WO2004035048A1 - Inhibiteur de fibrose hepatique - Google Patents

Inhibiteur de fibrose hepatique Download PDF

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Publication number
WO2004035048A1
WO2004035048A1 PCT/JP2003/013304 JP0313304W WO2004035048A1 WO 2004035048 A1 WO2004035048 A1 WO 2004035048A1 JP 0313304 W JP0313304 W JP 0313304W WO 2004035048 A1 WO2004035048 A1 WO 2004035048A1
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WO
WIPO (PCT)
Prior art keywords
group
carbon atoms
alkyl
pyrazolin
phenyl
Prior art date
Application number
PCT/JP2003/013304
Other languages
English (en)
Japanese (ja)
Inventor
Hitoshi Togashi
Sumio Kawata
Original Assignee
Mitsubishi Pharma Corporation
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 Mitsubishi Pharma Corporation filed Critical Mitsubishi Pharma Corporation
Priority to AU2003301398A priority Critical patent/AU2003301398A1/en
Publication of WO2004035048A1 publication Critical patent/WO2004035048A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C07D231/26—1-Phenyl-3-methyl-5- pyrazolones, unsubstituted or substituted on the phenyl ring
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a liver fibrosis inhibitor comprising a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.
  • Liver fibrosis is a common response to necrosis and damage of hepatocytes, and is caused by numerous factors. Hepatic fibrosis can be caused, for example, by processes that inhibit liver homeostasis (especially inflammation or toxic damage, alterations in hepatic blood flow), or by infections of the liver (virus, bacterial, fungal, or parasitic infections). It is known. In addition, various storage abnormalities due to congenital metabolic abnormalities are often associated with fibrosis, including lipid abnormalities (Gaucher disease), glycogenosis, ⁇ -antitrypsin deficiency, and iron overload syndrome due to storage of exogenous substances.
  • liver fibrosis Hemochromatosis and copper storage disease (Wilson's disease), accumulation of toxic metabolites (tyrosinemia, fructoseemia, galactosemia), and peroxisome abnormalities (Zellweger syndrome).
  • chemicals and drugs eg, alcohol, methotrexate, etc.
  • liver fibrosis impaired liver circulation (eg, chronic heart failure, Pad-Chiari syndrome, venous obstruction, portal vein thrombosis) and chronic obstruction of the biliary outflow tract can also cause liver fibrosis.
  • Liver fibrosis is common in some chronic liver diseases. For example, liver fibrosis plays an important role in the progression from viral hepatitis to cirrhosis.
  • Hepatic fibrosis suppression therapy for interferon ineffective patients.
  • extracellular matrix collagen, laminin, proteodalican
  • Hepatic stellate cells are the major producers of extracellular matrix in the liver, and their function is regulated by cytokines and growth factors produced by Kupffer cells and p-macrophages.
  • Platelet-derived growth factor (PDGF) is important in this process It plays a role and is involved in the activation and proliferation of hepatic stellate cells (HSCs), eventually leading to liver fibrosis. Therefore, if a drug that suppresses the proliferation of hepatic stellate cells by PDGF is developed, it is possible to suppress liver fibrosis and suppress the development of chronic human liver injury.
  • R 1 represents a hydrogen atom, aryl, alkyl having 1 to 5 carbons or alkoxycarbonylalkyl having 3 to 6 carbons
  • R 2 represents a hydrogen atom, aryloxy, aryl mercapto, carbon number Represents 1 to 5 alkyl or 1 to 3 hydroxyalkyl
  • R 1 and R 2 together represent an alkylene having 3 to 5 carbon atoms
  • R 3 is a hydrogen atom, and has 1 to 5 carbon atoms.
  • edaravone is a free radical scavenger that functions to prevent cell damage by eliminating various free radicals including active oxygen. Nevertheless, there have been no reports on whether edaravone is effective in suppressing liver fibrosis. Disclosure of the invention
  • An object of the present invention is to provide a drug capable of suppressing liver fibrosis in chronic liver injury such as viral hepatitis or alcoholic liver injury.
  • the present inventors have solved the above-mentioned problem by administering a pyrazolone derivative represented by the formula (I) to hepatic stellate cells known to be involved in the progression of hepatic fibrosis, The effect on the proliferation of stellate cells was examined. As a result, they found that the administration of the pyrazolone derivative suppressed the growth of hepatic stellate cells, and completed the present invention.
  • R 1 represents a hydrogen atom, an aryl group, an alkyl group having 1 to 5 carbon atoms or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms
  • R 2 represents a hydrogen atom, an aryloxy group, an aryl group
  • R 3 represents a mercapto group, an alkyl group having 1 to 5 carbon atoms or a hydroxyalkyl group having 1 to 3 carbon atoms
  • R 1 and R 2 together represent an alkylene group having 3 to 5 carbon atoms
  • a hepatic fibrosis inhibitor comprising, as an active ingredient, a pyrazolone derivative represented by or a physiologically acceptable salt thereof, or a hydrate or solvate thereof.
  • the pyrazolone derivative represented by the formula (I) is 3-methyl-11-phenyl-2-birazolin-5-one or a physiologically acceptable salt thereof, or a hydrate or solvent thereof. It is Japanese.
  • liver fibrosis inhibitor used for the treatment and / or prevention of chronic liver injury.
  • the chronic liver injury is viral hepatitis or alcoholic liver injury.
  • liver fibrosis inhibitor which suppresses liver fibrosis by suppressing the proliferation of hepatic stellate cells.
  • a pharmaceutically effective amount of the pyrazolone derivative represented by the above formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof includes a human.
  • a method for suppressing hepatic fibrosis comprising a step of administering to a mammal.
  • a pyrazolone derivative represented by the above formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof, for producing a liver fibrosis inhibitor for producing a liver fibrosis inhibitor.
  • Figure 1 shows the measurement of L1-900 cell proliferation when various concentrations of edaravone were added.
  • the hepatic fibrosis inhibitor according to the present invention comprises a bilazopine derivative represented by the formula (I) defined herein or a physiologically acceptable salt thereof, or a hydrate or solvate thereof. including.
  • the compound represented by the formula (I) used in the present invention can also have a structure represented by the following formula (I ′) or (1 ′′) due to tautomerism.
  • the active ingredient of the medicament of the present invention is represented by the following formula (1 ′)
  • a compound represented by (1 ") or a physiologically acceptable salt thereof, or a hydrate or solvate thereof may be used.
  • the aryl group in the definition of R 1 may be either a monocyclic or polycyclic aryl group.
  • a phenyl group, a naphthyl group or another such as a methyl group, a butyl group or another such an alkyl group, a methoxy group or a butoxy group, or another such alkoxy group, a chlorine atom or another such halogen atom, or a hydroxyl group or other such substituent.
  • -Rule group and the like The same applies to the aryl moiety in other substituents having an aryl moiety (such as an aryloxy group).
  • R ⁇ R 2 and alkyl groups of 1 to 5 carbon atoms in the definition of R 3 are straight chain, it may be either branched. Examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group and the like. Other substituents having an alkyl moiety (alkoxycarbonylalkyl groups) The same applies to the alkyl moiety in
  • Examples of the aryloxy group in the definition of R 2 include a p-methylphenoxy group, a ⁇ -methoxyphenoxy group, and —chlorochlorooxy group, p-hydroxyphenoxy group, and the like. Examples include a mercapto group, a p-methylphenylmercapto group, a p-methoxyphenylmercapto group, a p-chloromethylphenylmercapto group, and a p-hydroxyphenylmercapto group.
  • Examples of the hydroxyalkyl group having 1 to 3 carbon atoms in the definitions of R 2 and R 3 include a hydroxymethyl group, a 2-hydroxyethyl group, and a 3-hydroxypropyl group.
  • Examples of the cycloalkyl group having 5 to 7 carbon atoms in the definition of R 3 include a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
  • the alkoxycarbonyl group having a number of from 2 to 5 include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxy S-carboxy group, and the like
  • an alkylmercapto group having 1 to 3 carbon atoms includes , A methylmercapto group, an ethylmercapto group, a propylmercapto group, and the like.
  • Examples of the alkylamino group having 1 to 4 carbon atoms include a methylamino group, an ethylamino group, a propylamino group, a butylamino group, and the like.
  • Examples of the dialkylamino group having 2 to 8 carbon atoms include a dimethylamino group, a getylamino group, and a dipropylamino group. Examples include a mino group and a dibutylamino group.
  • the compound (I) preferably used as an active ingredient of the liver fibrosis inhibitor of the present invention for example, the following compounds can be mentioned.
  • the active ingredient of the liver fibrosis inhibitor of the present invention includes, in addition to the free form compound represented by the formula (I), Acceptable salts may be used.
  • Physiologically acceptable salts include salts with mineral acids such as hydrochloric acid, sulfuric acid, hydrogen bromide, and phosphoric acid; methanesulfonic acid, ⁇ -toluenesulfonic acid, benzenesulfonic acid, acetic acid, glycolic acid, glucuronic acid.
  • Salts with organic acids such as acids, maleic acid, fumanoleic acid, oxalic acid, asconoleic acid, cunic acid, salicylic acid, nicotinic acid, tartaric acid; salts with alkali metals such as sodium and potassium; magnesium and calcium Salts with alkaline earth metals; ammonium, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-11-propanol, ethanolamine, N-methyl Examples thereof include salts with amines such as glutamine and L-glutamine. Further, a salt with an amino acid such as glycine may be used.
  • organic acids such as acids, maleic acid, fumanoleic acid, oxalic acid, asconoleic acid, cunic acid, salicylic acid, nicotinic acid, tartaric acid
  • salts with alkali metals such as sodium and potassium
  • the type of the organic solvent forming the solvate is not particularly limited, and examples thereof include methanol, ethanol, ether, dioxane, and tetrahydrofuran.
  • the compound represented by the above formula (I) may have one or more asymmetric carbons depending on the type of the substituent, and may have a stereoisomer such as an optical isomer or a diastereomer. .
  • pure stereoisomers, arbitrary mixtures of stereoisomers, racemates and the like may be used.
  • the compounds represented by the formula (I) are all known compounds, and can be easily synthesized by those skilled in the art by the method described in Japanese Patent Publication No. 5-31523.
  • the dosage of the hepatic fibrosis inhibitor of the present invention is not particularly limited, but it is generally 0.1% per day in the case of oral administration generally as the weight of the compound represented by the formula (I) as an active ingredient. ⁇ 1000 mg / kg body weight, preferably 0.5 to 50 mg / kg body weight per day, and 0.01 to 100 mg / kg body weight per day for parenteral administration, preferably 0.1 to 10 mg. /kg Weight.
  • the above dose is preferably administered once a day or divided into two or three times a day, and may be appropriately increased or decreased depending on age, disease state and symptoms.
  • the compound represented by the above formula (I), a physiologically acceptable salt thereof, or a hydrate or solvate thereof may be administered as it is.
  • a pharmaceutical composition containing the above-mentioned substance as an active ingredient and a pharmacologically and pharmaceutically acceptable additive.
  • Pharmaceutically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coatings, pigments, diluents, bases, dissolving agents Alternatively, a solubilizing agent, a tonicity agent, a pH adjusting agent, a stabilizer, a propellant, an adhesive, and the like can be used.
  • compositions suitable for oral administration include, as excipients, excipients such as glucose, lactose, D-mannitol, starch, or crystalline cellulose; disintegration agents such as carboxymethylcellulose, starch, or carboxymethylcellulose calcium.
  • Binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl ⁇ pyrrolidone, or gelatin; lubricants such as magnesium stearate or talc; hydroxypropylmethylcellulose, Coating agents such as sucrose, polyethylene dalicol or titanium oxide; bases such as vaseline, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, and hard fat can be used.
  • compositions suitable for injection or infusion include solubilizing agents or solubilizing agents which can constitute aqueous or ready-to-use injections such as distilled water for injection, physiological saline, and propylene glycol; glucose, sodium chloride , D-mannitol, glycerin and the like; additives such as inorganic acids, organic acids, pH regulators such as inorganic bases and organic bases, and the like.
  • the form of the liver fibrosis inhibitor of the present invention is not particularly limited, and can take various forms available to those skilled in the art.
  • a drug suitable for oral administration for example, tablets, powders, granules, hard gelatin capsules, suppositories, or lozenges can be prepared using solid pharmaceutical additives. Syrup, syrup, Soft gelatin capsules and the like can be prepared.
  • injections, drops, inhalants, suppositories, transdermal absorbents, transmucosal absorbents, and the like can be prepared as pharmaceuticals suitable for parenteral administration.
  • a brain protectant (drip) containing the compound of the above formula (I) as an active ingredient is already used in clinical practice (generic name: edaravone, trade name: Radicut: manufactured by Mitsubishi Pharma Corporation)
  • the above-mentioned commercial preparations can be used as they are in the hepatic fibrosis inhibitor of the present invention.
  • the liver fibrosis inhibitor of the present invention is effective for suppressing liver fibrosis in chronic liver disorders such as viral hepatitis or alcoholic liver disorders. That is, the hepatic fibrosis inhibitor of the present invention acts as a prophylactic agent for preventing hepatic fibrosis and a therapeutic agent for inhibiting the progression of Z or hepatic fibrosis (more preferably, a hepatic fibrosis is restored to a normal state). And a therapeutic agent for recovery).
  • liver damage is interpreted in the broadest sense and includes all of liver damage due to tissue / cell damage, rupture of the liver, inflammation, liver function deterioration, liver failure and the like.
  • Specific liver diseases that cause liver damage include, for example, liver abscess, liver cancer, alcoholic liver injury, cirrhosis, amoebic liver abscess, autoimmune hepatitis, biliary obstruction, chronic active hepatitis, chronic persistent hepatitis, Coccidioidosis, haemomatosis, viral hepatitis (hepatitis A, B, C, D, E), hepatocellular carcinoma, primary biliary cirrhosis, suppurative liver abscess, rye Syndrome, sclerosing cholangitis, Wilson's disease and the like.
  • hepatic disorder referred to in the present invention is preferably a liver disorder accompanied by liver fibrosis.
  • Preferred specific examples of such a liver disorder include viral hepatitis (hepatitis A, B, and C). , Hepatitis D, E) or alcoholic liver injury.
  • the administration route of the liver fibrosis inhibitor of the present invention is not particularly limited, and it can be administered orally or parenterally.
  • the administration route of parenteral administration is not particularly limited, and it can be injected intravenously, intramuscularly, intradermally, or subcutaneously.
  • liver fibrosis inhibitor of the present invention can be administered prophylactically prior to the onset of liver fibrosis.
  • a liver fibrosis inhibitor of the present invention may be administered to a patient who has developed liver fibrosis for the purpose of preventing the worsening of symptoms or reducing the symptoms. Examples that can be administered
  • PDGF-BB Plate derived growth factor-BB, Austrial Biologicals, Catalog No .; GF-0 70-3) at various concentrations (50 ng / m1, 100 ng / ml, 200 ng) / m 1), and then kneaded with LI-90.
  • the proliferation of LI-90 was evaluated using WST-1 ATSSE (using Takara Shuzo WST 1 cell proliferation kit). In the WST-1 assay, an increase in absorbance corresponds to an increase in cell number.
  • ⁇ -SMA smooth muscle actin
  • Table 1 shows the results of measuring cell proliferation of LI-90 when various concentrations of Mn_TBAP or edaravone were added. Fig. 1 also shows the results when edaravone was added. table 1
  • Mn-TBAP of reactive oxygen species scavenger is PDGF-BB (200 ng / m1)
  • Mn-TB AP was inhibited by PDGF-BB (200 ng / m 1).
  • SMA serum-derived mononucleic acid
  • edaravone inhibited the proliferation of LI_90 by PDGF-II in a concentration-dependent manner. Unlike ⁇ -TBA ⁇ , cytotoxicity with increasing edaravone concentration was not observed up to 10 ⁇ .
  • ROS Reactive Oxygen Species
  • NAD ⁇ ⁇ oxidase plays a role as a signal transmitter. It is thought that it plays.
  • NA DPH oxidase produces superoxide, which is converted into hydrogen peroxide, hydric xyl radicals, and other organic ion radicals inside cells.
  • Mn-TBAP and edaravone which eliminate intracellular ROS, inhibited PDGF-BB-induced LI-190 proliferation in a concentration-dependent manner.
  • Mn-TBAP showed cytotoxicity with increasing concentrations, whereas edaravone was not cytotoxic with increasing concentrations and was effective at a wide range of concentrations.
  • the agent of the present invention is useful for suppressing liver fibrosis in chronic liver injury such as viral hepatitis or alcoholic liver injury.
  • the medicament of the present invention can suppress the proliferation of hepatic stellate cells without exhibiting cytotoxicity, and thus is clinically useful as a medicament for treating and / or preventing chronic hepatic injury with few side effects.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
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  • Gastroenterology & Hepatology (AREA)
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Abstract

L'invention concerne un médicament qui permet d'inhiber la fibrose hépatique en hépatopathie chronique telle que l'hépatopathie virale ou alcoolique. L'inhibiteur de fibrose hépatique contient en tant qu'ingrédient actif un dérivé de pyrazolone représenté par la formule suivante (I) dans laquelle R1 représente hydrogène, aryle, etc., et R2 représente hydrogène, aryloxy, etc., à condition que R1 et R2 peuvent représenter conjointement l'hydroxyalkyle C3-5 et R3 représente l'hydrogène, l'alkyle C1-5, le phényle, etc.), et un sel physiologiquement acceptable du dérivé ou un hydrate ou un solvate d'un des deux.
PCT/JP2003/013304 2002-10-18 2003-10-17 Inhibiteur de fibrose hepatique WO2004035048A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003301398A AU2003301398A1 (en) 2002-10-18 2003-10-17 Hepatic fibrosis inhibitor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002-304301 2002-10-18
JP2002304301A JP2006096664A (ja) 2002-10-18 2002-10-18 肝繊維化抑制剤

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Publication Number Publication Date
WO2004035048A1 true WO2004035048A1 (fr) 2004-04-29

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AU (1) AU2003301398A1 (fr)
WO (1) WO2004035048A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5591720B2 (ja) 2009-01-29 2014-09-17 株式会社林原 抗神経変性疾患剤
KR101184725B1 (ko) 2012-04-04 2012-09-20 주식회사 셀트리온제약 사포그릴레이트를 포함하는 간섬유화 또는 간경변의 치료 또는 예방용 약제학적 조성물

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0208874A1 (fr) * 1985-05-20 1987-01-21 Mitsubishi Kasei Corporation Agent prophylactique et thérapeutique pour maladies de circulation du sang

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0208874A1 (fr) * 1985-05-20 1987-01-21 Mitsubishi Kasei Corporation Agent prophylactique et thérapeutique pour maladies de circulation du sang

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANDO KENTARO ET AL.: "Shinki radical shokyozai 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186) no ippan yakuri sayo", BASIC PHARMACOLOGY & THERAPEUTICS, no. 25, SUPPL., 1997, pages 213 - 243, XP002976211 *
FRIEDMAN S. L.: "Molecular regulation of hepatic fibrosis an integrated cellular response to tissue injury", J. BIOL. CHEM., vol. 275, no. 4, 2000, pages 2247 - 2250, XP002976213 *
FUJIWARA KENJI ET AL.: "Kanshogai to sanka hensei (Sanka toka hensei busshitsu to shikkan 3)", BIOMEDICINE & THERAPEUTICS, vol. 32, no. 4, 1998, pages 492 - 494, XP002976212 *
KAWADA NORIHUMI: "Kan sen'ika no bunshi kiko to chiryo senryaku (Dai 38 kai nihon kanzobyo gakkai sokai luncheon seminar)", MINOPHAGEN MEDICAL REVIEW, 2003, vol. 48, no. 1, 14 June 2002 (2002-06-14), pages 1 - 11, XP002976214 *

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AU2003301398A1 (en) 2004-05-04

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