, a homogenizer such as a pressurized spray homogenizer or an ultrasonic homogenizer. Fat emulsions and the like that have been homogenized in one step can also be used as injections. In the same manner as described above, ginsenosides described in PCT / JP0 554 5 and PCT / JP0 0/104 102 can also be formulated. The daily dose of the pharmaceutical composition comprising the ginsenoside derivative of the present invention varies depending on the degree of symptoms, age, sex, body weight, administration route, etc. of the patient. It is 0 g or less, preferably 1 g or less, more preferably 100 mg or less, and even more preferably 10 mg or less. The topical dose is no more than 100 mg per day, preferably no more than 10 mg, more preferably no more than 1 mg.

Ginsenoside derivatives such as dihydroxy ginsenoside Rb or epoxy ginsenoside Rb can be used for culturing keratinocyte for skin transplantation in the same manner as ginsenoside Rbi described in WO 00/37848. Protection or preservation of sheet or composite cultured skin It is also effective for maintenance. In addition, not only the preservation of cultured skin but also the preservation and maintenance of cells for the preparation of cultured skin, the preservation and maintenance of stem cells for the preparation of artificial organs, and organs, tissues or cells for transplantation (liver, kidney, heart, It is also considered useful for preserving and maintaining the liver, lungs, meninges, bones, joints, ligaments, digestive tract, cornea, skin, blood vessels, peripheral nerves, etc.). Further, as described in Japanese Patent Application No. 2000-40032, ginsenoside derivatives can be used for preserving and maintaining blood cell components for blood transfusion and platelets, and for frozen cells (sperm, ovum, skin keratinocytes, It can also be used as a preservative composition for stem cells, etc.) and frozen cultured skin sheets (including composite cultured skin).

In the following, ginsenoside derivatives containing dihydroxy ginsenoside R bi or epoxy ginsenoside R b will be described briefly using the ginsenoside R bi derivative shown in FIG. 5 as an example. However, FIG. 5 does not include dihydroginsenoside R b 丄, which will be described later.

(1) in the upper left of FIG. 5 is an example of a derivative in which a hydroxyl group is acylated or acetylated, and these may be dihydrogenated. (2) is an example in which a double bond in the side chain is converted to a single bond and an arbitrary functional group (for example, one or more hydroxyl groups) is bonded to the same portion in addition to the acylation or acetylation. It is also possible to epoxidize the two hydroxyl groups by dehydration. (3) is an example of a derivative obtained by cleaving the double bond in the side chain in addition to the acylation or acetylation to make the terminal an aldehyde group, and (4) is an example of the derivative of the side chain in addition to the acylation or acetylation. (5) is an example in which, in addition to acylation or acetylation, a carboxyl group is bonded by cutting a double bond in a side chain in addition to acylation or acetylation. (6) is an example in which the double bond in the side chain is epoxidized in addition to acylation or acetylation, and (7) is an example in which the double bond in the side chain is cleaved to bond a propyloxyl group. Yes, an aldehyde group may be bonded in place of the propyloxyl group. (8) is obtained by substituting one methyl group at the terminal of the side chain with a hydrogen atom and substituting the other methyl group with an arbitrary functional group such as an alkyl group or a aryl group. This is an example in which a heavy bond is converted into a single bond, and an arbitrary functional group, for example, one or more hydroxyl groups is bonded to the same part. (10) is obtained by dehydrating two hydroxyl groups described in (9). This is an example of epoxidation. (11) In addition, protopanaxadiol, protopanaxatriol, damarane or a reduced form thereof is used as a basic bone. Any compound having a qualification is included in the category of ginsenoside R b derivative. This includes (12) ginsenoside R b side chain double bond with Die 1 s -A 1 der reaction using a gen compound such as cyclopentene gen. . Of course, the novel chemical derivatives that can be prepared by using ginsenoside R b as a lead compound are not limited to those described above. The derivatives of ginsenoside R b of the present invention include those described above in addition to these derivatives.

In addition to ginsenoside Rb, ginseng contains about 30 types of purified saponins, that is, natural ginsenosides or ginsenoside compounds, in addition to ginsenoside Rb (Junzo Shoji, Ginseng '95, PP251-261, Akira Kumagai, Kyoritsu Shuppan Co., Ltd.), purified saponins other than ginsenoside Rb, that is, natural ginsenosides (particularly protopanaxadiol-based saponins and protopanaxatriol-based saponins) As for Fig. 5, a chemical derivative can be prepared by reducing the side chain of the damarane skeleton (steroid-like skeleton) or by the same method as in Fig. 5. Also, Gin Senoside R. And the chemical derivatives of oleanolic acid are also as described above. Naturally, the above-mentioned ginsenoside derivatives are described in WO 0Z3 7481, WO0Z48 608, Japanese Patent Application No. 2000-248484, Japanese Patent Application 20 0 1-- 3 7 4 5 0 9, PCT / JP 0 0/04 1 0 2, PCT / JP 0 0/0 5 5 54 and Japanese Patent Application 2 0 0 0-4 0 3 2 0 3 It has all the effects, efficacy and uses of ginsenoside Rb or dihydroginsenoside Rb described in the above item.

As described above, ginsenoside derivatives such as dihydroxyxenosenoside Rb or epoxy ginsenoside Rb have an inhibitory effect on apoptosis-like cell death or It was revealed that it exhibited an anti-apoptotic effect. In addition, dihydroginsenoside Rb, one of the other ginsenoside derivatives, also has an anti-apoptotic action or an apoptotic-like cell death inhibitory action. And PCT // JP 00/05554. Therefore, ginsenoside R b dihydroxy ginsenoside R b epoxy ginsenoside R b dihydrozin genoside All R bi are considered to have common pharmacological activities, effects, indications, and uses. Therefore, in the specific examples below, among these four compounds, ginsenoside Rb and dihydrozinesenoside Rb! It will be clarified that when these are administered intravenously, topically for mucous membranes or topically for skin, excellent wound healing promoting action or tissue regeneration / reconstruction promoting action is observed. If ginsenoside Rb and / or dihydroginsenoside Rb exert an action of promoting wound healing and an action of promoting regeneration and reconstruction of living tissue (including animal tissue and plant tissue), dihydroxy ginsenoside All ginsenoside derivatives such as R b or epoxy ginsenoside R bi are considered to have a similar effect. First, the present inventors investigated the effect of low dose and low concentration of ginsenoside R bi on regeneration and reconstruction of living tissue. The effect of continuous intravenous infusion of ginsenoside Rbi on incision wounds in rats was examined. For this purpose, male Wistar rats (weight about 300 g) were used. The animals were housed in a light-dark cycle room every 12 hours, with free access to water and food. Make an incision about 3 cm in length on the back of the animal under inhalation anesthesia and dissolve ginsenoside R b: (60 g) in saline approximately 1 hour after joining with nylon thread The fluid was injected once intravenously. Thereafter, ginsenoside R bi was continuously infused intravenously for 7 days using an Alzamini osmotic pump (60 X g days).

In addition, a control animal in which a similar incision was made and sutured with nylon thread was intravenously administered only the same amount of physiological saline.

The animals were anesthetized with pentobarbital two days after the end of the continuous intravenous infusion of ginsenoside Rb or saline, and transcardially with 0.1 M phosphate buffer containing 4% paraformaldehyde. Perfusion fixed. Thereafter, the skin tissue including the incision suture was collected, post-fixed, and embedded in paraffin as usual. Paraffin sections having a thickness of about 5 x m were prepared and subjected to hematoxylin-eosin (HE) staining. Figure 6 shows the results. Figure 6 is a photograph replacing the drawing. Fig. 6'A shows an example of ginsenoside R administration, and Fig. 6B shows an example of physiological saline administration. "S" indicates a scar (sear).

As shown in FIG. 6A, in the ginsenoside Rb administration example, the physiological Compared with the saline-administered case, a number of skin appendages such as sweat glands, sebaceous glands, and hair follicles were observed immediately near the incision wound site. This suggests that sweat glands, sebaceous glands, hair follicles, and the cells constituting them were rapidly regenerated and reconstructed by intravenous administration of low-dose ginsenoside Rbi. Also, in the case of low-dose ginsenoside Rb administration, unlike the saline administration example, the epidermis, dermis, and subcutaneous tissue were regenerated, reconstructed, or recovered to a state close to normal, except for the wound site. Was. In other words, it can be said that intravenous administration of ginsenoside Rbi promptly regenerated and reconstructed wounded skin tissue, and as a result, wound healing was clearly promoted.

On the other hand, in the physiological saline administration example shown in FIG. 6B, scars, so-called scars, have grown to a large extent, but regeneration of the damaged tissue is hardly observed. That is, in conventional wound healing, only scars containing a large amount of abnormal collagen were increased, and the damaged tissue did not systematically regenerate and reconstruct. As shown in FIG. 6A, in the present invention, administration of ginsenoside Rbi not only reduces the scar part but also regenerates and reconstructs each wounded tissue. It is a big feature.

Therefore, judging from the fact that the intravenous administration of ginsenoside Rb promotes tissue regeneration and reconstruction up to the deep part of the skin tissue and progresses wound healing, suture failure is likely to occur. Intravenous administration of natural ginsenosides, especially ginsenoside Rbi, after preoperative surgery in elderly, malnourished, diabetic, immunodeficient, AIDS or cancer patients · It is expected to be effective. In addition, ginsenosides, especially ginsenoside Rb, may be administered intravenously before or after plastic surgery (including so-called cosmetic plastic surgery) or after the occurrence of disease due to skin damage, wounds, trauma or defects. It is thought that "the wound will heal faster and more reliably" through its excellent wound healing promoting effect and promoting tissue regeneration and reconstruction. As shown in Fig. 6A, in the ginsenoside Rb administration example, tissue regeneration and reconstruction proceeded smoothly, and collagen fibers (collagen fibers), elastic fibers, reticulum fibers, and extracellular matrix were normal in the dermis and subcutaneous tissue. As a result, scarring was reduced as compared with the saline-administered example in FIG. 6B.

Next, the inventors discovered that diseases that result in loss of skin tissue (pressure sores, skin ulcers, burns, frostbites, It was also investigated whether low-dose intravenous ginsenoside Rbi promotes skin tissue regeneration and remodeling in radiation damage, open wounds, ultraviolet damage, and electric shock. For this purpose, a 6 mm diameter punch biopsy was applied to the back of the animal under inhalation anesthesia using a male wispy rat (weight: about 300 g) to create an open wound and left to stand. . After about 1 hour, a single intravenous injection of a saline solution of ginsenoside Rbi (I 2 ng) was administered, and ginsenoside Rbi was intravenously administered for 7 days using an Alzamini osmotic pump. Continuous infusion (12 ig / day). In addition, the same amount of physiological saline alone was intravenously administered to a control animal in which a similar open wound was prepared and left as it was.

The animals were anesthetized with pentobarbital 2 days after the end of the continuous infusion of ginsenoside Rb or saline intravenously, and transcardially with 0.1 M phosphate buffer containing 4% paraformaldehyde. Was fixed by perfusion. Thereafter, the skin tissue including the open wound was excised, post-fixed, and embedded in paraffin as usual. Paraffin sections of about 5 thickness were prepared and subjected to hematoxylin-eosin (HE) staining. Figure 7 shows the results. Figure 7 is a photograph replacing the drawing. FIG. 7A shows an example of ginsenoside Rbi administration, and FIG. 7B shows an example of physiological saline administration. The left side of the arrows in FIGS. 7A and B indicates the healthy part, the right side of the arrow in FIG. 7A indicates the regenerated skin tissue, and the side from the arrow in FIG. 7B indicates mainly the scar (s). I have. In the regenerated skin tissue in Fig. 7A, a large number of hair follicles and dermal papillas and associated sebaceous glands and pilus muscles are found in the connective tissue (dermis or subcutaneous tissue) below the epidermis. There are a few scars (sc ar, s).

As shown in Fig. 7A, in the case of ginsenoside Rb administration, epithelialization occurred sufficiently compared with the case of administration of physiological saline in Fig. 7B, and the connective tissue of dermis with papillae and subcutaneous Tissue regeneration / reconstruction had progressed to a state close to normal tissue. In addition, in the case of ginsenoside Rbi administration, unlike in the case of administration of physiological saline, regenerating open wounds Abundant skin appendages such as hair follicles, dermal papilla, sebaceous glands, pilus muscle, and sweat glands were observed in the skin tissue. As a result, the vascular network had been regenerated, reconstructed, or recovered to a state close to normal tissue. Perhaps with the regeneration of such epidermis, connective tissue of the dermis, papillary dermis of the dermis, subcutaneous tissue, skin appendages, and blood vessels', the peripheral nerves that were cut at the time of creation of open wounds were also ginseno. It was considered that regeneration was caused by intravenous administration of Side Rbt. As shown in Fig. 7A, tissue regeneration and remodeling proceeded smoothly in the low-dose ginsenoside RbL-administered cases, and collagen fibers (collagen fibers), dermal fibers, reticular fibers, and cells in the dermis and subcutaneous tissues. The extramatrix was sufficiently produced and secreted to a state close to normal, and as a result, scarring was smaller than in the saline-administered example in FIG. 7B.

Next, the present inventors examined whether ginsenoside R b L was administered intravenously in advance before creating open wounds on the skin, and whether regeneration / reconstruction of skin tissue was promoted. A single intravenous injection of a saline solution of ginsenoside Rbt (12 g) was administered to a male Wistar rat (body weight: about 300 g) under inhalation anesthesia, followed by an Alzamini osmotic pump. Ginsenoside Rb was continuously infused intravenously for 4 days (1 day). Then, under inhalation anesthesia, a 6 mm diameter punch biopsy was applied to the back of the animal to create an open wound, and continuous intravenous infusion of ginsenoside Rbi was continued for another 3 days.

Control animals left with similar open wounds were given the same volume of saline only intravenously.

On the second day after the end of the continuous intravenous infusion of ginsenoside Rbi or saline, the animals were anesthetized with pentobarbital on day 5 after the preparation of the open wound and contained 4% paraformaldehyde. Perfusion fixation was performed transcardially with 1 M phosphate buffer. Thereafter, the skin tissue including the open wound was excised, post-fixed, and embedded in paraffin as usual. Paraffin sections of about 5 m thickness were prepared and subjected to Hematoxylin Eosin (HE) staining. Figure 8 shows the results. Figure 8 is a photograph replacing the drawing. FIG. 8A shows an example of ginsenoside Rb administration, and FIG. 8B shows an example of physiological saline administration.

'i' indicates skin (incrustion or eschar), epf or epidermis pidermis, stratified squamous epithelium, and 'bv,' indicates blood vessel (Mood vessel).

As shown in Fig. 8A, in the case of ginsenoside Rbi administration, the clear epidermis (stratified squamous epithelium) under the crust was already regenerated and reconstructed on the 5th day after the creation of the open wound. The epidermis (stratified squamous epithelium) has a large regenerative blood vessel or new blood vessel filled with red blood cells underneath, and a relatively thin blood vessel that seems to branch off from the blood vessel. Were densely present in the connective and subcutaneous tissues of the dermis. On the other hand, as shown in Fig. 8B, in the saline-administered example, the epidermis regeneration under the crust was extremely incomplete even on the fifth day after the creation of the open wound, and was just below the very thin epidermis. The regenerative blood vessels were also clearly smaller than those of ginsenoside Rbi administered intravenously. As a result, only a small number of extremely thin blood vessels were found in the connective tissue under the epidermis, which is thought to become scar in the future. Therefore, the intravenous administration of ginsenoside R bi clearly promotes the regeneration and remodeling of skin tissue, and once open rupture, regeneration of cut blood vessels, neoplasia, and remodeling, the ginsenoside R t vein is also used. It was invented that it would be facilitated by internal administration. Also, it is important to remember that the thick blood vessels just below the epidermis (stratified squamous epithelium) seen on the 5th day after the creation of open wounds in the case of ginsenoside Rbi administration as shown in Fig. 8A On the ninth day after puberty, it almost regressed, as shown in Fig. 7A, and the dermal connective tissue with papillae was found in the same area. In other words, in the case of ginsenoside Rbi administration, the regeneration or renewal of blood vessels occurs early after the creation of the open wound, and the revascularization occurs as the regeneration and reconstruction of the skin tissue is completed. The present invention, which proves that one compound can achieve the complex biological phenomenon of tissue regeneration and reconstruction so vividly, is truly the first in human history. In healthy tissues, no clear difference was observed between ginsenoside Rb-administered patients and saline-administered patients. This suggests that continuous intravenous administration of low doses of ginsenoside Rb has no appreciable effect on healthy tissues, but has favorable effects only on diseased or damaged (wounded) tissues. . In other words, ginsenosides, especially ginsenoside Rb, can be said to be a pharmaceutical composition with few side effects _(in this way, skin tissue once deficient due to an open wound can be quickly and almost brought into a normal state by intravenous administration of ginsenoside Rb. The results of this experiment that ginsenosides, especially ginsenoside R b, were regenerated and reconstituted into epidermal cells, epidermal keratinocytes, keratinocytes, Merkel cells, Langerhans cells, stem cells, fibroblasts, It also reveals that it promotes the division, proliferation, migration, differentiation, and adhesion of mesenchymal cells, vascular endothelial cells, cells of the pilo muscularis, and vascular smooth muscle cells, and differentiation of epidermal cells into hair follicles, sweat glands, and sebaceous gland cells In addition, the aforementioned cells, peripheral nerves, and blood vessels are organically regenerated and reconstructed by administering ginsenoside Rbi. As a result, positive It has been invented that the open wound of the skin is quickly recovered to a state close to the normal skin tissue. That is, low dose ginsenosides, especially ginsenosides

By continuous intravenous administration of Rbi, newly regenerated epidermal cells and fibroblasts are arranged in a manner similar to normal skin tissue at the skin defect, and extracellular matrix, collagen fibers, elastic fibers, reticulum fibers It can be said that these are regenerated and reconstructed to a state close to normal skin tissue. As shown in the results of this experiment (Figs. 7A and 8A), intravenous administration of ginsenoside Rb caused not only epidermal tissue but also dermis and subcutaneous tissue in open wounds (skin defect) on the skin. Since regeneration and remodeling are promoted, even if the open wound becomes epithelialized and then trauma is again applied to the same area, epithelial tissue detachment occurs in the open wound that has been epithelialized by ginsenoside Rbi administration. It is expected that it will hardly occur.

On the other hand, as shown in Fig. 7B and Fig. 8B, in the case of administration of physiological saline, scars were formed without regenerating and reconstructing the dermis and subcutaneous tissue, even though the epithelization was apparently occurring. However, epidermal tissue may be easily exfoliated simply by applying a slight external force to the same part. Incidentally, according to the experience of the inventors, epidermal growth factor (EGF), platelet derived growth factor (PDGF), basic fibroblast growth factor (b FGF) ) Is applied or sprayed to open wounds on rat skin, but their effect on promoting wound healing is far from the effect of continuous intravenous administration of low doses of ginsenoside Rbi. Such a low dose of ginsenoside Rb alone can regenerate and regenerate skin tissue alone or revitalize wound healing, which means that ginsenoside Rb alone has a role in skin treatment or regeneration / reconstruction of skin tissue. Tokines, growth factors or growth factors and their receptors or transcription factors (eg, EGF, TGF—; 31, TGF—H, erythropoietin, ets—10, Erb—B3, ND F, EGF R, TGF R, FG FR, PD GFR, HGFR, KGFR, F GF, VE GF, PDGF-BB, TGF- / 31 / PDGF-AB, VEGF R, Angiopoietin, Tie, ephrin- _{B 2, E ph - 4 B} , CXC R 4, she, SCL, SCF, IGFR ■ I GF, KGF, HGF, PD GF, TG F- | 3 2, TGF- | 3 3, F GF- 2, HIF , U-PA, 1: 1-PA, etc.) and the functions of blood cells and plasma components are also regulated by low-dose ginsenosides, especially ginsenoside Rb. The thing Talking. A review of Singer, A.J., Clark, and RAF (New Engl. J. Med., 341, 738-746, 1999) and the literature of Shibuya et al. As described in “Medical Science”, Vol. 17, No. 6, 1989, planning, Masashi Shibuya; Yodosha), it is possible to reduce complex life phenomena related to wound healing or tissue regeneration and reconstruction by using low doses. · It can be said that low concentration ginsenosides, especially ginsenoside R bi, were successfully achieved alone.

The results of this experiment show that the continuous administration of a low dose of ginsenoside Rbi intravenously after creating an open wound that causes skin defects promotes regeneration and remodeling of skin tissue, and markedly improves wound healing. Advanced. This indicates that low-dose ginsenosides, especially those that cause continuous skin deficits due to continuous intravenous administration of ginsenoside R bi (eg, pressure sores, skin ulcers, burns, frostbite, radiation damage, laser injury, vesicular skin) It shows that it is effective and effective for diseases, ultraviolet rays, electrical injuries, sunstroke, skin trauma, etc. In addition, diseases in which not only the skin but also other organs and tissues are partially lost (for example, peptic ulcer, ulcerative colitis, mucosal erosion, mucosal ulcer, gastrointestinal mucosal erosion, vaginal mucosal erosion, vaginal mucosal ulcer, chronic Ginsenosides, especially gastroenteritis, acute gastroenteritis, Crohn's disease, Behcet's disease, tympanic membrane damage, corneal damage, corneal erosion, osteoporosis, dysplastic osteoarthritis, corneal ulcer, bone loss, bladder-urethra ■ penis damage, etc. Is when intravenous or local administration of ginsenoside Rbi is effective. In addition, in the above-mentioned diseases, ginsenosides such as ginsenoside Rb may be administered by nasal administration, anal administration, vaginal administration, ear administration, ophthalmic administration, sublingual administration, or the like. Of course, for all other diseases that cause histopathological changes in various organs and tissues, low-dose ginsenosides, especially ginsenoside Rbi, can be used to regenerate and regenerate organs and tissues that have histopathological changes. The effect and efficacy are shown by encouraging construction. Diseases and conditions that cause such histopathological changes include wounds, burns, trauma, bites, skin ulcers, pressure ulcers, as well as books (current treatment guidelines; supervision, Hinohara Shigeaki, Abe Masakazu; Medical Shoin) All the diseases and conditions described in 1995) and specific diseases specified by the Ministry of Health and Welfare are considered.

In this experiment using open wounds on rat skin, continuous low-dose intravenous administration of ginsenoside Rb significantly promoted regeneration and remodeling of skin tissue. Needless to say, the skin has components common to other organs and tissues, such as the epidermis (stratified squamous epithelium), connective tissue, blood vessels, nerves, and secretory glands. Therefore, low dose ginsenosides In particular, the fact that the continuous intravenous administration of ginsenoside Rb: significantly promoted the regeneration and remodeling of skin tissue was demonstrated by the fact that the continuous intravenous administration of low-dose ginsenoside Rbi was effective in all other organs and tissues. Regenerate or regenerate (eg liver, kidney, heart, digestive tract, salivary gland, tent, muscle tissue, respiratory organs, sensory organs, urogenital organs, endocrine organs, bone, cartilage, cornea, mucous membrane, oral mucosa, nerve tissue, etc.) This indicates that restructuring is also promoted. That is, after partial hepatectomy, crash syndrome, acute tubular necrosis, acute renal failure, hepatitis, nephritis, Teng partial resection, peptic ulcer, ulcerative colitis, Crohn's disease, corneal injury, corneal ulcer, corneal ulcer In the pathology of stomatitis, phlegm-stomatitis, osteoporosis, knee osteoarthritis, oral mucosal damage, eardrum damage, etc., ginsenosides, especially ginsenoside R bi, are used to promote regeneration or reconstruction of the organ concerned. Administration or topical administration may be effective.

In this experiment, ginsenoside Rbi of the present invention also clearly promotes regeneration of blood vessels, reconstruction of peripheral nerves, regeneration of hair follicles, sweat glands, and sebaceous glands at sites of skin defects caused by open wounds. Was done. Based on these findings, low doses and low concentrations of ginsenosides, especially ginsenoside Rb, are diseases that are mainly caused by impaired blood flow (aortic inflammation group, peripheral arterial occlusion, obstructive thromboangiitis, obstructive artery). Sclerosis, Reino's disease, Raynaud's syndrome, thrombosis, DIC, angina pectoris, myocardial infarction, pulmonary embolism, cerebral infarction, liver, kidney, cardiac ischemia / reperfusion injury, cerebrovascular disorder, hemorrhoids, moyamoya disease, etc.) Prevention, treatment and treatment of hair loss, hair growth and hair growth composition, prevention of progression of alopecia (alopecia areata, androgenetic alopecia, and chronic alopecia), treatment and treatment or treatment of peripheral neuropathy and neuralgia It can be used as a therapeutic or therapeutic agent.

Based on the above experimental results, low-dose and low-concentration ginsenosides, especially intravenous preparations containing ginsenoside Rbi or a salt thereof, have excellent wound healing promoting effects or skin tissue regeneration / reconstruction It is clear that the promoting effect is useful for the treatment, prevention and treatment of skin damage, wounds (incision wounds, open wounds), diseases caused by trauma or defects or diseases that cause histopathological changes in the skin. Was done.

The low-dose and low-concentration ginsenosides of the present invention, particularly ginsenoside Rbi or a salt thereof, is known as a component of ginseng and is a substance having extremely few side effects. Next, the present inventors consider the diseases that cause skin tissue deficiency (pressure sores, skin ulcers, burns, Ginsenosides in wounds, radiation damage, open wounds, UV damage, electric shock, etc.

It was examined whether topical administration of R b to the skin exerts its effects. For this reason, for example, using a male Wistar rat (weighing about 300 g), the back of the animal was shaved under inhalation anesthesia, and then a punch biopsy with a diameter of 6 mm was applied to create three open wounds. did. Two of them were coated with 0.1% by weight or 0.01% by weight of ophthalmic white petrolatum (prototype) containing 0.11% by weight of ginsenoside Rbi. Only the same amount of ophthalmic white petrolatum (prototype) was applied to the wound. On day 9 after the creation of the open wound, a photograph of the skin including the wound was taken. Furthermore, the present inventors have found that the effect of applying 0.001% by weight, 0.001% by weight or 0.001% by weight of ginsenoside R b external application to the skin in a similar manner. Examined. The experimental animals were euthanized with an anesthetic just before taking the photograph, and the photograph was taken and the wound was taken or the wound was taken and photographed. Thereafter, the wound tissue was stored in a fixative. The results are shown in FIG. 9 and FIG. Figures 9 and 10 are photographs replacing the drawings.

The first from the top of Fig. 9 is an external application (external application) of only the plot after preparation of the open wound, and the red open wound (black open wound in the black and white photograph) is conspicuous. The second from the top in Fig. 9 is a topical application (external application to the skin) of a protein containing 0.001% by weight of ginsenoside Rbi. The open wound area was slightly reduced as compared to the case where only topical application was applied. On the other hand, the third open wound from the top, which had been topically applied (external application to the skin) with a 0.1% by weight ginsenoside Rbi-prote, showed no difference compared to the first control from the top. I was not able to admit. That is, a protocol containing 0.01% by weight of ginsenoside Rb (ie, a protocol containing 100 g of ginsenoside Rb per gram of ointment base) can be used for open wounds. It is believed that application does not significantly promote regeneration and remodeling of skin tissue, and therefore does not significantly promote wound healing and, as a result, scar formation.

Moreover, as shown from the top of the first 0 view to the second and third, 0.0 0 0 0 1 wt% (1 0 ⁵ wt%) or 0.0 0 0 0 0 1 wt% (1 0 ( ⁶ % by weight) ginsenoside Rbi showed a better effect than the one containing 0.0001% by weight ginsenoside Rbi. This means that low concentrations of ginseno Topical skin application consisting of side R bi is applied or sprayed on open wounds, and it has been shown that the same effect and efficacy as low-dose continuous intravenous ginsenoside R b can be obtained. . In addition, when the ginsenoside Rb was added to the skin in an amount of 0.000001% by weight, the hair growth was clearly observed from the regenerated open wound. In other words, the effects and efficacy of low-dose ginsenoside R bi by continuous intravenous administration. It can be said that this also applies to topical administration. In other words, topical application of low-concentration ginsenosides, especially ginsenoside Rb, to the skin can lead to epidermal tissue of the skin, connective tissue of the dermis, papillae of the dermis, blood vessels, sebaceous glands, nerves, sweat glands, dermal papilla, pilo muscularis, hair follicles It is thought that it will promote regeneration and reconstruction of the wound, etc., and hasten wound treatment. To the inventor's knowledge, the effect of the skin external administration of low concentrations of Jinsenosai de R b _t is far superior effect of the peptide factors (PDGF, EGF, b FGF) . The ointment or topical preparation containing a low concentration of ginsenoside Rbi used in this experiment may be used not only on the skin but also on any organ or tissue that causes damage or histopathological changes (cornea, oral cavity, outer ear, eardrum) Topical administration to the vagina, uterus, urethra, rectum, anus, etc.) to promote the regeneration and reconstruction of diseased tissue. From the results of this experiment, it was found that the amount of ginsenosides, especially ginsenoside Rb, per 10 g of the product was 0.1 mg or less, and preferably 0.001 mg or less. In other words, the topical dose of ginsenosides, especially ginsenoside Rb, to humans or vertebrates with skin diseases is much lower than previously thought, depending on individual differences and medical conditions of patients. . In this experiment, the effects of high concentrations of ginsenoside R bi (above 0.0001% by weight) varied among animals. In rats, even if the ginsenoside R bi at a high concentration of 0.001% by weight—0.0001% by weight is applied externally to the open wound, the animal often licks the open wound. As a result, it is considered that the concentration of ginsenoside R b in the open wound decreased, and a favorable effect was sometimes obtained. However, since the act of licking open wounds is unlikely in humans, a lower concentration (for example, less than 0.0002% by weight) of ginsenoside Rbi is topically administered to promote wound healing. Is preferred.

As mentioned above, topical application of low-concentration ginsenoside R bt to the skin epidermis Naturally, the fact that it promotes the regeneration and remodeling of tissue, connective tissue of the dermis, papillae of the dermis, subcutaneous tissue, blood vessels, pilates, sebaceous glands, sweat glands, hair nipples, hair follicles, etc. Skin application for epidermal cells, epidermal keratinocytes (keratinocytes), Merkel cells, melanocytes, Langerhans cells, keratinocytes, dermal and subdermal tissue fibroblasts, vascular endothelial cells, vascular smooth muscle cells, sebaceous glands It has also been shown to promote the regeneration and remodeling of cells, fat cells, cells of sweat glands, cells of hair follicles, cells of the pilo-ermis, mesenchymal cells, and stem cells of the skin. In other words, ginsenosides such as ginsenoside Rb are considered to promote the regeneration and reconstitution of all cells and their secretions constituting skin tissue. On the other hand, various skin symptoms associated with aging (skin atrophy, susceptibility, sagging, itching, bulkiness, cracks, sebum deficiency, keratinocyte exfoliation, horny layer exfoliation, cracks, irritations, spots, wrinkles, freckles, Hair loss, gray hair, dandruff, pigmentation, sunburn, dryness, etc.) are due to the fact that the cells constituting the skin tissue gradually die or become dysfunctional due to ultraviolet damage or aging of the living body. It is thought to be caused by the inability to reproduce in a state. For example, skin aging, aging, aging, depilation, cracking, keratinocyte detachment, horny layer detachment, cracks, dermis, sebum deficiency, and itching are caused by the cells of the sweat glands, hair follicles, and sebaceous glands of the skin. It is thought to be caused by dysfunction or death and not regenerating. In addition, sunburn, pigmentation, spots, freckles, etc. are thought to occur because even if skin cells exposed to sunlight or ultraviolet light die, they will not regenerate as before. In addition, wrinkles, sagging, atrophy, etc. of the skin associated with aging may be caused by fibroblasts or mesenchymal cells in the dermis or subcutaneous tissue that become dysfunctional or decrease in number with age, This can be attributed to the inability to retain sufficient collagen, elastic, reticulum, and extracellular matrix. On the other hand, dysfunction of melanocytes and Langerhans cells may cause gray hair and susceptibility.

The low-concentration ginsenosides of the present invention, particularly ginsenoside R bi, can promote the regeneration and reconstitution of all the cells constituting the skin tissue, and if used as a cosmetic composition, Depletion of skin constituent cells (cell death), various symptoms attributed to dysfunction (skin atrophy, susceptibility to infection, sagging, itching, dryness, sebum deficiency, exfoliation of keratinocytes, exfoliation of horny layer, cracks, rags, Spots, wrinkles, freckles, gray hair, Dandruff, hair loss, pigmentation, sunburn, poor reproduction, dryness, etc.) can be prevented, reduced or improved. Furthermore, ginsenoside R bi is a brain cell or neuronal cell protecting agent comprising ginsenoside R bi, which has been filed by the present inventors (Osakanaka, Tanaka) (WO 00/37848). CT / JP 00/041002, a ginseng-containing brain cell or neuronal cell protective agent) that enhances the expression of the cell death suppressor gene product Be1—, resulting in epidermal cells and keratinocytes. , Keratinocytes, sebaceous gland cells, hair follicle cells, pilo muscular cells, sweat gland cells, fibroblasts, stem cells, mesenchymal cells, vascular endothelial cells, vascular smooth muscle cells, fat cells, etc. Since it is thought to protect all skin cells, it is also possible to prevent the death or dysfunction of skin constituent cells due to aging and aging. Thus, ginsenosides, such as ginsenoside Rb, not only protect all the cells that make up the skin, but also regenerate those cells once the skin cells die or fail. Age-related skin aging symptoms (skin atrophy, susceptibility to infection, sagging, itching, fissures, keratosis, sebum deficiency, exfoliation of keratinocytes, stratum corneum, cracks, irritations, spots, wrinkles, freckles, gray hair Dandruff, hair loss, pigmentation, sunburn, poor reproduction, dryness, etc.). In other words, it can be said that ginsenosides, especially ginsenoside Rb, improve, prevent or alleviate the aging symptoms of skin with aging through two powerful actions of cytoprotective action and tissue / cell regeneration promoting action. Furthermore, as is clear from the experimental results of the present invention and the above-mentioned patents (WO 00/37848, WO 00/46808), ginsenosides, in particular, ginsenoside R b is a cytoprotective and cytoprotective effect when the extracellular fluid concentration in the affected tissue or skin tissue is lng / ml or less, preferably 10 pg / m1 or less, more preferably 100 fg / m1 or less. Tissue ・ Produces cell regeneration promoting action. In addition, as described in Examples described later, low-concentration / low-dose ginsenosides, particularly ginsenoside Rbt, can also promote regeneration and reconstruction of mucosal tissues, and can treat bites on oral mucosa. Accordingly, ginsenosides, especially natural products containing ginsenoside Rbt or ginsenoside Rbi or extracts thereof, may be used for any cosmetics and health products (such as lotions (skin lotions), emulsions (milk lotions), serums, massage agents, Packs, emulsions, foundations, creams, gels, lotions, emulsions, powders, Hair dye, hair manicure, cold cream, eye shadow, cleansing cream, facial cleansing foam, night cream, whitening cream, troche, throat, whitening, lipstick, bath salt, toilet soap, healthy drinking water, isotonic war Tar, water splitting ice, sherbet, ice cream, alcoholic beverages, eyewash, eyewash, face wash, mouthwash, shampoo, rinse, toothpaste, lip balm, base cream (makeup base), UV liquid Base, powder foundation, etc.) and maintain the extracellular solution concentration of ginsenosides, especially ginsenoside R bi at the local skin or mucous membrane at a low concentration as described above. Aging symptoms (atrophy, susceptibility, sagging Itching, fissure, dryness, poor regeneration, epithelial detachment, mucosal detachment, sebum deficiency, keratinocyte detachment, stratum corneum detachment, cracks, irritations, spots, wrinkles, freckles, gray hair, dandruff, hair loss, pigmentation, tanning, It has an excellent effect on drying. For example, with the aging and aging of the skin, the deficiency of skin fats (ie, sebum) alone can cause the skin to become bulky, cracked, dry, itchy, exfoliate keratinocytes, etc., but low concentrations of ginsenosides, especially ginsenosides By mixing Rb or ginsenoside Rb-containing natural product or its extract in any cosmetics, the protection, regeneration and reconstruction of the sebaceous glands is promoted, and the aforementioned aging symptoms of the skin associated with aging are prevented. , Improvement, or alleviation. In addition, any cosmetic containing a low concentration of ginsenosides, especially ginsenoside Rbi, not only protects epidermal cells (keratinocytes) or epidermal keratinocytes, but also promotes their regeneration. It also promotes the production and secretion of lipids and natural moisturizing factors, thereby preventing the skin from drying and swelling, and providing the skin with natural moisture. Ginsenosides, especially ginsenoside Rb, natural product extract containing ginsenoside Rb, crude ginseng crude saponin fraction, etc. are mixed at low concentration into mineral water, etc. Can improve, prevent, and treat disorders of the oral mucosa and gastrointestinal mucosa (especially the esophageal mucosa). Ginsenosides at low concentrations, especially natural product extracts containing ginsenoside Rb or ginsenoside Rb, are used as chemical peeling compositions in the entire process (before, during or after) chemical peeling. Or one or more of the excipients (ie, chemical peeling agents) Can be used. Of course, as described above, instead of ginsenoside R b, a natural product containing ginsenoside R bi, a natural product extract, ginseng, a ginseng extract, a crude ginseng crude saponin fraction, etc., for an external skin composition (Cosmetic composition, hair growth composition, composition for chemical peeling). In addition, the cosmetic composition of the present invention, a composition for hair growth and hair growth, a composition for chemical peeling (natural products containing ginsenoside R bi or extracts thereof, ginseng, ginseng extract, ginseng crude Bases of saponin fraction, ginsenosides, ginsenoside derivatives) include oils and fats, waxes, hydrocarbons, fatty acids, lower alcohols, higher alcohols, polyhydric alcohols, and esters. , A surfactant, and a water-soluble polymer compound. The composition for external use on the skin (cosmetic composition, composition for hair growth and hair growth, composition for chemical peeling) of the present invention includes other skin cell activators, hair growth and hair growth compositions, cosmetic compositions, anti-inflammatory agents, Active oxygen scavenger, whitening agent, humectant, UV absorber, antiseptic / antifungal agent, vitamins, minoxidil, emollient, known natural product extract, known crude drug extract, known natural product component, retinoic acid ac id) may be used in combination with one or more of them. The above-mentioned known natural product extract or natural component includes, but is not limited to, any crude drug, crude drug extract or crude drug component used in Chinese herbal prescriptions. When ginsenoside Rb is used almost alone as an external preparation for skin, an external preparation for mucous membrane, or an external composition for skin, its concentration should be less than 0.001% by weight, and other pharmaceutical compositions or external compositions for skin. When used together, the concentration is preferably less than 0.002% by weight. The upper limit of the concentration of the natural product containing ginsenoside R bi or its extract is considered to be less than 0.001% by weight. When a ginsenoside derivative such as dihydroxyzine senoside Rb or epoxy ginsenoside Rb is used as the above-mentioned external preparation or external composition, the concentration is 0.001% by weight or less, preferably less than 0.01% by weight. It is less than 0.0000% by weight. The upper limit of their concentration is 3% by weight, preferably 0.1% by weight or less.

Next, one of the present inventors (Sakanaka) himself confirmed whether or not the project containing a low concentration of ginsenoside Rbi was effective for biting the oral mucosa. Around 2:00 pm on May 2, 2002, Osaka was treated with dental anesthesia and infiltration of the third trigeminal nerve after periodontal treatment. Before drunkenness, he began to have a hungry, too late lunch. Within 15 minutes, he left his lower lip mucous membrane three times, and then sensed the taste (blood) of iron in the oral cavity. Defect was observed, and hematoma was observed in one more place. If left untouched, aphthous stomatitis would occur within a few days, and it was determined that it would take 1 week to 10 days for complete cure. Therefore, the low concentration ( (0.00001% by weight) of ginsenoside Rbi was applied topically in small amounts to 5 sites of erosion or defect of the oral mucosa bite and 1 site of hematoma. External application was performed before and after each meal and before and after a snack. After the meal, we decided to brush the teeth as much as possible before applying topically. That is, a probe containing 0.00001% by weight of ginsenoside Rbi was externally applied to the lip mucosa at the bite site in 6 to 10 times a day. A photograph of the lip mucosa 96 hours after the bite is shown in FIG. Figure 11 is a photograph replacing a drawing.

As shown in the photograph of Fig. 11, at 96 hours after the bite, a hematoma remains as indicated by a white arrowhead, but the bite of the labial mucosa indicated by a black arrowhead (that is, erosion or defect is not observed). The epithelium of the oral mucosa was slightly reddened, and the epithelization was almost complete. It was considered that the wound had clearly healed. After external application of a probe containing 0.0001% by weight of ginsenoside Rbi to the bite site, pain at the wound site was remarkably reduced. Presumably, the oral administration of ginsenoside Rb at a low concentration to the oral mucosa relieved pain because the peripheral nerve cut by the bite rapidly regenerated with epithelialization. In the inventor's experience, healing such a bite takes at least 7 to 10 days, but low concentrations of ginsenoside R b! It can be said that the topical administration clearly regenerated and reconstructed the labial mucosal tissue rapidly, and the healing of the bite (wound) was significantly accelerated within 96 hours. No bitter stomatitis occurred after the bite. Presumably, topical administration of ginsenosides, especially ginsenoside Rb, to the lesions 11 to 10 times a day is considered to be effective for mucosal lesions. In general, steroids such as dexartin ointment are often used in clinical settings for aphthous stomatitis, but as is well known, steroids reduce the pain of aphthous stomatitis. However, it has the side effect of slowing the healing of wounds and tissue defects. However, it is not always preferable to apply a topical steroid agent, which has an immune function-suppressing effect, on mucosal lesions in the oral cavity, where many germs are present, in view of concurrent infection.

On the other hand, external administration of low-concentration ginsenoside Rbi to the mucosa promotes wound healing and epithelialization and promotes regeneration of peripheral nerves in mucosal lesions. It is considered a law. In addition, low-concentration ginsenoside R bi does not show an immune function-suppressing effect, so it can be said that it is an extremely safe pharmaceutical composition.c It is expected that low-concentration ginsenoside R b can be used as a first-line drug for aphthous stomatitis in the future Be expected. Of course, ginsenosides such as ginsenoside Rb may be used as a dosage form such as an aphthatic patch.

Next, one of the present inventors (Sakanaka) re-opened the left lower lip mucous membrane during lunch on May 26, 2012, so that 0.001% by weight of ginsenoside R was used. The plot containing bi was applied externally to the bite site in the same manner. The photograph immediately after the bite is shown on the left side of FIG. 12, and the photograph 72 hours after the bite is shown on the right side of FIG. Figure 12 is a photograph replacing the drawing.

As shown in Fig. 12, it was found that external application of low-concentration ginsenoside Rb to mucous membranes quickly healed bites without causing aphthous stomatitis. Therefore, the low concentration of ginsenoside Rbt promotes the regeneration and reconstruction of not only skin tissue but also mucosal tissue including the human mucosal mucosa, and is thought to accelerate wound healing. Based on these facts, low concentrations of ginsenosides, especially ginsenoside Rbi, are effective against all diseases and conditions that cause histopathological changes in mucous membranes including oral mucosa and oral tissues. It can be said that it exerts its effects and effects through promoting tissue regeneration and reconstruction. Such diseases include caries, pulpitis, marginal periodontitis, stomatitis, glossitis, recurrent aphtha, intraoral aphtha, bad breath, oral abnormal sensation, dental infection, oral mucosal bite , Tongue bite, Oral mucosa burn, Tongue burn, Oral mucosal damage, Gingivitis, Dental pyorrhea, Catal stomatitis, Gangrene stomatitis, Wangsan stomatitis, Aphtha stomatitis, Acute herpetic gingivostomatitis, Herpangina, Shingles, oral mucosal erosion, oral mucosal ulcer, pressure sore, radiation stomatitis, pemphigus, oral candidiasis, lichen planus, R i ga—Fede habit, smooth tongue, red lingual tongue, corneal erosion, corneal ulcer, dry eye, shea-Darren syndrome, bacterial keratitis, fungal keratitis, dendritic keratitis, corneal herpes, acanthamoeba cornea Inflammation, corneal infiltration, corneal corneal infiltration, corneal fritten, silkworm corneal ulcer, discoid keratitis, necrotizing keratitis, granular corneal degeneration, lattice corneal degeneration, patchy corneal degeneration, glomerular drops Corneal degeneration, Schneider's corneal degeneration, cricoid corneal degeneration, zonal corneal degeneration, perusidic corneal degeneration, terien corneal degeneration, droplet corneas, Fuchs corneal endothelial degeneration, posterior polymorphic corneal endothelial degeneration, iris Examples include corneal endothelial syndrome, corneal endothelitis, keratoconus, recurrent corneal erosion, prolonged corneal epithelial defect, keratoconjunctivitis sicca, cataract, glaucoma, upper limbal keratoconjunctivitis, bullous keratopathy, and the like.

In addition, the fact that topical application of low-concentration ginsenoside Rb was effective for oral mucosa bite was due to the fact that ginsenosides, especially ginsenoside Rbi, Lamina propria, salivary gland, mucous gland, mixed gland, connective tissue, muscle tissue, blood vessels, peripheral nerves, epithelial cells, gland cells, myoepithelial cells, fibroblasts, stem cells, mesenchymal cells, vascular endothelial cells, smooth muscle cells It supports the promotion of regeneration or remodeling of muscle cells, extracellular matrix, collagen fibers, elastic fibers or reticulum fibers. External preparations containing low concentrations of ginsenosides, especially ginsenoside Rb, are used not only for oral mucosa but also for gastrointestinal mucosa, nasal mucosa, ocular mucosa (conjunctiva, cornea), vaginal mucosa, uterine mucosa, urethra When applied externally to all mucous membranes, such as mucosa, bladder mucosa, trachea and bronchial mucosa, it is highly effective against diseases and conditions that cause histopathological changes in these mucous membranes. In particular, topical administration of ginsenosides, especially ginsenoside Rbi, is effective for mucosal wounds, burns, inflammation, erosions, ulcers, defects, hay fever and spring catarrh. Furthermore, topical mucosal preparations containing low concentrations of ginsenosides, especially ginsenoside Rb, prevent and improve mucosal aging symptoms (atrophy, epithelial detachment, mucosal detachment, poor regeneration, cracks, dryness, etc.) It can also be used as a health drug for treatment. The effects, indications, and uses of ginsenoside R bi described so far are the effects and indications of ginsenoside derivatives such as dihydroxy ginsenoside R b epoxy ginsenoside R b or dihydroxy ginsenoside R bi. · It can be said that it is common to all applications. The action of dihydrozincenoside Rb: to promote skin wound healing will be described later. However, judging from the results of the culture experiment, ginsenoside derivatives It is considered that it can be used in a wider concentration range than Side Rb. Specifically, it is considered that an effective dose / concentration can be set within a range of about 1/1000 to 1000 times the administered dose / concentration of ginsenoside Rbi.

Next, the present inventors investigated whether ginsenosides, especially ginsenoside Rbi, promotes the regeneration, regeneration, or reconstruction of plant tissues as well as skin tissues and oral mucosal tissues. For this reason, pothos, one of the foliage plants, was selected as the plant tissue. Six similar cuttings were taken from the parent plant of Potos in one of the inventor's (Tanaka) rooms, three were hydroponically grown using only water, and the remaining three were 100 fg / m1 ginseno. Cultivated in water containing side R bi. Fig. 13 shows photographs of cuttings on the 13th day of cultivation. Figure 13 is a photograph replacing the drawing.

The left side of Fig. 13 shows the hydroponics of cuttings (pothos stems and branches) with water only, and the right side of Fig. 13 shows the low concentration of ginsenoside R bi (100 fg / m 1). Cuttings were hydroponically grown with the contained water. Clearly low ginsenoside R b

(100 fg / m1) promoted root elongation when potato cuttings were cultivated in water.

Next, the present inventors continued the hydroponic cultivation of the cuttings described above, and again photographed them on the 22nd day. The results are shown in FIG. Fig. 14 is a photograph that changes to a drawing. The left side of Fig. 14 shows three pothos cuttings cultivated with water alone for 22 days, and the right side of Fig. 14 shows low concentration of ginsenoside R bi (100 fg / m 1). Cuttings were cultivated with water containing water. Water for hydroponics or water containing ginsenoside R b was replaced once a week. Furthermore, the present inventors also observed the rooting site on the 27th day.

As shown in Fig. 14, when cuttings were cultivated for 22 days in water containing low concentration of ginsenoside R bi (100 fg / m 1), compared to pothos hydroponically cultivated with water alone, Many roots regenerated or regenerated and grew before contacting the hydroponic glass containers. Furthermore, on day 27, all three cuttings of pothos grown in water containing low concentrations of ginsenoside R bi (100 fg / m 1) showed secondary Rooting was observed. However, no secondary rooting was observed in any of the three young pothos grown on water alone. Therefore, from the results of this experiment Low-concentration and low-dose ginsenosides, especially ginsenoside R bi or natural products containing ginsenoside R bi or extracts thereof, include not only skin tissues, human oral mucosa tissues, but also rooting and germination of plant tissues. It was revealed that growth, differentiation, new generation, regeneration, and regeneration also promote restructuring.

In other words, ginsenosides such as ginsenoside Rbi promote the regeneration, renewal, and reconstruction of all living tissues (animal and plant tissues).

As shown in the above experiments, cultivation of plant tissues, such as pothos cuttings, in an aqueous solution containing 100 ig / ml ginsenoside Rbi clearly promotes root regeneration compared to control cuttings. You. Therefore, as described above, ginsenosides such as ginsenoside R b として can be used not only in animal tissues, but also as a composition for regulating growth in the rooting, germination, growth, differentiation, renewal, regeneration or regeneration of plant tissues. It can be said to promote.

Moreover, the extracellular fluid concentrations of Jinsenosai de R b _t to promote rooting, germination, growth, differentiation, neoplastic and regeneration or reconstruction of plant tissues, animal tissues (skin tissue, oral mucosa tissue) regeneration and re As in the case of constructing, extremely low values were found in the present invention. Therefore, ginsenosides such as ginsenoside Rb are used for plant cultivation-cultivation and preservation, and preservation of fresh flowers. It can be said that it can be used for cultivation and cultivation, tobacco cultivation and cultivation, mushroom cultivation, medicinal plant cultivation, tea leaf cultivation and cultivation, etc. A rooting, germination, growth, differentiation promoting agent or fertilizer composition comprising a ginsenoside such as ginsenoside Rb or a ginsenoside Rbt-containing natural product or an extract thereof is preferably used in any fertilizer at a low concentration ( 1% by weight or less, preferably 0.1% by weight or less, more preferably 0.01% by weight or less), provided that the extracellular solution concentration can be kept low as described above. It may be used alone as rooting, germination, differentiation, regeneration, reconstruction, renewal, growth promotion of plant tissue. Of course, ginsenoside derivatives such as dihydroxy ginsenoside R bh epoxy ginsenoside R b and dihydro ginsenoside R b are also similar to ginsenoside R b, so that rooting, germination, new growth, growth, and regeneration of plant tissue are possible.・ Promote differentiation or reconstruction, and cultivate agricultural products, plants, vegetables, etc. It can be used as a composition for adjusting the length. Further, the composition for regulating plant growth of the present invention can also be used as a rooting promoter, a germination promoter, a flower preservative, and the like. Ginsenosides The fact that ginsenosides such as R bi promotes rooting, germination, differentiation, growth, renewal, regeneration or restructuring of plant tissues as well as animal tissues (skin tissues and oral mucosal tissues) It indicates that ginsenosides such as de R bi promote rooting, germination, differentiation, growth, new generation, regeneration or reconstruction of all living tissues. Therefore, it can be said that ginsenosides such as ginsenoside Rbi can also be used as a composition for livestock, aquaculture fish and shellfish, ornamental fish, and pet feed as shown in Example 23 described later. For example, when cultivating fish and shellfish such as locusts, crustaceans, eel, pearl oysters, pearl oysters, quells and burrows, low concentrations of ginsenosides, especially ginsenoside R bi or ginsenoside R bi are contained. The addition of natural products or extracts thereof to seawater or freshwater along with normal feed is thought to promote the development of these marine or marine resources. Of course, ginsenosides such as ginsenoside Rb or natural products containing ginsenoside Rbi are marine and marine resources such as fish and shellfish, crustaceans, eel, que, and eel through their cytoprotective action. Can be protected from trauma, wounds, pathogenic microorganisms, biohazard, endocrine disruptors, environmental pollution, toxins, etc. That is, the feed composition or the composition for regulating animal growth of the present invention is indispensable to rescue human beings from the coming food crisis. Of course, ginsenoside derivatives such as dihydroxy ginsenoside R bh epoxy ginsenoside R bi or dihydro ginsenoside R bi are also used as the above-mentioned fisheries products as ginsenoside R bt as a composition for controlling animal growth. It can be used to promote the growth of resources or marine resources. Ginsenosides such as ginsenoside R bi, natural products containing ginsenoside R bi, or dihydroxy ginsenoside R b epoxy ginsenoside R b! Or ginsenoside derivatives such as dihydroginsenoside R b, when used as a plant growth regulating composition, a fertilizer composition, a feed composition, or an animal growth regulating composition as described above. Their concentration in plant growth regulators, fertilizers, feed or animal growth regulators is 1% by weight or less, preferably 0.1% by weight or less, more preferably 0.01% by weight or less, even more preferably 0.01% by weight. It is preferably at most 1% by weight. Of course, the composition is ginsengosa As long as the concentration of extracellular fluids in the cells can be kept low, larger amounts can be used.

Now, in the oral mucosa bites example above, the present inventors (Sakanaka) is 0.0 0 0 0 1 by weight% (1 0 ⁵ wt%) ginsenoside R b which contained pro downy oral mucosa ( When applied topically 6-10 times a day to the lower lip mucosa), oral mucosal tissue was quickly regenerated and reconstructed, indicating that the wound was healed and that aphthous stomatitis could be prevented. However, as a matter of course, even if the oral mucosa bite is externally coated with a 0.001% by weight ginsenoside Rb-containing protrate, saliva causes ginsenoside R cells near the bite. It is expected that the concentration of the external solution will soon decrease. Possibly, a probe containing 0.001% by weight of ginsenoside R b promotes regeneration and reconstruction of oral mucosa bite tissue even when diluted significantly by oral saliva. It is considered to be. In other words, ginsenoside Rt ^ is expected to exhibit its effect and efficacy in a concentration range much lower than 0.001% by weight. Therefore, when an external preparation containing ginsenoside Rb is applied to the wound of the skin, it is unlikely that the concentration of ginsenoside Rbi in the external preparation is significantly diluted with saliva or the like. 0 0 1 prefer to use Jinsenosai de R b _t of lower density than the weight% was considered preferable arbitrariness. Therefore, the present inventors applied topically a probe containing a lower concentration of ginsenoside Rb to the above-mentioned open wound of the rat skin, and examined the effect.

Under inhalational anesthesia, 6-diameter punch biopsies were applied to the back of the rat (n == 3) at six locations to create open wounds. Thereafter, each open wounds, Jinsenosai de R b, a, respectively it 0.0 0 0 1 wt% (1 0 ^4% by weight), 0.0 0 0 0 1 wt% (1 0 ⁵ wt%) , 0.0 0 0 0 0 1 wt% (1 0 ⁶ wt%), 0.0 0 0 0 0 0 1 wt%

(1 ^0-7 wt%), 0.0 0 0 0 0 0 0 at a concentration of 1 wt% (1 0 ⁸ wt%), the Puropeto having free daily single 0. I g 9 days external Applied. The control was externally applied with only the plot. Immediately after the animal was euthanized by anesthesia, the wound skin was collected and photographed. The collected skin tissue was stored in a fixative. The results are shown in Figure 15. Figure 15 is a photograph replacing the drawing.

The upper part of Fig. 15 shows the first example, the middle part shows the second example, and the lower part shows the third example. Show. Each has traces of open wounds in six places of the right and left three increments, if the top of the left of the 0 one ⁴ wt%, in the case of 1 0 ⁵ wt%, in the case of 1 0 ⁶ wt%, right from 1 0 one ⁷ wt% on the, for a 1 0 ⁸ wt% shows the case of 0% (control). Purobe bets (i.e. 1 0 ng / g 1 0 0 of pg / g concentration of Jinseno rhino containing the first 5 as shown in FIG. 1 0 ^-6 wt% 1 0 ⁸ wt% Jinsenosai de R b Topical application of de-Rb to open wounds clearly promoted wound healing compared to open-wounds with topical application of only the protope, and topical application of low-concentration ginsenoside Rbi in a clear hair wound healing portion was observed. Thus, when the Jinse Nosai earth especially the use of Jinsenosai de R bi as a skin external preparation, its concentration in the external preparation 1 0 ^8% by weight before and after Therefore, ginsenosides, especially ginsenoside Rbi, should be used as a composition for hair growth and hair growth, a composition for chemical peeling, or a cosmetic composition. Sometimes the concentration is 0.0 0 less than 1 wt%, preferably 0.0 0 0 0 less than 2 wt%, more preferably 0.0 0 0 0 1 wt% (1 0 ^5% by weight) or less, more preferred properly 0. 0 0 0 0 0 0 0 1 wt% (1 0 ^8% by weight) it is necessary to set below. However, Jinsenosai de R bt a chemical peeling composition, mucosal topical composition or mucosal external preparation When used as a composition, the upper limit of the concentration may be set to 0.1% by weight.

In the experimental example described above, the area of the open wound (red area) to which only the plot was externally applied was taken as the denominator, and the open wound to which 10 to ^{4 to} 10 to ⁸ % by weight of ginsenoside Rb was externally applied was used. The area of was taken as the numerator and the ratio was calculated. The results are shown in FIG. In FIG. 16, 11 = 3 indicates that there is a significant difference at the mark ** 0.05, and ** indicates that there is a significant difference at P <0.01. The test is based on Schefie's post hoc test.

As shown in FIG. 16, topical application of these low concentrations of ginsenoside Rbi to open wounds significantly promoted wound healing. Especially 0.0 0 0 0 0 0 1 wt% (1 0 one ⁷ wt%) topical administration of the following Jinsenosai de R b ie lng / g or less or 1 ng / m 1 following Jinsenosai de R bi is the open wound The fact that the size was significantly reduced was observed when ginsenoside R bi was less than 1 ng / m1 in the extracellular fluid concentration of the affected tissue. It strongly supports the promotion of the regeneration, regeneration or reconstruction of living tissue. Next, the present inventors have proposed that dihydroxyginsenoside R b! Ginsenoside derivatives such as epoxy ginsenoside Rb or dihydroginsenoside Rb promote tissue regeneration and remodeling at low concentration and low dose, similar to ginsenoside Rbi. Was. For this reason, dihydroginsenoside Rbi was selected as one of the ginsenoside derivatives, and the open wound therapeutic effect of the compound was examined. In addition, dihydro ginsenoside R b! PC No. PC TZ JP 0/0 4 1 0 2 (a brain cell or nerve cell protective agent consisting of ginseng) and PCT / JP 0 0 Z 0 5 5 5 4

(Skin tissue regeneration promoter consisting of ginsenoside R b). Under inhaled anesthesia, open wounds were created by applying punch biopsies of 6 mm diameter to the back of rats (n = 4) at five locations. Thereafter, each open wound, a dihydro ginsenosides Sai de R bi respectively are 0.0 0 0 1 wt% (1 0 ^4% by weight), 0.0 0 0 0 1 wt% d ^o-5 wt

%) 0.0 0 0 0 0 1 wt% (1 0 ⁶ wt%), 0.0 0 0 0 0 0 1 wt%

(1 0 ^7% by weight) at a concentration of 0 1 day single a Puropeto containing. And topical application I g 9 days. For the control, only the plot was externally applied. Immediately after the animals were euthanized by anesthesia, the wound skin was collected and photographed. The collected skin tissue was stored in a fixative. The results are shown in FIG. Figure 17 is a photograph replacing the drawing. FIG. 17 shows four examples, and the first example, the second example, the third example, and the fourth example are shown from the top. Each two on the left, there are traces of open wounds in total 5 places three increments to the right, when the top of the left side of the 1 0 ^4% by weight, in the case of 1 0 ⁵ wt%, from the top of the right 1 for 0 ⁶ wt% in the case of 1 ^0-7 wt%, shows the case of 0% (control).

The first 7-dihydro ginsenosides Sai de R b _t of 0.0 0 0 0 1 wt% as shown in FIG. (1 0 ⁵ wt%) 0 0 0 0 0 0 1 wt% (1 ^0-7 wt%) It is evident that topical application of dihydroginsenoside Rb at a concentration of 100 ng / g to IngZg to open wounds on open wounds compared to open wounds on which only the protocol was applied externally. In the case of topical administration of dihydroginsenoside Rb at a low concentration, obvious hair growth was observed in the wound healing area. Senoside R bi or Epoxyzine When ginsenoside derivatives such as cenoside Rbi are used as an external preparation for skin, the concentration in the external preparation is 0.001% by weight or less, preferably 0.00001% by weight or less. preferably 0. 0 0 0 0 0 0 1 wt% (1 ^0-7 wt%) were considered to be preferable to set the longitudinal or less. Therefore, as a hair growth composition, a composition for chemical peeling, a composition for external mucosa, and a cosmetic composition, dihydroginsenoside R b dihydroxy ginsenoside R bt or epoxy ginsenoside R b, etc. When ginsenoside derivatives of the formula (1) are used, their concentration in cosmetics, chemical peeling agents or health agents is not more than 0.001% by weight, preferably not more than 0.001% by weight, more preferably not more than 0.01% by weight. 0 0 0 0 1 wt% (1 0 one ^5% by weight) or less, more preferably 0.0 0 0 0 0 0 1 wt% (1 0 ⁷ weight

%) It is preferable to set the following. The upper limit of the concentration of a ginsenoside derivative in a hair growth agent, a chemical peeling agent, cosmetics, an external preparation for skin, and an external preparation for mucosa is 1% or less, preferably 0.1% or less.

In the experimental example described above, Ri bets in the denominator the area of open wound that topical application of Purobetonomi, 0.0 0 0 1 wt% 0.1 (1 0 ^4% by weight) 0 0 0 0 0 0 1 The area of the open wound to which topical application of 10% by weight (10 to ¹⁷ % by weight) of dihydroginsenoside Rb was applied was taken as the molecule, and the ratio was calculated. The results are shown in FIG. In FIG. 18, the symbol * indicates that there is a significant difference at P = 0.05 when n = 4. The test is based on Fisher's PLSD.

As shown in the first FIG. 8, 0.0 0 0 0 1 wt% (1 0 ⁵ wt%) regeneration and re following the di hydro ginsenosides Sai de R bi concentrations topically administered to open wound skin tissue Construction was accelerated, and wound healing was significantly accelerated. In particular, a dihydroginsenoside R bi of not more than 0.001% by weight (10- ^s weight%), that is, a dihydroginsenoside of 100 ng / g or less or 100 ng / m 1 or less. The fact that topical administration of de-Rb significantly reduced open wounds was attributed to ginsenoside derivatives such as dihydroginsenoside Rbi, dihydroxyzinenoside Rbt, or epoxyginsenoside Rbi. We strongly support that when the extracellular fluid concentration of the affected tissue is 100 g / m1 or less, preferably 100 ng / m1 or less, it significantly promotes the regeneration, regeneration, or reconstruction of living tissue. are doing. Next, the present inventors have determined that the dihydroginsenoside R bi is the ginsenoside R b described in WO 00/37848, the dihydroxy ginsenoside R bi and the epoxy ginsenoside of the present invention. In order to confirm that it has the same effects, efficacy, and uses as Rbi, an experiment was further performed using cultured neurons.

As described above, the present inventors (Sakanaka, Tanaka) and colleagues reported that short-term exposure of cultured neurons to the nitric oxide donor, nitroprusside sodium (SNP), resulted in neuronal apoptosis or apoptotic neuronal death. (Toku K. et al., J. Neurosci. Res., 53, 415-425, 1998). Using this culture experiment system, the present inventors have already determined that the ginsenoside Rb has an optimal extracellular solution concentration of 1 ng / m1 or less, more specifically 1 to 100 fg / m1. It has been found to inhibit apoptosis or apoptosis-like neuronal cell death in neural cells in the concentration range (WO 00/37 481, PCT / JP99 / 0 250 550, Ginsenosa Id Rb: a brain cell or nerve cell protecting agent). Furthermore, in the same experimental system, dihydroxy ginsenoside Rt or epoxy ginsenoside Rb also has an optimal cell content of 1 fg / ml to 1 ng / ml or 1 ng / ml to 10 ng / ml. It has been found in the present invention that apoptosis of nerve cells or apoptosis-like nerve cell death is inhibited in the external solution concentration range. Then, the present inventors examined the neuroprotective effect of dihydroginsenoside R b ^ using a similar experimental system.

Nerve cells were isolated from the fetal cerebral cortex of a 17-day-old rat using trypsin EDTA, and plated on a poly-lysine-coated 24-well plate. After culturing for 16 hours in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum, the culture is cultured in neural cells containing insulin, transferrin, etc. The medium was replaced with a serum-free medium and cultured for 3 to 4 days. On the third or fourth day of culture, two-mouthed sodium prusid (SNP) was added at a concentration of 300 zM and incubated for 10 minutes. The culture was then replaced with Eagle's minimum essential medium (EMEM) containing dihydroginsenoside Rb (0-1 ng / ml) and bovine serum albumin. Sixteen hours after SNP loading, neurons were lysed using Laemmli electrophoresis sample buffer, and polyacrylamide gel electrophoresis was performed. After transfer of the substance to a nitrocellulose membrane, immu- noblotting was performed using an antibody against the neuronal cell-specific protein MAP2. To quantify neuronal cell viability, immunostained MAP2 bands were analyzed by densitometry. The results are shown in FIGS. 19 and 20. Figure 19 is a photograph replacing the drawing. In Fig. 20, n = 5, the * mark indicates a significant difference at P <0.001, and the ** mark indicates a significant difference at P <0.001. . The test is based on Scheife's post hoc test.

Also shown dihydro ginsenosides Sai de R bi of NMR Chiya Ichito the (4 0 0 MH z, CD 3 0 D) in the second 1 Figure for reference.

FIG. 19 is a photograph in place of a drawing showing the results of the immunoblot of microtuble-associated protein 2 (MAP2). The first lane from the left is a control cultured neuron, in which a clear MAP2 band (ie, a band of neurons) was observed. The SNP treatment caused many neurons to undergo apoptosis or apoptotic neuronal death, so the MAP2 band was clearly weakened, as in the second lane from the left. If dihydro rosin senoside Rb is added to the culture medium at a concentration of 0.01 fg / m1 (lane 3) to 1 ng / m1 (lane 7), neuronal apoptosis by SNP or Apoptotic neuronal cell death was clearly suppressed, and as a result, a strong band of MAP2 was observed, which is an indicator of neuronal cell survival.

Fig. 20 shows the results of denimometry analysis of the above-mentioned MAP im- noblot experiment repeated five times. As shown in FIG. 20, dihydroginsenoside R b of 0.01 fg / m 1-1 ng Zm 1 significantly decreased the number of neurons in 7-potosis or apoptosis-like neurons. Turned out to be deterrent. That is, hydrin senoside R b! Is a ginsenoside R b! It is thought that it exerts a favorable effect on cells, especially nerve cells, in a slightly wider concentration range. Therefore, ginsenoside derivatives such as dihydroginsenoside Rb have an extracellular fluid concentration of 100 g / m1 or less, preferably 100 ng / m1 or less, more preferably 1 ng / m1 or less in the affected tissue. Inhibits apoptosis or apoptosis-like cell death of cells when m 1 or less, more preferably 0,000 lig / m 1-100 fg / m 1 Thus, it is thought to exert an excellent cytoprotective effect. Statistical analysis is a post hoc test of Scheif e. The * mark indicates P <0.01>, and the ** mark indicates P <0.01>.

Further, when judged from the experimental results described above that shows mercy Dorojinsenosai de R bt a 0.0 0 0 0 1 wt% (1 0 ⁵ wt%) the external preparation for skin containing an excellent open wound therapeutic effect, dihydric Ginsenoside derivatives such as drozincenoside R bh dihydroxydoxysenoside R b or epoxy ginsenoside R bi still have an extracellular fluid concentration of 100 gZm1 or less, preferably 10 g, in the affected tissue. Excellent regeneration / reconstruction of living tissue at 0 ng / m 1 or less, more preferably 1 ng / 1 or less, and even more preferably 0.00001 fg / m 1-100 fg / m 1 It can be said that it works.

Based on the above experimental results, ginsenoside derivatives such as dihydrozine senoside Rb and dihydroxyzine senoside Rbi and epoxy ginsenoside Rb are excellent at low concentration and low dose, similar to ginsenoside Rb. It has been shown to have a skin tissue regeneration / remodeling promotion action, a wound healing promotion action, and a cell protection action. In addition, in PCT / JP 00/04102 (a brain cell or nerve cell protective agent consisting of ginseng), a low dose of dihydrozine cenoside for a cerebral infarction rat weighing 300 g was used. R b! The present inventors have found that continuous intravenous administration of (6 μg / day) exerts an excellent cerebral infarction treatment effect similarly to ginsenoside Rbi. In addition, it has also been found that by increasing the number of experimental cases as described below, dihydrozincenoside Rbi has a significant therapeutic effect on cerebral infarction. In addition, as described below, the present inventors also applied intravenous administration of a low dose of dihydrozine cenoside Rb (1.2 g / day) to a spinal cord injury rat weighing 300 g, as described below. It has been confirmed that it shows an effect comparable to the intravenous administration (60 / zg / day) of ginsenoside Rb described in Z4866. Accordingly, ginsenoside derivatives such as dihydrozine senoside Rb, dihydroxyzine senoside Rbi or epoxy ginsenoside Rbt are disclosed in the present invention and the patents already filed (WO 00/37848). , WO 0 0 Z4 8608, Japanese Patent Application 200 0—2 4 8 4 58, Japanese Patent Application 200 0 — 4 0 3 023, PC TZ JP 0 0/0 4 1 No. 2, PCT / JP 0 0/0 5 5 5 4, Patent application 2 0 1 — 3 7 4 5 0 9, Effects and indications of ginsenoside R b described in Japanese Patent Application No. 200-1 — 365 5 282)

-It can be said that it has all uses. That is, ginsenoside derivatives such as dihydroginsenoside R b "dihydroxy ginsenoside R b or epoxy ginsenoside R bi are used for the renewal, regeneration, growth, and development of living tissues (plant tissues and animal tissues). It has a promoting effect on roots, germination, differentiation or remodeling. (1) A pharmaceutical composition or veterinary pharmaceutical composition for preventing, treating, or treating any disease (including pathological condition) that causes histopathological changes. 2) Cosmetic composition or skin external composition for preventing, ameliorating, reducing or treating aging symptoms of skin or mucous membranes, (3) Plants for cultivating, growing and preserving agricultural products, vegetables, plants and fresh flowers Growth regulating composition or fertilizer composition,

(4) Composition or feed composition for animal growth preparation to protect and grow marine resources, marine resources, livestock, and fish and shellfish for cultivation, (5) Prevention, treatment or treatment of any disease that causes cell death It is useful as a pharmaceutical composition for medical use. Ginsenoside derivatives such as dihydroginsenoside R b dihydroxy ginsenoside R bi or epoxy ginsenoside R bi can be used as a composition for external mucosa, a cosmetic composition, a composition for hair growth and hair growth, and a chemical pile. Composition, external preparation for mucous membrane, external preparation for skin, pharmaceutical composition, health medicine composition, composition for growth preparation, feed composition, fertilizer composition, plant rooting, germination, growth, and differentiation promoting agent, It can be used in the same manner as ginsenoside Rbi. However, ginsenoside derivatives such as dihydrozinosenoside Rb dihydroxy ginsenoside Rb or epoxyzinsenoside Rb can be used in a wider concentration range than ginsenoside Rbi (probably the effective concentration of ginsenoside Rb or It is necessary to select an appropriate dose, taking into account that it exerts a favorable effect on cells and tissues (within a range of 1/100 to 1/100 times the effective dose). .

Furthermore, the results of this experiment that dihydroginsenoside Rb exerts an excellent biological tissue regeneration / remodeling promotion effect indicate that ginsenosides, in particular, ginsenoside Rbi as an excellent lead Mucosal disease treatment, tissue regeneration

-Proving that new agents, rooting and germination promoters can be newly created. The idea of creating a pharmaceutical composition for promoting tissue regeneration and reconstruction by using ginsenosides such as ginsenoside Rb, for which a synthesis method has not been established at this time, as a lead compound is limited to the inventor's knowledge. It has never been before. As described above, ginsenoside derivatives such as dihydroginsenoside R b, dihydroxy ginsenoside R b 丄, or epoxy ginsenoside R b can be used in neuronal cells over a much wider concentration range than ginsenoside R bi. In vitro (in vitro) experimental systems have shown that apoptosis or apoptosis-like neuronal cell death is inhibited by dihydroginsenoside in in vivo (in vivo) experimental systems. R b! The present inventors next examined whether or not a ginsenoside derivative such as dihydroxy ginsenoside R bi or epoxy ginsenoside R bi exhibits a neuroprotective effect similarly to ginsenoside R bi. Therefore, an intravenous administration experiment of dihydroginsenoside Rbi, one of the ginsenoside derivatives, was performed using a cerebral infarction rat as follows.

Approximately 12 to 16-week-old male stroke-prone spontaneously hypertensive rats (SH—SP rat, weighing 280 to 320 g) were used. The animals were housed in a 12-hour light / dark cycle room with free access to water and food. Under inhalation anesthesia, the left middle cerebral artery cortical branch (MCA) of the animal was coagulated and dissected. A single intravenous infusion of dihydroginsenoside Rb (6 / zg) immediately after permanent occlusion of MC A, followed by continuous infusion of dihydroginsenoside Rbt intravenously for 24 hours using an Alzamini osmotic pump (6 ^ g / day) (n = 6). The details of this experimental technique are described in published papers of the present inventors (Sakanaka and Tanaka) (Igase K. et al., J. Cerebr. Blood Flow Metab., 19.298-306, 1999).

Control animals in which MCA was permanently occluded (ischemic control animals) were intravenously administered only the same amount of saline (vehicle carrier or vehicle) (n7). Twenty-four hours after MCA permanent occlusion, a lethal dose of pentovalpital was injected intraperitoneally into the rat. Immediately after the animal died, the brain was removed and a 2 mm thick forehead section was prepared. The sections were immersed in a 1% 2,3,5-triphenyltetrazolium chloride (2,3,5-triphenyl-tetrazolium chloride (TTC)) solution for 30 minutes at 37 t, and The cells were fixed in% formalin for 12 hours or more. The results are shown in FIGS. 22 and 23. FIG. 22 shows two cases in which physiological saline was administered, and FIG. 23 shows two cases in which dihydrozine cenoside Rbi was intravenously administered.

As shown in Fig. 22, in rats receiving saline after MCA permanent occlusion, A white cerebral infarction lesion not stained with TTC was clearly observed in the left cerebral cortex. On the other hand, as shown in FIG. 23, cerebral infarction lesions were significantly reduced in rats to which dihydroginsenoside Rb was intravenously administered after permanent MCA occlusion. The cerebral infarction area of cerebral infarction rat (n = 6) administered intravenously with dihydroginsenoside Rb: and the cerebral infarction area of cerebral infarction rat administered vehicle (carrier or vehicle) only (n = 7). The results are shown in FIG. As shown in Fig. 24, the cerebral infarction area of the group treated with dihydro ginsenoside Rbi (2H-Rbi) was 3 times smaller than that of the group treated with vehicle (saline). It was reduced to about one-third. Statistical analysis was performed using the Mann-Whitney U test.

From the above, it was found that the therapeutic effect of dihydroginsenoside Rbt on cerebral infarction was superior to the effect of ginsenoside Rbi disclosed in WO 00/37481. did. Similarly to ginsenoside R bi described in WO 00/48608, ginsenoside derivatives such as dihydroginsenoside R bi promote regeneration and / or reconstruction of blood vessels, particularly cerebral blood vessels. It was thought. Therefore, the present inventor further investigated whether or not the intravenous dose of dihydroginsenoside Rbi was doubled to obtain a therapeutic effect on cerebral infarction, and an unexpectedly superior effect was found. Did not. In other words, ginsenoside R bt in WO 00/3784 81 has an excellent therapeutic effect on cerebral infarction even at a dose of 60 μg / day for SH-SP rats weighing about 300 g. As shown, ginsenoside derivatives such as dihydroginsenoside Rb are not necessarily expected to exert a cerebral infarction treatment effect and / or a cerebral blood vessel regeneration / remodeling promotion effect at such a high dose. .

Therefore, the optimal dose of dihydroginsenoside R for a cerebral infarction rat with a body weight of about 300 g is lower than the optimal dose of ginsenoside R bt, and more preferably 60 agZ days or less. Was considered to be less than 1 2 / zg / day. Thus, in culture experiments, dihydroginsenoside Rb inhibits neuronal apoptosis or apoptotic-like neuronal cell death in a wider concentration range than ginsenoside Rb, but in vivo (in vivo). Dihydroginsenoside R bi has a superior cerebral infarction treatment effect and cerebral blood It can be said that it exerts the effect of promoting tube regeneration and reconstruction. However, dihydroxy ginsenoside R b! Alternatively, ginsenoside derivatives such as epoxy ginsenoside Rb are considered to exhibit the same effect and efficacy as ginsenoside at a dose and concentration equivalent to or approximately 100 times greater than that of ginsenoside Rbi.

In order to confirm that even lower doses of dihydroginsenoside R bi have a favorable effect on nervous tissue, the present inventor has proposed that dihydro ginsenoside R b be administered at a dose of 1.2 UL g / day. A spinal cord injury rat (about 300 g body weight) was continuously infused intravenously for 7 days. The present inventors (Osaka et al.) Found that administration of ginsenoside Rbi at a dose of 60 g / day or 12 g / day intravenously to a spinal cord injury rat erects a bedridden spinal cord injury rat. Naka, Tanaka) (WO 00/48680), but the optimal dose when using ginsenoside Rbi to treat spinal cord injury rats weighing about 300 g is 6 The present inventors found that CT g / day was 0 g / day.

No. 4,010,002 and WO 00/46806.

Under inhalation anesthesia with halothane and laughter, after applying a pressure of 20 g to the lower thoracic spinal cord of the rat for 20 minutes, 30 minutes or more later, dihydroginsenoside Rb! (1.n) was injected once, and dihydroginsenoside Rb (1.2 g / day) was continuously administered to the same vein using an Alzamini osmotic pump for 7 days. Control animals received the same amount of saline (vehicle, carrier or vehicle) on a similar schedule. The results are shown in FIGS. 25 and 26.

The left photographs in Figs. 25 and 26 show the saline administration rats on the second day after spinal cord injury, and the right photographs in Figs. 25 and 26 show the dihydroginsenoside at the same time. The R b (1.2 μg / day) administration rate is indicated. As shown in the left-hand photographs in Figs. 25 and 26, the saline-administered rats with 20 g of pressure applied to the lower thoracic spinal cord for 20 minutes were not only treated on the day of spinal cord injury, but also after spinal cord injury. On the second day, he had paraplegia in both lower limbs. However, when 20 g of pressure was applied to the lower thoracic cord for 20 minutes, continuous administration of dihydroginsenoside Rbi intravenously showed paraplegia of the lower limb on the day of spinal cord injury, but the results were shown in Figs. On the second day after spinal cord injury, paraplegia of both lower limbs improved remarkably, and the rat was able to stand up while holding onto an object, as shown in the right photograph in Fig. 26. In addition, dihydroginsenoside Rb was added at 8 g / day. Did not show an excellent effect when administered intravenously in spinal cord injury rats at a dose of 60 ^ g / day.

Based on the above, ginsenoside derivatives such as dihydroginsenoside R b dihydroxy ginsenoside R b or epoxy ginsenoside R b have superior spinal cord injury comparable to ginsenoside R b. · It has been found that it has a therapeutic effect on nerve trauma. Moreover, the optimal dose of dihydroginsenoside Rb for spinal cord injured rats weighing 300 g was considered to be around 1.2 ag / day or less. That is, dihydro ginsenosides Sai de a R b neurotrauma - when used as head trauma, spinal cord injury pharmaceutical composition for the treatment, the optimal dose Jinsenosai de R b _t 5 0 min 1 before and after or the It has been invented that: As mentioned above, dihydroginsenoside R b! Can produce high purity ginsenoside R b as a raw material in a 97% yield, so dihydro ginsenoside R b, is more efficient than ginsenoside R b, resulting in nerve trauma, stroke, etc. It could be used for the prevention, treatment and treatment of brain-neuropathy.

As described above, the present invention exerts a therapeutic effect on nerve trauma and stroke almost equivalent to that of ginsenoside Rb, and is more preferably used at lower doses and lower concentrations than ginsenoside Rb in an economical and efficient manner. It provides the resulting ginsenoside derivatives, especially dihydroginsenoside R b. However, ginsenoside derivatives such as dihydroxy ginsenoside Rb or epoxy ginsenoside Rb are effective for the above-mentioned diseases and conditions at doses and concentrations equivalent to or higher than ginsenoside Rb. It is considered to show efficacy.

When a segment of the spinal cord, such as the lower thoracic spinal cord, is overwhelmed with spinal cord injury, the gray matter nerve cells in the same area as well as the white matter pathway in the same area are damaged. By the way, the matter pathway consists of the processes of nerve cells (ie, axons or dendrites) and the myelin derived from oligodendrocytes that insulates them (myelin). The impairment of the white matter pathway further extends to the distal (caudal) side and is secondary to the cells that originate the pathway, or higher neuronal bodies that project fibers into the pathway (ie, the origin cells). Causes denaturation. In this way, impairment of the white matter pathways in the lower thoracic spine under pressure overload is caused by the origin of the pathways (neuronal cell bodies) and the pathways below the lower thoracic spinal cord (ie, lumbar spinal cord, sacral medulla). Secondary change of By causing sex, it causes paralysis of the lower limbs. In addition, since the lower thoracic spinal cord is injured, the innervation of the lumbar spinal cord and sacral cord from the upper brain is interrupted. Paralysis is irreversible. It is known that oligodendrocyte apoptosis and demyelination occur in parallel with these symptoms (Crown, MJ et al., Nature Med., 3, 73). -76, 1 997).

Furthermore, in spinal cord injury, in addition to the above-mentioned disorders specific to nerve tissue, the resulting neuropathic bladder, cerebral edema, edema of nerve tissue, edema, dysuria, defecation disorder, sexual dysfunction, skin ulcer, pressure Wounds and vascular damage occur. Many of these diseases, symptoms, or conditions are thought to be caused by injuries not only to motor nerves but also to autonomic nerves and sensory nerves due to spinal cord injury, resulting in malfunction. It is also known that vascular damage and edema easily occur when nerve tissue (spinal cord tissue) is subjected to excessive mechanical and physical pressure. The above-mentioned symptoms, diseases, lesions or conditions associated with spinal cord injury are also found in head trauma to varying degrees.

Therefore, judging from the experimental results of the present invention that dihydrozincenoside R bi elicits a bedridden spinal cord injury rat at a low dose and low concentration, dihydrozinsenoside R b, Alternatively, ginsenoside derivatives such as epoxy ginsenoside Rb may cause spinal cord injury or nerve trauma (including head trauma) in the same dose or concentration range as ginsenoside Rbi. It is considered useful for the prevention, treatment, and treatment of pathological conditions, symptoms, and diseases. Ginsenoside derivatives such as dihydrozine senoside Rbt, dihydroxyzine senoside Rbi, or epoxy ginsenoside Rb are expected to be indicated as pathological conditions, symptoms, and diseases in neural tissues. Secondary degeneration, edema, cerebral edema, edema of nerve tissue, apoptosis or apoptosis-like cell death of oligodendrocyte, demyelination, vascular damage, neurogenic bladder, autonomic dysfunction, sensory disturbance, dysuria , Defecation disorder, sexual dysfunction, skin ulcer, pressure sore, nerve palsy, peripheral circulatory failure, etc. Possibly, ginsenoside derivatives such as dihydrozincenoside Rb or dihydroxylzinosenoside Rbi or epoxy ginsenoside Rbt are obtained through regeneration and remodeling of central nervous tissue or cerebral spinal cord blood vessels. Also effective for the above pathological conditions, symptoms, diseases, It is considered to be effective.

In addition, intravenous administration of a ginsenoside derivative such as dihydrozine senoside Rb or epoxy ginsenoside Rb of the present invention provides a novel method for regenerating and reconstructing blood vessels or nerve tissues. Effects · Diseases that cause histopathological changes in blood vessels or nervous tissues, diseases that cause damage to blood vessels, or diseases that are mainly caused by impaired blood flow (eg, transient cerebral ischemic attack, Aortic syndrome, diabetes, heart failure, cardiomyopathy, acute peripheral arterial occlusion, thrombosis, thrombotic phlebitis, collagen disease, cerebrovascular disease, cerebral hemorrhage, subarachnoid hemorrhage, cerebral infarction, atherosclerosis, peripheral circulatory failure, Obstructive thromboangiitis, angina, myocardial infarction, anemia, malignant neoplasm, cancer, sarcoma, leukemia, aplastic anemia, vasculitis, diabetic nephropathy, central retinal arteriovenous obstruction, liver, kidney, heart , Cerebral ischemia / reperfusion injury, vascular injury, Behcet's disease, diabetic neurosis, hemorrhoids, obstructive arteriosclerosis, Reino's disease, Reino's syndrome, wound, burn, frostbite, electrolysis, corneal wound , Radiation injury, ultraviolet radiation injury, pressure sore, diabetic skin ulcer, diabetic retinopathy, diabetic nephropathy, Alzheimer's disease, Pick's disease, spinocerebellar degeneration, Parkinson's disease, demyelinating disease, chorea, poly Glutamine disease, cerebral palsy, amyotrophic lateral sclerosis, glaucoma, senile macular degeneration, AIDS encephalopathy, encephalitis, multiple sclerosis, diabetic neuropathy, retinal detachment, retinitis pigmentosa, carbon monoxide poisoning, Neonatal asphyxia, autonomic neuropathy, peripheral neuropathy, peripheral neuritis, hypoxic encephalopathy, Guillain-Barre syndrome, spastic paraplegia, progressive supranuclear palsy, spinal vascular disorders, mitochondrial encephalomyopathy, meningitis, Spine (lumbar spine) Disc herniation, spinal canal stenosis, spinal separation, spondylolisthesis, cervical spondylosis, compression of the spinal cord and nerve roots associated with ossification of the posterior longitudinal ligament, paralysis, facial paralysis, etc. . Of course, in diseases that cause histopathological changes in these blood vessels and nervous tissues, and in diseases whose main symptom is impaired blood flow, it is also possible to inhibit cell death in the tissues exposed to impaired blood flow. b It is an unforgettable effect of ginsenoside derivatives such as dihydroxyzine senoside R bt or epoxy ginsenoside R bt. Therefore, in the case of impaired blood flow, injuries, trauma or wounds of peripheral tissues, dihydrodinsenoside Rb dihydroxydoxysenoside Rb! Or ginsenoside derivatives such as epoxy ginsenoside Rb are thought to reduce tissue cell damage through at least two mechanisms of action. Pharmaceutical compositions consisting of ginsenoside derivatives such as dihydrozincenoside R b or dihydroxy ginsenoside R b or epoxy ginsenoside R b inhibit primary lesions and secondary lesions in areas of the brain that have synaptic communication So all neurodegenerative diseases, peripheral neuropathy, demyelination diseases, inflammatory brain and neurological diseases, toxic brain and neurological diseases, cerebrospinal vascular disorders (eg Alzheimer's disease, Pick's disease, progressive supranuclear palsy, spinal cord Cerebellar degeneration, Parkinson's disease, chorea, polyglutamine disease, carbon monoxide poisoning, cerebral palsy, neonatal asphyxia, hypoxic encephalopathy, AIDS encephalopathy, encephalitis, acute disseminated encephalomyelitis, acute cerebellar inflammation, transverse spinal cord Inflammation, amyotrophic lateral sclerosis, multiple sclerosis, etc.) and slow the progression of higher nervous dysfunction due to these diseases. Under the patient's QOL (quality of life, Quality of Life) is expected to increase. Specific examples of these cerebral and neurological disorders include those described in a compendium (Neurology Handbook, Differential Diagnosis and Treatment, Second Edition, Editing, Mikuno Mikuni, Medical Shoin 1993). Of course, as described in PCT / JP 00/04 102 (a brain cell or ginseng protective agent consisting of ginseng), these brain's nervous systems can be controlled via apoptosis-like nerve cell death inhibitory effect. Dihydrozine Senoside R bh Dihydrozine Senoside R b or Epoxy Gin Senoside R b! It is thought that ginsenoside derivatives such as these exert an effect.

Also, as described above, intravenous administration of ginsenoside derivatives such as dihydrozincenoside Rbh or dizinoxyzinosenoside Rbi of the present invention is considered to significantly improve paralysis in spinal cord injured animals. Can be As is well known, nervous tissue is the most vulnerable tissue to trauma compared to other peripheral tissues, so dihydrozincenoside Rb ^ dihydroxyzinosenoside Rb or epoxyzinsenoside Rb The fact that a pharmaceutical composition comprising a ginsenoside derivative of the present invention is remarkably effective in the treatment and treatment of spinal cord injury means that ginsenosides such as dihydrozinosine side Rb or dihydroxyzine sidenoid Rb or epoxy ginsenoside Rb. Derivatives indicate that they are also effective in trauma and wounds of peripheral tissues other than central nervous tissue (including burns, frostbite, electrolysis, radiation damage, ultraviolet damage, and visceral damage).

By the way, ginsenoside R b dihydrazine ginsenoside R b It has been described so far that synthenoside Rb or epoxy ginsenoside Rbi has a common effect, efficacy and use. The fact that R b is a composition for controlling animal growth or a feed composition as described above will be described based on experimental examples. For this reason, an experimental example using the freshwater fish "Yunago" as an animal is shown below.

Evening nago with a body length of 3 to 5 cm (Tyrekubara evening nago, Rhodeusoce 11 atusoce 11 1 atus) 1 9 animals were divided into 2 groups, and 10 were around 15 in fresh water (50 liters) only. For 10 days, 9 animals were bred under the same conditions for 10 days in fresh water containing ginsenoside Rb: (100 fg no m 1). After that, open wounds with a diameter of 2 mm were created in the midline of the left body near the tail fins of all the locusts. An open wound was created using an instrument for skin biopsy (trepan). The open wound was created by alternately using a freshwater evening locust and a freshwater locust containing ginsenoside Rb, and the evening locust was returned to the original aquarium immediately after the open wound creation. By the way, this open wound that was loaded on the evening nago can be said to be an open wound with damage to the femoral artery when compared to humans.

On the 8th day after the creation of the open wound, surviving locusts were observed. An artificial feed for medaka was fed to the locusts as bait. The results are shown in FIGS. 27, 28, and 29. Fig. 27, Fig. 28 and Fig. 29 are photographs replacing the drawings.

As shown in the representative example immediately after creation of the open wound in Fig. 27, open wounds with a diameter of 2 mm were created on all 19 evening reefs. On the 8th day after the creation of the open wound, 5 out of 10 nago reared in freshwater alone had died, and most of the surviving 5 were as shown in Fig. 28. ) Was almost missing the fins. On the other hand, as shown in Fig. 29, seven out of nine surviving locusts reared in freshwater containing ginsenoside (R bid OO fg / ml) Seven of them had little missing fins (ie, tissue distal to the open wound).

Therefore, ginsenoside Rbi is thought to be able to protect marine animals such as locusts from tissue deficiency or fatal trauma, vascular injury, and wounds. That is, ginsenoside R bi or natural products containing ginsenoside R bi are animals. It can be said that it was invented to be extremely useful as a composition for regulating growth or a feed composition.

From the above, it can be said that ginsenosides such as ginsenoside R bi or natural products containing ginsenoside R b can be used as compositions for livestock, ornamental fish, fish and shellfish for aquaculture, and pet feed. For example, low-concentration ginsenosides, especially ginsenoside Rb or ginsenoside, when cultivating or raising fish and shellfish, crustaceans, eel, pearl shellfish, ornamental fish, tropical fish, broiled carp, oyster shellfish, quell, burrow, etc. Addition of Rb-containing natural products or extracts thereof to seawater or freshwater together with ordinary feed is thought to promote the development, growth, and regeneration of these marine or marine resources. In particular, the feed composition or the composition for regulating the growth of animals of the present invention is useful for the growth, reproduction, protection, breeding or cultivation of eggs, sperm, fertilized eggs, fry or fry. Also, when transporting ornamental fish, edible fish, and marine animals over long distances, the growth-regulating composition of the present invention is preferably added to freshwater or seawater at a low concentration (1 ng / m1 or less). Effective against shellfish bleeding, impaired blood flow, trauma, wounds, injuries and infections. Of course, ginsenosides such as ginsenoside Rb, through their cytoprotective effects, can be used in fish, shellfish, crustaceans, penguins, Thailand, puffer fish, penis, hamachi, puri, lipstick, shrimp, It can protect marine and marine resources such as ryuji, kue, and scallop from trauma, wounds, pathogenic microorganisms, biohazard, endocrine disruptors, environmental pollution, and toxins. That is, the feed composition or the composition for regulating animal growth of the present invention is indispensable to rescue human beings from the coming food crisis. Of course, ginsenoside derivatives such as dihydroxy ginsenoside R b epoxy ginsenoside R b or dihydro ginsenoside R b, similarly to ginsenoside R b _t , can grow the aforementioned marine or marine resources. It can be used as a conditioning composition or a feed composition. Ginsenosides such as ginsenoside Rb, natural products containing ginsenoside Rb, or ginsenosides such as dihydroxyginsenoside Rb epoxy ginsenoside Rb or dihydroginsenoside Rbi When the derivative is used as a plant growth regulating composition, a fertilizer composition, a feed composition, or an animal growth regulating composition, its concentration in a growth regulator, fertilizer or feed is 1% by weight or less, Preferably less than or equal to 0.1% by weight, more preferably less than or equal to 0.01% by weight or It is more preferably less than 0.001% by weight or 0.002% by weight or less. When the composition for growth regulation or the growth regulator of the present invention is added to seawater or freshwater, its concentration, that is, the concentration in seawater or freshwater is 100 g / m1 or less, preferably 100 ηgm1 or less. Below, more preferably lng / m1 or less, even more preferably 0.OOOlfg / m1 to 10 pg / m1, Examples

Next, the present invention will be described in detail with reference to specific test examples, but the present invention is not limited to these specific examples. Example 1 (Production of dihydroxy ginsenoside R bi)

Next formula

The dihydroxy ginsenoside R bi represented by was produced by the method shown below.

(1) acetylation

Put ginsenoside R bt10.0 mg in an eggplant flask and add pyridine 1 ml. Then, add 0.5 ml of acetic anhydride and stir. Add 3 ml of water, stir and extract 3 times with CHC ls (3 ml). Concentrate the organic layer to obtain crystals. All the reactions were performed at room temperature.

(2) Osmium oxidation

0.5 mg of NMO, 1 ml of acetone and 1 ml of water were added and dissolved in the acetyl ester obtained above, and 0.3 ml of a 0 s C tertiary buthanol solution was added, followed by stirring for 5 hours. did. Then, the addition of N a _₂ S ₂ 0 _4, quenched and filtered. The filtrate is extracted three times with CHC1a (3 × 3 m 1), washed with water, and the organic layer is concentrated to obtain crystals. These reactions were also performed at room temperature.

(3) Hydrolysis

The Asechiru of diols of the, and stirred while maintaining the addition of methanol 5 m 1 to 0 ° C by addition of K ₂ C 0 _{3 3.} 5 hours. The solution was directly concentrated and isolated on a column. As the column, an ODS resin filled with methanol was used. After charging the column with water, a sample dissolved in water was placed on the column. As a solvent, first, only water was flowed, and then methanol was flown. Concentration of methanol yielded 9.4 mg of white crystals (yield 95.2%).

The melting point is 160.2-163.4 ° C. The melting point of ginsenoside R bi is 197 to 198 ° C (literature value). FIG. 1 shows an NMR chart (400 MHZ, CD ₃ 〇D). Example 2 (Experiment for analyzing anti-apoptotic action of dihydroxyginsenoside R bi) Next, the present inventors converted the dihydroxy ginsenoside R bi (code name: S2821) obtained by the above method into WO 0 0 Z 3 7 4 8 1, PCTZJP 0/0 5 5 5 4 or Japanese Patent Application No. 2 0 0 — 2 4 8 4 5 8 Ginsenoside R bi ゃ dihydroginsenoside R Similar to bi, we examined whether apoptosis or apoptosis-like cell death of neurons was inhibited.

The present inventors (Sakanaka and Tanaka) reported that short-term exposure of cultured neurons to the nitric oxide donor, sodium nitroprusside (SNP), resulted in neuronal apoptosis or apoptotic neuronal death. Is reported to be induced (Toku K. et al., J. Neurosci. Res., 53, 415, 1998). Using this culture experiment system, the present inventors have already inhibited apoptosis of neurons or apoptotic-like neuronal death at an optimal extracellular solution concentration range of ginsenoside Rb of 1 to 100 fg / m1. (W〇 0 0/3 7 4 8 1). Thus, using a similar experimental system, the neuroprotective effect of dihydroxydine cenoside Rb: was examined.

Nerve cells were isolated from the fetal cerebral cortex of a 17-day-old rat using trypsin-EDTA, and plated on polyerysine-coated 24-well plates. After culturing for 16 hours in DMEM (Dulbecco's modified Eagle's medium) containing 10% fetal calf serum, replace the culture with serum-free medium for nerve cell culture containing insulin, transferrin, etc., for 3 to 4 days Cultured. On day 3 or 4 of the culture, sodium nitroprusside (SNP) was added at a concentration of 300; M, and the mixture was incubated for 10 minutes. Thereafter, the culture solution was replaced with EMEM (Eagle's minimum essentia 1 medium) containing dihydroxyginsenoside Rbi (0 to 100 ng / m1) and bovine serum albumin. Sixteen hours after SNP loading, neurons were lysed using Laemmli electrophoresis sample buffer, polyacrylamide gel electrophoresis was performed, and the electrophoresed proteins were transferred to nitrocellulose membrane. Thereafter, immunoplotting was performed using an antibody against the nerve cell-specific protein MAP2. Figure 2 shows the results. The details of the experimental procedure of the MAP2 immunobolot are described in a previously published paper by the present inventors (Sakanaka, Tanaka) (Wen, TC. Et al., J. Exp. Med., 188). , 635-649, 1998).

The upper part of Fig. 2 is a photograph instead of a drawing showing the result of an imno plot of MAP 2 (microtuble-associated protein 2). The first lane from the left is the control cultured neurons, and a clear MAP2 band (ie, a band for a marker of neurons) was observed. The SNP treatment caused many neurons to undergo apoptosis or apoptotic neuronal death, so that the MAP2 band was clearly weakened, as in the second lane from the left. When dihydroxyginsenoside R b is added to the culture medium at a concentration of 0.001 fg / m 1 (lane 4) to 100 ng / ml (lane 10), neuronal cells induced by SNP Apoptosis or apoptosis-like neuronal death is clearly inhibited, resulting in neuronal survival and apoptosis. In the figure, a strong band of MAP2, which is an indicator of process elongation, was observed. Therefore, ginsenoside derivatives such as dihydroxy ginsenoside R b L can inhibit apoptosis or apoptosis-like cell death of cells, especially neurons, in an optimal extracellular solution concentration range wider than ginsenoside Rbt. It is thought to exert an excellent cytoprotective effect. That is, ginsenoside derivatives such as dihydroxy ginsenoside R bi are similar to ginsenoside R bi or dihydro ginsenoside R b described in PCT / JPOO / 04102, and all diseases and conditions that cause cell death. It has been invented to be a pharmaceutical composition for the prevention, treatment or treatment of the disease. The lower part of FIG. 2 shows the densitometric analysis of the intensity of the MAP2 band by repeating the above immnoblot experiment. Statistical analysis was performed by ANOVA + Fisher's-PLSD. The * mark indicates P <0.05, and the ** mark indicates P <0.01. Example 3 (Production of Epoxy Ginsenoside R b)

Next formula

Epoxy ginsenoside R bi represented by was manufactured by the method shown below, (1) acetylation

To 4.2 g of ginsenoside Rb14, 2 ml of pyridine was added and dissolved, and 1 ml of acetic anhydride was slowly added dropwise. The mixture was stirred overnight at room temperature (18 hours). The next day, a large amount of water was added to quench the reaction. Extracted with CHC 1 (3ml × 5), washed with water and concentrated the organic layer.

(2) Epoxidation

The Asechiru of the CHC 1 3m l was dissolved in (those prepared by dissolving the compounds in _{C HC 1 3) mC P BA} 2 0. 6 mg were added 1. was stirred for 5 hours. Was quenched reaction by adding N a ₂ C0 ₃ After confirming epoxidation reaction TL C (carrying layer chromatogram rough). The reaction was extracted with CH C 1 (3 m 1 X 5), washed with water, and the organic layer was concentrated. The obtained crystals were purified by applying to a column and concentrated again to obtain crystals.

(3) Deacetylation

To the above reaction product, 3 ml of MeOH and ₃ ml of water were added, and K ₂ C〇3 was further added, followed by stirring at 0 ° C. for 2 hours. The reaction was temporarily concentrated to remove the solvent, then dissolved in water and desalted on a column. Thereafter, the resultant was freeze-dried to obtain 13.5 mg of a white powder (yield: 91.8%).

The melting point is 157.8-161.2 ° C. The melting point of ginsenoside R bi is 197 to 198 ° C (literature value). In Figure 3 shows the NMR chart (4 0 0 MHZ, CD ₃ 〇 D). Example 4 (Experiment for analyzing anti-apoptotic action of epoxyginsenoside R bi) Next, the present inventors prepared the epoxy ginsenoside R b! (Code name: S 2 822) is WO 0 0 3 7 48 1, PCT / JP 0 0 0 5 5 5 4 or Japanese Patent Application 2 0 0 0—24 8 4 5 8 As with ginsenoside Rb and dihydroginsenoside Rb described in the above issue, it was examined whether apoptosis or apoptosis-like cell death of nerve cells was inhibited.

As described above, the present inventors (Sakanaka, Tanaka) and colleagues show that short-term exposure of cultured neurons to the nitric oxide donor, nitroprusside sodium (SNP), results in neuronal apoptosis or apoptosis. Report that neuronal death is induced (Toku K. et al., J. Neurosci. Res., 53, 415, 1998). Using this culture experiment system, the present inventors have already inhibited gland-induced apoptosis or apoptotic-like nerve cell death in the optimal extracellular solution concentration range of ginsenoside Rb of 1 to 100 fg / m1. (W〇 0 0/3 7 48 1). Thus, using a similar experimental system, the neuroprotective effect of the epoxyginsenoside Rbi was examined.

Nerve cells were isolated from the fetal cerebral cortex of a 17-day-old rat fetal cerebral cortex using trypsin EDTA, and plated on a polyerysine-coated 24-well plate. After culturing in DMEM (Dulbecco's modified Eagle's medium) containing 10% fetal calf serum for 16 hours, replace the culture with serum-free medium for nerve cell culture containing insulin, transferrin, etc., for 3 to 4 days Cultured. On day 3 or 4 of the culture, sodium nitroprusside (SNP) was added at a concentration of 300, and the mixture was incubated for 10 minutes. Thereafter, the culture medium was replaced with EMEM (Eagle's minimum essential medium) containing epoxy ginsenoside Rb (0 to 100 ng / ml) and bovine serum albumin. Sixteen hours after SNP loading, nerve cells were lysed using a Laemli (Laemm1i) sample buffer for electrophoresis, polyacrylamide gel electrophoresis was performed, and the electrophoresed proteins were transferred onto a nitrocellulose membrane. After transcription, immunoblotting was performed using an antibody against the neuronal cell specific protein MAP2. The results are shown in FIG. The details of the experimental technique of MAP2 immunoblot are described in a previously published paper by the present inventors (Sakanaka, Tanaka) (Wen, TC. Et al., J. χ χρ. Med., 188, 635-649, 1998).

The upper part of Fig. 4 is a photograph instead of a drawing showing the result of the immublot of MAP 2 (microtuble-associated protein 2). The first lane from the left is the control cultured neurons, and a clear MAP2 band (ie, a band for a marker of neurons) was observed. When treated with SNP, many of the neurons fell into apoptosis or apoptosis-like neuronal death, so that the MAP, 2 band was clearly weakened as in the second lane from the left. Epoxy ginsenoside Rbi can be added to the culture medium at a concentration of 1 fg / ml (lane 6) to 1 ng nom 1 (lane 9) to induce neuronal apoptosis or apoptotic neuronal death by SNP. Are clearly suppressed, and are thus indicators of neuronal survival and / or process extension. A strong band of MAP2 was observed. Therefore, ginsenoside derivatives such as epoxy ginsenoside Rbt inhibit apoptosis or apoptosis-like cell death of cells, especially nerve cells, in a wider optimal extracellular solution concentration range than ginsenoside Rbi. It is thought that by stopping the treatment, an excellent cytoprotective effect is exhibited. That is, ginsenoside derivatives such as epoxy ginsenoside R bi can be used in the same manner as ginsenoside R bi or dihydro ginsenoside R bi described in PCTZ JP 00/04102. It was invented to be a pharmaceutical composition for the prevention, treatment or treatment of any dying disease or condition. The lower part of FIG. 4 shows the densitometric analysis of the intensity of the MAP2 band by repeating the above-mentioned immnoblot experiment. Statistical analysis was performed by AN OVA + Fisher's PLSD. The * mark indicates P <0.05, and the ** mark indicates P <0.01. Example 5 (Incision wound treatment by intravenous infusion of ginsenoside Rb)

Male Wistar rat (weight of about 300 g) was used. The animals were housed in a 12-hour light-dark cycle room with free access to water and food. Under inhalation anesthesia, make an incision about 3 cm in length on the back of the animal, suture with nylon thread, and after about 1 hour, dissolve ginsenoside Rb (60 jg) in saline. A single intravenous infusion. Thereafter, ginsenoside Rb: was continuously infused intravenously for 7 days (60 / g / day) using an Alzamini osmotic pump.

On the second day after the end of continuous intravenous infusion of ginsenoside Rbt or saline, animals were anesthetized with pentobarbital and transcardially with 0.1 M phosphate buffer containing 4% paraformaldehyde. Perfusion fixed. Thereafter, the skin tissue including the incision suture was collected, post-fixed, and embedded in paraffin as usual. A paraffin section approximately 5 zm thick was prepared and subjected to hematoxylin-eosin (HE) staining. Figure 6 shows the results. FIG. 6A shows an example of ginsenoside Rbt administration, and FIG. 6B shows an example of physiological saline administration. Also, "s" indicates a scar.

As shown in Fig. 6A, in the ginsenoside Rbi administration example, the physiological Compared with the saline-administered case, scar formation was clearly less, and a number of skin appendages such as sweat glands, sebaceous glands, and hair follicles were observed in the immediate vicinity of the incision wound site. Also, in the case of ginsenoside Rbi administration, the epidermis, dermis, and subcutaneous tissue were regenerated, reconstructed, or recovered to a state close to normal, except for the wound site, unlike the saline administration example.

These facts indicate that the dihydroxy ginsenoside Rbi or the epoxide ginsenoside Rbt of the present invention has a similar activity. Example 6 (Treatment of open wound or skin defect by intravenous infusion of ginsenoside Rbi)

'Using a male Wistar rat (weighing about 300 g), a punch biopsy with a diameter of 6 mm was applied to the back of the animal under inhalation anesthesia to create an open wound and left. After about an hour, ginsenoside Rb! (12 g) of a saline solution was intravenously administered once, and then ginsenoside Rb was continuously infused intravenously (12 g Z days) for 7 days using an Alzamini osmotic pump.

On the second day after the end of the continuous infusion of ginsenoside R bi or physiological saline, the animals were anesthetized with pentovalpital and transcardially administered with 0.1 M phosphate buffer containing 4% paraformaldehyde. Perfusion fixation was performed. Thereafter, the skin tissue including the open wound was excised, post-fixed, and embedded in paraffin as usual. Paraffin sections of about 5 m thickness were prepared and subjected to hematoxylin-eosin (HE) staining. Figure 7 shows the results. FIG. 7A shows an example of ginsenoside Rb administration, and FIG. 7B shows an example of physiological saline administration. The left side of the arrows in FIGS. 7A and 7B indicates the healthy part, the right side of the arrow in FIG. 7A indicates the regenerated skin tissue, and the right side of the arrow in FIG. 7B indicates the scar part (sc ar, s). ing. In the reconstructed skin tissue in Fig. 7A, a large number of hair follicles and associated sebaceous glands and pilus muscles are found in the connective tissue (dermis or subcutaneous tissue) beneath the epidermis, and scars (see below) appear below the regenerated and reconstructed skin tissue. sc ar, s) are a little present.

As shown in Fig. 7A, in the case of ginsenoside Rb administration, scar formation was clearly reduced and epithelialization occurred sufficiently, as compared with the saline administration example in Fig. 7B. Regeneration and reconstruction of connective and subcutaneous tissues of the dermis with papillae had progressed to a state close to normal tissues. In addition, in the case of ginsenoside Rbi administration, unlike in the case of administration of physiological saline, abundant skin appendages such as hair follicles, dermal papilla, piloermis, sweat glands, and sebaceous glands were observed in the regenerated skin tissue of open wounds. The vascular network was also regenerated, reconstructed, or recovered to a state close to normal tissue.

These facts indicate that the dihydroxy ginsenoside R bt or the epoxy ginsenoside R b of the present invention has the same activity. Example 7 (Effect of Pre-injection of Ginsenoside Rb on Intravenous Wound or Skin Defect Improvement)

A single intravenous injection of a solution of ginsenoside Rb1 (12 g) in saline was administered to a male Wistar rat (body weight: about 300 g) under inhalation anesthesia, followed by use of an Alzamini osmotic pump. Ginsenoside R bi was continuously infused intravenously (12 g / day) for 4 days. Then, under inhalation anesthesia, a 6 mm diameter punch biopsy was applied to the back of the animal to create an open wound, and continuous intravenous infusion of ginsenoside Rbi was continued for another 3 days.

On the second day after the end of the continuous intravenous infusion of ginsenoside Rb or saline, the animals were anesthetized with pentobarbital on day 5 after the open wound was prepared and contained 4% paraformaldehyde. Perfusion fixation was performed transcardially with 1 M phosphate buffer. After that, the skin tissue including the open wound was excised and embedded in paraffin as usual. Paraffin sections approximately 5 in thickness were prepared and subjected to hematoxylin-eosin (HE) staining. Figure 8 shows the results. FIG. 8A shows an example of ginsenoside Rbi administration, and FIG. 8B shows an example of physiological saline administration. "i" indicates crust (incrustation or esch ar), ep 'indicates stratified squamous epithelium of epidermis (epidermis), and bv indicates blood vessel.

As shown in Fig. 8A, in the case of ginsenoside Rb administration, the epidermis (stratified squamous epithelial tissue) was clearly regenerated under the crust on day 5 after the open wound was created. There are thick regenerative blood vessels or new blood vessels filled with red blood cells underneath the epidermis (stratified squamous epithelium), and relatively thin blood vessels that seem to branch off from the blood vessels in the connective tissue and subcutaneous tissue of the dermis. -Existed densely. On the other hand, as shown in Fig. 8B, in the saline-administered example, the epidermis under the crust even on day 5 after the creation of the open wound

(Stratified squamous epithelium) Regeneration was extremely incomplete, and the regenerative blood vessels just below the very thin epidermal tissue were clearly smaller than those of ginsenoside Rbi intravenous administration. As a result, only a small number of extremely thin blood vessels were found in the connective tissue under the epidermis, which is thought to become scarred in the future. Therefore, the intravenous administration of ginsenoside Rb clearly promotes the regeneration and remodeling of the skin tissue, and the open wound regenerates the ruptured and cut blood vessels. In other words, it was invented to be promoted by intravenous administration.

According to the above examples, ginsenoside R bi can be administered to a patient intravenously before creating an open wound, or can be administered intravenously after creating an open wound.

• It can be said that it has a restructuring promoting effect. Ginsenoside derivatives such as dihydroginsenoside R bh dihydroxy ginsenoside R b i or epoxy ginsenoside R b i are considered to exhibit similar effects. Example 8 (Prevention, treatment, and treatment of suture failure caused by ginsenoside derivatives, particularly dihydroxy ginsenoside R b or epoxy ginsenoside R b)

Diabetes patients, the elderly, immunodeficiency patients, malnutrition patients, cancer patients, etc. often develop suture failure after surgery and are accompanied by infections, so it is essential to prevent them before they occur It is believed that. Therefore, ginsenoside derivatives, especially dihydroxy ginsenoside R bi or epoxy ginsenoside R b, are usually added at a dose of 0.005 mg or more, preferably 0, I Intravenous single or continuous infusion at a dose of ≥10 mg, more preferably ≥10 mg, significantly reduces the incidence of postoperative suture failure and speeds the recovery of surgical wounds Infections are also suppressed. In addition, ginsenoside derivatives, especially dihydroxy ginsenoside Rb or epoxy ginsenoside Rb are injected intravenously, and any or a known base such as a water-soluble base, an ointment base, or a fat-soluble base is used. Low concentration in agent A skin external preparation (cream, gel, cataplasm, spray, ointment, etc.) is prepared by mixing dihydroxyxenosenoside Rb or epoxyzinenoside Rbi from It may be applied until the wound has healed. In addition, a dinzenoside derivative, in particular, a dihydroxyzine senoside Rb or an epoxyzine senoside Rbi may be locally administered during surgery. At that time, the concentration of the extracellular solution of the ginsenoside derivative in the local part is 100 g / m 1 (about 90 / M) or less, preferably 100 ng / m 1 (about 90 nM) or less, more preferably Is adjusted to be 1 ng Zm 1 (about 0.9 nM) or less, more preferably 100 OOgZm 1 (about 90%) or less. That is, the amount of the ginsenoside derivative mixed into the external preparation for skin is preferably 0.1% by weight or less, more preferably 0.01% by weight or less. As a matter of course, dihydrinosenoside Rbt may be used as the ginsenoside derivative in the same amount as described above, or in an amount of 1/10 to 1/100 thereof. Example 9 (Treatment and treatment of radiation damage or burns with ginsenoside derivatives, especially dihydroxy ginsenoside Rb or epoxy ginsenoside Rbi) Patients with severe radiation damage or burns have extensive skin tissue. Degenerative shedding and skin culture sheet transplantation may not provide satisfactory results and may jeopardize the patient's prognosis. In order to promote regeneration of skin tissue from transplant culture sheets and division, proliferation, migration to lesions, and regeneration of diseased tissue by differentiation of transplanted tissue sheets, ginseng Derivatives, in particular, dihydroxyxenosenoside R bi or epoxy ginsenoside R bi at a dose of 0.005 mg or more, preferably 0.1 mg or more, more preferably 10 mg or more per day A single or continuous infusion every day until symptoms improve in the vein. Of course, ginsenoside derivatives, particularly dihydroxyzine senoside R bi or epoxy ginsenoside R bi were injected intravenously, and the ginsenoside derivatives were added to a water-soluble base or a fat-soluble base. In particular, a skin external preparation (cream, gel, lotion, poultice, spray, ointment, etc.) is prepared by mixing dihydroxyxenosenoside Rb or epoxyzine senoside Rb, and is applied to the skin lesion and its surroundings. Flesh improves and heals May be applied. At that time, ginsenoside derivatives, especially dihydroxy ginsenoside R b! Alternatively, the concentration of the extracellular solution of the epoxy ginsenoside Rbi is 100 ^ g / m1 (about 90 μM) or less, preferably 100 ng / m1 (about 90 nM) or less, more preferably Is less than 1 ng / m 1 (approximately 0.9 nM), more preferably 100 μg / m 1 (approximately 90 μM). Adjusts the amount of dihydroxy ginsenoside Rb or epoxy ginsenoside R bi to be mixed. Ginsenoside derivatives, especially dihydroxy ginsenoside R b or epoxy ginsenoside R b! Is preferably 0.1% by weight or less, more preferably 0.001% by weight or less. If the radiation injury or burn is relatively mild, only the topical skin preparation described above may be administered. Of course, dihydroginsenosides as ginsenoside derivatives

R b may be used in the same amount as described above or at a dose of 1/10 to 1/100. Example 10 (Prevention, treatment, and treatment of pressure sores with ginsenoside derivatives, especially dihydroxy ginsenoside Rbi or epoxy ginsenoside Rbi)

Pressure sores in bedridden patients and the elderly are skin diseases that can deteriorate the general condition and significantly impair quality of life (QOL). Redness of the affected skin is seen early in the pressure sore, but at this point, there are few external or intravenous preparations that are effective and effective when applied to the affected area and its surroundings. It is a big problem in the department. Of course, it is often difficult to treat pressure sore lesions that have skin tissue defects.

Ginsenoside derivatives, especially dihydroxy ginsenoside R bi or epoxy ginsenoside R b! Make a topical skin preparation (cream, poultice or ointment) and apply it constantly to the area of the pressure sore and its surroundings until the healing, shrinking or worsening of the sore. The concentration of ginsenoside derivatives, especially dihydroxy ginsenoside R bi or epoxy ginsenoside R b in the external preparation for skin may be 0.1% by weight or less, preferably 0.01% by weight or less. preferable. that time In addition, the concentration of the ginsenoside forehead derivative in the local area, in particular, the concentration of the extracellular fluid of dihydroxyxenosenoside R bi or epoxy ginsenoside R b is less than 100 ^ g / m 1, preferably 100 ng / m g 1 or less, more preferably 1 ng Z m 1 or less, and even more preferably 100 fg / m 1 or less, ginsenoside derivatives to the base, particularly dihydroxy ginsenoside Rb or epoxyzine. Adjust the amount of Senoside R b mixed. In addition, if necessary, intravenous administration of ginsenoside derivatives, in particular, dihydroxyzincenoside Rb or epoxyzinsenoside Rbi, as described in Example 8 and Example 9 . Ginsenoside derivatives such as dihydroxyxenosenoside Rb or epoxy ginsenoside Rbi, as described herein, inhibit the spread of pressure wound lesions through potent cytoprotection, It is considered that once a skin tissue has been deficient, a pressure wound lesion can have an excellent therapeutic effect by promoting regeneration and reconstruction of the skin tissue. Of course, dihydrozincenoside Rb may be used as a ginsenoside derivative in the same amount as described above or in a dose of 1/10 to 1/100. Example 11 (Treatment of Peptic Ulcer with Ginsenoside Derivatives, Especially Dihydroxyzine Senoside R b or Epoxy Ginsenoside R bi)

As drug treatment means ulcer and duodenal ulcer, H ₂ receptor inhibitors, pro Tonpo pump inhibitor, although gastrointestinal mucosa protective agent is mainly used, even if healed temporarily ulcerative lesions by agents, drugs Withdrawal often results in recurrence of the ulcer lesion. Ulcer lesions are also frequently seen in Crohn's disease and ulcerative colitis, which are designated as intractable gastrointestinal tract diseases, and worsen the prognosis of patients. After the onset of gastric ulcer, duodenal ulcer, ulcerative colitis, or Crohn's disease, apply ginsenoside derivatives as early as possible, especially with dihydroxy ginsenoside R bi or epoxy ginsenoside, while applying usual treatment. Intravenous infusion of R b, anal, vaginal, nasal, or external mucosal administration under an endoscope was performed, and healing or improvement of the lesion was confirmed with an endoscope Treatment until continued. Of course, dihydroginsenoside Rb may be used as a ginsenoside derivative. Example 12 (Treatment of diabetic skin ulcer with ginsenoside derivatives, especially dihydroxyzinenoside R b! Or epoxy ginsenoside R b)

Diabetic skin ulcer is an intractable disease accompanied by impaired blood flow at the lesion and loss of skin tissue, etc., but ginsenoside derivatives, particularly dihydroxide, which have the effect of promoting the regeneration and reconstruction of blood vessels and skin tissue The effect can be obtained by intravenous administration, local injection or topical application of cyginsenoside Rb or epoxyginsenoside Rbi. In other words, in patients with diabetic skin ulcer, in addition to the usual treatment, ginsenoside derivatives, especially dihydroxyzine senoside Rb: A single or continuous infusion intravenously at a dose of at least 0.05 mg, preferably at least 0.1 mg, more preferably at least 10 mg daily. If necessary, an external preparation for skin containing dihydroxyzine senoside Rbt or epoxyzinsenoside Rbi may be applied to the lesion and its peripheral region as described in Example 8. Alternatively, a ginsenoside derivative, in particular, dihydroxyxenosenoside R b or epoxy ginsenoside R b in a physiological saline solution or a glucose solution may be injected into the affected area. At this time, the extracellular solution concentration of the ginsenoside derivatives, particularly dihydroxyzine senoside Rb or epoxyzinsenoside Rb, in the lesion is 100 ^ g / m1 or less, preferably 100 g / m1 or less. gin / m 1 or less, more preferably 1 ng / m 1 or less, and even more preferably 100 fg / m 1 or less, ginsenoside derivatives to the base, especially dihydroxyzine cenoside R bi Or adjust the amount of epoxy ginsenoside R bi mixed or the amount of local injection of physiological saline (dissolving agent) containing them. Of course, dihydrozinenoside R bt may be used as the ginsenoside derivative in the same amount as described above or in a dose of 1/10 to 1/100. Example 13 (Treatment of open wound or skin defect with skin external preparation consisting of ginsenoside Rbi)

Using a male Wistar rat (body weight of about 300 g), the back of the animal was shaved under inhalation anesthesia and punch biopsy with a diameter of 6 mm was performed to create three open wounds. Of the two, 0.01% by weight or 0.01% by weight Ophthalmic white petrolatum (prototype) containing noside R bi was applied 0.1 g per day, and the remaining open wound was coated with the same amount of ophthalmic white petrolatum (prototype) only. . On day 9 after the creation of the open wound, the skin including the wound was photographed. In addition, we have found that in a similar manner, 0.001% by weight, 0.001% by weight or 0.001% by weight of ginsenoside Rbi skin external application effect. I also checked. The experimental animals were euthanized with an anesthetic just before taking the photograph, and the photograph was taken and the wound was taken, or the photograph was taken after the wound was taken. The wound tissue was then stored in fixative. The results are shown in FIG. 9 and FIG.

The first from the top of Fig. 9 is an external application (external application) of only the proto after the preparation of the open wound, and the red open wound (black open wound in the black and white photograph) stands out. External application of a plot containing 0.001% ginsenoside Rbi in the second from the top in Fig. 9

(External application to the skin), but the open wound area was slightly smaller than that when only the first plot from the top was applied externally. On the other hand, the third open wound from the top, which was topically applied (external administration) with a pro- tein containing 0.01% by weight of ginsenoside Rb, showed no difference compared to the first control wound from the top. I couldn't. In addition, as shown in the second and third figures from the top of FIG. 10, a plot containing 0.00001% by weight or 0.00001% by weight of ginsenoside R b was used. Is 0.0000% by weight of ginsenoside R b! Showed an effect superior to that of a probe containing. By topical administration of ginsenoside Rbi at 0-0001% by weight, clear hair growth was observed from the regenerated open wound. This is almost the same as the continuous intravenous administration of ginsenosides, especially ginsenoside R bi, even when a topical skin preparation consisting of ginsenosides, especially ginsenoside Rb, is externally applied or sprayed onto open wounds. Effects · Efficacy is obtained. It is also considered that dixenoside derivatives such as dihydroginsenoside R dihydroxyginsenoside Rb epoxy ginsenoside Rbi have the same effect and efficacy. Example 14 (Human oral mucosa bite treatment with ginsenoside Rbi: Part 1)

Next, one of the present inventors (Sakanaka) himself confirmed whether a probe containing a low concentration of ginsenoside Rb was effective for biting the oral mucosa. May 2, 2002

One S3- At around 2 pm, Sakanaka began to eat a very late lunch on an empty stomach before the awakening of infiltration anesthesia and periodontal anesthesia of the third branch of the left trifurcation nerve after dental treatment. Within 15 minutes, his left lower lip mucous membrane was swollen three times, and after that he sensed the taste (blood) of iron in the oral cavity. Or a defect was observed, and hematoma was observed in one more place. If left untouched, aphthous stomatitis would occur within a few days, and it was determined that it would take 1 week to 10 days for complete cure. (0.001% by weight of ginsenoside Rbi) was applied topically in small amounts to 5 eroded or defective areas of the oral mucosa and 1 hematoma site. External application was performed before and after each meal and before and after a snack. That is, a probe containing 0.001% by weight of ginsenoside R bi at the bite site was applied topically to the lip mucosa in 6 to 10 times a day. A photograph of the lip mucosa 96 hours after the bite is shown in FIG.

As shown in the photograph of Fig. 11, at 96 hours after the bite, a hematoma remains as indicated by a white arrowhead, but the bite of the labial mucosa indicated by a black arrowhead (that is, erosion or defect is not observed). The epithelium of the oral mucosa was slightly reddened, and the epithelization was almost complete. It was considered that the wound had clearly healed. In addition, since topical application of a probe containing 0.0001% by weight of ginsenoside Rbi to the bite site was started, pain at the wound site was also remarkably reduced.

These facts indicate that the dihydroxy ginsenoside R bi or the epoxy ginsenoside R bi of the present invention has a similar activity. Example 15 (Treatment of Oral Mucosa Bite with Ginsenoside R b: Part 2)

Next, one of the present inventors (Sakanaka) re-opened the left lower lip mucous membrane during lunch on May 26, 2012, so that 0.001% by weight of ginsenoside R was used. A plot containing bt was externally applied to the bite site in the same manner. The photograph immediately after the bite is shown on the left side of FIG. 12, and the photograph 72 hours after the bite is shown on the right side of FIG.

As shown in Fig. 12, low concentration of ginsenoside R b! It was found that bitumen healed quickly without topical aphthous stomatitis when topically applied to the mucosa.

From these facts, the dihydroxy ginsenoside R bi or the epoxyzine of the present invention Cenoside RbL is also shown to have similar activity. Example 16 (Effect of ginsenoside R bt for promoting the regeneration and regeneration of cuttings of pothos) The present inventors have found that ginsenosides, particularly ginsenoside R b, not only produce skin tissues and oral mucosal tissues, but also produce plant tissues. We examined whether it would also promote regeneration or reconstruction. For this reason, pothos (scientific name, Epipre munum aureum; Japanese name: o ゥ gonkazura; English name: golden pot os), one of the foliage plants, was selected as the plant tissue. Six similar cuttings were collected from the parent plant of Potos in the room of one of the inventors (Tanaka), three were hydroponically grown using only water, and the remaining three were 100 fg / m1 ginsenosides. Cultivated in water containing R bi. Fig. 13 shows a photograph of the cuttings on the 13th day of cultivation. <The left side of Fig. 13 shows the cuttings (pothos stems and branches) hydroponically grown with water only. The right side of Fig. 13 shows Cuttings were hydroponically grown with water containing low concentrations of ginsenoside R bi (100 fg / m 1). Clearly low ginsenoside R bt

(100 fg / m 1), the root elongation was promoted when pothos cuttings were cultivated hydroponically as compared to those cultivated with water alone.

Next, the present inventors continued the hydroponic cultivation of the cuttings described above, and again photographed them on the 22nd day. The results are shown in FIG. The left side of Fig. 14 shows three potato cuttings cultivated with water only for 22 days, and the right side of Fig. 14 shows low concentration of ginsenoside R bi (100 fg / m 1 Cuttings were hydroponically grown with water containing). Water for hydroponics or water containing ginsenoside R bi was replaced once a week. Further, on the 27th day, the rooting site was observed.

As shown in Fig. 14, when cuttings are cultivated for 22 days in water containing low concentration of ginsenoside R t ^ (100 fg / m 1), many roots are regenerated or regenerated, and glass for hydroponics is used. It stretched to touch the container. On the 27th day, secondary rooting was observed in all three cuttings of pothos grown in water containing low concentrations of ginsenoside (R bid OO ig / m 1). Was done. However, no secondary rooting was observed in any of the three cuttings of pothos grown on water alone. Therefore, natural products containing ginsenoside Rb! Or ginsenoside Rbt or extracts thereof at lower concentrations and lower doses than the results of this experiment, especially ginsenoside Rb! It has been invented to promote the regeneration, regeneration or reconstruction of not only skin tissue-human oral mucosal tissue but also plant tissue.

These facts indicate that the dihydroxy ginsenoside R bi or the epoxy ginsenoside R bi of the present invention has a similar activity. Example 1 7 (open wound treatment with pro pane you want to contain 1 0- ⁴ wt% to 1 0 ^8% by weight of Jinsenosai de R b)

Under inhalation anesthesia, 6 mm diameter punch biopsies were applied to the back of the rat (n = 3) at six locations to create open wounds. Thereafter, each open wounds, Jinsenosai de the R bi, respectively it 0.0 0 0 1 wt% (1 0 ^4% by weight), 0.0 0 0 0 1 wt% (1 0 ⁵ weight), 0 . 0 0 0 0 0 1 wt% (1 0 ⁶ wt%), 0.0 0 0 0 0 0 1 wt%

(1 ^0-7 wt%), 0.0 0 0 0 0 0 0 1 wt% (1 0 ^8% by weight) was up port pair Sorted daily coating single 0. lg nine days external containing . For the control, only the plot was applied externally. Immediately after the animal was euthanized by anesthesia, the wound skin was collected and photographed. The collected skin tissue was stored in a fixative. The result

See Figure 15.

First from 5 Jinsenosai de 1 0 one ⁶ wt% of 1 0 ⁸ wt% as shown in FIG R bi containing Puropeto (i.e. 1 O n gZm l 1 0 of O pg / ml concentration Jin Senosai de R b and Purobe Bok and apparently similarly containing Jinsenosai de R b 1 0 ⁵ wt% be externally applied to open wounds, Te ratio base to open wounds that topical application of Purobetonomi, wound healing was promoted. Therefore, when the Jinsenosai earths especially the use of Jinsenosai de R bi as a skin external preparation, it is preferable that the concentration is set at or less after 1 0- ^8% by weight before the external preparation Therefore, ginsenosides, especially ginsenoside R bi, ginseng crude saponin fraction, ginseng extract or ginseng, as cosmetic compositions, skin external compositions or health care compositions When using cosmetics, Its concentration in hair growth agents, chemical peels or health agents is less than 0.001% by weight, preferably less than 0.002% by weight, more preferably 0.0000. wt% (1 0 ⁵ wt%) or less, more preferably needs to be set to 0.0 0 0 0 0 0 0 1 wt% (1 0 ^8% by weight) or less. In the experimental example described above, Ri bets in the denominator the area of open wound that topical application of Purobetonomi, area of the open wounds from 1 0 ^4% by weight 1 0 ^8% by weight of Jinsenosai de R bi and topical application Was taken as the numerator, and the ratio was calculated. The results are shown in FIG. As shown in FIG. 16, topical administration of a low concentration of ginsenoside Rbt to open wounds significantly promoted wound healing. Statistical analysis is based on ANOVA + Scheife 'spost hoctes U. The * mark indicates P <0.05, and the ** mark indicates P <0.01. 1 0 - ^8% before and after Jinsenosai de R b! Topical application reduces the open wound area to about one-fourth that of the control group, so low concentrations of ginsenoside R b! It is thought that the volume of the open wound was reduced to approximately one-eighth of the control by topical administration of.

These results indicate that the dihydroxy ginsenoside R b or the epoxy ginsenoside R bi of the present invention has the same activity. Example 18 (treatment of oral mucosal burns or aphthous stomatitis with probe containing low concentration of ginsenoside Rbi or ginsenoside derivative)

When hot food is rapidly put into the oral cavity, the tongue mucosa, lip mucosa, hard palate mucosa, and soft palate mucosa often suffer burns, the mucosal epithelium falls off, and mucosal erosion and redness often appear. Of course, such burns are usually accompanied by pain. Also, after bite or burns on the oral mucosa or when the cause is not clear, often a stomatitis occurs, and from 1 week to 10 days, it is inconvenient to have pain in the oral cavity and eat regularly. Is often the case. 10 to less than ³ % by weight, preferably 2 × 10 to less than ⁵ % by weight, more preferably 10 to ⁵ % by weight or less, for the burnt stomatitis of the oral mucosa as described above. More preferably, 10 to ⁷ % by weight or less of ginsenoside R b! If applied to a mucosal lesion 11 to 10 times a day, especially before and after a meal, pain is reduced and the healing of mucosal defects or wounds is promoted. As a base when ginsenosides, particularly ginsenoside Rbi, is used as an oral mucosal external preparation, the same base as that of dexartin ointment ゃ enalog or Affatti may be used. Also, ginsenosides contained in oral mucosal external preparations, especially ginsenoside Rb! Is considered to be about 10 to 100 times higher than the optimum concentration of ginsenosides in the external preparation for skin. Of course, instead of ginsenosides, A ginsenoside derivative may be used at a higher concentration or about 1000 times higher. When ginsenoside Rb is used as a composition for an external mucosal preparation, the upper limit of the concentration is considered to be 0.1% by weight or less.

These results indicate that the dihydroxy ginsenoside R bi or the epoxy ginsenoside R b of the present invention has the same activity. Example 19 (Open wound treatment with skin external preparation containing dihydroginsenoside Rbt)

Next, the present inventors examined whether or not ginsenoside derivatives promote tissue regeneration and remodeling at low concentration and low dose, similarly to ginsenoside Rbi. For this reason, dihydroginsenoside Rbi was selected as one of the ginsenoside derivatives, and the open wound treatment effect of the compound was examined. Incidentally, dihydro ginsenosides Sai de R For b _t of detail P CT / JP 0 0/0 1 0 2 No. (ginseng Brain cell or nerve cell-protective agents comprising ginseng) and P CT / JP 0 0/0 5 No. 54 (Skin tissue regeneration promoter consisting of ginsenoside Rb). Under inhalational anesthesia, 6 mm diameter punch biopsies were applied to the back of the rat (n = 4) at five locations to create open wounds. Thereafter, each open wounds, dihydro ginsenosides Sai de R b each 0.0 0 0 1 wt% (1 0 - ^4% by weight), 0.0 0 0 0 1 wt% (1 0 ⁵ wt%) , 0.0 0 0 0 0 1 wt% (1 0 ⁶ wt%), 0.0 0 0 0 0 0 1 wt% (1 ^0-7 wt%), at a concentration of, a Puropeto having free 0.1 g once daily was applied externally for 9 days. For the control, only the plot was applied externally. Immediately after the animals were euthanized by anesthesia, the wound skin was collected and photographed. The collected skin tissue was stored in a fixative. The results are shown in FIG.

The first 7-dihydro ginsenosides rhino de of 0.0 0 0 0 1 wt% as shown in FIG. 0.0 0 0 0 0 0 1% by weight (1 0 ⁵ wt%) (1 ^0-7 wt%) Apparently, topical application of a prote containing Rbi (i.e., dihydroginsenoside Rbi at a concentration of lOOng g to lng / g) to open wounds revealed that only the protope was applied to open wounds. In comparison, wound healing was promoted. Also, low concentration of dihydroginsenoside Rb! In the case of topical application of, obvious hair growth was observed in the wound healing part. Therefore, gin When the Senosai de derivatives, especially the use of dihydro ginsenosides Sai de R bi as a skin external preparation, the concentration in the external preparation 0.0 0 0 0 0 0 1 wt% (1 ^0-7 wt%) before and after, or it It was considered preferable to set the following. Therefore, when a ginsenoside derivative, especially dihydroginsenoside Rb is used as a composition for external use on the skin (a composition for chemical healing, a composition for hair growth and hair growth, or a cosmetic composition) or a composition for external use on mucous membranes. , cosmetics, chemicals healing agent, its concentration in the hair growth tonic or health agents 0.0 0 1% by weight or less, preferably 0.0 0 0 0 1 wt% (1 0 ^5% by weight) or less, More preferably, the content is set to not more than 0.000% by weight (10% to ¹⁷ % by weight). Composition for external preparation for mucosa, composition for external preparation for skin, composition for preparation for intravenous administration, composition for cosmetics, composition for chemical peeling, composition for hair growth and hair growth, composition for external mucosa, dihydroginseno When using a dixenoside derivative such as side Rb1, dihydroxy ginsenoside Rbt or epoxy ginsenoside Rb, the upper limit of the concentration is 1% by weight or less, preferably 0.1% by weight. % By weight or less.

In the experimental example described above, taking the area of the open wounds that topical application of Puropetonomi (redness portion) in the denominator, 0.0 0 0 1 wt% (1 0 - ^4% by weight) from 0.0 0 0 0 0 0 takes 1 by weight% of the dihydro ginsenosides Sai de surface product of open wounds where the R bi and topical application of (1 ^0-7 wt%) in the molecule was calculated the ratio. The results are shown in FIG. Please especially shown in the first FIG. 8, 0.0 0 0 0 1 wt% (1 0 ⁵ wt%) Play · the following when the dihydro ginsenosides Size Lee de R bi concentrations topically administered to open wound skin tissue Remodeling was accelerated, and wound healing was significantly accelerated. Especially 0.0 0 0 0 1 wt% (1 0 ⁵ wt%) of the following dihydric Dorojinsenosai de R b ie 1 0 0 n GZG less or 1 0 0 ng / m 1 less dihydro ginsenosides Sai de R b The fact that topical administration significantly reduced open wounds is due to the fact that dihydrozincenoside R bi is preferably 100 ng / m 1 when the extracellular fluid concentration of the affected tissue is 100 β g / m 1 or less. It strongly supports that the following, more preferably 1 ng / ml or less, promotes the regeneration, regeneration or reconstruction of living tissue. Statistical analysis is by ANOVA + Fisher's PLSD. * Indicates P <0.05.

From these facts, the dihydroxy ginsenoside R bi or the epoxyzine of the present invention Cenoside R bi is also shown to have similar activity. Example 20 (Protection of cultured neurons by dihydroginsenoside R b)

Next, the present inventors confirm that dihydroginsenoside R bi has the same effect, efficacy and application as dihydroxy ginsenoside R bh epoxy ginsenoside R bi or ginsenoside R b. Therefore, experiments were further performed using cultured neurons.

The present inventors (Sakanaka, Tanaka) and colleagues reported that short-term exposure of cultured neurons to the nitric oxide donor, sodium nitroplumid sodium (SNP), resulted in neuronal apoptosis or apoptotic neuronal death. (Toku K. et al., J. Neurosci. Res., 53, 415-425, 1998). Using this culture experiment system, the present inventors have already found that ginsenoside Rbi has an optimal cell concentration of 1 ng / ml at an extracellular solution concentration of 1 ng / ml or less. It has been found that apoptosis or apoptosis-like nerve cell death of nerve cells is inhibited in the external concentration range (WO 00/37841, a brain cell comprising ginsenoside Rbi or a neuroprotective agent). ). Therefore, using a similar experimental system, the neuroprotective effect of dihydroginsenoside Rbi was examined.

Nerve cells were isolated from the fetal cerebral cortex of a 17-day-old rat using trypsin EDTA, and plated on a 24-well plate coated with po and lysyl lysine. After culturing in DMEM (Dulbecco's modified Eagle's medium) containing 10% fetal bovine serum for 16 hours, the culture medium was replaced with a serum-free medium for nerve cell culture containing insulin, transferrin, etc. Cultured for 3-4 days. On the third or fourth day of the culture, sodium nitroprusside (SNP) was added at a concentration of 300 / ΔtM, and the mixture was incubated for 10 minutes. Thereafter, the culture solution was replaced with EMEM (Eagle's minimum essential medium) containing dihydroginsenoside Rb (0 to 1 ng / m1) and bovine serum albumin. Sixteen hours after SNP loading, neurons were lysed using a Laemmli electrophoresis sample buffer, polyacrylamide gel electrophoresis was performed, and the electrophoretic proteins were transferred to nitrocellulose membrane. Immunoblotting was performed using an antibody against P2. Quantify neuronal cell viability Therefore, the immunostained MAP2 band was analyzed by densitometry. The results are shown in FIGS. 19 and 20. FIG. 21 shows an NMR chart (400 MHz, CD ₃ OD) of dihydroginsenoside R bi for reference.

FIG. 19 is a photograph instead of a drawing showing the result of immunoblot of MAP 2 (microtuble-associated protein 2). The first lane from the left is a control cultured neuron, in which a clear MAP2 band (ie, a band that is a marker for neurons) was observed. When treated with SNP, many neurons undergo apoptosis or apoptotic-like neuronal death, so the MAP2 band was clearly weakened, as in the second lane from the left. When dihydroginsenoside Rb is added to the culture medium at a concentration of 0.01 fg / m1 (lane 3) to 1 ng / m1 (lane 7), apoptosis of neurons by SNP or Apoptosis-like neuronal death was clearly suppressed, resulting in a strong band of MAP 2, an indicator of neuronal survival.

FIG. 20 shows a densitometric analysis of the results obtained by repeating the above MAP immunoblotting experiment five times. As shown in Figure 20, 0.1 Olf gZm l- 1 ng / m 1 of dihydroginsenoside Rb significantly inhibited neuronal apoptosis or apoptotic neuronal death. found. In other words, dihydroginsenoside Rb is considered to exert a favorable effect on cells, especially nerve cells, in an optimal concentration range wider than ginsenoside Rb. Therefore, ginsenoside derivatives such as dihydroginsenoside R b ^ dihydroxy ginsenoside R b or epoxy ginsenoside R b have an extracellular fluid concentration of 100 g / m 1 or less, preferably 100 g, in the affected tissue. Apoptosis or apoptosis-like cell death of cells at 0 ng / m 1 or less, more preferably 1 ng Zm 1 or less, and still more preferably 0.0000 fg Zm 1 — 100 fg Zm 1. It is thought that the inhibition will exert an excellent cytoprotective effect. The * mark indicates P <0.01>, and the ** mark indicates P <0.0001.

Also, from the above-mentioned experimental results that the external preparation for skin containing 0.001% by weight (10% by weight) of dihydrozine cenoside R b! Senoside R b Dihydroxyzine Senoside R b! or Ginsenoside derivatives such as epoxy ginsenoside Rbi still have an extracellular solution concentration of 100 μg / m1 or less, preferably 100 ng / m1 or less, more preferably 1 ng / m1 or less in the affected tissue. When m 1 or less, and more preferably 0.0000 fg / m 1 —100 fg / m 1, it can be said that excellent regeneration and reconstruction of living tissue can be exerted.

These results indicate that the dihydroxy ginsenoside R bi or the epoxy ginsenoside R b of the present invention also has a similar activity. Example 21 (Evaluation experiment for therapeutic effect of dihydroginsenoside Rbt on cerebral infarction)

As described above, ginsenoside derivatives such as dihydroginsenoside Rb can inhibit neuronal apoptosis or apoptosis-like neuronal death at a much higher extracellular fluid concentration range than ginsenoside Rbi. As revealed in an in vitro experimental system, in vivo experimental systems also show that ginsenoside derivatives such as dihydroginsenoside Rbi protect neurons in a wider dose range than ginsenoside Rbi The present inventor has investigated whether or not it has an effect. Therefore, an intravenous administration experiment of dihydroginsenoside Rbi was performed using a cerebral infarction rat as follows. Approximately 12- to 16-week-old male SH—SP rats (weight: 280—320 g) were used. The animals were housed in a 12-hour light / dark cycle room with free access to water and food. Under inhalation anesthesia, the left middle cerebral artery cortical branch (MCA) of the animal was coagulated and dissected. A single intravenous infusion of dihydroginsenoside Rb (6 xg) immediately after permanent MCA occlusion was followed by continuous infusion (6 fig g days) intravenously for 24 hours using an Alzamini osmotic pump. n = 6). The details of this experimental technique are described in published papers by the present inventors (Sakanaka and Tanaka) (Igase K. et al., J. Cerebr. Blood Flow Metab., 19.298- 306, 1999).

Control animals in which MCA was permanently occluded (ischemic control animals) were intravenously administered only the same amount of physiological saline (vehicle, carrier or vehicle) (n = 7). At 24 hours after permanent MCA occlusion, a lethal dose of pentovalpital was intraperitoneally injected into the rat. Immediately after the animal died, the brain was removed and a 2 mm thick forehead section was prepared. The same section was prepared by adding 1% 2,3,5-chlorinated triphenyltetrazolium (2, The sample was immersed in a 3,5-triphenyl-tetrazolium chloride (TTC)) solution for 30 minutes at 37 ^: and fixed with 10% formalin for 12 hours or more. The results are shown in FIGS. 22 and 23. FIG. 22 shows two cases in which physiological saline was administered, and FIG. 23 shows two cases in which dihydrozine cenoside R b was intravenously administered.

As shown in FIG. 22, in the rat to which saline was administered after permanent MCA occlusion, a white cerebral infarction lesion not stained with TTC was clearly observed in the left cerebral cortex. On the other hand, as shown in FIG. 23, cerebral infarction lesions were remarkably reduced in rats intravenously administered with dihydroginsenoside Rbi after permanent MCA occlusion. The cerebral infarction area of the cerebral infarction rat (n = 6) administered intravenously with dihydroginsenoside R b, and the cerebral infarction area of the cerebral infarction rat administered only vehicle (carrier or vehicle) (n = 7). The results are shown in FIG. As shown in Fig. 24, the cerebral infarction area of the group treated with dihydro ginsenoside R bi (2H-Rbι) was compared with the cerebral infarction area of the group treated with vehicle (saline). arctarea) was reduced to about one-third. In the statistical analysis method, the ** mark indicates P <0.01 by the Mann-WhitneyU test.

From the above, it was found that the therapeutic effect of dihydroginsenoside Rbt on cerebral infarction was superior to the effect of ginsenoside Rb disclosed in WO 00/374841. did. Therefore, the present inventor further investigated whether or not the intravenous dose of dihydroginsenoside Rb was doubled and similarly obtained a therapeutic effect for cerebral infarction, and found that an unexpectedly superior effect was obtained. I couldn't. In other words, ginsenoside Rb showed an excellent therapeutic effect on cerebral infarction even at a dosage of 60 ng Z-day against SH-SP rat weighing about 300 g in WO 00/37481. However, it was considered that dihydrogensenoside Rb did not necessarily exert a therapeutic effect on cerebral infarction at such a high dose.

Therefore, the optimal dose of dihydroginsenoside R for a cerebral infarction rat with a body weight of about 300 g is lower than the optimal dose of ginsenoside Rb, and more preferably 60 g / day or less. Was considered to be less than 12 g / day. Thus, in culture experiments, dihydroginsenoside Rb inhibits neuronal apoptosis or apoptotic-like neuronal death in a wider concentration range than ginsenoside Rbi. However, in vivo, it can be said that dihydroginsenoside Rb exerts an excellent therapeutic effect on cerebral infarction preferably in a lower dose range than ginsenoside Rb.

These facts indicate that the dihydroxy ginsenoside Rb or the epoxide ginsenoside R bi of the present invention has a similar activity. However, the dose is considered to be about the same or more than that of ginsenoside Rbi. Example 22 (Experiment for judging therapeutic effect of low-dose dihydroginsenoside Rbi on treatment of spinal cord injury) The present inventors have found that dihydroginsenoside Rb! Dihydroginsenoside Rb at a dose of 1.2 ^ g / day intravenously in spinal cord injured rats (approximately 300 g body weight) for 7 days to confirm that has a favorable effect on nerve tissue. Continuous infusion was performed. The present inventors (Sakanaka, et al.) Found that administration of ginsenoside Rbi at a dose of 60 g / day or 12 g / day intravenously in spinal cord-injured rats raises bedridden spinal cord-injured rats. , Tanaka) (W 00 0/48 680), but the optimal dose when using ginsenoside Rb to treat spinal cord injury rats weighing about 300 g is 60 gZ. The present inventors have disclosed that this is the day in PCTZ JP 00/04102 and WO 0/46806.

Under inhalational anesthesia with halothane and laughter, after applying a pressure of 20 g to the lower thoracic spinal cord of the rat for 20 minutes, 30 minutes or more later, dihydroginsenoside R was injected into the left femoral vein. A single infusion of bi (1.2 n) and intravenous dihydroginsenoside Rb! (1 day) was continuously administered for 7 days with an Alzamini osmotic pump. Control animals received the same amount of saline (vehicle, carrier or vehicle) on a similar schedule. The results are shown in FIGS. 25 and 26.

The left photographs in Figs. 25 and 26 show the saline administration rats on the second day after spinal cord injury, and the right photographs in Figs. 25 and 26 show the dihydroginsenoside at the same time. Rats administered with Rb1 (1.2 gZ days) are shown. As shown in the left-hand photographs in Figs. 25 and 26, rats administered physiological saline with 20 g of pressure applied to the lower thoracic spinal cord for 20 minutes were treated not only on the day of spinal cord injury but also after spinal cord injury. He also had paraplegia on both legs on day one. However, after applying 20 g of pressure to the lower thoracic cord for 20 minutes, When R bi was continuously administered intravenously, paraplegia of the lower limbs was exhibited on the day of spinal cord injury.On the second day after spinal cord injury, as shown in the right photographs in Figs. Paraplegia in the lower limbs improved significantly, and the rat was able to stand up while holding onto an object. No superior effect was observed when dihydrozincenoside Rbi was administered intravenously to a spinal cord injury rat at a dose of 16 g / day or 60 days.

From the above, ginsenoside derivatives such as dihydrozine senoside Rb and dihydroxyzine senoside Rb and epoxy ginsenoside Rb are not inferior to ginsenoside Rbi at all. Excellent spinal cord injury, head trauma, and nerve trauma were found to be effective. Furthermore, the optimal dose of dihydrozincenoside Rb for spinal cord injury rats weighing 300 g was considered to be around 1.2 ag / day or less. In other words, when dihydrozincenoside Rbt is used as a pharmaceutical composition for treating nerve trauma, head trauma, or spinal cord injury, the optimal dose is about one-fifth or less than that of ginsenoside Rbi. It was discovered. As mentioned above, dihydrozincenoside Rb is a high-purity ginsenoside Rb! Can be produced in 97% yield from raw material, so dihydridine senoside R bi is more efficient than ginsenoside R b and is used for prevention, treatment and treatment of cranial nerve diseases such as nerve trauma and stroke. You will get. However, Jinseno Sai de derivatives, such as dihydric de Loki hepcidin Seno Sai de R bh or epoxy ginsenosides Sai de R b _t, the disease or condition in Jinsenosai de R bi is equal to or higher doses, concentrations range than It is considered to be effective. Example 23 (Protection or regeneration of aquatic animals by ginsenoside Rbi)

Now, it has been described that ginsenoside Rbh dihydrozincenoside Rbh dihydroxyzincenoside Rbi or epoxy ginsenoside Rbi has a common effect, efficacy, and application. Ginsenoside Rb is selected from the compounds, and it will be described based on experimental examples that ginsenoside Rbi is a composition for regulating animal growth or a feed composition. For this reason, an experimental example using the freshwater fish "Evening Nago" as an animal is shown below. Evening locust with a body length of 3 to 5 cm (Rhodeusoce 1 1 atusoce 11 1 atus) 1 9 animals are divided into 2 groups, and 10 animals are around 15 ° C only in fresh water (5 ° liter). For 10 days, 9 animals were bred in fresh water containing ginsenoside R bi (100 fg / ml) under the same conditions for 10 days. After that, open wounds with a diameter of 2 mm were created in the midline of the left body near the tail fins of all the locusts. An open wound was created using an instrument for skin biopsy (trepan). The open wound was created by alternately using a freshwater locust and a freshwater evening nago containing ginsenoside R bi, and returned to the original aquarium immediately after the creation of the open wound. On the 8th day after the creation of open wounds, surviving locusts were observed. In addition, artificial feed for medaka was given as bait. By the way, the open wound of this locust is considered to be equivalent to an open wound with damage and rupture of the femoral artery when compared to humans. The results are shown in FIGS. 27, 28, and 29. Fig. 27, Fig. 28 and Fig. 29 are photographs replacing the drawings.

As shown in the representative example immediately after creation of the open wound in Fig. 27, open wounds with a diameter of 2 mm were created for all 19 locusts. On the 8th day after the creation of the open wound, 5 out of 10 locusts that had been reared in freshwater alone had died, and most of the surviving 5 ', as shown in Fig. Were almost missing the tail fin. On the other hand, as shown in Fig. 29, seven out of nine turkeys reared in freshwater containing ginsenoside R bi (100 fg / m In addition, seven surviving animals had little missing fins (ie, tissue distal to the open wound).

Therefore, ginsenoside R bt is considered to be able to protect marine animals, such as eveningago, from fatal trauma, vascular injury, and wounds. In other words, it can be said that it has been invented that ginsenoside Rbi or a natural product containing ginsenoside Rbi is extremely useful as a composition for regulating animal growth or a feed composition.

These facts indicate that the dihydroxy ginsenoside R b or the epoxy ginsenoside R b of the present invention has the same activity. Industrial applicability

The present invention relates to dihydroxy ginsenoside R b or epoxy ginsenoside R b A pharmaceutical composition for inhibiting apoptosis or apoptotic cell death, a pharmaceutical composition for treating an organic disease, a pharmaceutical composition for promoting skin tissue regeneration, a wound healing, comprising a ginsenoside derivative such as i as an active ingredient Pharmaceutical composition for promotion, Pharmaceutical composition for the treatment of brain / neurological disorders, External skin composition, External mucosal composition, Health drug composition, Chemical peeling composition, Cosmetic composition, Fertilizer composition, Feed composition, It is intended to provide a composition for regulating growth or a composition for growing and growing hair. In the present invention, an anti-apoptosis effect, an apoptosis-like cell death inhibitory effect, a cell protection effect, a regeneration of living tissue, and a superior activity in a wide range of optimal extracellular solution concentration range than ginsenoside R bi as a lead compound are considered. A new compound showing a remodeling promoting action has been invented. Low-concentration and low-dose ginsenoside derivatives In particular, dihydroxy ginsenoside Rb or epoxy ginsenoside Rbi is useful for promoting the regeneration and remodeling of living tissues or the anti-apoptosis action of living tissues. Prevention, treatment or treatment of any disease or condition that causes organic damage or cell death that causes histological changes, and cultivation, cultivation, and preservation of crops, marine products, marine animals, fresh flowers, ornamental fish or marine products · Used for aquaculture. The living tissue in the present invention includes human, vertebrate, invertebrate, or plant-derived tissue.

Claims

The following general formula (I),

Qualification (I)

(Wherein, RR ² is a hydroxyl group, or together with R ¹ and the adjacent carbon atom indicates R. ² guard緖to an oxygen atom to form a Okishiran ring.)

Or a metabolite thereof or a salt thereof.

The following general formula (I),

(In the formula, R ¹ and R ² represent a hydroxyl group, or R ¹ and R ² represent an oxygen atom together with an adjacent carbon atom to form an oxysilane ring.)

A pharmaceutical composition comprising dihydroxy or epoxy ginsenoside R b, or a metabolite thereof, or a salt thereof, represented by the formula:

3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

4. The pharmaceutical composition is for inhibiting cell apoptosis or apoptotic cell death, or for treating, preventing or treating a disease that causes apoptosis or apoptotic cell death of cells. The pharmaceutical composition according to claim 2 or 3.

5. The pharmaceutical composition according to claim 4, wherein the cell is a brain cell or a nerve cell.

6. The pharmaceutical composition according to claim 4, wherein the cells are cells of an organ for transplantation or a tissue for transplantation.

7. The pharmaceutical composition according to claim 2 or 3, wherein the pharmaceutical composition is for treating, preventing or treating brain / neurological diseases. ·

8. The pharmaceutical composition according to claim 7, wherein the cerebral / neurological disorder is cerebral infarction, stroke, transient ischemic attack, nerve injury, head injury or spinal cord injury.

9. The pharmaceutical composition according to claim 2 or 3, wherein the pharmaceutical composition is for preventing, treating, or treating an organic disease that causes histopathological changes in living tissue.

10. The method according to claim 9, wherein the prevention, treatment, or treatment of the organic disease is caused by regeneration and Z or reconstitution of a biological tissue or a cell of the tissue in which a histopathological change has occurred. Pharmaceutical composition.

11. The pharmaceutical composition according to claim 9 or 10, wherein the histopathological change is due to a wound.

12. The pharmaceutical composition according to claim 11, wherein the wound is an open wound, an open wound, a bite or a defect.

13. The pharmaceutical composition according to claim 11 or 12, wherein the wound is a suture defect after a surgical operation.

14. The pharmaceutical composition according to any one of claims 9 to 13, wherein the living tissue is a mucosal tissue including a skin tissue or an oral mucosal tissue.

15 5. Prevention, treatment, or treatment of skin tissue or mucosal tissue including oral mucosal tissue that has caused histopathological changes is performed by epidermis, epidermis, dermis, dermal papillae, or subcutaneous of mucous membrane containing skin or oral mucosal tissue Regeneration and / or regeneration of tissue, connective tissue, lamina propria, muscular tissue, mucous glands, mixed glands, sweat glands, sebaceous glands, mucous glands, serous glands, dermal papilla, hair follicles, pilo muscularis, vascular or peripheral nerves The pharmaceutical composition according to claim 14, which is constructed.

1 6. Prevention, treatment, or treatment of skin tissue or mucosal tissue including oral mucosal tissue that has caused histopathological changes is performed by epidermal cells, epidermal keratinocytes, or epithelial cells of mucosal tissue including skin tissue or oral mucosal tissue , Merkel cells, melanocytes, Langerhans cells, keratinocytes, stem cells, mesenchymal cells, fibroblasts, sebaceous gland cells, salivary gland cells, myoepithelial cells, sweat gland cells, smooth muscle cells, mucous gland cells, By regeneration and Z or remodeling of cells of the serous glands, cells of the mixed glands, muscle cells, vascular endothelial cells, cells of adipocytes or hair follicles, or collagen, elastic, reticulum or extracellular matrix The pharmaceutical composition for prevention, treatment or treatment according to claim 14.

17. The prevention, treatment, or treatment of skin tissue or histo-mucosal tissue, including oral mucosal tissue, that has caused histopathological changes, is due to hair growth or hair growth of the skin tissue that has caused histopathological changes. The pharmaceutical composition for prevention, treatment or treatment according to any one of Items 14 to 16 in the range.

18. Claims that the prevention, treatment, or treatment of mucosal tissues, including skin tissues or oral mucosal tissues that have undergone histopathological changes, is for the prevention, treatment, or improvement of aging symptoms of the skin or mucous membranes. Item 18. The pharmaceutical composition according to any one of Items 14 to 17.

1 9. Prevention, treatment or treatment of mucosal tissues including histopathological changes or mucosal tissues including oral mucosal tissues may result in epithelium of mucosal tissues including histopathological changes or mucosal tissues including oral mucosal tissues The pharmaceutical composition according to any one of Claims 14 to 18, which promotes the formation of a drug.

20. The pharmaceutical composition according to any one of claims 9 to 19, wherein the living tissue is an organ or tissue for transplantation.

21. The pharmaceutical composition according to any one of claims 2 to 20, wherein the pharmaceutical composition is a preparation for intravenous administration.

22. The pharmaceutical composition according to claim 21, wherein the preparation for intravenous administration is a single intravenous injection preparation or a preparation for continuous intravenous administration.

23. The pharmaceutical composition according to any one of claims 2 to 20, wherein the pharmaceutical composition is an external preparation for skin.

24. The pharmaceutical composition according to any one of claims 2 to 20, wherein the pharmaceutical composition is an external preparation for mucosa.

25. An external skin composition or an external mucosal composition comprising the compound according to claim 1.

26. The external skin composition according to claim 25, wherein the external skin composition is a cosmetic composition.

27. The external skin composition according to claim 25 or 26, wherein the external skin composition is for chemical peeling.

28. The external skin composition according to any one of claims 25 to 27, wherein the external skin composition is a composition for hair growth and hair growth.

29. Scope of Claim 25 to Claim 25 wherein the composition for external use on skin or mucous membrane is for protecting skin cells or mucous membrane cells or preventing, treating or ameliorating aging symptoms of skin or mucous membranes 29. The composition for external use on skin or the composition for external use on mucous membrane according to any one of Item 28.

30. Aging symptoms of the skin or mucous membranes include skin atrophy, susceptibility to infection, sagging, dandruff. Hair loss, itching, dryness, gray hair, cracks, sebum deficiency, exfoliation of keratinocytes, horny layer, cracks, and rags 29. The external skin composition according to claim 29, which is a spot, a wrinkle, a freckle, sunburn, poor reproduction, pigmentation or dryness or atrophy of mucous membrane, exfoliation, epithelial detachment, poor reproduction, cracked or dry. Or external composition for mucosa.

31. Growth for promoting the regeneration, regeneration, growth, reconstruction, differentiation, preservation, cultivation or cultivation of plant or animal tissues or cells comprising the compound according to claim 1. Conditioning composition.

3 2. Claim 3 wherein the composition for regulating growth is a composition for regulating plant growth for promoting the regeneration, regeneration, growth, and reconstruction of plant tissues or cells. Differentiation, storage, cultivation or cultivation. 2. The composition for adjusting growth according to item 1.

33. The composition for regulating plant growth according to claim 31 or 32, wherein the composition for regulating plant growth is a fertilizer composition.

34. The composition for regulating plant growth according to any one of claims 31 to 33, wherein the plant tissue or cell is a hydroponically grown plant.

35. The composition for regulating plant growth according to claim 34, wherein the hydroponically grown plant is a cutting of pothos.

36. The growth regulating composition is a marine product, a marine resource, a marine product, a marine resource, a marine animal. An animal growth regulating composition for breeding, protecting or cultivating a marine animal, pet or livestock. 31. The composition for adjusting growth according to item 1.

37. The composition for controlling growth according to claim 36, wherein the composition for controlling animal growth is a feed composition.

38. The composition for regulating growth of animals according to claim 36 or 37, wherein the animal is a locust.