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WO2012033261A1 - Pharmaceutical composition for preventing or treating sepsis, containing genipin or derivative thereof - Google Patents

Pharmaceutical composition for preventing or treating sepsis, containing genipin or derivative thereof Download PDF

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Publication number
WO2012033261A1
WO2012033261A1 PCT/KR2010/008866 KR2010008866W WO2012033261A1 WO 2012033261 A1 WO2012033261 A1 WO 2012033261A1 KR 2010008866 W KR2010008866 W KR 2010008866W WO 2012033261 A1 WO2012033261 A1 WO 2012033261A1
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Prior art keywords
sepsis
preventing
pharmaceutical composition
clp
derivative
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PCT/KR2010/008866
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French (fr)
Korean (ko)
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이선미
김태훈
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성균관대학교 산학협력단
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Publication of WO2012033261A1 publication Critical patent/WO2012033261A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating sepsis, including genipin or a derivative thereof.
  • the present invention relates to a food composition for improving sepsis comprising jennypin or a derivative thereof.
  • genipin is a non-sugar portion of the geniposide (geniposide), a natural component of the iridoid glycoside lineage is a component that represents the main pharmacological effect of the gardenia fruit (garia).
  • Geniposide is metabolized to intestinal bacteria by intestinal bacteria in the body, and geniposide is bilirubin, alanine aminotransferase (ALT) and blood in a hepatotoxicity model of mice induced with ⁇ -naphthylisothiocyanate. It has been shown to improve pathological tissue lesions as well as biochemical levels of aspartate aminotransferase (AST). It has also been found that jennypin promotes the secretion of gastric acid and inhibits antioxidant activity and nitric oxide (NO) production. However, no report has been disclosed regarding the prevention or treatment of sepsis with jennypin.
  • sepini from the sepsis model induced by CLP cecal ligation and puncture
  • CLP cecal ligation and puncture
  • One object of the present invention is to provide a pharmaceutical composition for preventing or treating sepsis, which comprises genipine or a derivative thereof as an active ingredient.
  • Still another object of the present invention is to provide a method for preventing or treating sepsis, which comprises administering a composition comprising jennypin or a derivative thereof.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of sepsis, comprising as an active ingredient nippin or a derivative thereof.
  • the term "genipin” in the present invention refers to a component that represents the main pharmacological efficacy of the gardenia fruit (garia) as a non-sugar portion of the geniposide, a natural component of the iridoid glycoside family, It can be represented as.
  • xenicin stimulates the secretion of gastric acid, inhibits antioxidant activity and nitric oxide (NO) production, or improves pathological tissue lesions in hepatotoxicity models
  • NO nitric oxide
  • the mortality is improved when treatment with nippin (see FIG. 1), and also inflammatory cytokines in the blood (TNF- ⁇ , interleukin-1 ⁇ , interleukin- 6, MCP-1 and HMGB-1) was confirmed to decrease the concentration (see Figures 2 to 6), these results demonstrate that the phenine of the present invention can treat sepsis.
  • the term "derived from jennypin” refers to the same activity as jennypin, and include compounds that have a preventive or therapeutic effect of sepsis, including, but not limited to, geniposide (geniposide), genipiodisic acid (genipiodisic acid) Penta-acetyl geniposide; Molecular Pharmacology, 70 (3), 997-1004, 2006, 6a-hydroxygeniposide, 6b-hydroxygeniposide, 6b-dhydroxygeniposide , 6a-methoxygeniposide, 6b-methoxygeniposide, and the like (Journal of Health Science, 52 (6), 743-747, 2006). Preferably it may be geniposide. It is apparent to those skilled in the art that zenithposide is metabolized to jennypin by the intestinal bacteria in the body at the time of ingestion.
  • the term "septicemia” refers to a condition in which a serious inflammatory response occurs in the whole body by infection with a microorganism. Fever symptoms that rise above 38 degrees or hypothermia below 36 degrees, respiratory rate increases above 24 times per minute (empty breathing), heart rate above 90 beats per minute (tachycardia), and increases or significant decreases in white blood cell counts on blood tests If you have more than two symptoms, this is called systemic inflammatory response syndrome (SIRS). This systemic inflammatory response syndrome is called sepsis when it is caused by infection of microorganisms.
  • SIRS systemic inflammatory response syndrome
  • Pathogens in the body's infectious paths are continuously or intermittently entered into the bloodstream and settled in various organ tissues to create lesions and show severe systemic symptoms, and are susceptible to weak, elderly, and weak people.
  • the causative organisms include Staphylococcus, Streptococcus, Escherichia coli, Pseudomonas aeruginosa, Mycobacterium tuberculosis, Pneumococcal bacteria, Fungi, and Anaerobic bacteria. To date, there is no clear treatment for this.
  • the present inventors confirmed that the survival rate of sepsis-induced mice was improved, and the concentration of inflammation-induced cytokines in the blood was suppressed, thereby confirming that nippine or a derivative thereof was useful for the prevention or treatment of sepsis.
  • compositions of the present invention can be used in the form of injections, pills, tablets or capsules commonly used in pharmaceutical preparation.
  • the pharmaceutical compositions according to the invention can be administered via several routes.
  • the route of administration of the pharmaceutical composition may be administered via any general route as long as the drug can reach the target tissue. Specifically, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, nasal administration, pulmonary administration, rectal administration, but is not limited thereto.
  • intraperitoneal administration intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, nasal administration, pulmonary administration, rectal administration, but is not limited thereto.
  • the oral composition since the peptide is digested, it is desirable to formulate the oral composition to coat the active agent or to protect it from degradation in the stomach. It may preferably be administered in the form of an injection.
  • the pharmaceutical composition may be administered by any device in which the active agent may migrate to the target cell.
  • the pharmaceutical composition of the invention can prevent or treat sepsis by inhibiting damage to organs caused by sepsis.
  • the organ is an organ damaged by septicemia, and any organ which can be prevented from being damaged by the composition of the present invention includes, but is not limited to, any one or more organs of the liver, kidney and heart.
  • the long-term damage indicators were analyzed by serum altine (ALT), aspartate aminotransferase (AST), AST (aspartate aminotransferase), LDH (lactate dehydrigenase), BUN (blood urea nitrogen) and creatinine (Creatinine) activity analysis. As a result, it was confirmed that the damage to the liver, kidney and heart was inhibited (see FIGS. 7 to 11).
  • Jenny pin or derivatives thereof of the present invention can perform the prevention or treatment of liver damage through the inhibition of blood concentration increase of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) in hepatocytes.
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • aspartate aminotransferase used in the present invention is also called aspartate aminotransferase, and is a primary enzyme for detecting liver damage. However, when the liver is damaged, the enzyme enters the blood and increases the AST level in the blood.
  • the normal range of AST is 5-40 units per liter of serum.
  • ALT alanine aminotransferase
  • alanine aminotransferase an enzyme that is present in large amounts in liver cells and is an enzyme that is specific for liver disease.
  • the normal range of ALT is 7-56 units per liter of serum. Both enzymes catalyze the chemical reaction in the cell that transfers amino groups from donor molecules to donor molecules, and AST is normally found in a variety of tissues including liver, muscle, heart and brain, but ALT is present in large amounts in hepatocytes. It is a specific indicator of liver status.
  • Jenny pin or derivatives thereof of the present invention can perform the prevention or treatment of kidney damage through the inhibition of the blood concentration increase of BUN or creatinine.
  • Jenny pin or derivatives thereof of the present invention can perform the prevention or treatment of heart damage through the inhibition of the increase in the blood concentration of LDH.
  • composition of the present invention may further comprise a pharmaceutically acceptable carrier, excipient or diluent.
  • the term "pharmaceutically acceptable carrier” refers to a carrier or diluent that does not irritate an organism and does not inhibit the biological activity and properties of the administered compound.
  • Acceptable pharmaceutical carriers in compositions formulated as liquid solutions are sterile and biocompatible, which include saline, sterile water, Ringer's solution, buffered saline, albumin injectable solutions, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary.
  • Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.
  • the pharmaceutical composition of the present invention may be formulated or used in combination with anti-inflammatory agents, antipyretic analgesics, anticoagulants, antibiotics, antibacterial agents and anti-allergic agents.
  • the present invention provides a method for preventing or treating sepsis, which comprises administering nippin or a pharmaceutical composition comprising the same.
  • the present invention provides the use of jennypin or derivatives thereof for the prevention or treatment of sepsis.
  • prevention refers to any action that inhibits or delays the development of cystosis by administration of the pharmaceutical composition of the present invention.
  • treatment refers to any action in which the symptoms of sepsis are improved or beneficially changed by administration of the pharmaceutical composition of the present invention.
  • administration refers to introducing a pharmaceutical composition of the present invention to a patient in any suitable manner, and the route of administration of the composition of the present invention may be various oral or parenteral routes as long as the target tissue can be reached. It can be administered through.
  • subject means an animal including, but not limited to, humans, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, axes or guinea pigs, In one embodiment it refers to a mammal and in another embodiment a human.
  • terapéuticaally effective amount used in combination with an active ingredient in the present invention means an amount of genipidine or a derivative thereof effective for treating or preventing a subject disease.
  • the method of treatment with jennypin of the present invention is the same as described above, the method of treatment of the present invention comprises administering to a subject in need thereof a therapeutically effective amount of nippine or a pharmaceutical composition thereof. . It will be apparent to those skilled in the art that a suitable total daily dose may be determined by the practitioner within the correct medical judgment. It may also be administered once or in divided doses.
  • the specific therapeutically effective amount for a particular patient is determined by the specific composition, including the type and extent of the reaction to be achieved, whether or not other agents are used in some cases, the age, weight, general health of the patient, It is desirable to apply differently depending on various factors and similar factors well known in the medical field, including sex and diet, time of administration, route of administration and rate of composition, duration of treatment, drugs used with or co-specific with the specific composition.
  • Individuals to which the composition of the present invention is administered include, but are not limited to, mammals including humans, for example, cows, pigs, horses, rabbits, mice, and humans.
  • the present invention provides a food composition for improving sepsis, including jennypin or derivatives thereof.
  • Food composition for improving sepsis of the present invention includes the form of pills, powders, granules, acupuncture, tablets, capsules or liquids, and the like to which the composition of the present invention can be added, for example, various foods, beverages , Gums, teas, vitamin complexes, and dietary supplements.
  • Jenny pin of the present invention or a derivative thereof is derived from a natural product, there is little side effect can be used as a food additive.
  • the composition having an anti-septic and therapeutic activity including the nippin or a derivative thereof, or an active ingredient thereof, or a pharmaceutically acceptable salt thereof is included.
  • the food supplement additive may further include food supplement additives, including food supplement additives conventional in the art, such as flavoring agents, flavoring agents, coloring agents, fillers, stabilizers, and the like.
  • natural carbohydrates examples include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. .
  • the food composition for improving sepsis of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors such as flavoring agents, colorants and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof.
  • Alginic acid and salts thereof organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like.
  • Others may contain pulp for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components can be used independently or in combination.
  • Sepsis improved food composition comprising the nippin of the present invention or derivatives thereof may be provided in the form of dietary supplements.
  • the term "health functional food” in the present invention refers to a food prepared and processed by a method of extracting, concentrating, refining, and mixing a specific ingredient as a raw material or contained in a food ingredient for the purpose of health supplement, It refers to foods that are designed and processed to sufficiently exert bioregulatory functions on the living body, such as biological defense, control of biological rhythms, prevention and recovery of diseases by the components, and the health functional foods are for the prevention of diseases and recovery of diseases. It can perform a function related to such.
  • the pharmaceutical composition for the treatment or prevention of sepsis and septic shock which comprises the Jenny pin or a derivative thereof of the present invention as an active ingredient, is effective for treating sepsis and the treatment of patients suffering from a situation where there is a shortage of therapeutic drugs. Will help.
  • the pharmaceutical composition of the present invention is a therapeutic agent based on natural products, it will not only exhibit a wide range of therapeutic actions but also significantly reduce side effects frequently occurring in chemicals. Therefore, the pharmaceutical composition of the present invention can be usefully used as a sepsis treatment or a supplement for improving sepsis.
  • Figure 1 shows the results of observation of the survival rate change according to the administration of nippin (1, 2.5 and 5 mg / kg) in the mouse sepsis model induced by CLP (Cecal ligation and puncture).
  • the survival rate of the mice was observed for 10 days after the administration of jennypin immediately after CLP.
  • nippin has been shown to improve mortality due to CLP-induced sepsis.
  • Figure 2 shows the results of confirming the effect of jennypin on the concentration of serum TNF- ⁇ at 6 hours after CLP in the CLP-induced multibacterial sepsis model.
  • Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ⁇ SEM of 9-11 mice per experimental group. ** Represents a significant difference (P ⁇ 0.01) from the sham group; + CLP Significant difference (P ⁇ 0.05) from the group.
  • FIG. 3 shows the results of confirming the effect of jennypin on the concentration of serum interleukin-1 ⁇ at 6 hours after CLP in the CLP-induced multibacterial sepsis model.
  • Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ⁇ SEM of 9-11 mice per experimental group. ** Represents a significant difference (P ⁇ 0.01) from the Siamese group; ++ CLP Significant difference (P ⁇ 0.01) from the group.
  • FIG. 4 shows the results of confirming the effect of jennypin on the concentration of serum interleukin-6 at 6 hours after CLP in the CLP-induced multibacterial sepsis model.
  • Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ⁇ SEM of 9-11 mice per experimental group. ** Represents a significant difference (P ⁇ 0.01) from the Siamese group; ++ CLP Significant difference (P ⁇ 0.01) from the group.
  • Figure 5 shows the results confirming the effect of jennypin on the concentration of serum MCP-1 at 6 hours after CLP in the CLP-induced multibacterial sepsis model.
  • Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ⁇ SEM of 9-11 mice per experimental group. ** Represents a significant difference (P ⁇ 0.01) from the Siamese group; + CLP Significant difference (P ⁇ 0.05) from the group.
  • Figure 6 shows the results of confirming the effect of jennypin on the concentration of serum HMGB1 24 hours after CLP in the CLP-induced multibacterial sepsis model.
  • Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg.
  • Values represent mean ⁇ SEM of 6 mice per experimental group. ** Represents a significant difference (P ⁇ 0.01) from the Siamese group; + CLP Significant difference (P ⁇ 0.05) from the group.
  • the above shows representative Western blot bands for each group.
  • Figure 7 confirms the effect of jennypin on the concentration of serum ALT at 1, 3, 6, 12, 24 and 48 hours after CLP in the CLP-induced multibacterial sepsis model.
  • Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ⁇ SEM of 6 mice per experimental group. * And ** Represents a significant difference (P ⁇ 0.05, P ⁇ 0.01) from the Siamese group; + And ++ CLP Significant differences (P ⁇ 0.05, P ⁇ 0.01) from the group are shown.
  • Figure 8 confirms the effect of jennypin on the concentration of serum AST at 1, 3, 6, 12, 24 and 48 hours after CLP in the CLP-induced multibacterial sepsis model.
  • Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ⁇ SEM of 6 mice per experimental group. ** Represents a significant difference (P ⁇ 0.01) from the Siamese group; + And ++ CLP Significant differences (P ⁇ 0.05, P ⁇ 0.01) from the group are shown.
  • Figure 9 confirms the effect of jennypin on the concentration of serum BUN at 1, 3, 6, 12, 24 and 48 hours after CLP in the CLP-induced multibacterial sepsis model.
  • Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ⁇ SEM of 6 mice per experimental group. * And ** Represents a significant difference (P ⁇ 0.05, P ⁇ 0.01) from the Siamese group; + CLP Significant difference (P ⁇ 0.05) from the group.
  • Figure 10 confirms the effect of jennypin on serum creatinine concentrations at 1, 3, 6, 12, 24 and 48 hours after CLP in the CLP-induced multibacterial sepsis model.
  • Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ⁇ SEM of 6 mice per experimental group. * And ** Represents a significant difference (P ⁇ 0.05, P ⁇ 0.01) from the Siamese group; ++ CLP Significant difference (P ⁇ 0.01) from the group.
  • Figure 11 confirms the effect of jennypin on the concentration of serum LDH at 1, 3, 6, 12, 24 and 48 hours after CLP in the CLP-induced multibacterial sepsis model.
  • Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ⁇ SEM of 6 mice per experimental group. ** Represents a significant difference (P ⁇ 0.01) from the Siamese group; ++ CLP Significant difference (P ⁇ 0.01) from the group.
  • the pharmaceutical composition of the present invention significantly improved mortality due to sepsis in sepsis model mice induced by cecal ligation and puncture (CLP), a clinical sepsis-like model. It has been shown to improve multiple organdysfunction syndrome (hereinafter referred to as 'MODS') by inhibiting damage to major organs that significantly affect mortality such as the heart. This will be described with reference to specific embodiments and drawings.
  • CLP group is a group of CLP-induced sepsis model mice administered with an injection containing physiological saline instead of jennypin, and sham is a mouse that does not induce sepsis as a control.
  • mice were inhaled anesthesia with ether and then sepsis was induced via CLP according to the method reported in Chaudry et al., Surgery, 85 (2): 205-211, 1979.
  • the end of the cecal valve was ligated with 3.0 silk sutures to prevent intestinal obstruction, and the 20-gauge needle was Two holes in the cecum were used to drain a certain amount of fecal material. 4 ml / 100 g b.
  • wt. saline was injected via subcutaneous injection.
  • Drug administration was performed by dissolving jennypin (1, 2.5 and 5 mg / kg) in physiological saline and then intravenously 0 hours after CLP.
  • a vehicle is a physiological saline injection instead of jennypin.
  • jennypin has an effect of improving mortality due to sepsis induced by CLP (FIG. 1).
  • the anti-inflammatory response of sepsis induction was observed, and the anti-inflammatory effects of nippin administration were confirmed by measuring the concentrations of inflammatory cytokines (TNF- ⁇ , interleukin-1 ⁇ , interleukin-6, and MCP-1).
  • TNF- ⁇ , interleukin-1 ⁇ , interleukin-6, and MCP-1 inflammatory cytokines
  • jennypin inhibits the production of inflammatory cytokines in CLP-induced sepsis, thereby inhibiting the over-inflammatory response in sepsis.
  • Serum was isolated by collecting blood 24 hours after CLP.
  • the concentration of HMGB1 in the isolated serum was measured by Western blot immunoassay. More specifically, the protein quantified in the separated serum was separated by SDS-PAGE, followed by electrophoresis on a polyvinyllidene fluoride (PVDF) membrane (Millipore, USA) using a semi-dry transblot device (Bio-Rad Laboratories, USA).
  • the membrane was washed with TBS / T (Tris-Buffered Saline / Tween 20) and then blocked with TBS / T containing 5% (w / v) skim milk for 1 hour at room temperature.
  • TBS / T Tris-Buffered Saline / Tween 20
  • HMGB-1 primary antibody (1: 1000 dilution, Abcam, USA) at 4 ° C for one day, and then reacted with HRP-horseradish peroxidase-conjugated secondary antibody (ERP) to detect ECL ( iNtRON Biotechnology, Korea) induced color development.
  • ERP HRP-horseradish peroxidase-conjugated secondary antibody
  • Each band was evaluated by ImageQuant TM TL (Amersham Biosciences / GEHealthcare, USA) density measurement.
  • ALT alanine aminotransferase
  • BUN blood urea nitrogen
  • 'LDH' lactate dehydrigenase
  • Injectables were prepared by mixing the above components according to the conventional method for preparing injectables, filling them into brown bottles and sterilizing them.
  • the above ingredients were mixed and refilled to a size of five or five rings using a conventional pill manufacturing method to prepare a pill.
  • the tablets were prepared by mixing the above components and tableting according to a conventional method for preparing tablets.
  • the capsules were prepared by mixing the above components and filling the gelatin capsules according to a conventional method for preparing capsules.
  • Vitamin B2 ... .0.15 mg
  • Vitamin B6 ... ..0.5 mg
  • Vitamin B12 ... .0.2 ⁇ g
  • Nicotinic Acid Amide ... 1.7 mg
  • composition ratio of the above-mentioned vitamin and mineral mixtures is a composition which is a composition suitable for a relatively healthy food in a preferred embodiment, and may be changed arbitrarily.
  • Vitamin E (powder) ......................................... .100 g
  • Vitamin A ... .... 0.2 g
  • Vitamin B1 ... ..0.25 g
  • Vitamin B2 ... ... 0.3 g
  • the prepared solution was filtered and placed in a sterile 2 L container.
  • the container was sealed and sterilized and stored in a refrigerated state before being used for preparing a healthy beverage composition.
  • the pharmaceutical composition comprising the active ingredient of Jenny pin or derivatives of the present invention is a therapeutic agent based on natural products, it not only has a wide range of therapeutic actions but also significantly reduces side effects frequently seen in chemicals, thereby treating sepsis and septic shock or It can be usefully used for prevention.

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Abstract

The present invention relates to a pharmaceutical composition for preventing or treating sepsis, containing genipin or a derivative thereof. While being far short of an effective method or medicine for treating sepsis, the pharmaceutical composition of the present invention can be useful for preventing or treating sepsis or septic shock. In addition, the pharmaceutical composition of the present invention is a therapeutic agent based on natural products, and thus it is possible to reduce side effects which frequently appear using chemical materials in addition to having a wide range of therapeutic effects.

Description

제니핀 또는 이의 유도체를 포함하는 패혈증 예방 또는 치료용 약학적 조성물Pharmaceutical composition for the prevention or treatment of sepsis, including jennypin or derivatives thereof
본 발명은 제니핀(genipin) 또는 이의 유도체를 포함하는 패혈증 예방 또는 치료용 약학적 조성물에 관한 것이다. 또한 본 발명은 제니핀 또는 이의 유도체를 포함하는 패혈증 개선용 식품 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating sepsis, including genipin or a derivative thereof. In another aspect, the present invention relates to a food composition for improving sepsis comprising jennypin or a derivative thereof.
패혈증은 전 세계적으로 중환자실 이환율 및 사망률의 주요한 원인으로 알려져 있고 미국의 경우 해마다 750,000명의 패혈증 환자가 발생하며 국내에서도 정확한 통계는 없지만 매우 높은 발병률을 나타내고 있다. 치사률 또한 40% 정도로 매우 높은 편이나, FDA 승인을 받은 치료제는 한가지뿐이며 아직까지 효과적인 치료법이나 치료약물은 매우 부족한 실정이다. 따라서 패혈증 치료약물의 개발은 임상적으로 상당한 의의를 가지며 치료제의 시장성도 매우 크다고 할 수 있다. 이를 바탕으로 국내외적으로 현재 패혈증 치료제를 개발하기 위한 연구가 활발히 이루어지고 있다. 패혈증의 진행과정에서 나타나는 임상적 특성의 하나가 체내 염증계가 과활성화되는 것이므로, 패혈증의 치료를 위하여 이러한 염증반응을 수반하거나 촉진하는 TNF-α, 인터루킨-1, 인터루킨-6 및 HMGB1 등의 염증 유발 매개체를 억제하려는 수많은 시도가 있어왔으나 환자의 생존율을 개선하지 못하였다. Sepsis is known worldwide as a leading cause of morbidity and mortality in the ICU. In the United States, 750,000 sepsis patients occur each year. The mortality rate is as high as 40%, but there is only one FDA-approved treatment and there are still very few effective treatments or medications. Therefore, the development of sepsis therapeutic drug has significant clinical significance and the market of the therapeutic agent is very large. Based on this, there are active researches to develop sepsis treatments at home and abroad. One of the clinical features in the progression of sepsis is the over-activation of the inflammatory system in the body, which induces inflammation such as TNF-α, interleukin-1, interleukin-6, and HMGB1 that accompany or promote this inflammatory response for the treatment of sepsis. Numerous attempts have been made to inhibit the mediator but have not improved patient survival.
한편, 제니핀(genipin)은 이리도이드 배당체 계통의 천연 성분인 제니포사이드(geniposide)의 비당부분으로서 치자나무 과실(치자)의 주요 약리 효능을 나타내는 성분이다. 제니포사이드는 체내 장내 세균에 의해 제니핀으로 대사되며, 제니포사이드는 α-나프틸아이소티오시아네이트(α-naphthylisothiocyanate)로 유도한 생쥐의 간독성 모델에서 혈중 빌리루빈(bilirubin), ALT(alanine aminotransferase)및 AST(aspartate aminotransferase) 등의 생화학적 수치뿐만 아니라 병리학적 조직 병변을 개선시킴이 확인되었다. 또한 제니핀은 위산의 분비를 촉진하고 항산화작용 및 산화질소(NO) 생성을 저해하는 것이 밝혀졌다. 그러나, 제니핀을 이용한 패혈증의 예방 또는 치료에 대해서는 어떠한 보고도 개시된 바 없다. On the other hand, genipin (genipin) is a non-sugar portion of the geniposide (geniposide), a natural component of the iridoid glycoside lineage is a component that represents the main pharmacological effect of the gardenia fruit (garia). Geniposide is metabolized to intestinal bacteria by intestinal bacteria in the body, and geniposide is bilirubin, alanine aminotransferase (ALT) and blood in a hepatotoxicity model of mice induced with α-naphthylisothiocyanate. It has been shown to improve pathological tissue lesions as well as biochemical levels of aspartate aminotransferase (AST). It has also been found that jennypin promotes the secretion of gastric acid and inhibits antioxidant activity and nitric oxide (NO) production. However, no report has been disclosed regarding the prevention or treatment of sepsis with jennypin.
이와 같은 배경하에, 본 발명자들은 천연물 유래의 패혈증 치료용도의 물질을 찾기 위해 예의 노력한 결과, 제니핀 또는 이의 유도체가 임상적 패혈증 유사모델인 CLP(cecal ligation and puncture)로 유도된 패혈증 모델에서 패혈증으로 인한 사망률을 현저히 개선시키며, 패혈증 초기 및 후기 염증 유발 사이토카인의 농도를 저하시킴으로써 패혈증시 과염증 반응을 억제하는 효과가 있음을 확인하고 본 발명을 완성하였다. Against this background, the present inventors have diligently tried to find a substance for the treatment of sepsis derived from natural products, and as a result, sepini from the sepsis model induced by CLP (cecal ligation and puncture), which is a clinical sepsis-like model, may be used as a result of Significantly improve the mortality caused by, and confirmed that there is an effect of inhibiting the over-inflammatory response in sepsis by lowering the concentration of early and late inflammation-induced cytokines sepsis and completed the present invention.
본 발명의 하나의 목적은 제니핀(genipin) 또는 이의 유도체를 유효성분으로 포함하는 패혈증 예방 또는 치료용 약학적 조성물을 제공하는 것이다. One object of the present invention is to provide a pharmaceutical composition for preventing or treating sepsis, which comprises genipine or a derivative thereof as an active ingredient.
본 발명의 또 다른 목적은 제니핀 또는 이의 유도체를 포함하는 조성물을 투여하는 단계를 포함하는 패혈증 예방 또는 치료하는 방법을 제공하는 것이다.Still another object of the present invention is to provide a method for preventing or treating sepsis, which comprises administering a composition comprising jennypin or a derivative thereof.
본 발명의 다른 목적은 제니핀 또는 이의 유도체를 포함하는 패혈증 개선용 식품 조성물을 제공하는 것이다.It is another object of the present invention to provide a food composition for improving sepsis, which comprises nippin or a derivative thereof.
상기 목적을 달성하기 위한 하나의 양태로서, 본 발명은 제니핀 또는 이의 유도체를 유효성분으로 포함하는 패혈증 예방 또는 치료용 약학적 조성물을 제공한다. As one embodiment for achieving the above object, the present invention provides a pharmaceutical composition for the prevention or treatment of sepsis, comprising as an active ingredient nippin or a derivative thereof.
본 발명에서의 용어 "제니핀(genipin)" 이란 이리도이드 배당체 계통의 천연 성분인 제니포사이드(geniposide)의 비당부분으로서 치자나무 과실(치자)의 주요 약리 효능을 나타내는 성분을 의미하며, 하기 화학식 1로 나타낼 수 있다. 제니핀은 위산의 분비를 촉진하고 항산화작용 및 산화질소(NO) 생성 저해작용 또는 간독성 모델에서 병리학적 조직 병변을 개선시킴이 보고된 바가 있으나, 본 발명에서 밝힌 패혈증 치료용도는 본 발명자에 의해 최초로 규명되었다.The term "genipin" in the present invention refers to a component that represents the main pharmacological efficacy of the gardenia fruit (garia) as a non-sugar portion of the geniposide, a natural component of the iridoid glycoside family, It can be represented as. Although it has been reported that xenicin stimulates the secretion of gastric acid, inhibits antioxidant activity and nitric oxide (NO) production, or improves pathological tissue lesions in hepatotoxicity models, the use of sepsis in the present invention was first described by the present inventors. It was identified.
화학식 1
Figure PCTKR2010008866-appb-C000001
 Formula 1
Figure PCTKR2010008866-appb-C000001
본 발명의 일 구현예에 따르면 CLP로 패혈증 유도 후, 제니핀을 처리하였을때 사망률이 개선되는 것을 확인하였으며(도 1 참고), 또한 혈중내의 염증성 사이토카인(TNF-α, 인터루킨-1β, 인터루킨-6, MCP-1 및 HMGB-1)의 농도가 감소하는 것을 확인하였으며(도 2 내지 6 참고), 이와 같은 결과는 본 발명의 제니핀이 패혈증을 치료할 수 있음을 입증하는 것이다.According to one embodiment of the present invention, after the induction of sepsis with CLP, it was confirmed that the mortality is improved when treatment with nippin (see FIG. 1), and also inflammatory cytokines in the blood (TNF-α, interleukin-1β, interleukin- 6, MCP-1 and HMGB-1) was confirmed to decrease the concentration (see Figures 2 to 6), these results demonstrate that the phenine of the present invention can treat sepsis.
본 발명에서의 용어 "제니핀의 유도체"란 제니핀과 동일한 활성을 나타내며, 패혈증 예방 또는 치료효과가 있는 화합물은 제한없이 포함되나, 그 예로 제니포사이드(geniposide), 제니피오다이식산(genipiodisic acid), 펜타-아세틸제니포사이드(penta-acetyl geniposide; Molecular Pharmacology, 70(3), 997-1004, 2006), 6a-하이드록시제니포사이드(6a-hydroxygeniposide), 6b-하이드록시제니포사이드(6b-dhydroxygeniposide), 6a-메톡시제니포사이드(6a-methoxygeniposide), 6b-메톡시제니포사이드(6b-methoxygeniposide) 등이 포함된다(Journal of Health Science, 52(6), 743-747, 2006). 바람직하게는 제니포사이드 일 수 있다. 제니포사이드는 섭취시 체내 장내 세균에 의해서 제니핀으로 대사되므로, 제니핀과 동일한 효과가 있음은 당업자에게 자명할 것이다. In the present invention, the term "derived from jennypin" refers to the same activity as jennypin, and include compounds that have a preventive or therapeutic effect of sepsis, including, but not limited to, geniposide (geniposide), genipiodisic acid (genipiodisic acid) Penta-acetyl geniposide; Molecular Pharmacology, 70 (3), 997-1004, 2006, 6a-hydroxygeniposide, 6b-hydroxygeniposide, 6b-dhydroxygeniposide , 6a-methoxygeniposide, 6b-methoxygeniposide, and the like (Journal of Health Science, 52 (6), 743-747, 2006). Preferably it may be geniposide. It is apparent to those skilled in the art that zenithposide is metabolized to jennypin by the intestinal bacteria in the body at the time of ingestion.
본 발명에서의 용어 "패혈증"이란 미생물에 감염되어 전신에 심각한 염증 반응이 나타나는 상태를 말한다. 체온이 38도 이상으로 올라가는 발열 증상 혹은 36도 이하로 내려가는 저체온증, 호흡수가 분당 24회 이상으로 증가(빈호흡), 분당 90회 이상의 심박수(빈맥), 혈액 검사상 백혈구 수의 증가 혹은 현저한 감소 중 두 가지 이상의 증상을 보이는 경우, 이를 전신성 염증 반응 증후군(systemic inflammatory response syndrome; SIRS)이라고 부른다. 이러한 전신성 염증 반응 증후군이 미생물의 감염에 의한 것일 때 패혈증이라고 한다. 신체의 감염병소에서 병원균이 지속적 또는 단속적으로 혈류에 들어와 여러 장기조직에 정착하여 병소를 만들고 심한 전신증상을 보이는 것으로, 유약자, 고령자, 쇠약자가 걸리기 쉽다. 원인균으로는 포도상구균, 연쇄상구균, 대장균, 녹농균, 결핵균, 폐렴간균, 진균, 혐기성균군 등이 있다. 현재까지 이에 대한 명확한 치료제가 없는 실정이다. As used herein, the term "septicemia" refers to a condition in which a serious inflammatory response occurs in the whole body by infection with a microorganism. Fever symptoms that rise above 38 degrees or hypothermia below 36 degrees, respiratory rate increases above 24 times per minute (empty breathing), heart rate above 90 beats per minute (tachycardia), and increases or significant decreases in white blood cell counts on blood tests If you have more than two symptoms, this is called systemic inflammatory response syndrome (SIRS). This systemic inflammatory response syndrome is called sepsis when it is caused by infection of microorganisms. Pathogens in the body's infectious paths are continuously or intermittently entered into the bloodstream and settled in various organ tissues to create lesions and show severe systemic symptoms, and are susceptible to weak, elderly, and weak people. The causative organisms include Staphylococcus, Streptococcus, Escherichia coli, Pseudomonas aeruginosa, Mycobacterium tuberculosis, Pneumococcal bacteria, Fungi, and Anaerobic bacteria. To date, there is no clear treatment for this.
본 발명자들은 패혈증이 유도된 생쥐의 생존률이 개선되고, 혈중의 염증 유발 사이토카인의 농도가 억제되는 것을 확인하여 제니핀 또는 이의 유도체가 패혈증의 예방 또는 치료에 유용하다는 것을 확인하였다.The present inventors confirmed that the survival rate of sepsis-induced mice was improved, and the concentration of inflammation-induced cytokines in the blood was suppressed, thereby confirming that nippine or a derivative thereof was useful for the prevention or treatment of sepsis.
본 발명의 조성물은 약학적 제조에 통상적으로 사용되는 주사제, 환제, 정제 또는 캡슐제의 형태로 사용될 수 있다.The compositions of the present invention can be used in the form of injections, pills, tablets or capsules commonly used in pharmaceutical preparation.
또한, 본 발명에 따른 약학적 조성물은 여러 경로를 통해 투여될 수 있다. 상기 약학조성물의 투여 경로는 약물이 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 구체적으로, 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비내 투여, 폐내 투여, 직장내 투여 될 수 있으나, 이에 제한되지는 않는다. 그러나 경구 투여시, 펩타이드는 소화가 되기 때문에 경구용 조성물은 활성 약제를 코팅하거나 위에서의 분해로부터 보호되도록 제형화하는 것이 바람직하다. 바람직하게는 주사제 형태로 투여될 수 있다. 또한, 제약 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다.In addition, the pharmaceutical compositions according to the invention can be administered via several routes. The route of administration of the pharmaceutical composition may be administered via any general route as long as the drug can reach the target tissue. Specifically, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, nasal administration, pulmonary administration, rectal administration, but is not limited thereto. However, upon oral administration, since the peptide is digested, it is desirable to formulate the oral composition to coat the active agent or to protect it from degradation in the stomach. It may preferably be administered in the form of an injection. In addition, the pharmaceutical composition may be administered by any device in which the active agent may migrate to the target cell.
바람직하게 발명의 약학적 조성물은 패혈증으로 인한 장기의 손상을 억제하는 것에 의하여 패혈증을 예방 또는 치료할 수 있다. 상기 장기는 패혈증으로 인하여 손상된 장기로 본 발명의 상기 조성물에 의해 장기 손상이 억제될 수 있는 장기는 제한없이 포함되나, 바람직하게는 간장, 신장 및 심장 중 어느 하나 이상의 장기일 수 있다. 본 발명의 일 구현예에 따르면, 혈청 내 ALT(alanine aminotransferase), AST(aspartate aminotransferase), LDH(lactate dehydrigenase), BUN(blood urea nitrogen) 및 크레아티닌(Creatinine) 활성분석을 통한 장기 손상지표를 분석한 결과, 간장, 신장 및 심장의 손상을 억제하는 것을 확인하였다(도 7 내지 11 참고).Preferably the pharmaceutical composition of the invention can prevent or treat sepsis by inhibiting damage to organs caused by sepsis. The organ is an organ damaged by septicemia, and any organ which can be prevented from being damaged by the composition of the present invention includes, but is not limited to, any one or more organs of the liver, kidney and heart. According to an embodiment of the present invention, the long-term damage indicators were analyzed by serum altine (ALT), aspartate aminotransferase (AST), AST (aspartate aminotransferase), LDH (lactate dehydrigenase), BUN (blood urea nitrogen) and creatinine (Creatinine) activity analysis. As a result, it was confirmed that the damage to the liver, kidney and heart was inhibited (see FIGS. 7 to 11).
본 발명의 제니핀 또는 이의 유도체는 간세포에서 AST(aspartate aminotransferase) 또는 ALT(alanine aminotransferase)의 혈중 농도 증가의 억제를 통해 간 손상의 예방 또는 치료를 수행할 수 있다.Jenny pin or derivatives thereof of the present invention can perform the prevention or treatment of liver damage through the inhibition of blood concentration increase of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) in hepatocytes.
본 발명에서 사용되는 용어 "AST(aspartate aminotransferase)"란 아스파테이트 아미노전이효소라고도 하며, 간손상을 알아내는 일차적인 효소로 정상 상태에서는 AST가 간세포 내에 존재한다. 그러나 간이 손상을 받게 되면 상기 효소는 혈중으로 유입되어 혈액 내 AST 수치가 높아진다. AST의 정상 범위는 혈청 1 리터당 5~40 단위이다. The term "AST (aspartate aminotransferase)" used in the present invention is also called aspartate aminotransferase, and is a primary enzyme for detecting liver damage. However, when the liver is damaged, the enzyme enters the blood and increases the AST level in the blood. The normal range of AST is 5-40 units per liter of serum.
본 발명에서 사용되는 용어 "ALT(alanine aminotransferase)"란 알라닌 아미노전이효소라고도 하며, 간세포에 다량 존재하는 효소로 간질환에 특이적인 지표가 되는 효소이다. ALT의 정상범위는 혈청 1 리터당 7~56 단위이다. 상기 두 효소 모두 아미노 그룹을 공여 분자에서 수여분자로 전이시키는 세포 내의 화학반응을 촉매하며, AST의 경우 정상적으로 간, 근육, 심장, 뇌를 포함한 다양한 조직에서 발견되나, ALT의 경우 간세포에 다량 존재하므로 간 상태를 나타내는 특이적인 지표가 된다.As used herein, the term "ALT (alanine aminotransferase)" is also referred to as alanine aminotransferase, an enzyme that is present in large amounts in liver cells and is an enzyme that is specific for liver disease. The normal range of ALT is 7-56 units per liter of serum. Both enzymes catalyze the chemical reaction in the cell that transfers amino groups from donor molecules to donor molecules, and AST is normally found in a variety of tissues including liver, muscle, heart and brain, but ALT is present in large amounts in hepatocytes. It is a specific indicator of liver status.
본 발명의 제니핀 또는 이의 유도체는 BUN 또는 크레아티닌의 혈중 농도 증가의 억제를 통해 신장 손상의 예방 또는 치료를 수행할 수 있다.Jenny pin or derivatives thereof of the present invention can perform the prevention or treatment of kidney damage through the inhibition of the blood concentration increase of BUN or creatinine.
본 발명의 제니핀 또는 이의 유도체는 LDH의 혈중 농도 증가의 억제를 통해 심장 손상의 예방 또는 치료를 수행할 수 있다.Jenny pin or derivatives thereof of the present invention can perform the prevention or treatment of heart damage through the inhibition of the increase in the blood concentration of LDH.
바람직하게 본 발명의 약학적 조성물은 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 추가로 포함할 수 있다.Preferably the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, excipient or diluent.
본 발명에서 용어, "약학적으로 허용가능한 담체"란 생물체를 자극하지 않고 투여 화합물의 생물학적 활성 및 특성을 저해하지 않는 담체 또는 희석제를 말한다. 액상 용액으로 제제화되는 조성물에 있어서 허용되는 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다.As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not irritate an organism and does not inhibit the biological activity and properties of the administered compound. Acceptable pharmaceutical carriers in compositions formulated as liquid solutions are sterile and biocompatible, which include saline, sterile water, Ringer's solution, buffered saline, albumin injectable solutions, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary. Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.
바람직하게, 본 발명의 약학적 조성물은 항염증제, 해열진통제, 혈액응고억제제, 항생제, 항균제 및 항알러지제 등과 함께 제제화하거나 병용하여 사용할 수 있다.Preferably, the pharmaceutical composition of the present invention may be formulated or used in combination with anti-inflammatory agents, antipyretic analgesics, anticoagulants, antibiotics, antibacterial agents and anti-allergic agents.
다른 하나의 양태로서, 본 발명은 제니핀 또는 이를 포함하는 약학적 조성물을 투여하는 단계를 포함하는 패혈증의 예방 또는 치료 방법을 제공한다. 또한, 본 발명은 제니핀 또는 이의 유도체를 패혈증의 예방 또는 치료에 사용하는 용도를 제공한다.In another aspect, the present invention provides a method for preventing or treating sepsis, which comprises administering nippin or a pharmaceutical composition comprising the same. In addition, the present invention provides the use of jennypin or derivatives thereof for the prevention or treatment of sepsis.
본 발명에서 용어, "예방"은 본 발명의 약학적 조성물의 투여로 패형증의 발병을 억제 또는 지연시키는 모든 행위를 말한다. 본 발명에서 용어, "치료"는 본 발명의 약학적 조성물의 투여로 패혈증의 증세가 호전되거나 이롭게 변경되는 모든 행위를 말한다. 본 발명에서 용어, "투여"는 어떠한 적절한 방법으로 환자에게 본 발명의 약제학적 조성물을 도입하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있다. As used herein, the term "prevention" refers to any action that inhibits or delays the development of cystosis by administration of the pharmaceutical composition of the present invention. As used herein, the term "treatment" refers to any action in which the symptoms of sepsis are improved or beneficially changed by administration of the pharmaceutical composition of the present invention. As used herein, the term "administration" refers to introducing a pharmaceutical composition of the present invention to a patient in any suitable manner, and the route of administration of the composition of the present invention may be various oral or parenteral routes as long as the target tissue can be reached. It can be administered through.
본 발명에서 "대상"은 인간, 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 또끼 또는 기니아 피그를 포함하나 이에 한정되지 아니하는 동물을 의미하고, 일 실시예에서는 포유류를, 또 다른 실시예에서는 인간을 의미한다. As used herein, "subject" means an animal including, but not limited to, humans, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, axes or guinea pigs, In one embodiment it refers to a mammal and in another embodiment a human.
본 발명에서 유효성분과 결합하여 사용된 "치료학적으로 유효한 양"이란 용어는 대상 질환을 치료 또는 예방하는데 유효한 제니피딘 또는 그의 유도체의 양을 의미한다.The term "therapeutically effective amount" used in combination with an active ingredient in the present invention means an amount of genipidine or a derivative thereof effective for treating or preventing a subject disease.
본 발명의 제니핀을 이용한 치료 방법은 상기에서 설명하는 바와 동일하며, 본 발명의 치료방법은 치료적으로 유효한 양의 제니핀 또는 이의 약학적 조성물을 이를 필요로 하는 대상에게 투여하는 단계를 포함한다. 적합한 총 1일 사용량은 올바른 의학적 판단범위 내에서 처치의에 의해 결정될 수 있다는 것은 당업자에게 자명한 일이다. 또한, 1회 또는 수회로 나누어 투여할 수 있다. 그러나 본 발명의 목적상, 특정 환자에 대한 구체적인 치료적 유효량은 달성하고자 하는 반응의 종류와 정도, 경우에 따라 다른 제제가 사용되는지의 여부를 비롯한 구체적 조성물, 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 구체적 조성물과 함께 사용되거나 동시 사용되는 약물을 비롯한 다양한 인자와 의약 분야에 잘 알려진 유사 인자에 따라 다르게 적용하는 것이 바람직하다. 본 발명의 상기 조성물을 투여하는 개체는 인간을 포함한 포유동물을 제한없이 포함하나, 그 예로 소, 돼지, 말, 토끼, 쥐, 인간 일 수 있다.The method of treatment with jennypin of the present invention is the same as described above, the method of treatment of the present invention comprises administering to a subject in need thereof a therapeutically effective amount of nippine or a pharmaceutical composition thereof. . It will be apparent to those skilled in the art that a suitable total daily dose may be determined by the practitioner within the correct medical judgment. It may also be administered once or in divided doses. However, for the purposes of the present invention, the specific therapeutically effective amount for a particular patient is determined by the specific composition, including the type and extent of the reaction to be achieved, whether or not other agents are used in some cases, the age, weight, general health of the patient, It is desirable to apply differently depending on various factors and similar factors well known in the medical field, including sex and diet, time of administration, route of administration and rate of composition, duration of treatment, drugs used with or co-specific with the specific composition. Individuals to which the composition of the present invention is administered include, but are not limited to, mammals including humans, for example, cows, pigs, horses, rabbits, mice, and humans.
다른 하나의 양태로서, 본 발명은 제니핀 또는 이의 유도체를 포함하는 패혈증 개선용 식품 조성물을 제공한다. As another aspect, the present invention provides a food composition for improving sepsis, including jennypin or derivatives thereof.
본 발명의 패혈증 개선용 식품 조성물은 환제, 분말, 과립, 침제, 정제, 캡슐 또는 액제 등의 형태를 포함하며, 본 발명의 조성물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있다. 본 발명의 제니핀 또는 이의 유도체는 천연물 유래로서, 부작용이 적어 식품첨가물로 이용될 수 있다.Food composition for improving sepsis of the present invention includes the form of pills, powders, granules, acupuncture, tablets, capsules or liquids, and the like to which the composition of the present invention can be added, for example, various foods, beverages , Gums, teas, vitamin complexes, and dietary supplements. Jenny pin of the present invention or a derivative thereof is derived from a natural product, there is little side effect can be used as a food additive.
본 발명의 패혈증 개선용 식품 조성물에서 포함할 수 있는 필수 성분으로 상기 제니핀 또는 이의 유도체를 포함하는 패혈증 예방 및 치료 활성을 갖는 조성물 또는 그의 유효 성분, 또는 그의 약제학적으로 허용 가능한 염을 함유하는 외에는 다른 성분에는 특별히 제한이 없으며 통상의 식품과 같이 여러가지 생약추출물, 식품 보조 첨가제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 또한, 상기 언급한 바와 같이 식품보조첨가제를 추가로 첨가할 수도 있는바 식품보조첨가제는 당업계에 통상적인 식품보조첨가제, 예를 들어 향미제, 풍미제, 착색제, 충진제, 안정화제 등을 포함한다.As an essential ingredient that may be included in the food composition for improving sepsis, the composition having an anti-septic and therapeutic activity including the nippin or a derivative thereof, or an active ingredient thereof, or a pharmaceutically acceptable salt thereof, is included. There is no restriction | limiting in particular in another component, Like conventional food, it can contain various herbal extract, food supplement additive, or natural carbohydrate, etc. as an additional component. In addition, as mentioned above, the food supplement additive may further include food supplement additives, including food supplement additives conventional in the art, such as flavoring agents, flavoring agents, coloring agents, fillers, stabilizers, and the like. .
상기 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 Ａ, 글리시르히진 등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다.Examples of such natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. .
상기 외에 본 발명의 패혈증 개선용 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 천연 과일쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. In addition to the above, the food composition for improving sepsis of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors such as flavoring agents, colorants and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof. , Alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like. Others may contain pulp for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components can be used independently or in combination.
본 발명의 제니핀 또는 이의 유도체를 포함하는 패혈증 개선용 식품 조성물은 건강기능식품의 형태로 제공될 수 있다. 본 발명에서의 용어 "건강기능식품"이란, 건강보조의 목적으로 특정성분을 원료로 하거나 식품 원료에 들어있는 특정성분을 추출, 농축, 정제, 혼합 등의 방법으로 제조, 가공한 식품을 말하며, 상기 성분에 의해 생체방어, 생체리듬의 조절, 질병의 방지와 회복 등 생체조절기능을 생체에 대하여 충분히 발휘할 수 있도록 설계되고 가공된 식품을 말하는 것으로서, 상기 건강기능식품은 질병의 예방 및 질병의 회복 등과 관련된 기능을 수행할 수 있다.Sepsis improved food composition comprising the nippin of the present invention or derivatives thereof may be provided in the form of dietary supplements. The term "health functional food" in the present invention refers to a food prepared and processed by a method of extracting, concentrating, refining, and mixing a specific ingredient as a raw material or contained in a food ingredient for the purpose of health supplement, It refers to foods that are designed and processed to sufficiently exert bioregulatory functions on the living body, such as biological defense, control of biological rhythms, prevention and recovery of diseases by the components, and the health functional foods are for the prevention of diseases and recovery of diseases. It can perform a function related to such.
상기한 바와 같이 본 발명의 제니핀 또는 이의 유도체를 유효성분으로 포함하는 패혈증 및 패혈증성 쇼크의 치료 또는 예방용 약학적 조성물은 패혈증에 대한 효과적인 치료법이나 치료약물이 턱없이 부족한 상황에서 발병 환자들의 치료에 도움이 될 것이다. 또한 본 발명의 약학적 조성물은 천연물을 소재로 한 치료제이므로 폭넓은 치료작용을 나타낼 뿐만 아니라 화학물질에서 빈번히 나타나는 부작용도 현저히 감소시킬 것이다. 따라서 본 발명의 약학적 조성물은 패혈증 치료제 또는 패혈증 개선용 건강보조식품으로 유용하게 사용될 수 있다.As described above, the pharmaceutical composition for the treatment or prevention of sepsis and septic shock, which comprises the Jenny pin or a derivative thereof of the present invention as an active ingredient, is effective for treating sepsis and the treatment of patients suffering from a situation where there is a shortage of therapeutic drugs. Will help. In addition, since the pharmaceutical composition of the present invention is a therapeutic agent based on natural products, it will not only exhibit a wide range of therapeutic actions but also significantly reduce side effects frequently occurring in chemicals. Therefore, the pharmaceutical composition of the present invention can be usefully used as a sepsis treatment or a supplement for improving sepsis.
도 1은 CLP(Cecal ligation and puncture)로 유도된 생쥐 패혈증 모델에서 제니핀(1, 2.5 및 5 mg/kg) 정맥투여에 따른 생존율 변화를 관찰한 결과를 나타낸 것이다. CLP 후 즉시 제니핀을 투여한 후 10일 동안 생쥐의 생존율을 관찰한 것이다. CLP 직후 제니핀을 투여한 결과 제니핀은 CLP로 유도된 패혈증으로 인한 사망률을 개선시키는 작용을 나타내었다. Figure 1 shows the results of observation of the survival rate change according to the administration of nippin (1, 2.5 and 5 mg / kg) in the mouse sepsis model induced by CLP (Cecal ligation and puncture). The survival rate of the mice was observed for 10 days after the administration of jennypin immediately after CLP. As a result of the administration of nippin immediately after CLP, nippin has been shown to improve mortality due to CLP-induced sepsis.
도 2는 CLP-유도 다세균성 패혈증 모델에서 CLP 후 6시간째에 혈청 TNF-α의 농도에 대한 제니핀의 영향을 확인한 결과를 나타낸 것이다. 제니핀은 2.5 mg/kg의 용량으로 CLP 후 즉시 정맥투여하였다. 수치는 실험 그룹당 마우스 9-11마리의 평균±SEM을 나타낸다. **는 샴(sham) 그룹과 유의적인 차이(P<0.01)를 나타낸다; +는 CLP 그룹과 유의적인 차이(P<0.05)를 나타낸다. Figure 2 shows the results of confirming the effect of jennypin on the concentration of serum TNF-α at 6 hours after CLP in the CLP-induced multibacterial sepsis model. Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ± SEM of 9-11 mice per experimental group.**Represents a significant difference (P <0.01) from the sham group;+CLP Significant difference (P <0.05) from the group.
도 3은 CLP-유도 다세균성 패혈증 모델에서 CLP 후 6시간째에 혈청 인터루킨-1β의 농도에 대한 제니핀의 영향을 확인한 결과를 나타낸 것이다. 제니핀은 2.5 mg/kg의 용량으로 CLP 후 즉시 정맥 투여하였다. 수치는 실험 그룹당 마우스 9-11마리의 평균±SEM을 나타낸다. **는 샴 그룹과 유의적인 차이(P<0.01)를 나타내고; ++는 CLP 그룹과 유의적인 차이(P<0.01)를 나타낸다. FIG. 3 shows the results of confirming the effect of jennypin on the concentration of serum interleukin-1β at 6 hours after CLP in the CLP-induced multibacterial sepsis model. Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ± SEM of 9-11 mice per experimental group.**Represents a significant difference (P <0.01) from the Siamese group;++CLP Significant difference (P <0.01) from the group.
도 4는 CLP-유도 다세균성 패혈증 모델에서 CLP 후 6시간째에 혈청 인터루킨-6의 농도에 대한 제니핀의 영향을 확인한 결과를 나타낸 것이다. 제니핀은 2.5 mg/kg의 용량으로 CLP 후 즉시 정맥투여하였다. 수치는 실험 그룹당 마우스 9-11마리의 평균±SEM을 나타낸다. **는 샴 그룹과 유의적인 차이(P<0.01)를 나타내고; ++는 CLP 그룹과 유의적인 차이(P<0.01)를 나타낸다. FIG. 4 shows the results of confirming the effect of jennypin on the concentration of serum interleukin-6 at 6 hours after CLP in the CLP-induced multibacterial sepsis model. Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ± SEM of 9-11 mice per experimental group.**Represents a significant difference (P <0.01) from the Siamese group;++CLP Significant difference (P <0.01) from the group.
도 5는 CLP-유도 다세균성 패혈증 모델에서 CLP 후 6시간째에 혈청 MCP-1의 농도에 대한 제니핀의 영향을 확인한 결과를 나타낸 것이다. 제니핀은 2.5 mg/kg의 용량으로 CLP 후 즉시 정맥 투여하였다. 수치는 실험 그룹당 마우스 9-11마리의 평균±SEM을 나타낸다. **는 샴 그룹과 유의적인 차이(P<0.01)를 나타내고; +는 CLP 그룹과 유의적인 차이(P<0.05)를 나타낸다. Figure 5 shows the results confirming the effect of jennypin on the concentration of serum MCP-1 at 6 hours after CLP in the CLP-induced multibacterial sepsis model. Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ± SEM of 9-11 mice per experimental group.**Represents a significant difference (P <0.01) from the Siamese group;+CLP Significant difference (P <0.05) from the group.
도 6는 CLP-유도 다세균성 패혈증 모델에서 CLP 후 24시간째에 혈청 HMGB1의 농도에 대한 제니핀의 영향을 확인한 결과를 나타낸 것이다. 제니핀은 2.5 mg/kg의 용량으로 CLP 후 즉시 정맥 투여하였다. 수치는 실험 그룹당 마우스 6마리의 평균±SEM을 나타낸다. **는 샴 그룹과 유의적인 차이(P<0.01)를 나타내고; +는 CLP 그룹과 유의적인 차이(P<0.05)를 나타낸다. 위는 각 그룹의 대표적인 웨스턴 블롯 밴드를 나타내었다.Figure 6 shows the results of confirming the effect of jennypin on the concentration of serum HMGB1 24 hours after CLP in the CLP-induced multibacterial sepsis model. Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ± SEM of 6 mice per experimental group.**Represents a significant difference (P <0.01) from the Siamese group;+CLP Significant difference (P <0.05) from the group. The above shows representative Western blot bands for each group.
도 7은 CLP-유도 다세균성 패혈증 모델에서 CLP 후 1, 3, 6, 12, 24 및 48시간째에 혈청 ALT의 농도에 대한 제니핀의 영향을 확인한 것이다. 제니핀은 2.5 mg/kg의 용량으로 CLP 후 즉시 정맥 투여하였다. 수치는 실험 그룹당 마우스 6마리의 평균±SEM을 나타낸다. * 및 **는 샴 그룹과 유의적인 차이(P<0.05, P<0.01)를 나타내고; + 및 ++는 CLP 그룹과 유의적인 차이(P<0.05, P<0.01)를 나타낸다. Figure 7 confirms the effect of jennypin on the concentration of serum ALT at 1, 3, 6, 12, 24 and 48 hours after CLP in the CLP-induced multibacterial sepsis model. Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ± SEM of 6 mice per experimental group.* And**Represents a significant difference (P <0.05, P <0.01) from the Siamese group;+ And++CLP Significant differences (P <0.05, P <0.01) from the group are shown.
도 8은 CLP-유도 다세균성 패혈증 모델에서 CLP 후 1, 3, 6, 12, 24 및 48시간째에 혈청 AST의 농도에 대한 제니핀의 영향을 확인한 것이다. 제니핀은 2.5 mg/kg의 용량으로 CLP 후 즉시 정맥 투여하였다. 수치는 실험 그룹당 마우스 6마리의 평균±SEM을 나타낸다. **는 샴 그룹과 유의적인 차이(P<0.01)를 나타내고; + 및 ++는 CLP 그룹과 유의적인 차이(P<0.05, P<0.01)를 나타낸다. Figure 8 confirms the effect of jennypin on the concentration of serum AST at 1, 3, 6, 12, 24 and 48 hours after CLP in the CLP-induced multibacterial sepsis model. Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ± SEM of 6 mice per experimental group.**Represents a significant difference (P <0.01) from the Siamese group;+And++CLP Significant differences (P <0.05, P <0.01) from the group are shown.
도 9는 CLP-유도 다세균성 패혈증 모델에서 CLP 후 1, 3, 6, 12, 24 및 48시간째에 혈청 BUN의 농도에 대한 제니핀의 영향을 확인한 것이다. 제니핀은 2.5 mg/kg의 용량으로 CLP 후 즉시 정맥 투여하였다. 수치는 실험 그룹당 마우스 6마리의 평균±SEM을 나타낸다. * 및 **는 샴 그룹과 유의적인 차이(P<0.05, P<0.01)를 나타내고; +는 CLP 그룹과 유의적인 차이(P<0.05)를 나타낸다. Figure 9 confirms the effect of jennypin on the concentration of serum BUN at 1, 3, 6, 12, 24 and 48 hours after CLP in the CLP-induced multibacterial sepsis model. Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ± SEM of 6 mice per experimental group.*And**Represents a significant difference (P <0.05, P <0.01) from the Siamese group;+CLP Significant difference (P <0.05) from the group.
도 10은 CLP-유도 다세균성 패혈증 모델에서 CLP 후 1, 3, 6, 12, 24 및 48시간째에 혈청 크레아티닌의 농도에 대한 제니핀의 영향을 확인한 것이다. 제니핀은 2.5 mg/kg의 용량으로 CLP 후 즉시 정맥 투여하였다. 수치는 실험 그룹당 마우스 6마리의 평균±SEM을 나타낸다. * 및 **는 샴 그룹과 유의적인 차이(P<0.05, P<0.01)를 나타내고; ++는 CLP 그룹과 유의적인 차이(P<0.01)를 나타낸다. Figure 10 confirms the effect of jennypin on serum creatinine concentrations at 1, 3, 6, 12, 24 and 48 hours after CLP in the CLP-induced multibacterial sepsis model. Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ± SEM of 6 mice per experimental group.*And**Represents a significant difference (P <0.05, P <0.01) from the Siamese group;++CLP Significant difference (P <0.01) from the group.
도 11은 CLP-유도 다세균성 패혈증 모델에서 CLP 후 1, 3, 6, 12, 24 및 48시간째에 혈청 LDH의 농도에 대한 제니핀의 영향을 확인한 것이다. 제니핀은 2.5 mg/kg의 용량으로 CLP 후 즉시 정맥 투여하였다. 수치는 실험 그룹당 마우스 6마리의 평균±SEM을 나타낸다. **는 샴 그룹과 유의적인 차이(P<0.01)를 나타내고; ++는 CLP 그룹과 유의적인 차이(P<0.01)를 나타낸다.Figure 11 confirms the effect of jennypin on the concentration of serum LDH at 1, 3, 6, 12, 24 and 48 hours after CLP in the CLP-induced multibacterial sepsis model. Zenipine was administered intravenously immediately after CLP at a dose of 2.5 mg / kg. Values represent mean ± SEM of 6 mice per experimental group.**Represents a significant difference (P <0.01) from the Siamese group;++CLP Significant difference (P <0.01) from the group.
이하, 본 발명을 구체적으로 설명하기 위해 실시예 및 제조예를 들어 상세하게 설명하기로 한다. 그러나 본 발명에 따른 실시예 및 제조예 들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 아래에서 상술하는 실시예 및 제조예들에 한정되는 것으로 해석되어서는 안 된다. 본 발명의 실시예 및 제조예들은 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해서 제공되는 것이다.Hereinafter, the present invention will be described in detail with reference to Examples and Manufacturing Examples. However, embodiments and preparations according to the present invention can be modified in many different forms, and the scope of the present invention should not be construed as being limited to the embodiments and preparations described in detail below. Examples and preparations of the present invention are provided to more fully explain the present invention to those skilled in the art.
본 발명의 약학적 조성물은 임상적 패혈증 유사모델인 맹장 결찰 및 천공(cecal ligation and puncture, 이하 'CLP'라 함)으로 유도된 패혈증 모델 생쥐에서 패혈증으로 인한 사망률을 현저히 개선시켰으며 간장, 신장 및 심장 등 사망률에 크게 영향을 주는 주요 장기의 손상을 억제하여 다장기기능부전증후군(multiple organdysfunction syndrome, 이하 'MODS'라 함)을 개선함이 확인되었다. 이를 구체적인 실시예와 도면을 참조하여 설명한다. 이하 설명 및 도 1 내지 도 11에서 CLP군은 제니핀 대신 생리 식염수를 포함시킨 주사제를 투여한 CLP로 유도된 패혈증 모델 생쥐군이고, 샴(sham)은 대조군으로 패혈증을 유도하지 않은 생쥐이다.The pharmaceutical composition of the present invention significantly improved mortality due to sepsis in sepsis model mice induced by cecal ligation and puncture (CLP), a clinical sepsis-like model. It has been shown to improve multiple organdysfunction syndrome (hereinafter referred to as 'MODS') by inhibiting damage to major organs that significantly affect mortality such as the heart. This will be described with reference to specific embodiments and drawings. In the following description and in FIGS. 1 to 11, the CLP group is a group of CLP-induced sepsis model mice administered with an injection containing physiological saline instead of jennypin, and sham is a mouse that does not induce sepsis as a control.
실시예 1. 제니핀의 패혈증에 대한 생존율 평가분석Example 1. Evaluation of survival rate for sepsis of jennypin
1-1.1-1. CLP(cecal ligation and puncture)로 패혈증 유도Induce sepsis with cecal ligation and puncture (CLP)
생쥐를 에테르로 흡입 마취시킨 후 문헌[Chaudry 등, Surgery, 85(2): 205-211, 1979]에 보고된 방법에 따라 CLP를 통해 패혈증을 유발시켰다. 즉, 복강 정중부를 약 15 mm 절개한 후 맹장(cecum)을 외부로 노출시킨 후, 장폐색(intestinal obstruction)이 일어나지 않도록 회맹장판(cecal valve)의 말단을 3.0 실크 봉합선으로 결찰하고 20-게이지 바늘을 이용하여 맹장에 두 개의 구멍을 만들어 일정량의 분변(fecal material)을 유출시켰다. 분변을 포함하여 맹장을 다시 복강 내에 넣고 봉합한 후 탈수화가 일어나지 않게 하기 위하여 4 ml/100 g b. wt.의 생리식염수를 피하주사를 통해 주입하였다.Mice were inhaled anesthesia with ether and then sepsis was induced via CLP according to the method reported in Chaudry et al., Surgery, 85 (2): 205-211, 1979. In other words, about 15 mm of the abdominal cavity was incised and the cecum was exposed to the outside, and the end of the cecal valve was ligated with 3.0 silk sutures to prevent intestinal obstruction, and the 20-gauge needle was Two holes in the cecum were used to drain a certain amount of fecal material. 4 ml / 100 g b. To prevent dehydration after suture of the cecum, including feces, back into the abdominal cavity and sutured. wt. saline was injected via subcutaneous injection.
1-2. 약물 투여방법1-2. Drug Administration
약물 투여는 제니핀(1, 2.5 및 5 mg/kg)을 생리식염수에 용해시킨 후, CLP 후 0시간째에 정맥 주사하였다. Drug administration was performed by dissolving jennypin (1, 2.5 and 5 mg / kg) in physiological saline and then intravenously 0 hours after CLP.
1-3. 생존율 관찰1-3. Survival rate
CLP 후 0시간째에 약물을 투여한 후 24시간째부터 10일째까지 24시간 간격으로(1, 2, 3, 4, 5, 6, 7, 8, 9 및 10일) 하루 한번 사망여부를 확인하여 생존율을 관찰하였다. 비히클(vehicle)은 제니핀 대신 생리식염수만을 주사한 것이다.Confirmation of death once a day at 24 hour intervals (1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 days) from 24 hours to 10 days after administration of drug at 0 hours after CLP The survival rate was observed. A vehicle is a physiological saline injection instead of jennypin.
그 결과, 제니핀은 CLP로 유도된 패혈증으로 인한 사망률을 개선시키는 작용을 나타내는 것을 확인하였다(도 1).As a result, it was confirmed that jennypin has an effect of improving mortality due to sepsis induced by CLP (FIG. 1).
실시예 2. 패혈증에 대한 제니핀의 항염증 효능평가Example 2 Evaluation of the Anti-Inflammatory Effect of Jennypin on Sepsis
2-1. 혈중 염증성 사이토카인 농도분석2-1. Blood Inflammatory Cytokine Concentration Analysis
패혈증 유도시 나타나는 과염증 반응을 관찰하고 제니핀 투여에 따른 항염증 효과를 염증 유발 사이토카인(TNF-α, 인터루킨-1β, 인터루킨-6 및 MCP-1)의 농도 측정을 통하여 확인하였다. 즉, CLP 후 6시간째에 혈액을 채취하여 혈청을 분리하여 분리한 혈청에서 TNF-α, 인터루킨-1β, 인터루킨-6 및 MCP-1 농도를 ELISA 어세이 키트(BD Biosciences, USA)를 사용하여 측정하였다. The anti-inflammatory response of sepsis induction was observed, and the anti-inflammatory effects of nippin administration were confirmed by measuring the concentrations of inflammatory cytokines (TNF-α, interleukin-1β, interleukin-6, and MCP-1). In other words, blood collected at 6 hours after CLP, serum was isolated, and the concentrations of TNF-α, interleukin-1β, interleukin-6, and MCP-1 in serum were determined using an ELISA assay kit (BD Biosciences, USA). Measured.
그 결과, CLP로 유도된 패혈증을 가진 생쥐의 혈청에서 제니핀의 투여 후 TNF-α, 인터루킨-1β, 인터루킨-6 및 MCP-1 농도가 감소하는 것을 확인하였다(도 2 내지 5). 따라서 제니핀은 CLP로 유도된 패혈증에서 염증유발 사이토카인의 생성을 억제하여 패혈증시 과염증반응을 억제하는 것을 알 수 있다.As a result, it was confirmed that the concentration of TNF-α, interleukin-1β, interleukin-6 and MCP-1 decreased after administration of jennypin in the serum of mice with sepsis induced by CLP (Figs. 2 to 5). Therefore, it can be seen that jennypin inhibits the production of inflammatory cytokines in CLP-induced sepsis, thereby inhibiting the over-inflammatory response in sepsis.
2-2. 혈중 HMGB-1 농도 분석2-2. Blood HMGB-1 Concentration Analysis
CLP 후 24시간째에 혈액을 채취하여 혈청을 분리하였다. 분리한 혈청에서 HMGB1의 농도를 웨스턴 블럿 면역분석법으로 측정하였다. 보다 상세하게는 분리한 혈청에서 정량한 단백질을 SDS-PAGE로 분리한 후 세미-드라이 트랜스 블랏 장치(Bio-Rad Laboratories, USA)를 이용하여 PVDF(Polyvinyllidene fluoride) 멤브레인(Millipore, USA)에 전기영동하고 멤브레인을 TBS/T(Tris-Buffered Saline/Tween 20)로 세척한 후 5%(w/v) 탈지우유(skim milk)를 넣은 TBS/T로 상온에서 1시간 동안 블로킹하였다. 블로킹한 후 HMGB-1 1차 항체(1:1000 희석, Abcam, USA)와 4℃에서 하룻동안 인큐베이션한 후, HRP-이차항체(HRP:horseradish peroxidase-conjugated secondary antibody)에 반응시켜 ECL 검출 방법(iNtRON Biotechnology,Korea)을 통해 발색을 유도하였다. 각각의 밴드는 ImageQuantTMTL(AmershamBiosciences/GEHealthcare, USA) 밀도측정법으로 평가하였다. Serum was isolated by collecting blood 24 hours after CLP. The concentration of HMGB1 in the isolated serum was measured by Western blot immunoassay. More specifically, the protein quantified in the separated serum was separated by SDS-PAGE, followed by electrophoresis on a polyvinyllidene fluoride (PVDF) membrane (Millipore, USA) using a semi-dry transblot device (Bio-Rad Laboratories, USA). The membrane was washed with TBS / T (Tris-Buffered Saline / Tween 20) and then blocked with TBS / T containing 5% (w / v) skim milk for 1 hour at room temperature. After blocking, the cells were incubated with HMGB-1 primary antibody (1: 1000 dilution, Abcam, USA) at 4 ° C for one day, and then reacted with HRP-horseradish peroxidase-conjugated secondary antibody (ERP) to detect ECL ( iNtRON Biotechnology, Korea) induced color development. Each band was evaluated by ImageQuant ™ TL (Amersham Biosciences / GEHealthcare, USA) density measurement.
그 결과, CLP로 유도된 패혈증을 가진 생쥐의 혈청에서 제니핀의 투여 후 HMGB-1의 농도가 감소하는 것을 확인하였다. 따라서 제니핀은 CLP로 유도된 패혈증에서 염증유발 사이토카인의 생성을 억제하여 패혈증시 과염증반응을 억제하는 것을 알 수 있다(도 6). 이와 같은 결과는 본 발명의 제니핀이 패혈증을 치료 또는 예방할 수 있음을 시사하는 것이다.As a result, it was confirmed that the concentration of HMGB-1 decreased after the administration of jennypin in the serum of mice with CLP-induced sepsis. Therefore, it can be seen that jennypin suppresses the production of inflammatory cytokines in CLP-induced sepsis, thereby suppressing the over-inflammatory response in sepsis (FIG. 6). These results suggest that the present invention can treat or prevent sepsis.
2-3. 혈청 내 ALT, AST, LDH, BUN 및 크레아티닌 활성분석을 통한 장기손상지표 분석2-3. Analysis of long-term damage index through analysis of serum ALT, AST, LDH, BUN and creatinine activity
CLP 후 조제 용매인 생리식염수 또는 제니핀(2.5 mg/kg)을 투여하였다. 투여 후, 1, 3, 6, 12, 24 및 48시간째에서 혈액을 채취하여 혈청을 분리하여 분리한 혈청에서 알라닌 아미노트랜스퍼레이즈(alanine aminotransferase, 이하 'ALT'라고 함) 및 아스파테이드 아미노트랜스퍼레이즈(aspartate aminotransferase, 이하 'AST'라 함)를 측정하여 간장기능의 손상 정도를 평가하였고, 혈액 내 요소 질소(blood urea nitrogen, 이하 'BUN'이라고 함) 및 크레아티닌 농도를 측정하여 신장기능의 손상 정도를 관찰하였으며, 락테이트 디하이드로게네이즈(lactate dehydrigenase, 이하 'LDH'라 함)를 측정하여 심장기능의 손상 정도를 평가하였다(Life Science, 79(21): 2010-2016, 2006). After CLP, physiological saline or nippin (2.5 mg / kg) was administered as a preparation solvent. Blood was taken at 1, 3, 6, 12, 24 and 48 hours after administration, and serum isolated and separated from alanine aminotransferase (ALT) and aspartate aminotransfer. Hepatic function was assessed by measuring aspartate aminotransferase (hereinafter referred to as AST), and kidney function damage was measured by measuring blood urea nitrogen (BUN) and creatinine concentrations. The extent of heart failure was assessed by measuring lactate dehydrigenase (hereinafter referred to as 'LDH') (Life Science, 79 (21): 2010-2016, 2006).
그 결과, CLP로 유도된 패혈증을 가진 생쥐의 혈청에서 제니핀의 투여 후 ALT, AST, BUN, 크레아티닌 및 LDH 농도가 감소하는 것을 확인하였다(도 7 내지 11). 이와 같은 결과는 제니핀이 CLP로 유도된 패혈증에서 혈중 ALT, AST, BUN, 크레아티닌 및 LDH 농도 증가의 억제를 통해 간장, 신장 및 심장 기능의 손상을 억제할 수 있음을 시사하는 것이며, 이에 의해 패혈증을 예방 또는 치료할 수 있음을 뒷받침하는 것이다. As a result, it was confirmed that the concentrations of ALT, AST, BUN, creatinine and LDH decreased after administration of jennypin in the serum of mice with CLP-induced sepsis (FIGS. 7 to 11). These findings suggest that phenine can inhibit impairment of liver, kidney and heart function by inhibiting elevated levels of ALT, AST, BUN, creatinine and LDH in blood in CLP-induced sepsis. It is to support the prevention or treatment.
제조예 1. 주사제의 제조Preparation Example 1 Preparation of Injection
제니핀 또는 그의 유도체 .....................................10 ㎎Jenny pin or derivatives thereof ........................................ 10 mg
주사용 증류수 ................................................ 적량Distilled water for injection ... Appropriate amount
주사용 증류수를 가하여 전체 부피를 25 ㎖로 맞추었다. 통상의 주사제의 제조방법에 따라 상기 성분들을 혼합한 다음, 갈색병에 충전하고 멸균시켜 주사제를 제조하였다.Distilled water for injection was added to adjust the total volume to 25 ml. Injectables were prepared by mixing the above components according to the conventional method for preparing injectables, filling them into brown bottles and sterilizing them.
제조예 2. 환제의 제조Preparation Example 2 Preparation of Pill
제니핀 또는 그의 유도체 .....................................10 ㎎Jenny pin or derivatives thereof ........................................ 10 mg
옥수수 전분 ............................................... 100 ㎎Corn Starch ........................... 100 Mg
결합제 ...................................................... 적량Binder ... ..... appropriate
상기의 성분들을 혼합하고, 통상의 환제 제조방법으로 오자대 혹은 대환의 크기로 제환하여 환제를 제조하였다.The above ingredients were mixed and refilled to a size of five or five rings using a conventional pill manufacturing method to prepare a pill.
제조예 3. 정제의 제조Preparation Example 3 Preparation of Tablet
제니핀 또는 그의 유도체 .....................................10 ㎎Jenny pin or derivatives thereof ........................................ 10 mg
유당 ...................................................... 100 ㎎Lactose ... ..... 100 mg
전분 ...................................................... 100 ㎎Starch ..................... ..... 100 mg
스테아린산 마그네슘 ........................................ 적량Magnesium Stearate ...............
상기의 성분들을 혼합하고 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.The tablets were prepared by mixing the above components and tableting according to a conventional method for preparing tablets.
제조예 4. 캡슐제의 제조Preparation Example 4 Preparation of Capsule
제니핀 또는 그의 유도체 .....................................10 ㎎Jenny pin or derivatives thereof ........................................ 10 mg
유당 ........................................................ 50 ㎎Lactose ... ....... 50 mg
전분 ........................................................ 50 ㎎Starch ..................... ....... 50 mg
탈크 ......................................................... 2 ㎎Talc ........................ ........ 2 mg
스테아린산 마그네슘 .......................................... 적량Magnesium Stearate .........................
상기의 성분들을 혼합하고 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.The capsules were prepared by mixing the above components and filling the gelatin capsules according to a conventional method for preparing capsules.
제제예 5: 건강식품의 제조Formulation Example 5 Preparation of Health Food
제니핀 또는 그의 유도체 .....................................10 ㎎Jenny pin or derivatives thereof ........................................ 10 mg
비타민 혼합물 ................................................적량Vitamin Blend ... Quantity
비타민 A 아세테이트 .........................................70 ㎍Vitamin A Acetate ......................... 70 μg
비타민 E ...................................................1.0 ㎎Vitamin E ... ... 1.0 mg
비타민 B1 .................................................0.13 ㎎Vitamin B1 ... .0.13 mg
비타민 B2 .................................................0.15 ㎎Vitamin B2 ... .0.15 mg
비타민 B6 ..................................................0.5 ㎎Vitamin B6 ... ..0.5 mg
비타민 B12 .................................................0.2 ㎍Vitamin B12 ... .0.2 μg
비타민 C ....................................................10 ㎎Vitamin C ... .... 10 mg
비오틴 ......................................................10 ㎍Biotin ... ..... 10 ㎍
니코틴산아미드 .............................................1.7 ㎎Nicotinic Acid Amide ... 1.7 mg
엽산 ........................................................50 ㎍Folic Acid ... ....... 50 μg
판토텐산 칼슘 ..............................................0.5 ㎎Calcium Pantothenate ......................................... 0.5 mg
무기질 혼합물 ................................................적량Mineral Mixture ... Quantity
황산제1철 .................................................1.75 ㎎Ferrous Sulfate ................................. ... 1.75 mg
산화아연 ..................................................0.82 ㎎Zinc Oxide ... ..0.82 mg
탄산마그네슘 ..............................................25.3 ㎎Magnesium Carbonate ......................................... 25.3 mg
제1인산칼륨 .................................................15 ㎎Potassium monophosphate ......................................... ... 15 mg
제2인산칼슘 .................................................55 ㎎Dibasic Calcium Phosphate ......................................... ... 55 mg
구연산칼륨 ..................................................90 ㎎Potassium Citrate ... ..90 mg
탄산칼슘 ...................................................100 ㎎Calcium Carbonate ... ... 100 mg
염화마그네슘 ..............................................24.8 ㎎Magnesium Chloride ......................................... 24.8 mg
통상의 건강식품 제조방법에 따라 상기의 성분들을 혼합하여 과립을 제조한 후, 이를 통상의 방법에 따라 건강식품 조성물의 제조에 사용할 수 있다.After preparing the granules by mixing the above components according to a conventional health food production method, it can be used for the preparation of a health food composition according to a conventional method.
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분들을 바람직한 실시예로 혼합 조성한 것으로, 그 배합비를 임의로 변경 실시하여도 무방하다. The composition ratio of the above-mentioned vitamin and mineral mixtures is a composition which is a composition suitable for a relatively healthy food in a preferred embodiment, and may be changed arbitrarily.
제제예 6: 건강음료의 제조Formulation Example 6 Preparation of Health Beverage
제니핀 또는 그의 유도체 .....................................10 ㎎Jenny pin or derivatives thereof ........................................ 10 mg
비타민 C .....................................................15 gVitamin C ... ..... 15 g
비타민 E(분말) ..............................................100 gVitamin E (powder) ......................................... .100 g
젖산철 ....................................................19.75 gIron Lactate ... .... 19.75 g
산화아연 ....................................................3.5 gZinc Oxide ... .... 3.5 g
니코틴산아미드 ..............................................3.5 gNicotinic Acid Amide ......................................... 3.5 g
비타민 A ....................................................0.2 gVitamin A ... .... 0.2 g
비타민 B1 ..................................................0.25 gVitamin B1 ... ..0.25 g
비타민 B2 ...................................................0.3 gVitamin B2 ... ... 0.3 g
물 ...........................................................정량Water ... ..........dose
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합하고 약 1시간 동안 85℃에서 교반 가열한 후, 제조된 용액을 여과하여 멸균된 2 ℓ 용기에 담았다. 이 용기를 밀봉 멸균하여 냉장 보관한 후 건강음료 조성물의 제조에 사용하였다.After mixing the above components and stirring and heating at 85 ℃ for about 1 hour according to the conventional healthy beverage preparation method, the prepared solution was filtered and placed in a sterile 2 L container. The container was sealed and sterilized and stored in a refrigerated state before being used for preparing a healthy beverage composition.
본 발명의 제니핀 또는 이의 유도체를 유효성분으로 하는 약학적 조성물은 천연물을 소재로 한 치료제이므로 폭넓은 치료작용을 가질 뿐만 아니라 화학물질에서 빈번히 나타나는 부작용도 현저히 감소되어 패혈증 및 패혈증성 쇼크의 치료 또는 예방에 유용하게 사용될 수 있다.Since the pharmaceutical composition comprising the active ingredient of Jenny pin or derivatives of the present invention is a therapeutic agent based on natural products, it not only has a wide range of therapeutic actions but also significantly reduces side effects frequently seen in chemicals, thereby treating sepsis and septic shock or It can be usefully used for prevention.

Claims (13)

  1. 제니핀(genipin) 또는 이의 유도체를 포함하는 패혈증 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating sepsis, including genipin or a derivative thereof.
  2. 제1항에 있어서, 상기 유도체가 제니포사이드(geniposide), 제니피오다이식 산(genipiodisic acid), 펜타-아세틸 제니포사이드(penta-acetyl geniposide), 6a-하이드록시제니포사이드(6a-hydroxygeniposide), 6b-하이드록시제니포사이드(6b-dhydroxygeniposide), 6a-메톡시제니포사이드(6a-methoxygeniposide) 및 6b-메톡시제니포사이드(6b-methoxygeniposide)로 이루어진 군으로부터 선택되는 것인 패혈증 예방 또는 치료용 약학적 조성물.The method of claim 1, wherein the derivative is geniposide, genipiodisic acid, penta-acetyl geniposide, 6a-hydroxygeniposide, 6b Pharmaceutical composition for preventing or treating sepsis, which is selected from the group consisting of 6b-dhydroxygeniposide, 6a-methoxygeniposide and 6b-methoxygeniposide. .
  3. 제1항에 있어서, 패혈증으로 인한 장기의 손상을 억제하는 것인 패혈증 예방 또는 치료용 약학적 조성물.The pharmaceutical composition for preventing or treating sepsis according to claim 1, which inhibits organ damage due to sepsis.
  4. 제3항에 있어서, 장기가 간장, 신장 및 심장 중 어느 하나 이상의 장기인 것인 패혈증 예방 또는 치료용 약학적 조성물.The pharmaceutical composition for preventing or treating sepsis according to claim 3, wherein the organ is any one or more organs of liver, kidney and heart.
  5. 제1항 내지 제4항 중 어느 한 항에 있어서, 약학적으로 허용가능한 담체, 부형제 또는 희석제를 추가로 포함하는 것인 패혈증 예방 또는 치료용 약학적 조성물.The pharmaceutical composition for preventing or treating sepsis according to any one of claims 1 to 4, further comprising a pharmaceutically acceptable carrier, excipient or diluent.
  6. 제1항 내지 제4항 중 어느 한 항에 있어서, 항염증제, 해열진통제, 혈액응고억제제, 항생제, 항균제 및 항알러지제로 이루어진 군으로부터 선택되는 약제와 함께 제제화하거나 병용하여 사용되는 것인 패혈증 예방 또는 치료용 약학적 조성물.The method for preventing or treating sepsis according to any one of claims 1 to 4, which is formulated or used in combination with an agent selected from the group consisting of anti-inflammatory agents, antipyretic analgesics, anticoagulants, antibiotics, antibacterial agents and anti-allergic agents. Pharmaceutical composition for.
  7. 제니핀 또는 이의 유도체를 포함하는 패혈증 개선용 식품 조성물.Food composition for improving sepsis comprising jennypin or derivatives thereof.
  8. 제7항에 있어서, 상기 유도체가 제니포사이드(geniposide), 제니피오다이식 산(genipiodisic acid), 펜타-아세틸 제니포사이드(penta-acetyl geniposide), 6a-하이드록시제니포사이드(6a-hydroxygeniposide), 6b-하이드록시제니포사이드(6b-dhydroxygeniposide), 6a-메톡시제니포사이드(6a-methoxygeniposide) 및 6b-메톡시제니포사이드(6b-methoxygeniposide)로 이루어진 군으로부터 선택되는 것인 패혈증 개선용 식품 조성물.The method of claim 7, wherein the derivative is geniposide, genipiodisic acid, penta-acetyl geniposide, 6a-hydroxygeniposide, 6b -A food composition for improving sepsis, which is selected from the group consisting of 6b-dhydroxygeniposide, 6a-methoxygeniposide and 6b-methoxygeniposide.
  9. 치료적으로 유효한 양의 제니핀 또는 이의 유도체를 이를 필요로 하는 대상에게 투여하는 단계를 포함하는, 대상에게서 패혈증을 예방 또는 치료하는 방법.A method of preventing or treating sepsis in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of nippin or a derivative thereof.
  10. 제9항에 있어서, 상기 유도체가 제니포사이드(geniposide), 제니피오다이식 산(genipiodisic acid), 펜타-아세틸 제니포사이드(penta-acetyl geniposide), 6a-하이드록시제니포사이드(6a-hydroxygeniposide), 6b-하이드록시제니포사이드(6b-dhydroxygeniposide), 6a-메톡시제니포사이드(6a-methoxygeniposide) 및 6b-메톡시제니포사이드(6b-methoxygeniposide)로 이루어진 군으로부터 선택되는 것인, 대상에게서 패혈증을 예방 또는 치료하는 방법.The method of claim 9, wherein the derivative is geniposide, genipiodisic acid, penta-acetyl geniposide, 6a-hydroxygeniposide, 6b Preventing or treating sepsis in a subject selected from the group consisting of 6b-dhydroxygeniposide, 6a-methoxygeniposide and 6b-methoxygeniposide. How to.
  11. 제9항에 있어서, 항염증제, 해열진통제, 혈액응고억제제, 항생제, 항균제 및 항알러지제로 이루어진 군으로부터 선택되는 약제가 병용 투여되는 것인, 대상에게서 패혈증을 예방 또는 치료하는 방법.The method of preventing or treating sepsis in a subject according to claim 9, wherein a medicament selected from the group consisting of anti-inflammatory agents, antipyretic analgesics, anticoagulants, antibiotics, antibacterial agents and anti-allergic agents is administered in combination.
  12. 제니핀 또는 이의 유도체를 패혈증의 예방 또는 치료에 사용하는 용도.Use of genipine or derivatives thereof for the prevention or treatment of sepsis.
  13. 제12항에 있어서, 상기 유도체가 제니포사이드(geniposide), 제니피오다이식 산(genipiodisic acid), 펜타-아세틸 제니포사이드(penta-acetyl geniposide), 6a-하이드록시제니포사이드(6a-hydroxygeniposide), 6b-하이드록시제니포사이드(6b-dhydroxygeniposide), 6a-메톡시제니포사이드(6a-methoxygeniposide) 및 6b-메톡시제니포사이드(6b-methoxygeniposide)로 이루어진 군으로부터 선택되는 것인 용도.The method of claim 12, wherein the derivative is geniposide, genipiodisic acid, penta-acetyl geniposide, 6a-hydroxygeniposide, 6b -6b-dhydroxygeniposide, 6a-methoxygeniposide and 6b-methoxygeniposide.
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