TW201018469A - Prophylactic and therapeutic agent for sepsis - Google Patents

Abstract

Disclosed is a prophylactic and therapeutic agent for sepsis, which comprises at least one component selected from the group consisting of a cyclic tetrasaccharide of which a constituent saccharide is glucose, a cyclic pentasaccharide of which a constituent saccharide is glucose and derivatives of the cyclic tetrasaccharide and the cyclic pentasaccharide as an active ingredient. The prophylactic and therapeutic agent for sepsis can prevent and treat sepsis without inducing any adverse side effect such as hemolysis .

Description

201018469 VI. Description of the invention: c. 4 chairs and mussels belonging to the invention] Field of the Invention The present invention relates to a prophylactic and therapeutic agent for sepsis, and uses thereof. In the case of a bacterial infection such as pneumonia or peritonitis, or a chemotherapy for a malignant tumor, a bacterial infection such as a bacterial infection caused by a decrease in immunity affects the whole body. Symptoms such as fever, rapid breathing, tachycardia, and increased white blood cells, if continued to develop, can lead to circulatory failure such as disturbance of consciousness and blood pressure, and can cause kidney, lung, liver, coagulation, etc. Organ dysfunction. Moreover, if it is severe, it will be accompanied by acute respiratory distress syndrome (A RD S ) or diffuse intravascular coagulation syndrome (D j c ), etc., so that the heartbeat is stopped due to septic shock. Death and other extremely serious consequences. Because sepsis will worsen with the development of the stage and the mortality will increase, it is necessary to conduct early diagnosis and early treatment in the early stage. The treatment of sepsis can be carried out by infusion resuscitation or antibiotics for inhibiting the production of lipopolysaccharide (LPS) or non-steroidal anti-inflammatory drugs for inhibiting inflammatory reactions. For severe sepsis, clinical improvement can be made. Administration of a hypotensive therapeutic agent or a steroid-inhibiting steroid, a blood coagulation blocker, or the like. The known septicemia drug Xiglis (Drotrecogin alfa, activated: Eli Lilly and Company) is a preparation of active protein c. Although 201018469 has the effect of inhibiting blood coagulation and inhibiting apoptosis, it is ineffective for patients with initial sepsis. Only for patients with severe sepsis. In addition, for the administration of infusion, antibiotics, anti-inflammatory drugs, and the like, a satisfactory therapeutic effect cannot be obtained' only for the symptomatic treatment in the critical stage. Therefore, in the case of sepsis, it is desired to develop an agent that takes into consideration the prognosis and actively exerts the therapeutic effect from the initial stage. However, a cyclic sugar collection mainly used for food additives is known, in which 6 to 8 molecules of glucose are bonded by α-1,4 bonds to form α_, dot-Φ and cyclodextrin of a cyclic structure. These cyclodextrins, stone-cyclodextrin, and tau-cyclodextrin are effective for the diagnosis of sepsis (see Patent Document 1 below). However, 10,000-cyclodextrin has a problem of so-called hemolysis (see Non-Patent Document 1, Non-Specialized Literature 2, etc.), and 5-/5-dextrin has nephrotoxicity, 7-cyclodextrin. There are various problems such as insufficient _ political achievements. Therefore, in terms of α-cyclodextrin, /3-cyclodextrin and cyclodextrin, it cannot be said that the demand as a therapeutic agent for sepsis is sufficiently satisfied. [PRIOR ART DOCUMENT] [Patent Document 1] Japanese Laid-Open Patent Publication No. Hei No. 3-133931 [Non-Patent Document] [Non-Patent Document 1] International Journal of Pharmaceutics Vol. 101, NO. 1/2 PAGE.97- 103 1994 [Non-Patent Document 2] Journal of Pharmaceutical Sciences Vol. 86, No. 2 PAGE. 147-162 1997 4 201018469 [Ming. 3 SUMMARY OF THE INVENTION PROBLEM TO BE SOLVED BY THE INVENTION The present invention has been made in view of the above problems of the prior art. The main purpose of the present invention is to provide a preventive and therapeutic agent for sepsis which has a sufficient therapeutic effect on sepsis but has no side effects. Means to solve the problem

The present inventors conducted repeated and intensive studies to achieve the above object. As a result, it has been found that a cyclic tetrasaccharide, a cyclic pentasaccharide, and a derivative thereof, which have not been used as a therapeutic agent for sepsis, have a strong effect on sepsis from the early stage of silk, and have no hemolysis. The side effects of sex or nephrotoxicity and the like are completed, and the present invention is completed here. That is, the present invention provides the following prophylactic and therapeutic agent for sepsis and a book and treatment of sepsis containing a derivative selected from the group consisting of glucose as a cyclic sugar of a constituent sugar, glucose as a constituent sugar, and the like. The composition of at least one species of the cockroach consisting of 2 is a kind of prevention and treatment of sepsis, which contains a ring selected from the group of 6) _α-D-° 喃 葡萄 grape (four)-(1 - 3) 1 Glucose bud and 6)-α-D-glucopyranoside~(丨~)-a~D-η ratio to glucosamine}, ring {-6]-α-D-port Glucoside _(1 - glucopyranoside-(1->6)-α~η α glucopyranoside _(1~ aD-glucopyranoside-(15} - glucopyranon 5 201018469 glycoside-( 1~>4)- a -D_glucopyranoside _(1 -4) - α _D n glucopyranoside-(1 ^ 4)- a -D-glucopyranoside 4) - α~ n A component which is at least one of a group consisting of a group of glucosamine-(1^}' and its derivatives is an active ingredient. The preventive and therapeutic agent for sepsis according to the above item 1, which is a liquid for injection. The preparation or the solid preparation for dissolution. , 4· The prophylactic and therapeutic agent for sepsis according to the above item 3 is for intravenous administration. 5. A cyclic pentasaccharide selected from the group consisting of glucose as a sugar-containing cyclic tetrasaccharide, glucose as a sugar, and the like The use of at least one component of the group consisting of derivatives is used for the manufacture of a prophylactic and therapeutic agent for sepsis. 6. - The species is selected from the ring 6) - a_D-n is a glucosamine - (1 - 3 b n _ Pyranoglucosyl-(1-6)_α-D_D is more than glucosinolate-(Bu 3)-«D-glucopyranyl-glucose {-6)_a_D n-pyranose----------------- More than glucopyranol _ (Bu 6) 1 - d-n than glucosinolate - (l ~ > 4) - aD ~ n than glucosamine - (1_}, cyclobu Φ 6) a D-pyranose —(卜斗)^ _D 〇 喃 glucoside (1 4) α D n than glucosinolate _(i —4)-aD-. Chewing glucoside-(l-4)-aD-〇pyranose The use of at least one component of the group consisting of _(1-}, and derivatives thereof, is for the prevention and treatment of sepsis. 7. A method for preventing and treating sepsis, which system will contain Selected from glucose 8. A prophylactic and therapeutic agent for sepsis which is at least one component of a group consisting of a cyclic tetrasaccharide of sugar, a ring of glucose 6 and a derivative of sugar, and a derivative thereof, is administered to a human body. - a method for preventing and treating arrhythmia, which system will contain a ring selected from the group consisting of 6) aD-0, glucosinolate-(1 -3)_ 〇:-D-°, glucosamine--(1-6) - α -D-glucopyranoside-(1 -3)_ α -D-glucopyranose -(1—}, cyclohexane 6)-aD-glucopyranose: g:-(144)_a —Dn Glucopyranoside-(1-6)-α-D-glucopyranoside-(1— 44) α-D-° ratio 13 nascent glucose _-(1— }, ring {->6)- a -D-nlt»South glucoside-(1-4)-α-D-purine glucoside-(1 -4)- a -D-glucopyranoside-(1 - 4)- a -D- The prevention and treatment of sepsis for at least one component of a group consisting of glucopyranoside-(1 - 4)-α-D-glucopyranoside (1〇丨, and its derivatives) Doing medicine. 9. A component selected from the group consisting of glucose as a cyclic tetrasaccharide constituting a sugar, a cyclic pentose having glucose as a constituent sugar, and a derivative thereof, at least one of which is used for sepsis. Prevention and treatment methods. 10. - Species selected from the ring {-> 6) a _D_glucopyranoside - α -D-glucopyranoside - (1 - 6) _α _D - glucopyranoside _ (1 ~ 3) α-D-0 is more than glucosamine (1—丨, ring {—6)-a-D_o glucopyranoside-(1 -> 4)-α-D-. Glucosinolate-(丨-6)_α-D-glucopyranoside-(1—4)-〇:-D-glucopyranoside-(1—丨, ring {—6)-a—D -° glucosinolate-(1—►4)- a -D-° glucopyranoside-(1-^4)- a-D-pyrene-pyranose--------------------------------------------- A component selected from the group consisting of glycosides (14)-α_D_0 glucosinolates and derivatives thereof is used for the prevention and treatment of sepsis. The following is a detailed description of the prevention and treatment of the stagnation of the present invention (IV) and its use. Active ingredient The prophylactic and therapeutic agent for sepsis according to the present invention contains at least a component selected from the group consisting of glucose as a sugar-constituting tetrasaccharide, glucose as a sugar-containing cyclic pentasaccharide, and the like. As an active ingredient. The cyclic tetrasaccharide in which glucose is a constituent sugar refers to a compound in which four glucose bonds are bonded to form a ring, and the cyclic pentasaccharide in which glucose is a constituent sugar refers to a compound in which five glucoses are connected in a ring shape. For the cyclic tetrasaccharide and the cyclic pentasaccharide, there are a plurality of types depending on the respective bonding positions, but each of the present invention can be used. In the present invention, in particular, the following cyclic tetrasaccharides and cyclic pentasaccharides are suitable for each of the production amount, the production cost, the efficacy, the in vivo dynamics, and the side effects (hemolysis, etc.). . Ring {—6)-a -D-glucopyranoside-(1 -3)-α-D-glucopyranose--(1-6)-a-D-0 than glucosamine-(1 — 3)- α -D-0 鸣 glucose (alias: Cyclic Nigerosylnigerose; hereinafter referred to as "CNN"). Ring {-6)-〇: -D-glucopyranoside-(1 -4)-α - D-glucopyranose-(1—·6)- a-D-° than glucosamine-(1—4)- a-D-0-glucopyranoside-(1—} (alias: Cyclic Maltosylmaltose; Hereinafter referred to as 201018469. It is "CMM"). Ring {-6]-α-D-glucopyranoside-(1-4)- a-D-. Glucopyranoside-(1 - 4)- 〇; -D-0 glucopyranoside-(1 - 4)- a -D-0 ratio 0 glucosinolate-(1 -4)-aD-glucopyranose Glycoside-(1—} (alias:

Isocyclomaltopentaose; hereinafter referred to as "ICG5") Among the above cyclic tetrasaccharides, CNN is a compound discovered by Gregory.L.C0t6 et al. (European Journal of Biochemistry, 226, _ 640994), and then by Linyuan Biochemistry The Institute implemented its quantitative method from starch. CNN itself exhibits high solubility (46.1 g dissolved in 100 g of water at 20 ° C), low sweetness (sweetness is 27% of granulated sugar), pH stability, and good thermal stability. Although there are some reports of expected medical uses for the use of CNN, the effects of prevention and treatment of sepsis are not fully known. 'CMM is a compound found by the Hayashibara Biochemical Research Institute, and it is described in JP-A-2005-95148. Like CNN, CMM is a compound that exhibits high solubility and stability, although its use is currently being studied. There is no report on the prevention and treatment of sepsis. The cyclic pentasaccharide ICG5 is a compound found by the Linyuan Biochemical Research Institute, and is described in WO2006/35725. ICG5 is a compound which exhibits little sweetness and shows solubility and stability of hydrazine. For its use, research is currently underway', but there is no report on the prevention and treatment effects of sepsis. Further, the cyclic tetrasaccharide and the cyclic pentasaccharide may be those obtained by substituting a hydrogen atom in one or more hydroxyl groups among the glucose residues constituting the cyclic saccharide with various substituents. Such a derivative is not particularly limited, and a derivative having an arbitrary substituent can be used for 9 201018469, and examples thereof include a deuterated derivative; an etherified derivative; a sulfur-containing derivative; a saccharide derivative. The 'deuterated derivative' may be exemplified by an acetamidine derivative, a propylated derivative, a butylated derivative, a pentose derivative, a hexylated derivative, a heptatinized derivative, etc., and has a carbon number. A lower calcined derivative substituted with a lower alkyl alkane group of an alkyl group of about 66. Further, examples of the enzyme-derived derivative include a lower alkyl ether derivative having a carbon number of 1-6 or the like, such as mystery, diethyl ether, propyl ether, dibutyl ether, pentyl ether or hexyl ether. The sulfur-containing derivative may be a sulfonated derivative. Examples of the saccharide derivative include a branched product in which a saccharide such as glucose is bonded by a hydrazone bond. For example, a CNN saccharide derivative is described in Cao 2〇2/72594, and a saccharide derivative of CMM is described in JP-A 2 〇〇7_84462. In the present invention, the above-mentioned cyclic tetrasaccharide, cyclic pentasaccharide, and the like may be used alone or in combination of two or more. The sepsis prophylactic and therapeutic agent of the present invention The prophylactic and therapeutic agent for sepsis of the present invention can be prepared in various dosage forms containing the above-described effective knife formation. Especially in the critical stage of the treatment of sepsis, in order to obtain sufficient effect and immediate effect, it is desirable to administer an intravenous injection. The injection can be exemplified by a liquid preparation, in particular, a liquid preparation for injection as a suitable example. The aqueous medium in the liquid preparation for injection may, for example, be water or an aqueous medium. As the water, general sterilized water can be used, and sterilized water containing no heat-generating substance is preferable. The medium containing water is a known solvent to be used in a pharmaceutical preparation, and examples thereof include physiological saline, PBS (phosphate buffered saline), and lactic acid mixed Ringer's injection. In the sepsis prophylaxis and therapeutic agent of the present invention, the technique 201018469 == Addition force can be suitably used. Such an application can be exemplified by, for example, glucose, sorbitol, sodium glycol, glycerin, propylene glycol, polyethylene glycol, and the like. : Western buffer, citric acid buffer, citric acid buffer, granule 1 acid buffer, and the like. Examples of the analgesic agent include albumin, a polyhydric alcohol such as monopropyl alcohol, xycaine hydrochloride, benzyl alcohol and the like. In the prevention and treatment of dysfunction of the month, in order to regulate yang, it may also contain

= various genticular agents commonly used in the field of arthritis. The pH adjusting agent may be a phthalic acid or a base. The private property is specifically 5, and the acid may, for example, be ascorbic acid, r, gluconic acid, acetic acid, lactic acid, boric acid, phosphoric acid, sulfuric acid, tartar, or bar acid. The test may, for example, be a hydrogenolysis, a hydroxide, a sodium hydroxide, a barium magnesium oxide, a monoethanolamine, a diethanolamine or a triethylamine. Other pH adjusters may also use amino acids such as glycine, histidine, ε-aminocaproic acid and the like. The liquid preparation for the main shot of this month can be manufactured according to the usual method. For example, the component (hereinafter referred to as 3 knives) contained in the liquid preparation of the fourth (Note) related to the present invention is first dissolved in an aqueous medium. The mixing order of the components is contained, and the components are contained in the same manner. Alternatively, a part of the components may be contained in the aqueous medium, and then the remaining components may be combined to form the rugged (four) system of the present invention. The total concentration of the active ingredient, that is, the total concentration of the cyclic tetrasaccharide, the cyclic pentasaccharide, and the like, is, for example, about 0.1 to 7 〇 W/V% (mass/vol%). Then, the obtained solution is usually subjected to, for example, a film-passing device, and is subjected to a heat sterilization treatment such as a heat sterilization treatment by a sterilization method such as a sterilization method using a 6-pressure steam sterilizer. It is suitable that the solution obtained by such treatment has a pH of about 6 to 8 or so. The obtained liquid preparation is filled in, for example, an infusion bag or an ampoule and sealed. On the other hand, an additive which is usually used may be used as needed, and a solid preparation which is dissolved in an aqueous medium at the time of use, that is, a "solid preparation for dissolution" may be used. The liquid preparation for injection in the above-mentioned solution state is dried by a known drying method such as freeze drying or reduced-pressure drying, and then prepared into a powder or granule to prepare the above-mentioned "solid preparation for dissolution". The solid preparation is dissolved in an infusion solution containing, for example, sterilized water; physiological saline; an electrolyte, a saccharide 'amino acid, a vitamin, a trace element or the like, to form an active ingredient of the present invention, for example, 01 to 70 W/ Available when V% (mass/volume%) or so. The liquid preparation for injection according to the present invention may be one in which the solid preparation for dissolution in use is filled in a chamber of a multi-chamber container, and the other chamber is filled with sterilized water; physiological saline; electrolyte, sugar, amino acid, vitamin, An infusion solution such as a trace element or the like, which is mixed and used in a dissolved form. The administration method of the prophylactic and therapeutic agent for sepsis according to the present invention is not particularly limited, and may be administered by a method corresponding to the dosage form, age, sex, other conditions, degree of disease, and the like. The amount of the drug to be administered varies depending on the patient's symptoms and age, and the amount of the active ingredient per 1 kg of body weight per day is generally about 0.001 to ig, and it is preferably administered in a range of from about 0.1 to about 8.8 g. In the case of a drug administration method such as a liquid preparation for injection, it is administered alone in the vein, intraarterial, intramuscular, intradermal, subcutaneous, intrathoracic, intraperitoneal, or the like. Further, the liquid preparation for injection can be mixed with the infusion solution, and the mixture of the liquid preparation for injection and the infusion solution of the present invention can be specifically administered to the vein. There is no special restriction on the liquid mixture mixed with the liquid preparation for injection, and the round liquid which is available or used in the frost industry. Specific examples of such an infusion include glucose injection, xylitol injection, D-mannitol injection, candied fruit injection, physiological saline, polydextrose 40 injection, polydextrose 70 injection, and amino acid injection. Liquid, Ringer's injection, lactated Ringer's injection - liquid, sugar, electrolyte, amino acid, multivitamin solution, etc. According to the prophylactic and therapeutic agent for sepsis of the present invention, it is possible to prevent and treat sepsis which does not cause side effects such as blood rolling. Further, since the half-life of the sister component is shortened, it is possible to treat the sepsis which develops rapidly, and if necessary, to avoid the exposure to the drug, and to prevent the treatment of the severely ill-conquered disease. C. Mode for Carrying Out the Invention Hereinafter, the present invention will be described in more detail by way of examples and test examples. Example 1 x The cyclic tetrasaccharide CNN with glucose as a constituent sugar (manufactured by Hayashibara Biochemical Research Institute, gas phase _, gasification slant i5g, gasification 13 201018469 and sodium lactate 1.55g dissolved in water for injection) Into 35 〇 mL, water for injection was added to prepare a total amount of 500 mL. The mixture was filtered and sterilized, and each 100 mL was filled in a bag to seal the injection to prepare an injection. The injection was made to have an active ingredient concentration of 10% (W/V). %) The preventive and therapeutic agent for sepsis in Example 1. Example 2 CNN (manufactured by Rinkube Biochemical Research Institute) 丨〇g was dissolved in 100 mL of pBS (phosphate buffered saline). It is dried and dried to form a powder, which is filled in a glass vial per lg, and sealed to prepare an injection for the prevention and treatment of sepsis which is dissolved and used. Example 3 CNN (Invitrogen Institute of Biochemistry) 10) dissolved in 100 mL of water for injection, filtered and sterilized, dried by freeze-drying, and then made into a powder. The physiological saline l〇〇mL was filled in the lower chamber in advance, and the powder was filled in a high pressure according to the usual method. Steam sterilized plastic In the upper chamber of the container, a kit for the prevention and treatment of sepsis was prepared. Example 4 5 g of CNN (manufactured by Hayashibara Biochemical Research Laboratory Co., Ltd.) was dissolved in 5 mL of water for injection, and it was filtered and sterilized. It is dried by lyophilization and then made into a powder. 300 mL of the amino acid infusion is filled in the upper chamber, 600 mL of the sugar electrolyte infusion is filled in the lower chamber, and the powder is filled in a plastic sterilized by autoclaving according to the conventional method. In the chamber of the chamber container, a kit of products for the prevention and treatment of sepsis is prepared. Example 5 5 g of a cyclic tetrasaccharide CMM (manufactured by Linyuan Biotechnology 14 201018469 Chemical Research Institute) containing glucose as a constituent sugar, gasification Calcium strontium, strontium 2 g, potassium chloride 〇. 〇 3 g, gasified sodium strontium. 6 g and sodium lactate 0.3 lg were dissolved in 85 mL of water for injection, and water for injection was added to make a total amount of 100 mL. The mixture was filtered and sterilized to prepare an injection solution. The injection was prepared as a sepsis prophylactic and therapeutic agent of Example 5 in which the concentration of the active ingredient was 5% (W/V%). Example 6 5 g of CMM (manufactured by Ryohara Biochemical Research Laboratory Co., Ltd.) was dissolved in pBS ( Squama buffered saline) in 100 mL. Sterile After filtration, it is dried by lyophilization, and then it is made into a powdery form. It is filled in a glass vial per lg, and sealed, and it is set as an injection for the prevention and treatment of sepsis which is used for dissolution. Example 7 CMM (Shinji, Ltd.) 2 g of the biochemical research institute was dissolved in 100 mL of water for injection, and it was filtered and sterilized, and dried by lyophilization to obtain a powder. The physiological saline was filled in the lower chamber in advance, and the powder was filled in accordance with the usual method. A set of products for preventing and treating sepsis is prepared in the upper chamber of a plastic-made laboratory container which has been subjected to steam sterilization. Example 8 5% of CMM (manufactured by Hayashibara Biochemical Research Laboratory Co., Ltd.) was dissolved in 50 mL of water for injection, sterilized by filtration, and dried by freeze-drying to obtain a powder. 3 mL of the amino acid infusion was filled in the upper chamber in advance, and 600 mL of the sugar electrolyte infusion was filled in the lower chamber, and the powder was filled in a small plastic chamber container which was autoclaved by autoclaving. A kit made into a sepsis prophylaxis and therapeutic agent. Example 9 15 201018469 The cyclic pentasaccharide ICG5 (manufactured by Hayashibara Biochemical Research Institute), which contains glucose as a sugar, lGg' gasification hunger 2g, gasified potassium sputum. G3g, gasified samarium and sodium lactate 0.31 g was dissolved in 7 mL of water for injection, and water for injection was added to make a total amount of 100 mL. The mixture is filtered and sterilized to produce an injection. This injection was prepared as a sepsis prophylactic and therapeutic agent of Example 9 having an active ingredient concentration of 1% by weight (W/V%). Example 10 ICG5 (manufactured by Linyuan Biochemical Research Institute) 3〇g, gasification mother O.Olg, gasification potassium 〇.〇15g, gasified sodium 〇.3g and sodium lactate 〇.155g dissolved in water for injection In 30 mL, 'injection water was added to make a total amount of 5 mL. It is filtered and sterilized to produce an injection. Example 11 25 g of ICG5 (manufactured by Hayashibara Biochemical Research Laboratory Co., Ltd.) was dissolved in 100 mL of water for injection, sterilized by filtration, and dried by lyophilization to obtain a powder. In advance, 100 mL of physiological saline was filled in the lower chamber, and the powder was filled in a set of products of a sepsis prophylaxis and therapeutic agent in an upper chamber of a plastic-filled multi-chamber container which was subjected to a south-pressure steam sterilization treatment. Example 12 5 g of ICG5 (manufactured by Hayashibara Biochemical Research Laboratory Co., Ltd.) was dissolved in 50 mL of water for injection, filtered, and dried by freeze-drying to obtain a powder. 300 mL of the amino acid infusion solution was previously filled in the upper chamber, and 600 mL of the sugar-electrolyte infusion solution was filled in the lower chamber, and the powder was filled in a chamber of a plastic-made double-chamber container which was autoclaved by a conventional method to prepare sepsis. Kits for prophylactic and therapeutic agents. 201018469 Example 13

5 g of CG5 (manufactured by Hayashibara Biochemical Research Laboratory Co., Ltd.) 5 g of CG5 (manufactured by Hayashibara Biochemical Research Laboratory Co., Ltd.) was dissolved in 5 mL of water for injection, filtered, and dried by drying. Made into a powder. 300 mL of the amino acid infusion solution was previously filled in the upper chamber, and the sugar and electrolyte infusion 6 mL was filled in the lower chamber. The powder was filled in a small plastic chamber container which was autoclaved by autoclaving. A kit made into a sepsis prophylaxis and therapeutic agent. Test Example 1 Verification of the septicemia effect of CNN by the LPS model rat Six-week-old SD male rats (purchased from Japan Charles River Co., Ltd.) were designed to have an insulting time of 7 days or more (free intake of standard feed AIN- 93G: Sakamoto Agro-Industrial Co., Ltd.), divided into three groups (n=15), the group of the preventive and therapeutic agents (CNN group), the comparison group, and the control group of the administration example 1. In the CNN group, after a hunger strike for a day and night (after a fasting to the end of the experiment), the injection 1 mL/kg obtained in Example 1 was used as a test solution, and the drug was administered via the tail vein within 1 second of the administration time. In order to induce septic shock immediately afterwards, a physiological saline solution (20 mg/mL) derived from endotoxin five co/, · 0111 : B4 lipopolysaccharide (hereinafter referred to as "LPS") was administered at a dose of 1 mL/kg. The drug was administered intraperitoneally within 1 second. On the other hand, the control group was treated in the same manner as the CNN group except that the injection liquid of the composition of Example 1 containing no CNN as the test solution was administered at a dose of 1 mL/kg. 17 201018469 Chemical research, the group 'heart ring (four) (Linyuan Biological Co., Ltd. (4) sample plot:: dissolved into the same concentration ~ ejaculation as the number of deaths detected every 4 hours after the test == rrLpss drug, observe survival 峨咏Table 1 of each group in the hour group Survival rate at each time after administration of LPS (%) Elapsed time after administration (hours) ----- 4 8 ---- 12 16 CNN group 100.0 100.0 80.0 66.7 Comparison group 100.0 80.0 66.7 60.0 86.7 60.0 ____ 26.7 26.7 20 24 66.7 66.7 53.3 53.3 20.0 20.0

From the above results, it was found that the CNN group' of the sepsis prophylaxis and therapeutic agent of the administration example 1 showed a high survival rate as compared with the comparison group of the administration cyclodextrin. The active ingredient of the sepsis prophylaxis and therapeutic agent of the present invention can be confirmed

CNN has an effect on sepsis and reveals that it can be effectively used from the butterfly stage. Test Example 2 Verification of the septicemia effect of CMM and ICG5 by the LPS model rats The 6-week-old SD male rats (purchased from Japan's gears rjver Co., Ltd.) were designed for 7 days or more of domestication time (free intake of standard feed AIN-93G). In the injection group (CMM group) of the administration example 5, the injection group (ICG5 group) of the administration example 9, and the control group (n=15). 18 201018469 In the CMM group, after a hunger strike for a day and night (after the hunger strike to the end of the experiment), 2 mL/kg of the injection obtained in Example 5 was used as the test solution, and the drug was administered via the tail vein within 10 seconds of the administration time. In order to induce septic shock immediately afterwards, a physiological saline solution (2 〇 mg/mL) derived from endotoxin: B4 lipopolysaccharide (hereinafter referred to as "LpS") was administered at a dose of 1 mL/kg for 10 seconds at the administration time. The drug is administered intraperitoneally in the bell. The ICG5 group was treated in the same manner as the CMM group except that the injection lm?/kg obtained in Example 9 was administered as the test liquid. On the other hand, the administration of the control group was carried out in the same manner as in the CMM group except that the test solution containing the composition of Example 1 was not contained (1 mL/kg of the injection sample of Example 1). For each group, every 4 hours after the administration of LPS was measured. The number of deaths was observed at 24 hours. The survival rate (%) of each group at the time of LPS administration was not as shown in Table 2. Table 2 Survival rate at each time after LPS administration (% Time elapsed after administration (hours) 4 8 12 16 20 24 CMM group 100.0 73.3 66.7 66.7 66.7 66.7 ICG5 group 100.0 100.0 86.7 86.7 86.7 86.7 Control group 93.3 73.3 53.3 46.7 46.7 46.7 From the above results, administration example 5 or implementation In the CMM group and the ICG5 group of the sepsis prophylaxis and therapeutic agent of Example 9, the effect of improving the survival rate was observed in comparison with the control group, thereby confirming the active components CMM and ICG5 of the sepsis prophylaxis and therapeutic agent of the present invention, each of which was septicemia It has a preventive effect and can be effectively used from the initial stage. 19 201018469 Test Example 3 Verification of CNN sepsis treatment effect by LPS model rats SD-age SD male rats of week age (from Japanese charles river strain) After purchasing the domestication time of 7 days or more (free intake of standard feed AIM-93G: Japan Agri-Industrial Co., Ltd.), the sepsis prevention and treatment group (CNN group) and the control group were divided into the administration example ι. Group (n=15) In the CNN group, after a hunger strike for a day and night (after the hunger strike to the end of the experiment), the LPS physiological saline solution (2〇mg/mL) was administered at a dose of 丨mL/kg for 10 seconds at the administration time. The intraperitoneal administration was carried out intraperitoneally. After 2 hours, the injection solution obtained in Example 1 was further used as a test solution, and the drug was administered via the tail vein within 1 second of the administration time. The inflammatory interleukin was additionally measured. It was confirmed that sepsis was caused at the time of administration of the test liquid. On the other hand, except that the injection group containing 1 ml/kg of the composition of the control group containing no c NN was administered as the test liquid, it was treated in the same manner as the cnn group. The number of deaths per 4 hours after administration of LPS was measured in each group, and the survival rate was observed at 24 hours. The survival rate (%) of each group per * hour after administration of LPS is shown in Table 3 below. Table 3 LPS Survival rate at each time after administration (%) Time after administration 4 8 1 2 ---! (hours) 16 20 24 CNN group 93.3 93.3 86.7 40.0 33.3 33.3 Control group 86.7 46.7 26.7 20.0 20.0 20.0 From the above results, it is known that the CNN group and the control group show high survival 20 201018469 : rate. From this, it was confirmed that the active ingredient of the sepsis prophylaxis and therapeutic agent of the present invention CNN has a therapeutic effect after infection on sepsis. Test Example 4 Effect of CNN on Hemolysis of Red Blood Cells (Comparison with Cyclodextrin and Effect of (:]^]^ Concentration) Blood of males and females of 4 to 6 months old golden hamsters Friends: Finished with heparin) 25mL was separated by centrifugation (2〇〇〇rpmx ^ 15min) at room temperature to separate blood cell components and plasma. Then use Pasteur pipette to remove the uppermost part of the blood cell layer (buffy coat: white blood cell layer) To which PBS (0.15 M NaCl + 10 mM linalic acid buffer, pH 7.4) was added, the blood cells were suspended and centrifuged again (2000 rpm x 15 min), and the operation was repeated three times to obtain red 'blood cells. The suspension was suspended in PBS 25 mL. Prepare a 6.07×1010/mL silo-murine suspension. Dissolve 5 mL of a solution with a CNN concentration of 0 mM, 1 mM, 5 mM or 10 mM in PBS, and add 4 mL of PBS to the φ preparation prepared by the above method. The hamster red blood cell suspension was dissolved in lmL and allowed to react at 37 ° C for 30 minutes. Then, the reaction solution after centrifugation was centrifuged, and the supernatant was measured (12,000 rpm x 15 min) to determine the absorbance at 577 nm. The relative value of the blood absorbance at 577 nm is 100, which is used as hemolysis In addition, as a comparison group, instead of CNN, a solution was prepared; S-cyclodextrin was added to a PBS solution of 5 mM or 10 mM instead of CNN, and the absorbance was measured in the same manner as the above method to calculate the hemolysis rate. The absorbance and hemolysis rate (〇/0) of the liquid centrifugation supernatant at 577 nm are shown in Table 4 below. 21 201018469 Table 4 Absorbance at 577 nm (n=l) Hemolysis rate (%): when complete hemolysis is 100 Relative value Δ Abs. at 577nm Hemolysis rate (%) Complete hemolysis 6.357 100 No added sugar 0.041 0.64 CNN ImM 0.005 0.08 5mM 0.011 0.17 10mM 0.033 0.52 β-ring 5mM 3.634 57.2 Dextrin 10mM 6.162 96.9

From the above results, it was found that the case where the hemolysis rate (%: relative value when complete hemolysis is 100) obtained by the absorbance of the reaction supernatant is increased as compared with the case where 10,000-cyclodextrin is added. value. From this, it was found that CNN did not show the effect of strong red blood cell lysis seen in yS-cyclodextrin. C diagram simple description 3

(none) [Explanation of main component symbols] (none) 22

Claims (1)

201018469 VII. Patent application scope: 1. A prophylactic and therapeutic agent for sepsis, which comprises a cyclic tetrasaccharide selected from the group consisting of glucose as a sugar, a cyclic pentasaccharide containing glucose as a sugar, and the like derivatives thereof. At least one component of the composed ethnic group is used as an active ingredient. 2. A prophylactic and therapeutic agent for sepsis, which comprises a compound selected from the group consisting of a ring {-6]-α-D-glucopyranoside-(1 -3)-α-D-glucopyranoside-(1 - A 6)- a -D-° glucopyranoside-(1 - 3)- a -D-° glucopyranoside-(1—}, ring {—·6)-D than glucosamine-(1 — 4) -aD-0 is more than glucosyl-(1 - 6)- a 0 than glucosinolate-(1 4)- α -D-glucopyranoside-(1—}, ring {—6)-α -D-glucopyranoside-(1 -4)- <2 -0-° glucopyranoside-(1 - 4)- a -D-°pyranose-(1 - 4)- a - D-11 is an active ingredient of at least one component of a group consisting of glucopyrano-(1 - 4)-a-D- glucosinolate-(1-}, and derivatives thereof. The prophylactic and therapeutic agent for sepsis according to the first aspect of the invention, which is a liquid preparation for injection or a solid preparation for dissolving in use. 4. The prophylactic and therapeutic agent for disappointing jk as described in claim 3, It is used for intravenous administration. 5. - a cyclic tetrasaccharide selected from the group consisting of glucose as a constituent sugar, and a cyclic pentasaccharide containing glucose as a constituent sugar, and the like. The use of at least one component of the group consisting of the substance is used for the manufacture of a prophylactic and therapeutic agent for sepsis. 6. - selected from the ring {-6)-aD-glucopyranoside-(1 -3) - aD- ° ratio π south glucoside _(1 - 6)- a -D-° pyranose-(1 - 3)- α 23 4 201018469 -D-α glucopyranoside-(I — 6)~α- 〇~. Bi-vine-(1-^4)-α-D-glucopyranoside_(1 glycoside-(1 -4)-aD-glucopyranoside-1 (1~}, 丨---D-1 South Glucoside-(1—4)-a-Dn is more than 糠 糠 糠 4 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) The use of at least one component of the group consisting of -1, glucosinolate, and the like, is a prophylactic and therapeutic agent for the manufacture of sepsis. A method for preventing and treating sepsis, which comprises at least one selected from the group consisting of a cyclic tetrasaccharide comprising glucose as a constituent sugar, a cyclic pentasaccharide containing glucose as a constituent sugar, and derivatives thereof. - The component of the prevention and treatment of ash ash is administered to the human body. 8. A method for preventing and treating sepsis, which comprises containing a ring {—θα -D-glucopyranoside_(1,_α-D_glucopyranoside (Bu 6)- a-D-pyran Grape end (1 - 3) - α _D - glucopyranose - U~}, ring {-6)-a: -D-glucopyranoside _(1 - 4)_a D-glucopyranoside-( 1—6)-aD-glucopyranoside, south glucoside _(1—丨, cyclobu 6)_α _di vine grape _ U~4)-α-D-glucopyranoside—ο — 4) α _D_ glucopyranose bud-(1 - 4)-a-D_» is a group consisting of glucosinolate (1_4)_a D-biting glucoside _(1~}, and its derivatives At least a component of a prophylactic and therapeutic agent for sepsis is administered to a human body. The species is selected from the group consisting of glucose as a cyclic tetrasaccharide constituting a sugar, glucose as a cyclic sugar of a constituent sugar, and the like. At least 24 of the ethnic group 201018469 An ingredient for the prevention and treatment of sepsis. 10·- species selected from the ring {—^ 6)- <2 -D-〇比喃glucose--(1—· 3) - α -D-glucopyranoside-(1 - 6)-a -D-glucopyranose Glycosyl-(1 - 3)-α-D-°pyranoside-(1—}, ring{—6)-α: -D-°pyranoside-(1->4)- a - D-° glucosinolate-(1-6)- a-D-. Glucose __(1 -4)_a_D-α is more than glucosamine-(1-}, ring {-6)--D-glucopyranoside-(1 -4)-〇: -D-pyran Glucoside-(ΙΑ-a-D-°pyranoside-(1->4)- a-D-°pyranoside-(1-^)- ο: -D-nit-glucopyr- (1— } At least one component of the group consisting of 'and its derivatives is used for the prevention and treatment of sepsis. 25 201018469 IV. Designated representative map: (1) The representative representative of the case is: Fig. (none) (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: