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WO2006043783A1 - Compositions pharmaceutiques contenant du polysaccharide acide de ginseng rouge et de l'extrait de champignon chiitake, destinees a la prevention et au traitement du cancer - Google Patents

Compositions pharmaceutiques contenant du polysaccharide acide de ginseng rouge et de l'extrait de champignon chiitake, destinees a la prevention et au traitement du cancer Download PDF

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Publication number
WO2006043783A1
WO2006043783A1 PCT/KR2005/003492 KR2005003492W WO2006043783A1 WO 2006043783 A1 WO2006043783 A1 WO 2006043783A1 KR 2005003492 W KR2005003492 W KR 2005003492W WO 2006043783 A1 WO2006043783 A1 WO 2006043783A1
Authority
WO
WIPO (PCT)
Prior art keywords
rgap
lentinus edodes
composition
antitumor
edodes extract
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2005/003492
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English (en)
Inventor
Jong Dae Park
Jae Joon Wee
Yi Seong Kwak
Yong Bum Song
Jong Su Kyung
Jai Won Yang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KT&G Corp
Korea Ginseng Corp
Original Assignee
KT&G Corp
Korea Ginseng Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by KT&G Corp, Korea Ginseng Corp filed Critical KT&G Corp
Publication of WO2006043783A1 publication Critical patent/WO2006043783A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/25Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258Panax (ginseng)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7012Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06Fungi, e.g. yeasts
    • A61K36/07Basidiomycota, e.g. Cryptococcus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/04Antineoplastic agents specific for metastasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/04Immunostimulants

Definitions

  • This invention relates to a pharmaceutical composition which is useful for the treatment of tumors, in a manner that its selective augmentation on the level of im ⁇ munoglobulin IgM may lead to rapid recovery of immunity in the body, thus promoting longevity and maximizing antitumor activity.
  • Antitumor agents are largely divided into chemotherapeutics and biological drugs.
  • Biological drugs such as cytokine, immunotherapy, gene therapy and antian- giogenetic agent, attempt to stimulate the immune system to reject and destroy tumors.
  • Immunotherapy is a form of medical treatment based upon a concept of modulating the immune system to achieve a therapeutic goal by potentiating the activity of the host defense mechanism.
  • cytostatic agents More recently, a large body of work has been devoted to cytostatic agents with higher selectivity to tumors instead of cytotoxic therapy that is limited by poor delivery and drug resistance.
  • inhibition of tumors using promising natural drugs with fewer side effects has also become a major area of research in oncology.
  • red ginseng is a herbal preparation processed by Korea's specific technology. It has an antitumor, anti-diabetic and immunomodulatory properties.
  • Red ginseng contains red ginseng acidic polysaccharide (hereinafter referred to as
  • RGAP RGAP
  • the antitumor activity of RGAP is assumed to be due to its immunomodulatory property.
  • the major effects include the augmented proliferation of immune cells including macrophage and natural killer (NK) cells.
  • RGAP is involved in the activation of immune cells to produce cytokines (e.g., nitric oxide, tumor necrosis factor- alpha), that play a significant role in the regulation of the extent of the immune response.
  • cytokines e.g., nitric oxide, tumor necrosis factor- alpha
  • Nitric oxide performs a variety of tasks in the body. At high concentration it acts against bacteria and cancer cells. Some of the activities attributed to NO include mitogenic effects on fibroblasts and activation of T-cells.
  • TNF- ⁇ induces hemorrhagic necrosis of tumors in both animals and humans with its role of a mediator of septic shock.
  • RGAP has an immunomodulatory property as described above, one can expect the increasing level of immunoglobulin by RGAP that plays a major role in the body's immune system.
  • IgM antibodies increase in a dose-dependent manner during the administration of RGAP, which is discovered by the inventor et al.
  • IgM antibodies are the largest type of antibody. They are found in blood and lymph fluid and are the first type of antibody produced in response to an infection. They also cause other immune system cells to produce compounds that can destroy invading cells. In this respect, they can be mobilized at an early de ⁇ velopment of tumors.
  • Lentinus edodes has a polysaccharide compound called LC-33, separated from its fruit body, which exhibits a potent antitumor activity on Sarcoma- 180 and cellular immune response (Chihara, G., Hamuro, T. and Maeda, Y., Fractionation and pu ⁇ rification of the polysaccharide with marked antitumor activity especially lentinan from Lentinus edodes, Cancer Res., 30: 2776-2781, 1970. Maeda, Y. and Chihara, G., Lentinan a new immuno- accelerator of cell medicated response. Nature, 229: 634, 1971).
  • PBP is believed to induce the generation of interferon that may in turn potentiate the activity of the host defense mechanism through indirect inhibition of tumor cells (Tsunoda, A, A mushroom agents and their mechanisms, lentinan, a T-cell oriented im- munopotentiator, NY and Basel, vol. 19, p.436, 1985).
  • Lentinan is a purified polysaccharide with a high molecular weight (beta- 1,3 glucan) separated from its fruit body, that strengthens the immune system show to anticancer activity (Suga, T., Dhiio, T. Maeda, Y, Y. and Chihara, G, Antitumor activity of lentinan in murine syngeneic and autotochthonous hosts and its suppressive effect 3-methylcholanthrene-induced carcinogenesis, Cancer Res., 44: 5132-5137, 1984).
  • both RGAP and Lentinus edodes extract contribute to specifically selective augmentation of the level of immunoglobulin IgM in a dose-dependent manner, leading to the manufacture of a pharmaceutical composition containing both RGAP and Lentinus edodes extract as the alternative material to RGAP with a minimum therapeutic dosing level of RGAP.
  • the inventor et al. has consummated this invention by manufacturing a pharmaceutical composition which is useful for the treatment of tumors, in a manner that its selective augmentation of the level of immunoglobulin IgM may lead to rapid recovery of immunity in the body, thus promoting longevity and maximizing antitumor activity.
  • An object of this invention is to provide a pharmaceutical composition containing both RGAP and Lentinus edodes extract as an alternative material to RGAP.
  • Another object of this invention is to provide a pharmaceutical composition which is useful for the treatment of tumors, in a manner that its selective augmentation of the level of immunoglobulin IgM may lead to rapid recovery of immunity in the body, thus promoting longevity and maximizing antitumor activity.
  • An object of this invention is to provide a combined composition comprising both
  • RGAP and Lentinus edodes as active ingredients.
  • RGAP and Lentinus edodes used for this invention may be administered in a minimum therapeutic dosing level.
  • the pharmaceutical composition of this invention achieves antitumor effect that is equal to or better than a single admin ⁇ istration of RGAP or Lentinus edodes.
  • composition of this invention is useful for the treatment of tumors, in a manner that its selective augmentation of the level of immunoglobulin IgM may lead to rapid recovery of immunity in the body, thus promoting longevity and maximizing antitumor activity.
  • the level of IgM may be significantly increased by the pharmaceutical composition containing both RGAP and Lentinus edodes extract with the weight ratio of 1:1, leading to better survival rate and antitumor effects.
  • RGAP of this invention is manufactured by the conventional method using red ginseng, preferably by the method described in the Korean Patent Unexamined Publication No. 2002-94725.
  • Lentinus edodes extract of this invention is manufactured by the conventional method using water or alcohol, preferably by the method of using hot water (higher than 9O 0 C).
  • Lentinus edodes extract of this invention may contain one or more components selected from the group consisting of polysaccharide LC-33, beta- 1,3 glucan lentinan or PBP (protein-bound polysaccharide).
  • RGAP and Lentinus edodes extract is mixed in an ap ⁇ basementte weight ratio, preferably in the weight ratio of 1:1.
  • the composition of this invention is useful for the treatment of tumors, in a manner that its selective augmentation of the level of im ⁇ munoglobulin IgM may lead to rapid recovery of immunity in the body and contribute to better survival rate in an earlier stage of cancer, and then exhibits synergistic antitumor effects by maximizing the longevity in animal tumor models as well as solid tumor growth inhibition effects.
  • the pharmaceutical composition of this invention is characterized by a smaller use of RGAP that may demonstrate equal to or better than a single large use of RGAP.
  • composition of this invention containing RGAP and Lentinus edodes extract, which is mixed in the weight ratio of 1:1, has proven its better therapeutic outcome in terms of selectively augmented level of IgM, better survival rate and solid tumor inhibition, in comparison with a single administration of RGAP and the composition employing weight ratios exceeding 2:1.
  • the composition of this invention may contain one or more of pharmaceutically acceptable carriers and be formulated in a variety of dosage forms, such as oral preparations (e.g., tablet, hard/soft capsule, pill, powder, oral solution, syrup, suspension) or non-oral preparations (e.g., injection).
  • oral preparations e.g., tablet, hard/soft capsule, pill, powder, oral solution, syrup, suspension
  • non-oral preparations e.g., injection
  • the daily dosage of the composition of this invention in human may vary depending on types of cancer, severity, age and body conditions of individual patients, but in general, the daily dosage of the composition is preferably in the range of 5-150 mg/kg, more preferably in the range of 10-100 mg/kg.
  • the pharmaceutical composition of this invention is characterized by a smaller use of RGAP that may demonstrate equal to or better than a single large use of RGAP. That is, even a significance-undetectable minimum dose of RGAP can be effective, when administered in a mixed form with Lentinus edodes.
  • composition of this invention is advantageous in that (1) its selective aug ⁇ mentation of the level of immunoglobulin IgM may lead to rapid recovery of immunity in the body, thus promoting longevity and maximizing antitumor activity, and (2) its synergistic antitumor effects may inhibit the development of chemically induced tumors at an earlier stage.
  • the inventor et al. determined the level of immunoglobulins, IgG and IgM in tumor-bearing mice treated with the pharmaceutical composition of this invention. [60]
  • RGAP was prepared in the same manner as described in the Korean Patent Ap ⁇ plication No. 2001-33115.
  • 1 kg of red ginseng was added to 1OL of 85% ethanol and was extracted three times at 7O 0 C.
  • the dried material was extracted in 1OL of water four times at 8O 0 C to obtain a water-soluble extract.
  • the extract was dialyzed against distilled water at a refrigerator, using a dialysis membrane with a cut-off value of more than 12kD.
  • the inner dialysate solution having a cut-off value of more than 12kD, so obtained, was centrifuged at 8,000 rpm for 20 minutes, to obtain a supernatant.
  • 85% ethanol corresponding to a 5-fold amount of the supernatant was added to the supernatant for precipitation.
  • the precipitated material was further centrifuged at 8,000 rpm for 30 minutes and lyophilized to obtain RGAP fraction.
  • Lentinus edodes extract was prepared in a manner that Lentinus edodes was extracted in hot water (9O 0 C), followed by filtration and concentration processes.
  • Specimen 1 This specimen was prepared by mixing both RGAP and Lentinus edodes extract in the weight ratio of 1:1.
  • Specimen 2 This specimen was prepared by mixing both RGAP and Lentinus edodes extract in the weight ratio of 1:2.
  • Specimen 3 This specimen was prepared by mixing both RGAP and Lentinus edodes extract in the weight ratio of 1:3.
  • the level of IgM in three groups receiving each specimen (1, 2, 3) was 29.4+9.8, 26.4+9.1, 25.9 mg/dl, respectively; these figures of three groups were higher than that of a single treatment group.
  • the levels of IgM in three groups were increased by 306.3%, 275.0% and 269.8%, respectively.
  • specimen- 1 showed the highest concentration increase rate.
  • the increase rate of the level in the specimen- 1 group receiving 50 mg/kg of RGAP was higher than 296.9% of the specimen-2 groups receiving 100 mg/kg of RGAP.
  • the pharmaceutical composition of this invention is useful for an earlier treatment of rapidly growing tumors through its role to selectively induce the augmented level of immunoglobulin IgM, leading to rapid recovery of immunity in the body and maximizing antitumor activity.
  • the antitumor effects of the pharmaceutical composition of this invention was better than that of RGAP as monotherapy, in that a significance-un- detectable minimum dose of RGAP is administered in a mixed form with Lentinus edodes.
  • the level of IgM was significantly increased in the pharmaceutical composition containing both 50mg/kg of RGAP and 50mg/kg of Lentinus edodes extract in the weight ratio of 1:1, suggesting that the said composition ratio may contribute to the maximization of antitumor activity.
  • the inventor et al. determined the longevity of cancer-bearing animals by the phar ⁇ maceutical composition of this invention.
  • mice by RGAP 50, 100 mg/kg
  • Lentinus edodes extract 50, 100, 150 mg/kg
  • the survival rates of three specimens were 70%, 60%, and 60%, respectively.
  • the survival rate of the specimen- 1 group receiving RGAP 50 mg/kg was equal to that of the group receiving RGAP 100 mg/kg alone.
  • the survival rate of the pharmaceutical composition of this invention is was higher than that of RGAP as monotherapy, in that a significance-undetectable minimum dose of RGAP was effective, when is administered in a mixed form with Lentinus edodes.
  • Example 3 Solid tumor inhibition test [111] The inventor et al. determined the synergistic effect of the pharmaceutical composition of this invention using a solid tumor model.
  • the solid tumor growth inhibition rate of the pharmaceutical composition of this invention was generally higher than RGAP as monotherapy, in that a significance- undetectable minimum dose of RGAP was effective when administered in a mixed form with Lentinus edodes.
  • the solid tumor growth inhibition rate by two specimens containing RGAP and Lentinus edodes extract with the weight ratio of 1 : 1 and 1 :2 was sig ⁇ nificantly higher than that of a monotherapy group containing 2-fold RGAP or Lentinus edodes extract.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Mycology (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Botany (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

L'invention concerne une composition pharmaceutique utilisée dans le traitement des tumeurs, qui contient du RGAP ainsi qu'un extrait de champignon chiitake comme principes actifs. L'augmentation sélective du taux d'immunoglobulines M que procure cette composition pharmaceutique peut favoriser la récupération rapide de l'immunité du corps, ce qui a pour effet d'augmenter la longévité et d'optimiser l'activité antitumorale.
PCT/KR2005/003492 2004-10-22 2005-10-19 Compositions pharmaceutiques contenant du polysaccharide acide de ginseng rouge et de l'extrait de champignon chiitake, destinees a la prevention et au traitement du cancer Ceased WO2006043783A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020040084717A KR100590999B1 (ko) 2004-10-22 2004-10-22 홍삼 산성다당체 및 표고버섯 함유 항종양 약학조성물
KR10-2004-0084717 2004-10-22

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WO2006043783A1 true WO2006043783A1 (fr) 2006-04-27

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Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101102031B1 (ko) * 2008-04-11 2012-01-04 주식회사 한국인삼공사 면역질환 예방 또는 치료용 조성물

Citations (8)

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KR20040086497A (ko) * 2003-04-02 2004-10-11 주식회사한국신약 홍삼 및 펠리누스 속 균주의 균사체에서 추출한 다당류를함유하는 기능성식품

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KR20040086497A (ko) * 2003-04-02 2004-10-11 주식회사한국신약 홍삼 및 펠리누스 속 균주의 균사체에서 추출한 다당류를함유하는 기능성식품
KR20040068526A (ko) * 2004-07-13 2004-07-31 (주)바이오피아 면역 및 항암증진에 효과가 있는 이뮤노지의 제조방법

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KR20060035289A (ko) 2006-04-26

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