JP2002128679A - Erythrocyte deformability improver - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new erythrocyte deformability improver having high stability and percutaneous absorbability, capable of improving erythrocyte deformability through effectively acting safely and at low doses, thus capable of treating hemokinetic disorders including microcirculation insufficiency. SOLUTION: This erythrocyte deformability improver comprises a chromanol glycoside of formula (1) (wherein, R1, R2, R3 and R4 are each H or a lower alkyl; R5 is H, a lower alkyl or a lower acyl; X is a monosaccharide residue or oligosaccharide residue wherein the hydrogen atom(s) of hydroxy group(s) may be substituted with lower alkyl group(s) or lower acyl group(s); (n) is an integer of 0-6; and (m) is an onteger of 1-6).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel erythrocyte deformability improving agent. More specifically, the present invention relates to an erythrocyte deformability improving agent containing a water-soluble chromanol glycoside as an active ingredient.

[0002]

2. Description of the Related Art Erythrocytes have a characteristic shape of a biconcave disc and have a diameter of about 8 .mu.m in humans, which is larger than the average diameter of capillaries of 5 to 6 mm. Thus, the red blood cells will deform and pass through the capillaries. Therefore, it is considered that the deformability of red blood cells is the heaviest factor that affects the blood flow velocity and blood flow in the capillaries. Furthermore, since the proportion of red blood cells in the blood is about half in volume due to the demand for oxygen transport, the fluidity of blood, not only in capillaries but also in thick blood vessels, largely depends on the red blood cell deformability. Blood flow disorders such as microcirculatory insufficiency due to such reduced erythrocyte deformability include peripheral blood circulation disorders such as atherosclerosis, cerebral atherosclerosis, Burger's disease, Burger's disease, cerebral thrombosis, cerebral infarction, cerebrovascular disorder, etc. It is known that it has a significant effect on sequelae, hypertension, organ circulation disorder, and the like. Several erythrocyte deformability improving agents have been developed for the purpose of treating these disorders, but none have yet been satisfied.
Development of a drug having an excellent erythrocyte deformability improving effect has been desired.

[0003] On the other hand, the chromanol glycoside used in the present invention is a known compound (JP-A-7-118287, JP-A-9-249688, JP-A-11-21-2).
No. 1291). The chromanol glycoside has two of the chroman rings of α-tocopherol, a typical vitamin E.
It is obtained by substituting the phytyl group at the position with an alcohol and further linking a sugar, and has high water solubility and excellent antioxidant action. However, it has not been known to use the chromanol glycoside as the above-mentioned erythrocyte deformability improving agent.

[0004]

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned problems of the prior art, and it is an object of the present invention to effectively act in a small dose without causing side effects and to deform erythrocytes. It is an object of the present invention to provide a novel erythrocyte deformability improving agent which can improve blood flow and treat blood flow disorders such as microcirculation failure.

Another object of the present invention is to provide a novel erythrocyte deformability improving agent which can be used as an aqueous preparation containing an active ingredient at a high concentration and which is excellent in stability and transdermal absorption. .

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies on blood flow disorders such as microcirculation insufficiency, and as a result, it has been found that the chromanol glycosides extremely effectively improve the erythrocyte deformability and improve the disorder. And found that the present invention can be treated, and completed the present invention.

That is, the present invention provides the following general formula (1)

[0008]

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(Wherein, R ¹ , R ² , R ³ and R ⁴ represent the same or different hydrogen atoms or lower alkyl groups, R ⁵ represents a hydrogen atom, a lower alkyl group or a lower acyl group; Represents a monosaccharide residue or an oligosaccharide residue in which a hydrogen atom of a hydroxyl group in the sugar residue may be substituted with a lower alkyl group or a lower acyl group, n is an integer of 0 to 6, and m is Which is an integer of 1 to 6).

In the present invention, the chromanol glycoside may be 2- (α-D-glucopyranosyl) methyl-2,5,
The agent for improving erythrocyte deformability, which is 7,8-tetramethylchroman-6-ol.

[0011] The present invention further provides the erythrocyte deformability improving agent which is an aqueous preparation.

The present invention also relates to atherosclerosis, cerebral atherosclerosis, peripheral blood circulation disorder, sequelae of cerebral thrombosis, sequelae of cerebral infarction, sequelae of cerebrovascular disorder, organ circulation disorder, hypertension, periodontal disease, frostbite, frostbite And the erythrocyte deformability improving agent, which is a therapeutic agent for cracks, cranes or red ants.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The erythrocyte deformability improving agent of the present invention comprises
It is characterized in that the chromanol glycoside represented by the general formula (1) is used as an active ingredient.

In the general formula (1), R ¹ , R ² ,
As the lower alkyl group for R ³ , R ⁴ and R ^5, a lower alkyl group having 1 to 8, preferably 1 to 6 carbon atoms is preferable. Group, isobutyl group, pentyl group, isopentyl group, hexyl group, heptyl group, octyl group and the like. Of these, a methyl group or an ethyl group is preferred. As the lower acyl group for R ^5, a lower acyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms is preferable, and examples thereof include a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, and a valeryl group. , Isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl and the like. Among these,
An acetyl, propionyl or butyryl group is preferred. Further, as the monosaccharide residue of X, glucose, galactose, fucose, xylose, mannose, rhamnose, fructose, arabinose, lyxose, ribose, allose, altrose, idose, talose, deoxyribose, 2-deoxyribose, quinobiose,
Sugar residues such as avequose; Examples of the oligosaccharide residue of X include those in which 2 to 4 of the above monosaccharides are bonded, for example, sugar residues of maltose, lactose, cellobiose, raffinose, xylobiose, and sucrose. Among them, monosaccharide residues such as glucose, galactose, fucose, xylose, rhamnose, mannose and fructose are preferred. Further, the hydrogen atom of the hydroxyl group in the sugar residue of X is a lower alkyl group, preferably a lower alkyl group having 1 to 8 carbon atoms, or a lower acyl group, preferably a lower acyl group having 1 to 10 carbon atoms. May be substituted. Further, n is 0 to 6, preferably 1 to 4
And m is an integer of 1 to 6, preferably 1 to 3. Preferred examples of the chromanol glycoside represented by the general formula (1) include 2- (α-D-glucopyranosyl).
Methyl-2,5,7,8-tetramethylchroman-6
All, 2- (β-D-galactopyranosyl) methyl-
2,5,7,8-tetramethylchroman-6-ol,
2- (β-L-fucopyranosyl) methyl-2,5,7,
8-tetramethylchroman-6-ol, 2- (α-L
-Rhamnopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol, 2- (β-D-xylopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol, 2- (Β-D-glucopyranosyl)
Methyl-2,5,7,8-tetramethylchroman-6
All, 2- (β-D-fructofuranosyl) methyl-
2,5,7,8-tetramethylchroman-6-ol,
2- (α-D-mannopyranosyl) methyl-2,5
7,8-tetramethylchroman-6-ol and the like.

Chromanol glycosides used in the present invention are described, for example, in JP-A-7-118287 and JP-A-9-118287.
According to the methods described in JP-A-249688 and JP-A-11-21291, the following general formula (2):

[0016]

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(Where R ¹ , R ² , R ³ ,
R ⁴ , R ⁵ and n are as defined above)
An enzyme comprising reacting a substituted alcohol and an oligosaccharide in the presence of a corresponding enzyme that catalyzes the translocation of sugar, and binding a specific hydroxyl group of the sugar specifically to the hydroxyl group at the 2-position of the 2-substituted alcohol. It is produced by a reaction (enzymatic method).

The one used as a raw material in the above reaction
2-substituted alcohol represented by the general formula (2) (hereinafter simply referred to as
"A 2-substituted alcohol") is a known substance,
For example, Japanese Patent Publication No. 1-33755 and Japanese Patent Publication No.
No. 135, etc.
You. Further, for example, in the general formula (2), R¹, R^Two, R ^Three
And R^FourIs a methyl group, R^FiveIs a hydrogen atom, and n is 1
Is a 2-substituted alcohol
The phytyl group at the 2-position of the romantic ring is substituted with a carboxyl group.
6-Hydroxy-2,5,7,8-te having a modified structure
Tramethylchroman-2-carboxylic acid (trade name "Tororo
(Trolox) ”for lithium aluminum hydride
Reflux treatment in diethyl ether in the presence of
It can be easily obtained by processing.

It is preferable that the enzyme used in the above reaction to catalyze the translocation of sugar is selectively used as follows depending on the type of sugar used in the reaction.

(1) When a glucose residue is bonded to a 2-substituted alcohol by an α-bond: (a) α-glucosidase (α-glucose) is used for maltooligosaccharides from maltose to maltotetraose
sidase, EC 3.2.1.20). As α-glucosidase, those derived from almost all origins can be used. Specifically, Saccharomyces (Toyobo Co., Ltd.)
romyces sp. ) -Derived α-glucosidase,
Saccharomyces manufactured by Oriental Yeast Industry Co., Ltd.
Saccharomyces cere
α-glucosidase from Aspergillus niger (Aspergil) manufactured by Amano Pharmaceutical Co., Ltd.
α-glucosidase derived from L. niger, Saccharomyces (Sacch) manufactured by Wako Pure Chemical Industries, Ltd.
aromyses sp. ) -Derived α-glucosidase, bakery yeast (B) manufactured by SIGMA
α-glucosidase from akeers yeast).
Α-glucosidase derived from the genus Bacillus and the like.

(B) 4 for soluble starch or starch
-Α-glucanotransferase (4-α-D-gl
ucanotransferase, EC 2.4.1.
25) is desirably applied.

(2) When a glucose residue or maltooligosaccharide residue is bound to the 2-substituted alcohol by α-bonding: For maltooligosaccharide, soluble starch, starch, cyclodextrin (α, β, γ), etc. Cyclodextrin glucanotransferase (cyclodex)
trin glucanotransferase, E
C2.4.1.19) is desirable. Representative examples include cyclodextrin glucanotransferase derived from Bacillus macerans manufactured by Amano Pharmaceutical Co., Ltd., and Bacillus stearothermophilus manufactured by Hayashibara Biochemical Laboratory Co., Ltd.
m. philus cyclodextrin glucanotransferase, Bacillus megaterium (Bacillus megaterium), Bacillus circulans ATCC 9995 (Bac
illus circulans ATCC 999
5) Cyclodextrin glucanotransferase and the like.

(3) When a glucose residue is bound to a 2-substituted alcohol by a β-bond: (a) β-glucosidase (β) is used for an oligosaccharide having a β-linkage such as cellobiose, curdlan or laminaran. -Glucosidase, EC 3.2.1.
It is desirable to make 21) work.

(B) For cellobiose in the presence of phosphoric acid, cellobiose phosphorylase (cellbiobio)
se phosphorylase, EC 2.4.1.
It is desirable to make 20) work.

(4) When a galactose residue is bonded to a 2-substituted alcohol by α-bonding: α-galactosidase (α
-Galactosidase, EC 3.2.1.2
It is desirable to make 2) work.

(5) When a galactose residue is bound to a 2-substituted alcohol by β-bonding: (a) For lactose and the like, β-galactosidase (EC 3.2.1.
23) is desirably applied.

(B) For arabinogalactan and the like, endo-1,4-β-galactanase (Endo-1,
4-β-galactanase, EC 3.2.1.8
It is desirable to make 9) work.

(6) When a fructose residue is bound to a 2-substituted alcohol by a β-bond: (a) Levansucrase (levansucra) for sucrose, raffinose, melibiose, etc.
se, EC 2.4.1.10).

(B) For sucrose, β-fructofuranosidase (β-fructofuranosidas)
e, EC 3.2.1.26).

(C) Inulin fructotransferase (inulin fructotransferase)
otransferase, EC 2.4. 1.93).

The reaction conditions in the above reaction differ depending on the type of chromanol glycoside and enzyme used. For example, a chromanol glycoside in which m in the general formula (1) is 1 is synthesized using α-glucosidase. If you do,
It is desirable to dissolve the substituted alcohol in the sugar solution.
To this end, it is desirable to add an organic solvent. Examples thereof include dimethyl sulfoxide, N, N-dimethylformamide, methanol, ethanol, acetone, and acetonitrile. Considering that the transfer activity of α-glucosidase is enhanced, dimethyl sulfoxide is considered. And N, N-
Dimethylformamide is preferably used. The concentration of the organic solvent to be added is 1 to 50 (vol / vol)%, and preferably 5 to 35 (vol / vol)% in view of the reaction efficiency.

It is desirable that the concentration of the 2-substituted alcohol be a saturated concentration or a concentration close to the saturated concentration in the reaction solution. The type of the sugar used is preferably a low molecular weight from maltose to maltotetraose, and preferably maltose. The concentration of the sugar is 1 to 70 (mass / volume)%, preferably 30 to 60 (mass / volume)%. pH 4.5
-7.5, preferably 5.0-6.5. The reaction temperature is from 10 to 70C, preferably from 30 to 60C. The reaction time is 1 to 40 hours, preferably 2 to 24 hours.
However, it goes without saying that these conditions are affected by the amount of enzyme used and the like. After the reaction is completed, the reaction solution is
By subjecting to a column chromatography using D (Organo Co., Ltd.) as a carrier, the desired chromanol glycoside can be obtained with high purity.

For example, when a chromanol glycoside in which m in the general formula (1) is 1 is synthesized using cyclodextrin glucanotransferase, the reaction conditions are as follows. It is desirable to make it. For that purpose, addition of an organic solvent is desirable,
Examples include dimethyl sulfoxide, N, N-dimethylformamide, methanol, ethanol, acetone, and acetonitrile. The concentration of the organic solvent to be added is 1
５０50 (vol / vol)%, preferably 5 to 35 (vol / vol)% considering reaction efficiency. It is desirable that the concentration of the 2-substituted alcohol be a saturated concentration or a high concentration close to the saturated concentration in the reaction solution.

Examples of the type of sugar used in the above reaction include maltooligosaccharides having a degree of polymerization of maltotriose or higher, soluble starch, starch, and cyclodextrin (α, β, γ). The concentration of the sugar is 1 to 70 (mass / volume)%, preferably 5 to 50 (mass / volume)%. The pH is between 4.5 and 8.5, preferably between 5.0 and 7.5. The reaction temperature is from 10 to 70C, preferably from 30 to 60C. Reaction time is 1 to 60 hours,
Preferably, it is 2 to 50 hours. However, these conditions are affected by the amount of enzyme used. The chromanol glycoside obtained by such a reaction is a mixture in which the number of m is 1 to 8. Thus, by treating this mixture with glucoamylase (EC 3.2.1.3), only the chromanol glycoside in which m in the general formula (1) is 1 can be obtained. The reaction temperature at this time is 20-7.
0 ° C., preferably 30 to 60 ° C., and the reaction time is 0.1 ° C.
It is 1 to 40 hours, preferably 1 to 24 hours. However,
These conditions are affected by the amount of enzyme used.
Next, the liquid after the glucoamylase treatment was subjected to column chromatography using XAD (Organo Corporation) as a carrier, whereby m in the general formula (1) was 1
Is obtained in high purity.

In order to obtain a chromanol glycoside wherein m in the general formula (1) is 2, under the same conditions as above, m in the general formula (1) obtained by the cyclodextrin glucanotransferase is 1 Chromanol glycosides having the form of a mixture at position 8 to β-amylase (E
By acting C3.2.1.2), only a chromanol glycoside in which m in the general formula (1) is 1 or 2 can be obtained. The reaction temperature at this time is 20 to 70 ° C,
Preferably, it is 30 to 60 ° C, and the reaction time is 0.1 to 4
0 hours, preferably 1 to 24 hours. However, these conditions are affected by the amount of enzyme used. The liquid after β-amylase treatment was subjected to column chromatography using XAD (Organo Co., Ltd.) as a carrier.
A chromanol glycoside in which m in the general formula (1) is 2 can be obtained with high purity, and at the same time, m in the general formula (1)
Is also obtained.

In order to obtain a chromanol glycoside wherein m in the general formula (1) is 3 or more, m in the general formula (1) obtained by the cyclodextrin glucanotransferase is 1 under the same conditions as described above. Chromanol glycosides in the form of a mixture at positions 8 to 8 were analyzed by HPLC
Chromanol glycosides of high purity can be obtained for each m by preparative chromatography using, for example.

In the above embodiment, an embodiment in which a glucose residue or a maltooligosaccharide residue is bonded to a 2-substituted alcohol as a sugar residue has been described. However, a galactose residue, a mannose residue, a fructose residue, etc., may be added to a sugar residue. 2-
When binding to a substituted alcohol, the desired chromanol glycoside can be obtained by performing the same operation as in the above-described embodiment except that each of the appropriate enzymes described in the section on the enzyme catalyzing the sugar-transferring action is used. (JP-A-9-249688 and JP-A-11-2)
No. 1291).

On the other hand, the chromanol glycoside used in the present invention is obtained by protecting the hydroxyl group at the 6-position of the 2-substituted alcohol with a protecting group by the method described in Japanese Patent Application No. 10-75599 (hereinafter referred to as “sugar”). (Acceptor)) and a sugar derivative in which a leaving group is introduced at the anomeric position and another hydroxyl group is protected with a protecting group (hereinafter, referred to as “sugar donor”). Law).

The sugar acceptor 6 used in the above reaction
Examples of the protecting group for protecting the hydroxyl group at the position include acetyl, benzoyl, bivaloyl, chloroacetyl, levulinoyl, benzyl, p-methoxybenzyl, allyl, t-butyldimethylsilyl, and t-butyldiphenyl. Examples thereof include a silyl group, a trimethylsilyl group, and a trityl group, and an acetyl group and a benzoyl group are particularly preferable.

The leaving group introduced into the anomeric position of the sugar donor used in the above reaction includes halogen atoms such as chlorine, bromine and fluorine, sulfur compounds such as thiomethyl group, thioethyl group and thiophenyl group, and trichloroacetate. Examples thereof include an imide group, and particularly preferred are bromine, chlorine, a thiomethyl group, a thioethyl group, a thiophenyl group, and a trichloroacetimide group. Further, as a protecting group for protecting a hydroxyl group other than the anomeric position, an acetyl group, a benzoyl group, a pivaloyl group, an acyl-based protecting group such as a chloroacetyl group and a levulinoyl group, and a benzyl group, a p-methoxybenzyl group, an allyl group, ether-based protecting groups such as t-butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group and trityl group;
Among them, an acyl protecting group, particularly an acetyl group, is preferred.

These sugar donors can be easily prepared by introducing a protecting group into all hydroxyl groups of the sugar by a well-known method, and then substituting the anomeric position with a leaving group.

As to the condensation reaction between the sugar acceptor and the sugar donor, first, the sugar acceptor and the sugar donor are dissolved in a non-polar solvent. The charged amounts of the sugar acceptor and the sugar donor are such that the molar ratio of the sugar donor to the sugar acceptor is 1.0 to 1.5, preferably 1.1 to 1.3. Examples of the non-polar solvent include methylene chloride and benzene.

Next, a condensation reaction of the sugar donor and the sugar acceptor is performed in the presence of an activator under anhydrous conditions. As the activator, trifluoroboric acid / ether complex, silver perchlorate, silver trifluoromethanesulfonate, mercury bromide, mercury cyanide, N-iodosuccinimide-trifluoromethanesulfonic acid, dimethylmethylthiosulfonium triflate, Examples include p-toluenesulfonic acid. Particularly, when bromine is used as a leaving group of a sugar derivative, it is preferable to use a heavy metal salt such as silver perchlorate. Reaction temperature is 5
-30 ° C, preferably 10-25 ° C, and the reaction time is 12-48 hours, preferably 20-30 hours.

Next, the obtained reaction product is purified by silica gel column chromatography or the like, and the protecting group is deprotected with sodium hydroxide, methanolic hydrochloric acid or the like to give 2- (β-L-fucopyranosyl) methyl-2,2. 5,
7,8-tetramethylchroman-6-ol, 2- (α
-L-rhamnopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol, 2- (β-D-xylopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol and the like (Japanese Patent Application No. Hei 1)
0-75599).

Chromanol glycosides obtained by the above-mentioned enzymatic method or organic synthesis method generally have extremely high water solubility (about 100 g / 100 ml) and are also oil-soluble (octanol / water partition coefficient). > 3) Amphiphilic molecules. In other words, it can be said that the chromanol glycoside according to the present invention is a water-soluble vitamin E with high lipophilicity. Therefore, unlike conventional water-insoluble or poorly soluble vitamin E derivatives, the chromanol glycosides according to the present invention maintain a high lipophilicity even when used in water, so that they can penetrate cell membranes and It can also enter the inside, dramatically improving the erythrocyte deformability.
Further, the chromanol glycoside obtained by the above reaction,
Tocopherol also for heat stability and pH stability,
It is significantly improved as compared with trolox or 2-substituted alcohol.

The erythrocyte deformability-improving agent of the present invention may be orally or parenterally administered as a composition comprising the chromanol glycoside mixed with a pharmaceutically acceptable carrier or dissolved or suspended in a pharmaceutically acceptable solvent. Can be administered to patients.

When the present preparation is to be used for oral administration, the above-mentioned chromanol glycoside is added to a suitable additive such as lactose, sucrose, mannitol, corn starch, synthetic or natural gum, crystalline cellulose, etc. Agents, binders such as starch, cellulose derivatives, gum arabic, gelatin, polyvinylpyrrolidone, disintegrants such as carboxymethylcellulose calcium, sodium carboxymethylcellulose, starch, corn starch, sodium alginate, and lubricating agents such as talc, magnesium stearate, sodium stearate. Solid preparations such as tablets, powders (powder), pills, and granules can be appropriately mixed with fillers or diluents such as powder, calcium carbonate, sodium carbonate, calcium phosphate, and sodium phosphate. it can. Further, capsules may be prepared using hard or soft gelatin capsules or the like. These solid preparations may be provided with an enteric coating using a coating base such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, methacrylate copolymer and the like. Further, the chromanol glycoside is dissolved in a commonly used inert diluent such as purified water, and if necessary, a wetting agent, an emulsifier, a dispersing aid, a surfactant, a sweetener is added to the solution. Liquid preparations such as syrups and elixirs can be prepared by adding an appropriate amount of a flavor, an aromatic substance or the like.

When the erythrocyte deformability improving agent of the present invention is to be used for parenteral administration, the chromanol glycoside may be purified water, a suitable buffer such as a phosphate buffer, physiological saline, or the like.
Physiological saline solutions such as Ringer's solution and Locke's solution, sterile aqueous solutions, non-aqueous solutions, suspensions, liposomes or emulsions suitably combined with ethanol, glycerin and commonly used surfactants, preferably sterile for injection It is administered as an aqueous solution intravenously, subcutaneously, intramuscularly, and the like. At this time, the liquid preparation preferably has a physiological pH, preferably a pH in the range of 6 to 8. Also,
The erythrocyte deformability-improving agent of the present invention is a liquid preparation such as a lotion, a suspension, an emulsion, a semisolid preparation such as a gel, a cream, an ointment, a powder, a powder, or a granule for dissolving and applying at the time of use. As a solid preparation such as an agent, it may be transdermally administered to a target site and its surrounding site. In addition, it can be administered as a suppository using a pellet or embedded in a suppository base. Of the above, preferred preparations, dosage forms, and the like are selected by the attending physician.

The concentration of the chromanol glycoside contained in the erythrocyte deformability-improving agent of the present invention varies depending on the administration form, the type and severity of the disease, the intended dose, and the like. It is 0.1 to 100% by mass, preferably 1 to 90% by mass, based on the total mass of the raw materials. In particular, when the formulation of the present invention is orally administered, the amount is 1 to 100% by mass, preferably 5 to 90% by mass relative to the total mass of the raw material,
When administered parenterally, the amount should be 0,1 relative to the total volume of the ingredients.
It is preferably from 1 to 90% by volume, preferably from 1 to 80% by volume. At this time, if the concentration of the chromanol glycoside exceeds the upper limit, no improvement effect commensurate with the excessive dose cannot be obtained, and if the concentration is less than the lower limit, the improvement effect cannot be sufficiently expected, and neither is preferable.

The above dose of the erythrocyte deformability improving agent of the present invention varies depending on the age, weight and condition of the patient, the intended dosage form and method, therapeutic effect, treatment period, etc., and the exact amount is determined by a physician. Usually, when the drug is orally administered, the dose is 0.1 to 10000 mg / kg body weight / day in terms of the dose of chromanol glycoside, It is administered in 1 to 3 divided doses. At this time, if the daily oral dose is large,
A plurality of preparations such as tablets may be administered at one time. Also,
When the erythrocyte deformability improving agent of the present invention is administered parenterally, it is 0.01 to 1 in terms of a chromanol glycoside dose.
000 mg / kg body weight / day
~ 3 divided doses.

[0051]

EXAMPLES The effect of improving the erythrocyte deformability of the erythrocyte deformability improving agent of the present invention was confirmed by the following pharmacological tests.

As chromanol glycosides, JP-A-7-17-1
2- (α-D-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman- represented by the following formula (3) produced by the method described in Example 1 of JP 18287
6-ol (TMG) was used.

[0053]

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Test for confirming the effect of improving erythrocyte deformability Blood was collected from humans using a vacuum blood collection tube (trade name: Benoject) containing sodium heparin manufactured by Terumo Corporation.
ml was collected. Then, the blood is centrifuged (3500 rpm
m, 10 minutes, 4 ° C.) to remove plasma and buffy coat. 100 ml of a phosphate buffer solution (PBS) was added to the obtained erythrocyte layer, followed by centrifugation (3000 rpm, 10 minutes, 4 ° C.), and the supernatant containing the buffy coat was discarded. This operation was performed three times in total. Then, hematocrit value is set to 1 using physiological saline.
It was adjusted to 1%.

The red blood cell suspension 360 prepared above
Add 40 μl of 100 μM TMG to μl, and in the dark,
Incubate at 37 ° C. for 30 minutes. At this time, the final concentration of TMG was 10 μM. 40 μl of PBS was added instead of TMG, and the mixture treated similarly was used as a control.

The erythrocyte deformability is described in Yuji Kikuchi et al., "Cell Microrheology Measuring Apparatus MC-FAN," Vol.
No. 27-30, a microchannel array having a channel system of 7 μm width and 30 μm length in a cell microrheology measuring apparatus.
7 (both manufactured by Hitachi Haramachi Electronics Co., Ltd.)
Evaluation was made by measuring the time required for 100 μl of the above prepared solution to pass at a water column difference of 0 cm. Table 1 shows the results.

[0057]

[Table 1]

From the results shown in Table 1, when TMG was added,
The transit time was significantly shorter than that of the control, indicating that TMG significantly enhanced erythrocyte deformability.

Acute toxicity test An acute toxicity test was performed on the erythrocyte deformability improving agent of the present invention to confirm its safety. Four to five-week-old ICR mice were used as a group of three mice, and the same TMG as a chromanol glycoside was suspended in 5% gum arabic solution.
500 mg / kg in terms of MG was orally administered and observed for one week. At this time, 5% gum arabic solution was added as a control group in 0.1 g.
3 ml was orally administered. As a result, no death cases of the mice were observed in any of the administration groups.

Formulation Example 1 100 g of TMG, 800 g of lactose and 100 g of corn starch were mixed in a blender to obtain a powder.

Formulation Example 2 After 100 g of TMG, 450 g of lactose and 100 g of low-substituted hydroxypropylcellulose were mixed, 350 g of a 10% aqueous solution of hydroxypropylcellulose was added and kneaded. This was granulated using an extruder and dried to obtain granules.

Formulation Example 3 100 g of TMG, 550 g of lactose, 215 g of corn starch, 130 g of crystalline cellulose and 5 g of magnesium stearate were mixed in a blender, and the mixture was tabletted with a tablet machine to obtain tablets.

Formulation Example 4 TMG 10 g, lactose 110 g, corn starch 5
After mixing 8 g and 2 g of magnesium stearate using a V-type mixer, the capsules were obtained by filling 180 mg each in No. 3 capsules.

Formulation Example 5 200 mg of TMG and 100 mg of glucose were dissolved in 2 ml of purified water and filtered, and the filtrate was dispensed into 2 ml ampules, sealed and sterilized to obtain an injection.

Formulation Example 6 1 g of TMG, 3 g of ethanol, 0.2 g of hydroxyethyl cellulose and 0.1 g of methyl paraoxybenzoate
Was mixed and dissolved in 100 ml of purified water to obtain a lotion.

[0066]

As described above, since the erythrocyte deformability improving agent of the present invention contains a water-soluble chromanol glycoside as an active ingredient, the erythrocyte deformability is dramatically improved, and blood dysfunction such as microcirculation failure is improved. Flow disorders can be treated.

The erythrocyte deformability improving agent of the present invention of the present invention comprises
Since a chromanol glycoside having high water solubility is used as an active ingredient, an aqueous preparation containing the active ingredient at a high concentration can be obtained, and storage stability is high. Further, it has excellent transdermal absorbability, and can be administered transdermally to an affected part as an external preparation. By making it into an aqueous preparation, it can be effectively used in a small dose to improve erythrocyte deformability, and can be used extremely safely because it has no side effects.

The erythrocyte deformability-improving agent of the present invention can be used for various diseases caused by impaired blood flow such as microcirculation failure, for example, peripheral blood circulation such as atherosclerosis, cerebral atherosclerosis, Burger's disease and Burger's disease. Especially useful when used for the treatment of disorders, sequelae of cerebral thrombosis, cerebral infarction, cerebrovascular disorder, etc., liver diseases, pancreatitis, organ circulatory disorders such as renal failure, hypertension, periodontal disease, frostbite, frostbite, cracks, red ash etc. It is.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61P 9/10 101 A61P 9/10 101 9/12 9/12 17/00 17/00 17/02 17/02 // C07H 15/26 C07H 15/26

Claims (4)

[Claims] [Claim 1] The following general formula (1) ^{(Wherein, R 1, R 2, R} 3 and R ⁴ represent the same or different hydrogen atom or a lower alkyl group, R ⁵
Represents a hydrogen atom, a lower alkyl group or a lower acyl group, and X represents a monosaccharide residue or an oligosaccharide residue in which a hydrogen atom of a hydroxyl group in a sugar residue may be substituted with a lower alkyl group or a lower acyl group. Wherein n is an integer of 0 to 6, and m is an integer of 1 to 6). 2. The chromanol glycoside is 2- (α-D
The erythrocyte deformability improving agent according to claim 1, which is -glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol. 3. The erythrocyte deformability improving agent according to claim 1, which is an aqueous preparation. 4. Atherosclerosis, cerebral atherosclerosis, peripheral blood circulation disorder, sequelae of cerebral thrombosis, sequelae of cerebral infarction, sequelae of cerebrovascular disorder, organ circulation disorder, hypertension, periodontal disease, frostbite, frostbite, crack or The erythrocyte deformability improving agent according to any one of claims 1 to 3, which is a therapeutic agent for red oak.