KR20140128710A - Pharmaceutical composition for prevention or treatment of inflammatory or allergic diseases comprising the extract Cinnamomum cambodianum or compound marliolide isolated therefrom as an active ingredient - Google Patents

Pharmaceutical composition for prevention or treatment of inflammatory or allergic diseases comprising the extract Cinnamomum cambodianum or compound marliolide isolated therefrom as an active ingredient Download PDF

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KR20140128710A
KR20140128710A KR1020130047466A KR20130047466A KR20140128710A KR 20140128710 A KR20140128710 A KR 20140128710A KR 1020130047466 A KR1020130047466 A KR 1020130047466A KR 20130047466 A KR20130047466 A KR 20130047466A KR 20140128710 A KR20140128710 A KR 20140128710A
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allergic
extract
inflammatory
disease
pharmaceutical composition
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KR1020130047466A
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Korean (ko)
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김재화
오세량
강호범
지다정
채희성
김정희
류형원
안경섭
이형규
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한국생명공학연구원
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH

Abstract

The present invention relates to a composition containing an extract of Cinnamomum cambodianum, fractions thereof, or marliolide isolated therefrom or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or treating inflammatory or allergic diseases. The extract of Cinnamomum cambodianum, the fractions thereof, or the marliolide isolated therefrom significantly reduces the activation of protein kinase D1 (PKD1) in KM12c, SW620, HCT116, and A549 cell lines and suppresses the activity of NF-kappaB so that inflammatory or allergic reactions are reduced and the expression of proteins inducing allergic activity is significantly suppressed in BMMCs, thereby being useful as an active ingredient of a composition for preventing or treating inflammatory or allergic diseases.

Description

FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition for preventing or treating an inflammatory disease or an allergic disease comprising an extract of Cambodia spp., A fraction thereof or a maroliide isolated therefrom as an active ingredient. The present invention relates to a pharmaceutical composition for prevention or treatment of inflammatory or allergic diseases comprising extract Cinnamomum cambodianum or compound marliolide isolated therefrom as an active ingredient}

The invention Sinai momum Cambodia num (Cinnamomum The present invention relates to a pharmaceutical composition for the prophylaxis or treatment of inflammatory diseases or allergic diseases comprising, as an active ingredient, Cambodianum extract, fractions thereof or Maroliolide isolated therefrom.

Inflammation refers to the pathological condition of abscesses formed by the infiltration of external infectious agents (bacteria, fungi, viruses, various allergens). Specifically, when external bacteria invade a specific tissue and proliferate, the leukocyte of the living body recognizes it and actively attacks the proliferated foreign germs. In this process, the death of leukocytes is accumulated in the invaded tissue At the same time, the cell debris of invading microorganisms killed by leukocytes melts into the invading tissues and abscess forms. The treatment of abscess due to inflammation can be promoted through an anti-inflammatory action. Anti-inflammatory action is to inhibit the proliferation of invading microorganisms by using an antibacterial agent or to activate cells that digest foreign substances accumulated in the abscess, thereby digesting and excreting the foreign substances And the action of stimulating the inflammation and the like.

The inflammatory cytokines and mediators are regulated by nuclear elements. For example, NF-κB (nuclear factor-kappa B) is a nuclear protein of the Rel gene family. In the cytoplasm, NF-κB is associated with IκB (inhibitory kappa B) IκB kinase is activated by various stimuli such as reactive oxygen, chemokines such as TNF-α and phorbol myristate acetate (PMA), and phosphorylation is carried out to remove IκB. NF-κB, composed of a heterodimer of p50 and p65, is known to promote the expression of genes (tumor necrosis factor or cyclooxide synthase) that are activated and then migrate to the nucleus to induce an inflammatory response (Oh GT et al ., Artherosclerosis , 159 (1): 17-26, 2001; Epstein FH et al . , The New England Journal of Medicine , 336 (15): 1066-1071,1997; Zhang WJ et al ., FASEB J , 15 (130): 2423-2431, 2001; A Denk et al . , J. Biol . Chem . , 276 (30): 28451-28458, 2001; Sahnoun Z et al . , & Lt ; / RTI > Phsiology , 53 (4): 315-339,1998; Lindner V Pathobiology , 66 (6): 311-320, 1998; Landry DB meat al ., Am. J. Pathol ., 151 (4): 1085-1095,1997; ; Gerritsen ME et al . , Am . J. Pathol ., 147 (2): 278-292, 1995).

On the other hand, recent studies of plant-induced anti-inflammatory or anti-allergic compounds have focused on the potential inhibitory activity of natural products using in vivo and in vitro models. This is because plants are less toxic.

Cinnamomum cambodianum is a camphor plant and its shell has been used as a scent. It has traditionally been used as an anticonvulsant and disinfectant, and has been shown to have excellent anti-convulsive, detoxifying, antibacterial, and sedative properties. However, effects associated with inflammation or allergic diseases have not been reported.

As a result of efforts to find a plant having excellent anti-inflammatory or anti-allergic effect, the present inventors have found that the extract of Cinnabarin Cambodia nematum, its fraction or the compound Maroliolide isolated therefrom, The present invention has been accomplished by confirming that the present invention can be effectively used as an effective ingredient of a composition for the prevention and treatment of inflammatory diseases or allergic diseases by significantly inhibiting PKD1 and NF-kappaB activity.

An object of the present invention or when momum Cambodia num (Cinnamomum The present invention also provides a pharmaceutical composition for preventing or treating inflammatory diseases or allergic diseases comprising the cambodianum extract or a fraction thereof as an active ingredient, or a health food.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating an inflammatory disease or an allergic disease comprising Maroliolide or a pharmaceutically acceptable salt thereof as an active ingredient, Food is to provide:

[Chemical Formula 1]

Figure pat00001
.

In order to achieve the above object, the present invention relates to a method for producing Cinnamomum The present invention also provides a pharmaceutical composition for preventing or treating inflammatory diseases or allergic diseases or a health food containing the cambodianum extract or fractions thereof as an active ingredient.

The present invention also relates to a pharmaceutical composition for the prevention or treatment of inflammatory diseases or allergic diseases comprising the compound Maroliolide or a pharmaceutically acceptable salt thereof as an active ingredient, Lt; / RTI >

[Chemical Formula 1]

Figure pat00002
.

Or when in the present invention momum Cambodia num (Cinnamomum cambodianum extract, fractions thereof or maroliolide isolated therefrom significantly reduce the activation of PKD1 (Protein kinase D1) from KM12c, SW620, HCT116 and A549 cells and inhibit the activity of NF-kappaB, Allergic response, and exhibits an effect of significantly inhibiting the expression of an allergen activity inducing protein in BMMCs. Therefore, it can be effectively used as an active ingredient of a composition for the prevention and treatment of inflammatory diseases or allergic diseases.

Figure 1 is a graphical representation of Cinnamomum < RTI ID = 0.0 > cambodianum ) extract on the activation of inflammatory mediators.
FIG. 2 is a diagram showing the results of Western blot and RT-PCR for the expression of COX-2 protein and mRNA expression in BMMCs treated with the extract of Cinnamomum cambodiae genus. As a standard control for quantification, beta-actin was used.
3, Fig. 3 is a diagram showing the chemical structure of a Maroliolide compound isolated from a cinnabar extract of Cambodia.
FIG. 4 is a graph showing inhibition of PKD1 protein activation depending on the concentrations treated in the marigold-treated KM12c, SW620, HCT116, and A549 cells.
Figure 5 It is shown that the activation of IKK protein is inhibited according to the concentration treated with KM12c and A549 cells treated with malialolide.
6, This shows that the activation of NF-kappaB (p65) protein is inhibited depending on the concentrations treated in the KM12c and A549 cells treated with malialolide.

Hereinafter, terms of the present invention will be described.

In the present invention, the term "inflammation " refers to a defense reaction of biological tissue against a certain stimulus, and refers to a complicated lesion involving tissue degeneration, circulatory disorder and exudate, and tissue proliferation. In addition, various types of infection and expression in the in vivo defense system against irritants in metabolites in vivo, various chemical mediators are involved in the mechanism of expression of inflammation, and the pathogenesis thereof is very complicated. It is a topical protective response caused by tissue injury or destruction, which acts to destroy, weaken or mask both injurious and injurious tissues. The characteristic of this inflammation is that the microvessels are perforated, the blood components leak into the interstitial space, and the white blood cells migrate to the inflammatory tissues, usually accompanied by clinical symptoms such as erythema, edema, hyperalgesia and pain.

The term "interleukin-6 (IL-6)" in the present invention is a kind of cytokine involved in various biological activities such as cell proliferation, differentiation and maturation in host cells. It also induces differentiation and differentiates B cells into plasma cells to increase the amount of antibody produced. Interleukin-6 is a phosphoglyco protein that is secreted from various cells such as monocytes, fibroblasts and keratinocytes, as well as T cells and B cells. Lt; / RTI > In the present invention, it was confirmed that the expression of IL-6 mediating the inflammatory response was decreased in a concentration-dependent manner in the cells treated with the extract of Cinnamomum cambodia genus. This confirms that the composition of the present invention is effective for inflammatory diseases.

The term "prostagladin D2 (PGD2) and leukotriene C4 (LTA4)" in the present invention refers to a local functional hormone produced in the biosystem from arachidonic acid. The biosynthesis of leukotrienes indicates that the enzyme acts on arachidonic acid To produce an epoxide known as prostaglandin D2 and leucotriene C4 (LTC4), which is converted to other prostaglandins and leukotrienes by a continuous enzymatic reaction step. Leukotrienes may be used in the treatment of pulmonary diseases such as asthma, chronic bronchitis and related obstructive airways diseases, allergic and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis, Inflammatory bowel disease, pain, skin disorders such as psoriasis, irritable eczema, cardiovascular disorders such as myocardial ischemia, hypertension, platelet aggregation, and the like. In the examples of the present invention, it was confirmed that PGD2 and LTC4 were reduced by Phenotypic and A23187-induced allergic models by the extract of Cynomorhia cambodiaeum, which supports the effect on allergic diseases.

In the present invention, the term "β-hexosaminidase (β-HEX)" is a substance expressed in association with an inflammation and an allergic reaction. It is an N-acetyl-β-D-hexosaminidase N -Acetyl-D-hexaamine, which is a deglycosylation marker of BMMCs. In the examples of the present invention, the expression level of β-HEX was examined in BMMCs treated with the extract of Cinnamomum cambodia gingivalis. As a result, the composition of the present invention has an effect of inhibiting the expression of β-HEX, Means that a composition containing an extract as an active ingredient can be used for the purpose of preventing or alleviating allergic diseases.

The term "allergy " in the present invention is a biochemical phenomenon that indicates a specific and modified reaction to a foreign substance (antigen, Allergen). When the released substance causes a symptom, it is called allergen, It is called disease. It is a pathological process of the organism resulting from an antigen-antibody reaction which is the cause of the allergy. It is generally classified as 1 ~ 4 type according to the time required for reaction and presence of complement involvement.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease or an allergic disease comprising Cinnamomum cambodianum extract or a fraction thereof as an active ingredient.

Preferably, the Cinnabar extract of Cambodia is prepared by a manufacturing method comprising the following steps, but is not limited thereto:

1) Extracting the extract of Cinnamomum vannamei Cambodia with an extraction solvent;

2) filtering the extract of step 1); And

3) Concentrating the filtered extract of step 2) under reduced pressure and drying.

In the above method, the step 1) of Cinnamomum cambodia can be used without limitation such as cultivated or marketed. It is more preferable to use the stem shell, but not limited to, the leaf, the stem, the flower, the fruit or the root.

In the above method, it is preferable to use water, an alcohol or a mixture thereof in the extraction solvent in the step 1). As the alcohol, a C 1 to C 2 lower alcohol is preferably used, and it is preferable to use ethanol or methanol as the lower alcohol.

As the above extraction method, it is preferable to use hot water extraction, immersion extraction, supercritical extraction, subcritical extraction, high temperature extraction, high pressure extraction, shaking extraction, Soxhlet extraction or reflux extraction and an extraction device such as a reflux cooling extraction and an ultrasonic extraction Or a method of using an adsorption resin including XAD and HP-20, can be used, and it is preferable to heat and reflux or extract at room temperature, but the present invention is not limited thereto.

The extraction solvent is preferably added by 2 to 200 times, preferably 10 to 30 times, to the amount of dried Cinnabarum Cambodianum, but is not limited thereto. The extraction temperature is preferably 15 to 30, but is not limited thereto.

Further, the extraction time is preferably 24 to 96 hours, more preferably 48 to 72 hours, but is not limited thereto.

In addition, the extraction number is preferably 3 to 5 times, more preferably 3 times, but not limited thereto.

In the above method, it is preferable to use a vacuum decompression concentrator or a vacuum rotary evaporator for the decompression concentration in step 3), but it is not limited thereto. The drying is preferably performed under reduced pressure, vacuum drying, boiling, spray drying or freeze drying, but not always limited thereto.

In the above method, it is preferable to use a vacuum decompression concentrator or a vacuum rotary evaporator for the decompression concentration in step 3), but it is not limited thereto. The drying is preferably performed under reduced pressure, vacuum drying, boiling, spray drying or freeze drying, but not always limited thereto.

In addition, the fraction according to the present invention

1) adding the above-mentioned Camphor dandruff with water, a lower alcohol of C 1 -C 2 or a mixture thereof to obtain an extract of Cambodia sp. And

2) fractionating the extract obtained in step 1) with hexane, chloroform, ethyl acetate and butanol to obtain a fraction.

Specifically, the fraction was suspended in water (450 g) of Cinnamomum cambodia genome obtained in the above step 1), and then hexane, chloroform and ethyl acetate were sequentially added thereto to separate the respective layers, and then the chloroform layer was vacuum- Concentrate and dry to obtain the chloroform fraction (70 g), but it is not limited thereto.

At this time, the vacuum concentration is preferably performed using a vacuum rotary evaporator, but is not limited thereto.

The drying is preferably carried out under reduced pressure, vacuum drying, boiling, spray drying, room temperature drying or freeze drying, more preferably, but not exclusively, freeze drying.

In addition, the inflammatory disease may be selected from inflammatory bowel disease (IBD), Alzheimer's disease, multiple sclerosis, tuberculosis, sarcoidosis, , Hepatitis, cholecystitis, fungal infections, gastric ulcer, asthma, atopic dermatitis, tendinitis or nephritis, but is not limited thereto.

The allergic disease is preferably, but not limited to, asthma, hypersensitivity, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, contact dermatitis, urticaria, insect allergies, food allergies or drug allergies .

In a specific example of the present invention, in order to examine the effect of the extract of Bombyx mori Cambodia on COX-2 and interleukin-6 (IL-6) activity in bone marrow-derived mast cells (BMMCs) (CMA), and calcium ion carrier A23187 (Calcymycin; C 29 H 37 N 3 ) to increase the expression of the mediating proteins involved in inflammation, after treatment with BMMCs isolated from rats. O 6 ) and the amounts of PGD2 (Prostaglin D2), LTC 4 (leukotriene C4), and β-hexosaminidase were measured by RT-PCR analysis and spectrophotometric analysis. As a result, (Fig. 1 and Fig. 2). In addition, it was confirmed that the extract of Cinnamomum cambodia nematum significantly inhibited the expression of these proteins mediating the inflammatory reaction and the expression of mRNA.

In addition, inhibition of PKD1 and NF-kappaB in KM12c, SW620, HCT116 and A549 cells by Maroliolide isolated from Cinnabar extract from Cambodia sp. Showed that KM12c, SW620, HCT116 and A549 PKD1 activation was clearly evident in the cells (see FIG. 4), and activation of the KM12c, SW620, HCT116, and A549 cells was significantly inhibited when the maroliade was pretreated. In addition, when the activation of IKK related to the activation of NF-kappaB was confirmed, activation of IKK was inhibited in a concentration-dependent manner (see FIG. 5).

In addition, it was confirmed that NF-kappaB activation by PMA showed a significant increase in the effect of malialide in KM12c and A549 cells (see FIG. 6).

Accordingly, the fractions of the present invention of the present invention of Cambodia nematum, its fractions, significantly reduce the activation of PKD1 (protein kinase D1) from KM12c, SW620, HCT116 and A549 cells and inhibit the inflammatory and allergic response by inhibiting the activity of NF-kappaB And exhibits an effect of remarkably suppressing the expression of an allergen activity inducing protein in BMMCs. Therefore, it can be effectively used as an active ingredient of a composition for the prevention and treatment of inflammatory diseases or allergic diseases.

In addition, the pharmaceutical composition of the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of medicaments.

The pharmaceutical composition according to the present invention can be formulated in the form of oral, granule, tablet, capsule, suspension, emulsion, syrup, aerosol or the like oral preparation, external preparation, suppository and sterilized injection solution according to a conventional method Can be used. Examples of carriers, excipients and diluents that can be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium Silicates, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, (sucrose), lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.

The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may be determined depending on the condition of the patient, The range varies depending on sex, diet, excretion rate, severity of disease, drug type, administration time, administration method, administration route and administration period. The daily dose is 0.0001 mg / kg to 500 mg / kg, preferably 0.001 mg / kg to 100 mg / kg, when the extract or fraction according to the present invention is lyophilized, It can be administered in divided doses.

The pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

The present invention also relates to the use of Cinnamomum < RTI ID = 0.0 > The present invention provides a health food for preventing or ameliorating an inflammatory disease or an allergic disease comprising cambodianum extract or a fraction thereof as an active ingredient.

Accordingly, the fractions of the present invention of the present invention have a significant reduction of activation of PKD1 (protein kinase D1) from KM12c, SW620, HCT116 and A549 cells, and suppression of NF-kappaB activity thereby reducing inflammation and allergic responses And exhibits an effect of remarkably suppressing the expression of an allergen activity inducing protein in BMMCs, and thus can be effectively used as an active ingredient of a health food for the prevention or amelioration of an inflammatory disease or an allergic disease.

The health food of the present invention can be used as it is, or can be used in combination with other food or food ingredients, and can be suitably used according to conventional methods.

There is no particular limitation on the kind of the health food. Examples of foods that can be added with the above-mentioned Cnomatophyllum cambodiae extract include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, Tea, a drink, an alcoholic beverage, and a vitamin complex, all of which include health foods in a conventional sense.

The health beverage composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. The natural carbohydrates are sugar saccharides such as monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 of the composition of the present invention. In addition to the above, the health food of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acids and salts thereof, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, , A carbonating agent used in carbonated drinks, and the like. It may also contain flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not critical, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.

The present invention also provides a pharmaceutical composition for the prophylaxis or treatment of inflammatory diseases or allergic diseases comprising, as an active ingredient, a compound of the following formula (1) or a pharmaceutically acceptable salt thereof:

Figure pat00003

The compound of the above formula (1) is Mariolide.

The Maroliolide of the formula 1 can be obtained by carrying out the extraction and fractionation steps of the extract of Cinnamomum cambodiaeum according to the present invention and performing a silica gel column chromatography on the fraction of Cinnamomum cambodia nemco chloroform obtained by separating the compound And further performing a purification step.

Specifically, the silica gel column chromatography is preferably repeated one to several times. As the mobile phase, solvents such as n-hexane-EtOAc (40: 1 to 1: 1, and CHCl 3 -MeOH = 10: 1 to 1: 1, v / v) may be used. At this time, the used solvent is eluted and separated by a concentration gradient elution method in which the solvent is sequentially increased from nonpolar to polar, and the desired therapeutic fraction is obtained by measuring the therapeutic effect of the collected inflammatory diseases or allergic diseases.

Accordingly, the compound of formula (I) of the present invention significantly reduces activation of PKD1 (protein kinase D1) from KM12c, SW620, HCT116, and A549 cells and reduces inflammation and allergic responses by inhibiting the activity of NF-kappaB, Since BMMCs exhibit an effect of remarkably inhibiting the expression of allergen activity inducing protein, they can be effectively used as an effective ingredient of a pharmaceutical composition for the prevention or treatment of allergic diseases.

The present invention includes all of the compounds represented by the above formula (1) or pharmaceutically acceptable salts thereof, and possible solvates, hydrates, racemates, or stereoisomers thereof.

Can be used in the form of a compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof of the present invention, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Sulfonate, methanesulfonate, propanesulfonate, naphthalene-1-sulphonate, naphthalene-1-sulphonate, , Naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving a compound represented by the formula (1) in an excess amount of an acid aqueous solution, and mixing the salt with a water-miscible organic solvent such as methanol, ethanol, And precipitating with acetonitrile.

Further, it may also be prepared by heating the same amount of a compound represented by the formula (1) and an acid aqueous solution or alcohol, followed by drying the mixture by evaporation or by suction filtration of the precipitated salt.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

In addition, the present invention provides a health food for preventing or ameliorating an inflammatory disease or an allergic disease comprising the above-mentioned formula 1 or a pharmaceutically acceptable salt thereof.

Accordingly, the compound of formula (I) of the present invention significantly reduces activation of PKD1 (protein kinase D1) from KM12c, SW620, HCT116, and A549 cells and reduces inflammation and allergic responses by inhibiting the activity of NF-kappaB, Since BMMCs exhibit an effect of remarkably inhibiting the expression of allergen activity inducing protein, they can be effectively used as an active ingredient of health foods for the prevention or amelioration of inflammatory diseases or allergic diseases.

Hereinafter, the present invention will be described in detail with reference to Examples and Production Examples.

EXAMPLES The following examples and preparative examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention to the following examples and preparative examples.

< Example  1> Sina Mori Cambodia ( Cinnamomum cambodianum ) And the production of maroliides ( Marliolide ) detach

Cinnamomum Cambodia cambodianum) extracts the three times repeatedly at room temperature from the stem bark of a scenario momum num Cambodia (Cambodia) and extracted with methanol to obtain a dry powder of 450g. The methanol extract was suspended in water, using n -hexane, CHCl 3, and EtOAc and extracted with a solvent in a row. Among them, 70 g of the extract was obtained from the CHCl 3 fraction. The CHCl 3 fractions were purified by silica gel column chromatography using n-hexane-EtOAc (40: 1 to 1: 1, and CHCl 3 -MeOH = 10: 1 to 1: 1, v / Maroliolide was isolated as a solvent (Fig. 3).

To identify the separated maroliolide, a white powder was obtained from the hexane layer and confirmed by 1 H and 13 C NMR.

As a result, as shown in Table 1, Mariolide (4-methyl-3-Hydroxy-2,10-tetradecene-g-lactone) was confirmed to be marylide by 1 H and 13 C NMR spectral data (Table 1).

Figure pat00004

< Example  2> Cell preparation

<2-1> Bone marrow derived mast cells ( Mouse bone marrow - derived mast cells ; BMMCs ) Preparation

Bone marrow cells isolated from female Balb / cJ mice were suspended in 50% nutrient medium (RPMI 1640 supplemented with 2 mM L-glutamine, 0.1 mM nonessential amino acid, antibiotic, and 10% fetal bovine serum) and 50 % WEHI-3 cell conditioned medium for 10 weeks.

Murakami et al., J Exp Med., 1982). It was confirmed that more than 98% of the cells were bone marrow-derived mast cells (BMMCs) after 3 weeks. 1995; 182 (1): 197-206).

<2-2> Cell culture

Cultures of human cell lines (KM12c, SW620, HCT116 and A549) were carried out under humidified conditions of 37 ° C, 5% CO 2 . KM12c, SW620, HCT116 and A549 were purchased from the American Type Culture Collection (ATCC). KM12c, SW620, HCT116 and A549 cells were cultured in DMEM supplemented with 10% FBS (HyClone, Logan, UT), 2 mM L- glutamate, 100 占 퐂 / ml penicillin, 100 占 퐂 / ml streptomycin Technologies) in DMEM (Life Technologies, Germany) medium.

< Example  3> Sina Mori Cambodia ( Cinnamomum cambodianum ) Extracts inhibited the production of inflammatory mediators

<3-1> ELISA ( Enzyme - Linked Immunosorbent Assay ) Analysis of inflammatory cytokines

In order to confirm the inhibitory effect on the production of the inflammatory mediator of the extract of Cinnabarum cambodiae, the BMMCs isolated from the rats were treated with the Cinnabarum cambodiaeum extract prepared in Example 1 and confirmed by ELISA analysis. Specifically, the BMMCs were inoculated into a 24-well culture vessel at a concentration of 1 x 10 6 / ml per well and various concentrations of active extracts (5, 10, and 20 μg / ml) After pre-treatment for minutes, stimulation with PMA (50 nM) supplemented with A23187 (1 μM). After 2 hours and 15 minutes of stimulation, the supernatant was transferred to a new microcentrifuge tube and the level of IL-6 was measured using the ELISA kit (BD Bioscience, USA), prostaglandin D2 and leukotriene C4 LTC4) levels were measured using an ELISA kit (Cayman Chemical Ann Arbor, USA). All experimental procedures were performed at room temperature and all reference samples and samples were tested in two sets.

As a result, as shown in Fig. 1, it was confirmed that the extract of Cymamontana Cambodia sp. Inhibited the production of interleukin-6, prostaglandin D2 and leukotriene C4 in a concentration-dependent manner (Fig. 1).

&Lt; 3-2 > Hexaaminidase (β- hexosaminidase ) Emission measurement

The extracts of Bombyx mori L. cambodia were treated with BMMCs isolated from rats by the same conditions and methods as in Example <3-1>, and β-hexosaminidase (β-HEX), a degranulation marker of BMMCs, 2-acetamido-2-deoxy-β-D-glucopyranoside hydrolysis (Sigma Chemical Co., USA). Specifically, prepare 15 μl of IgE storage solution (1 mg / ml) in 30 ml (passage 3 or more) of T175 culture flask (2.5-5 × 10 5 cells / ml) and then sensitize. The experiments were carried out in Tyrode buffer (135 mM NaCl, 5 mM KCl, 20 mM HEPES, 5.6 mM Glucose, 1.8 mM CaCl 2 , 1 mM MgCl 2 , 0.05% BSA, pH 7.4) Then, 2.0 × 10 5 cells / ml are dispensed into each 1.5 ml tube. First, centrifuge at 13,000 rpm for 3 minutes, discard the supernatant, treat the tyrode buffer solution and the test material in consideration of the volume of the tyrode buffer solution per tube, and pre-react at 37 ° C for 30 minutes. Next, the cells were stimulated with 25 ng / DNP-BSA (antigen) for 10 minutes, and the reaction was stopped by placing in ice for 5 minutes. The reaction was then stopped by centrifuging at 1,3000 rpm for 3 minutes. The supernatant was transferred to an e-tube , And the cells remaining in the tube are lysed with 1% Triton X-100. In summary, after recovering the supernatant, the cells were lysed by adding the same volume of the same three times of the freezing / thawing cycle. The supernatant and the lysed cells were incubated in 96 wells-plates with 1 mM p-nitrophenyl-N-acetyl-2-deoxy-beta-D-glucopyranoside -β-D-glucosaminide), and then incubated for 1 hour at 37 ° C in a constant-temperature bath. Then, 0.1 M Carbonate buffer solution was added and the absorbance at 405 nm was measured.

As a result, as shown in Fig. 1, It was confirmed that the release of beta -hexosaminidase was significantly inhibited in BMMCs (Fig. 1).

<3-3> Reverse transcription - Polymerase  Chain reaction Reverse Transcription -Polymerase Chain Reaction , RT - PCR ) analysis

In order to examine the expression of COX-2, a mediator of mRNA, on the BMMCs cells isolated from mice by the same conditions and methods as those in Example <3-1>, RT-PCR Analysis was used.

Specifically, total cellular RNA was isolated using an easy-BLUE ™ RNA extraction kit (iNtRON biotechnology, Korea) according to the manufacturer's instructions. The PCR product was separated on 1.5% agarose gel and stained with EtBr (ethidium bromide). The annealing conditions for iNOS were 45 sec at 56 ° C, annealing at 45 ° C for 45 sec, and annealing at 45 ° C for 45 sec. The annealing condition of -6 was 45 seconds at 57 캜 and was repeated 30 times. 3 '(sense, SEQ ID NO: 1) and 5'-GATTAGTACTGTAGGGTTAATG-3' (antisense, SEQ ID NO: 2) were used as COX-2 primers and 5'-ATGAAGATCCTGACCGAGCGT- (Sense, SEQ ID NO: 3) and 5'-AACGCAGCTCAGTAACAGTCCG-3 '(antisense, SEQ ID NO: 4) were used.

As a result, as shown in Fig. 2, it was confirmed that the extract of Cinnamomum cambodia genus significantly inhibited the production of COX-2 as the concentration increased (Fig. 2).

< Example  4> Sina Mori Cambodia  Extracted from the extract Marliolide's  PKD1 and IKK Confirming the inhibitory effect of

In order to confirm the effect of Maroliolide isolated in Example 1 on PKD1 and IKK, KM12c, SW620, HCT116 and A549 cells were injected with Maroliolide ) Were processed and confirmed using Western blot analysis. Specifically, the cells were inoculated into a 24-well culture vessel at a concentration of 1 x 10 6 / ml per well, and various concentrations of Maroliolide (0.1, 1, and 10 μg / Ml) was pretreated for 30 minutes and stimulated with PMA (1 [mu] M). As a control, the cells were stimulated with PMA (1 μM) alone for 5, 10, 20 and 30 minutes, respectively. After the stimulation, the cells were washed once with 10 mM phosphate buffer, and the cells at a concentration of 1 × 10 7 cells / ml were dissolved in PBS supplemented with 0.1% SDS and 10 mM β-mercaptoethanol. The cell lysate (1 × 10 5 cells) were loaded for a 10% SDS- polyacrylamide gel. After separation on the gel, the protein bands were blotted onto a nitrocellulose membrane (Millipore, USA) using a semi-dry blotter (MilliBlot-SDE system, Millipore, USA) according to the manufacturer's instructions. The membrane was washed once in 10 mM Tris buffer (TBS, pH 7.2) supplemented with 0.1% tween-20 (TBS-T) and fixed in TBS-T supplemented with 3% skim milk for 1 hour. After washing the membrane with TBS-T, the antibody labeled with anti-COX-2, p-PKD1, PKD1, p-IKK, IKK, β- actin and NF-kappaB (p65) &Lt; / RTI &gt; The membrane was washed three times and incubated for 1 hour and the membrane was treated with horseradish peroxidase-conjugated goat anti-rabbit IgG (1: 1000 dilution, Santa Cruz, USA) for 1 hour in TBS-T buffer. Finally, protein bands were visualized using an enhanced chemiluminescence (ECL) system (Amersham Corp, USA).

As a result, as shown in Fig. 4, when PMA was treated, activation of PKD1 was clearly observed in KM12c, SW620, HCT116 and A549 cells (Fig. 4). When Marioliad was pretreated, KM12c, SW620, HCT116 And A549 cells, respectively. In addition, it was confirmed that the activation of IKK associated with the activation of NF-kappaB also inhibited the activation of IKK in a manner dependent on the concentration of the marinolide (Fig. 5).

< Example  5> Sina Mori Cambodia  Extracted from the extract Marliolide's  Inhibition of the activity of NF-kappaB protein

<5-1> Western Blot  analysis

In order to confirm the effect of the NF-kappaB protein of Maroliolide isolated in Example 1, marlide was treated with KM12c and A549 cells to perform Western blot analysis. Specifically, the cells were inoculated into a 24-well culture vessel at a concentration of 1 x 10 < 6 > / ml per well, and various concentrations of maloiride (0.4, 2 and 10 [mu] g / Was pretreated for 30 min and stimulated with PMA (1 [mu] M). Then, it was analyzed using the Western blot method of Example 4 above.

As a result, as shown in Fig. 6, it was confirmed that the p65 was significantly decreased in the concentration-dependent manner in the group treated with the Mariolide as compared with the group not treated with the Mariolide (Fig. 6).

<5-2> Immunofluorescent staining ( Immunofluoresence ) Method analysis

The inhibitory effect of the NF-kappaB (p65) protein on KM12c cells of the marial lead isolated in Example 1 was confirmed by immunofluorescence.

About 2 x 10 4 Cells were aliquoted in Permanox chambered plastic slides (Nunc, USA), cultured in the same manner as described above, and then the supernatant was removed. After washing with phosphate buffered saline (PBS), the cells were blocked with 3% bovine serum albumin at room temperature for 30 minutes. After blocking, the primary antibody was reacted at 4 캜 for one day. After washing three times with phosphate buffered saline, the COX-2 antibody was transferred to Texas red; Santa Cruz Biotechnology, USA) were incubated with a secondary antibody (Santa Cruz Biotechnology, USA), and the secondary antibody to which Alexa Fluor 488 (Invitrogen, USA) was linked was reacted for 3 hours at room temperature. Washed three times with phosphate buffer, mounted with ProLong Gold Antifade reagent (Invitrogen, USA) and photographed with a confocal microscope (LSM510m Carl Zeiss, Germany).

As a result, as shown in Fig. 6C, the expression of p65 was markedly decreased in the cells treated with the Mariolide compared to the cells not treated with the Mariolide (Fig. 6C).

&Lt; Preparation Example 1 > Preparation of medicine

1. Manufacturing of powder

The extracts of the present invention, fractions thereof or marinolide 500 ng

Lactose 1 g

The above components were mixed and packed in airtight bags to prepare powders.

2. Preparation of tablets

The extracts of the present invention, fractions thereof or marinolide 500 ng

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

3. Preparation of capsules

The extracts of the present invention, fractions thereof or marinolide 500 ng

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

4. Preparation of injections

The extracts of the present invention, fractions thereof or marinolide 500 ng

180 mg mannitol

Na 2 HPO 4 · 2H 2 O 26 mg

Distilled water 2974 mg

According to the conventional method for preparing an injectable preparation, an injectable preparation was prepared by incorporating the aforementioned components in the amounts indicated.

&Lt; Preparation Example 2 > Preparation of health food

1. Manufacture of health food

The extracts of the present invention, fractions thereof or marinolide 500 ng

Vitamin mixture quantity

70 [mu] g of vitamin A acetate

Vitamin E 1.0 mg

0.13 mg of vitamin

0.15 mg of vitamin B2

Vitamin B6 0.5 mg

0.2 [mu] g vitamin B12

Vitamin C 10 mg

Biotin 10 μg

Nicotinic acid amide 1.7 mg

Folic acid 50 mg

Calcium pantothenate 0.5 mg

Mineral mixture quantity

1.75 mg of ferrous sulfate

0.82 mg of zinc oxide

Magnesium carbonate 25.3 mg

Potassium monophosphate 15 mg

Secondary calcium phosphate 55 mg

Potassium citrate 90 mg

Calcium carbonate 100 mg

Magnesium chloride 24.8 mg

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

2. Manufacture of health drinks

The extracts of the present invention, fractions thereof or marinolide 500 ng

Citric acid 1000 mg

100 g of oligosaccharide

Plum concentrate 2 g

Taurine 1 g

Purified water was added to a total of 900 ml

The above ingredients were mixed according to the usual health drink manufacturing method, and the mixture was stirred and heated at 85 for about 1 hour. The resulting solution was filtered to obtain a sterilized 2-liter container, which was sealed and sterilized, And used for manufacturing.

Although the composition ratio is relatively mixed with the ingredient suitable for the favorite drink, it is also possible to arbitrarily modify the blending ratio according to the regional and national preference such as the demand class, the demanding country, and the use purpose.

Claims (11)

Cinnamomum Cambodia cambodianum ) extract or fractions thereof as an active ingredient, for the prophylaxis or treatment of inflammatory diseases or allergic diseases.
The pharmaceutical composition for preventing or treating inflammatory disease or allergic disease according to claim 1, wherein the Cinnabarum Cambodiaeum extract is an extract obtained from the stem skin of Cinnabarum Cambodia nymph.
The method of claim 1, wherein the extract is water, C 1 to C 2 lower alcohol or a mixture thereof is extracted with a solvent.
2. The pharmaceutical composition according to claim 1, wherein the lower alcohol is ethanol or methanol. 2. A pharmaceutical composition for preventing or treating an inflammatory disease or allergic disease according to claim 1, wherein the lower alcohol is ethanol or methanol.
[Claim 5] The method according to claim 1, wherein the fraction is further extracted from any one selected from the group consisting of hexane, chloroform, ethylacetate and butanol, for the prevention or treatment of an inflammatory disease or an allergic disease. Gt;
The method of claim 1, wherein the inflammatory disease is selected from the group consisting of bronchitis, gastritis, arteriosclerosis, diabetes, arthritis, obesity, inflammatory bowel disease (IBD), Alzheimer's disease, multiple sclerosis, A pharmaceutical composition for preventing or treating an inflammatory disease or an allergic disease, which is characterized by being sarcoidosis, hepatitis, cholecystitis, fungal infection, gastric ulcer, asthma, atopic dermatitis, tendinitis or nephritis.
The method of claim 1, wherein the allergic disease is selected from the group consisting of asthma, hypersensitivity, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, contact dermatitis, urticaria, insect allergies, food allergies, A pharmaceutical composition for preventing or treating.
A health food for preventing or ameliorating an inflammatory disease or an allergic disease comprising an extract of Cinnamomum cambodia genus or a fraction thereof as an active ingredient.
A pharmaceutical composition for the prophylaxis or treatment of inflammatory diseases or allergic diseases, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]
Figure pat00005
.
[Claim 11] The pharmaceutical composition according to claim 9, wherein the compound of formula (I) is isolated from an extract of Cambodia genus.
A health food composition for preventing or ameliorating an inflammatory disease or an allergic disease comprising the compound of the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
KR1020130047466A 2013-04-29 2013-04-29 Pharmaceutical composition for prevention or treatment of inflammatory or allergic diseases comprising the extract Cinnamomum cambodianum or compound marliolide isolated therefrom as an active ingredient KR20140128710A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017104887A1 (en) * 2015-12-16 2017-06-22 경북대학교병원 Pharmaceutical composition for preventing or treating allergic diseases, containing pdk inhibitor as active ingredient
KR102007282B1 (en) * 2018-05-31 2019-08-06 태남메디코스 주식회사 Antioxidant composition comprising marliolide derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017104887A1 (en) * 2015-12-16 2017-06-22 경북대학교병원 Pharmaceutical composition for preventing or treating allergic diseases, containing pdk inhibitor as active ingredient
KR102007282B1 (en) * 2018-05-31 2019-08-06 태남메디코스 주식회사 Antioxidant composition comprising marliolide derivatives

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