KR20090071871A - Pharmaceutical composition for sepsis and septic shock - Google Patents

Abstract

A pharmaceutical composition for treating sepsis and septic shock is provided to suppress multiple organ dysfunction syndrome related to organ damage and lower mortality. A pharmaceutical composition for treating sepsis and septic shock comprises a compound of the chemical formula 1 or its pharmaceutically allowable salt as an active ingredient. In the chemical formula 1, R1, R2, and R3 are hydrogen, or residue of the chemical formula 2. In the chemical formula 1, R4 is hydrogen, alkyl group of 1-6 carbon atoms. The compound of the chemical formula 1 is chlorogenic acid, and comprises 3-caffeoylquinic acid, 4-caffeoylquinic acid, 5-caffeoylquinic acid, 3,4-caffeoylquinic acid, 3,5-caffeoylquinic acid, or 4,5-dicaffeoylquinic acid. The pharmaceutical composition suppresses organic damage by the sepsis. The organ is liver, kidney, or heart. The pharmaceutical composition further comprises carrier, excipient, or diluents.

Description

Pharmaceutical composition for sepsis and septic shock}

The present invention relates to sepsis and septic shock therapy.

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. However, there is only one FDA-approved treatment and there are still very few effective treatments or medications.

One of the clinical features in the progression of sepsis is the overactivation of the inflammatory system in the early stages of sepsis, so TNF-α, interleukin-6, interleukin-1, and interleukin that accompany or promote this inflammatory response for the treatment of sepsis. Numerous attempts have been made to suppress mediators such as -8 but have not improved patient survival.

On the other hand, the compounds of chlorogenic acids are a kind of polyphenol compounds widely distributed in plants and play an important role in plant metabolism.

Compounds of chlorogenic acids have the effect of inhibiting the production of lipid peroxide in vivo, the inhibitory effect of cholesterol biosynthesis and antioxidant activity, anticancer activity. It has also been shown to slow glucose release into the blood after meals, prevent heart disease, increase hepatic concentrations of glycogen and glucose-6-phosphate, and reduce blood sugar levels. Other studies are known to improve the distribution of minerals, reduce plasma and liver fat, and improve glucose tolerance.

However, no reports of chlorogenic acids have been disclosed for sepsis and septic shock therapeutic activity.

It is an object of the present invention to provide a pharmaceutical composition for treating sepsis and septic shock.

The present invention is characterized by a pharmaceutical composition for treating sepsis and septic shock using the compound of Formula 1 or a pharmaceutical salt thereof as an active ingredient.

R ₁ , R ₂ and R ₃ are each selected from hydrogen and residues of the following Formula 2, at least one of R ₁ , R ₂ and R ₃ is a residue of Formula 2,

R ₄ is any one selected from hydrogen or an alkyl group having 1 to 6 carbon atoms.

In addition, the pharmaceutical composition of the present invention is characterized by suppressing damage to organs due to sepsis.

In addition, the pharmaceutical composition of the present invention is another feature of inhibiting damage to any one or more organs of the liver, kidney and heart due to sepsis.

In addition, the pharmaceutical composition of the present invention is another feature that further comprises a carrier, excipient or diluent commonly used.

The compound of the formula (1) used in the present invention can be used by, for example, a commercially available or prepared by a known method from the fruits and leaves of various dicotyledonous plants, such as varieties or asteraceae, eggplants. .

Compounds of formula (I) of the present invention include chlorogenic acids structurally similar to chlorogenic acids, specifically, 3-cafeoylquinic acid, 4-cafeoylquinic acid, 5-cafeoylquinic acid, 3,4-dicaoylquinic acid, 3, 5-dicafeoylquinic acid, 4,5-dicafeoylquinic acid, 3-ferilyl quinic acid, 4-ferrulylquinic acid, 5-ferrulylquinic acid and 3-ferruly-4-cafeoylquinic acid, and the like, are preferable. Preferably, it is a compound in which R ₄ in Formula 2 is hydrogen, more preferably chlorogenic acid.

The compound of Formula 1 of the present invention can be used in the form of a salt to improve water solubility and increase physiological effectiveness. These salts may be pharmaceutically acceptable salts. As such a base material for salt formation, For example, hydroxide of alkali metals, such as lithium hydroxide, sodium hydroxide, potassium hydroxide; Hydroxides of alkaline earth metals such as magnesium hydroxide and calcium hydroxide; Basic amino acids such as inorganic bases such as ammonium hydroxide, arginine, lysine, histidine and ornithine; Organic bases such as monoethanolamine, diethanolamine and triethanolamine are used, but hydroxides of alkali metals or alkaline earth metals are particularly preferred. In the present invention, these salts may be prepared, and then added in a composition composed of other components, or the compound of formula (1) and the salt-forming component may be separately added to the composition to form a salt therein.

As described above, the pharmaceutical composition for the treatment of sepsis and septic shock using any one or more components selected from the compound of Formula 1 and pharmaceutically acceptable salts of the present invention as an active ingredient is effective in treating or treating sepsis. It is thought to be helpful for the treatment of patients with poor conditions. In addition, since it is a natural-based therapeutic agent, it is thought to reduce not only the wide range of therapeutic actions but also the side effects frequently encountered in chemicals.

Hereinafter, the present invention will be described in detail with reference to Examples, Preparation Examples and Experimental Examples. These are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

The pharmaceutical composition comprising any one or more components selected from the compound of formula 1 and pharmaceutically acceptable salts thereof of the present invention as an active ingredient, respectively, powders, granules, tablets, capsules, suspensions, emulsions, Oral formulations such as syrups, aerosols, external preparations, suppositories and sterile injectable solutions.

Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, mineral oil, etc. are mentioned.

When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations contain at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin, and the like. Mix is prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

The preferred dosage of the pharmaceutical composition of the present invention depends on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art. However, for the desired effect, the pharmaceutical composition of the present invention is administered at 0.01 to 1000 mg / kg, preferably 0.1 to 1000 mg / kg, more preferably 1 to 1000 mg / kg, based on chlorogenic acid. It is good. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.

The extract of the present invention can be administered to mammals such as mice, mice, livestock, humans, etc. by various routes. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or cerebrovascular injections.

Hereinafter, a method for preparing a formulation of the pharmaceutical composition of the present invention will be described by way of example. The pharmaceutical composition of the present invention can be administered in the following formulations, and the following formulation examples are merely illustrative of the present invention, whereby the content of the present invention is not limited.

Production Example  1. Preparation of Injection

3-Cape Oil Quinic Acid ... 500 mg

Distilled water for injection ... Appropriate amount

Distilled water for injection was added to adjust the total volume to 25 ml. Injectables were prepared by mixing the above ingredients according to a conventional method for preparing injectables, filling them into brown bottles and sterilizing them.

Production Example  2. Pilled  Produce

3,4-Dicapoyl quinic acid ....................... 25 mg

Corn starch ........................... 100 mg

Binder ... .... appropriate

The above components were mixed, and refilled to a size of quintet or large ring by a conventional pill manufacturing method to prepare a pill.

Production Example  3. Preparation of Tablets

3-Perulyl Quinate ... 25 mg

Lactose ... ... 100 mg

Starch ..................... ... 100 mg

Magnesium Stearate ...............

The above components were mixed and compressed into tablets according to a conventional method for preparing tablets.

Production Example  4. Preparation of Capsules

3-Cape Oil Quinic Acid ... Mg

Lactose ... 50 mg

Starch ..................... 50 mg

Talc ........................ ..... 2 mg

Magnesium Stearate ...............

The capsules were prepared by mixing the above components and filling the gelatin capsules according to a conventional method for preparing capsules.

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 organ dysfunction syndrome (hereinafter referred to as 'MODS') by suppressing damage to major organs that significantly affect mortality. This will be described with reference to specific experimental examples and drawings.

Experimental Example  1. Evaluation of survival rate for sepsis

1. In the mouse sepsis model induced by CLP, the survival rate change according to the injection of Preparation Example 1 was observed.

2. Anesthesia was intraperitoneally injected into mice, and sepsis was induced through CLP. That is, after cutting the median of the abdominal cavity, exposing the cecum to the outside, ligation of the end of the ileocecal valve with silk suture, making two holes in the cecum using a needle, and then a certain amount of fecal material ) Was spilled. The caecum, including fecal matter, was put back into the abdominal cavity and sutured, followed by physiological saline injection. Mice were administered the injection or vehicle of Preparation Example 1 immediately after the induction of sepsis in the tail vein.

3. Test sample: Injection of Preparation Example 1, and 4-caffeoylquinic acid (5-caffeoylquinic acid), 5-, instead of chlorogenic acid (Chlorogenic acid) in the method of Preparation Example 1, 3, Injection was prepared using 5-diaffeoylquinic acid and 3-ferulylquinic acid, and a vehicle was used as a control, except for the active ingredient.

4. Test Result:

(1) Survival rate was 60% after 10 days of chlorogenic acid 10, 20, 30 and 40 mg / kg in sepsis-induced mice (Fig. 1).

(2) Survival was 40% after 10 days of administration of 4-cafeoylquinic acid to 10 and 20 mg / kg of sepsis-induced mice (FIG. 2).

(3) Survival rates were 50% and 60% after 10 days of administration of 10- and 20 mg / kg of 5-caffeoylquinic acid in sepsis-induced mice, respectively (FIG. 3).

(4) The survival rate was 60% after 10 days of inoculation of 3,5-dicafeoylquinic acid in 10 and 20 mg / kg of sepsis-induced mice (FIG. 4).

(5) Survival after 10 days of 10 and 20 mg / kg administration of 3-ferulylquinic acid, respectively, to the sepsis-induced mice was 50% and 60%, respectively. It was significantly higher (FIG. 5).

Therefore, the pharmaceutical composition of the present invention was found to significantly lower mortality due to sepsis.

Experimental Example  2. Hepatic Function Test

1. Observation of hepatic impairment during sepsis induction and changes in hepatic impairment following administration of injection of Preparation Example 1 alanine aminotransferase (hereinafter referred to as 'ALT') and aspartate aminotransferase (aspartate) aminotransferase, hereinafter referred to as 'AST').

2. Blood was collected at 1, 3, 6, 12, 24 and 48 hours after CLP to separate serum. ALT and AST concentrations were measured in the separated serum to observe the degree of hepatic impairment and are shown in FIGS. 2 and 3, respectively. As a control group, mice were not administered the injection of Preparation Example 1 after induction of CLP sepsis, and Sham was a mouse that did not induce sepsis.

3. Experimental results: The results are the same as in Figs. 6 and 7 and the injection of Preparation Example 1 significantly suppressed the rise of ALT and AST concentrations indicating hepatic damage due to sepsis.

Experimental Example  3. Renal Function Drug Evaluation

1. Observe renal function impairment during sepsis induction and change the degree of organ damage following injection of Preparation Example 1 in the blood urea nitrogen (BUN) and creatinine (CRE). It was confirmed by measuring the concentration.

2. Blood was collected at 1, 3, 6, 12, 24 and 48 hours after CLP to separate serum. BUN and CRE concentrations were measured in the isolated serum to observe the extent of renal function impairment.

3. Experimental results: The results are the same as in Figs. 8 and 9 and the injection of Preparation Example 1 significantly suppressed the increase in the concentration of BUN and CRE indicating kidney damage due to sepsis.

Experimental Example  4. Cardiac Function Test

1. Observation of cardiac function damage during sepsis induction was observed, and changes in organ damage according to injection of Preparation Example 1 were confirmed by measuring lactate dehydrogenase (hereinafter referred to as “LDH”).

2. Blood was collected at 1, 3, 6, 12, 24 and 48 hours after CLP to separate serum. LDH concentration was measured in the serum and the degree of damage to heart function was observed.

3. Experimental Results: The results are shown in FIG. 10. The injection of Preparation Example 1 significantly suppressed the increase in LDH concentration indicating heart damage due to sepsis.

On the other hand, the pharmaceutical composition of the present invention can be formulated or used in combination with anti-inflammatory agents, antipyretic analgesics, anticoagulants, antibiotics, antibacterial agents and anti-allergic agents.

1 to 5 are graphs showing the survival rate change by administering the pharmaceutical composition of one embodiment of the present invention to sepsis model mice.

Figure 6 is a graph measuring the change in concentration of alanine aminotransferase for 48 hours after administration of the pharmaceutical composition in order to confirm the hepatic damage inhibitory effect of the pharmaceutical composition of one embodiment of the present invention.

Figure 7 is a graph measuring the change in the concentration of aspartate aminotransferase for 48 hours after administration of the pharmaceutical composition to confirm the hepatic damage inhibitory effect of the pharmaceutical composition of one embodiment of the present invention.

Figure 8 is a graph measuring the change in the concentration of urea nitrogen in the blood for 48 hours after administration of the pharmaceutical composition in order to confirm the inhibitory effect of renal damage of the pharmaceutical composition of one embodiment of the present invention.

Figure 9 is a graph measuring the change in the concentration of creatinine for 48 hours after administration of the pharmaceutical composition in order to confirm the inhibitory effect of renal damage of the pharmaceutical composition of one embodiment of the present invention.

Figure 10 is a graph measuring the change in the concentration of lactate dehydrogenase for 48 hours after administration of the pharmaceutical composition to confirm the inhibitory effect of the pharmaceutical composition of the embodiment of the present invention.

Claims (6)

A pharmaceutical composition for treating sepsis and septic shock using the compound of Formula 1 or a pharmaceutical salt thereof as an active ingredient: [Formula 1]

R ₁ , R ₂ and R ₃ are each selected from hydrogen and residues of the following Formula 2, at least one of R ₁ , R ₂ and R ₃ is a residue of Formula 2, [Formula 2]

R ₄ is any one selected from hydrogen or an alkyl group having 1 to 6 carbon atoms. The method of claim 1, The R ₄ is hydrogen, characterized in that the pharmaceutical composition for treating sepsis and septic shock. The method according to claim 1 or 2, R ₂ and R ₃ is hydrogen, characterized in that the pharmaceutical composition for treating sepsis and septic shock. The method according to claim 1 or 2, Pharmaceutical composition for the treatment of sepsis and septic shock, characterized by inhibiting the damage of organs due to sepsis. The method of claim 4, wherein The organ is sepsis and sepsis shock treatment pharmaceutical composition, characterized in that any one or more organs of the liver, kidney and heart. The method according to claim 1 or 2, Pharmaceutical composition for the treatment of sepsis and septic shock, characterized in that it further comprises a carrier, excipient or diluent commonly used in the manufacture of the pharmaceutical composition.

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