WO2000027413A1 - Composition pharmaceutique pour le traitement de l'hepatite c comprenant de la corilagine ou de l'acide carboxylique de brevifoline - Google Patents

Composition pharmaceutique pour le traitement de l'hepatite c comprenant de la corilagine ou de l'acide carboxylique de brevifoline Download PDF

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Publication number
WO2000027413A1
WO2000027413A1 PCT/KR1999/000190 KR9900190W WO0027413A1 WO 2000027413 A1 WO2000027413 A1 WO 2000027413A1 KR 9900190 W KR9900190 W KR 9900190W WO 0027413 A1 WO0027413 A1 WO 0027413A1
Authority
WO
WIPO (PCT)
Prior art keywords
corilagin
carboxylic acid
hbv
brevifolin carboxylic
hepatitis
Prior art date
Application number
PCT/KR1999/000190
Other languages
English (en)
Inventor
Tai Ho Chung
Chong Chan Chung
Seok Yoon
Original Assignee
Hepaguard Co., Ltd.
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
Priority claimed from KR1019980048244A external-priority patent/KR20000031970A/ko
Priority claimed from KR1019980048245A external-priority patent/KR20000031971A/ko
Application filed by Hepaguard Co., Ltd. filed Critical Hepaguard Co., Ltd.
Publication of WO2000027413A1 publication Critical patent/WO2000027413A1/fr

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Classifications

    • 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
    • A61K36/13—Coniferophyta (gymnosperms)
    • 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)
    • A61K36/47—Euphorbiaceae (Spurge family), e.g. Ricinus (castorbean)

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a corilagin or brevifolin carboxylic acid, which shows a therapeutic activity for hepatitis B.
  • Hepatitis B virus is a kind of Hepadnaviridae and those infected by HBV may go through a latency period ranging from 60 to 110 days, followed by varying degrees of symptoms. Although 90 to 95% of the infected may eventually recover, some of them may develop chronic active hepatitis, cirrhosis or hepatocellular carcinoma. Chronic hepatitis B frequently causes chronic viral infection, lymphoma and/or chronic nephropathy, leading to the possible death of the patient.
  • HBV vaccine Since a HBV vaccine was developed in 1981, vaccination against HBV has been performed on those who are considered to be susceptible including neonates; however, no significant drop in the number of HBV carriers has been witnessed yet. This may be attributable to the fact that vertical transmission of HBV from mother to fetus is a major cause of becoming a HBV carrier. While babies born from hepatitis B e antigen (HBeAg) -positive carriers are seldom infected through their placenta, they may become immunologically defective against HBV and turn into chronic HBV carriers when exposed to HBV during their birth, or through a damaged placenta, or when sensitized by HBeAg through the placenta .
  • HBeAg hepatitis B e antigen
  • HBV treating agents presently in use, e.g., Interferon- ⁇ (Roche Pharmaceuticals, U.S.A.) and Adenine Arabinoside (Mochita Pharmaceuticals, Japan) are effective only in temporarily lowering the serum transaminase activity, but are not suitable for the treatment of chronic hepatitis B.
  • Thymosin(SciClone Co., U.S.A.) has an effect of immuno- therapeutic activity but it is not a true HBV treating agent .
  • a pharmaceutical composition for treating hepatitis B which comprises a therapeutically effective amount of a gallic acid derivative selected from the group consisting of corilagin, brevifolin carboxylic acid and a mixture therof , and a pharmaceutically acceptable carrier.
  • Fig. 1 reproduces the image of HBV particles observed under an electron microscope .
  • Figs. 2 and 3 are photographs of the liver tissues cultured with or without added corilagin or brevifolin carboxylic acid (A: liver tissues cultured in the presence of corilagin or brevifolin carboxylic acid and B:
  • a gallic acid derivative having the structure of formula I (corilagin) or formula II (brevifolin carboxylic acid) is an anti-HBeAg antibody (HBeAb) -like substance, having the ability to inhibit the activity of HBV DNA polymerase and causes a serious deformation of HBV virus particles, while exhibiting little toxicity or mitogenicity to mammals.
  • HBeAb anti-HBeAg antibody
  • Corilagin and brevifolin carboxylic acid are gallic acid derivatives that can be extracted from Phyllanthus sp . plants . urinaria employed in the present invention is an annual herbaceous plants belonging to the genus
  • Corilagin and brevifolin carboxylic acid may be prepared in accordance with the following preferred -embodiment .
  • P. urinaria is washed with water, air-dried at room temperature, and then chopped into small pieces.
  • the plant pieces are extracted with a aqueous alcohol solution, preferably 30% ethanol at a suitable temperature, preferably 60°C to obtain a crude extract.
  • the crude extract is concentrated to obtain a powder.
  • corilagin and brevifolin carboxylic acid inhibit the activity of HBV DNA polymerase at a concentration of 10 ⁇ g/ t and 25 ⁇ g/ ⁇ ? or more, respectively, the inhibitory effect escalating with increasing concentration thereof.
  • corilagin and brevifolin carboxylic acid show little toxicity or mitogenicity in tests using mice. More specifically, corilagin and brevifolin carboxylic acid exhibit no toxicity when these are intraperitoneally administered to mice at a dosage level of 500 mg/kg and
  • corilagin and brevifolin carboxylic acid have no adverse effects on the liver function, judging from the fact that the sGOT, sGPT, ALP (alkaline phosphatase) and bilirubin levels of test mice remain unchanged when corilagin or brevifolin carboxylic acid is administered to normal mice.
  • Corilagin and brevifolin carboxylic acid also exhibit positive clinical effects in human patients. Specifically, when corilagin or brevifolin carboxylic acid is administered to chronic active hepatitis B patients in an amount of 4 mg/kg body weight/day, the presence of HBV DNA becomes - no longer detectable after several months from the administration thereof.
  • corilagin and brevifolin carboxylic acid give rise to remarkable improvements in the serum GOT and GPT levels of chronic active hepatitis B patients with complicated hepatocirrhosis .
  • corilagin or brevifolin carboxylic acid can be used as an effective pharmaceutical agent for the treatment of hepatitis B, which has little toxicity and causes no adverse effect.
  • the present invention provides a pharmaceutical composition for the treatment of hepatitis B, which comprises corilagin or brevifolin carboxylic acid as an active ingredient, in combination with pharmaceutically acceptable excipients, carriers or diluents .
  • a pharmaceutical formulation may be prepared by using the composition in accordance with any of the conventional procedures.
  • the active ingredient is preferably admixed or diluted with a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid or liquid material acting as a vehicle, excipient or medium for the active ingredient.
  • the formulations may be in the form of a tablet, pill, powder, sachet, elixir, suspension, emulsion, solution, syrup, aerosol, soft and hard gelatin capsule, sterile injectable solution, sterile packaged powder and the like.
  • Suitable carriers, excipients, and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, mi c r o c ry s t a 11 i ne cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoates, propylhydroxybenzoates, talc, magnesium stearate and mineral oil.
  • the formulations may additionally include fillers, anti-agglutinating -agents, lubricating agents, wetting agents, flavoring agents, emulsifiers, preservatives and the like.
  • the compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after their administration to a patient by employing any of the procedures well known in the art.
  • the pharmaceutical formulations can be administered via various routes including oral, transdermal , subcutaneous, intravenous and intramuscular introduction.
  • a typical daily dose of the active ingredient may range from about 4 to 12 mg/kg body weight, preferably 4 to 8 mg/kg body weight, and can be administered in a single dose or in divided doses.
  • the amount of the active ingredient actually administered ought to be determined in light of various relevant factors including the condition to be treated, the chosen route of administration, the age, sex and body weight of the individual patient, and the severity of the patient's symptom; and, therefore, the above dose should not be intended to limit the scope of the invention in any way.
  • Phyllanthusurinaria growing in the field of Daegu, Republic of Korea was harvested and dried. About 600g of dried E ⁇ _ urinaria was chopped into small pieces and extracted with 30% ethanol at 60°C for 4 hours to obtain an crude extract . The crude extract thus obtained was concentrated under a reduced pressure to obtain 90g of a powdery extract.
  • the powdery extract was dissolved in water and subjected to sepadex LH-20 column chromatography (45mm D x 90mm L(Sigma, U.S.A.), wherein water was used as an eluent, and then, a water-methanol mixture was used as an eluent while increasing the concentration of methanol from 20% to 40%, 60%, 80% and 100% to obtain five 500m fractions (I to V).
  • fractions thus obtained were lyophilized to obtain residues and a portion of each of the residues was subjected to thin layer chromatography. Tests for the presence of tannic acid using 2% FeCl3 in ethanol showed that fractions II, III and IV contained tannic acid.
  • step (1) The fraction III obtained in step (1) was subjected to column chromatography ( column : MCI-gel CHP2 OP (Mitsubishi Chemical, Japan) , Toyopearl HW 40F (Sigma, U.S.A.) and RP-18 (Merck, Germany, wherein a mixture of water and methanol (5 : 5) ) was used as an eluent to obtain 2.7g of corilagin as a white powder having the following properties:
  • step (1) The fraction IV obtained in step (1) was subjected to column chromatography ( column : MCI-gel
  • a liver tissue obtained from a traumatized patient having HBsAg, HBsAb, HBeAg and HBeAb-negative serum was immersed in a 10% FCS/DMEM solution (Dulbcco' s Modified Eagle medium, containing 10% fetal calf serum) , containing 100 unit/m penicillin and 100 ⁇ g/m 1 streptomycin washed six times with the same solution and chopped into 0.5 - 1mm 3 pieces. The chopped liver tissue was transferred into a 10% FCS/DMEM solution containing 0.5mg/m collagenase and 200 unit/mi dispase and shaken gently for 15 minutes.
  • FCS/DMEM solution Dulbcco' s Modified Eagle medium, containing 10% fetal calf serum
  • HBV particles 0.5 m! of a serum sample taken from an HBsAg and HBV DNA-positive patient was centrifuged at 150,000 xg for 5 hours to obtain HBV particles.
  • the pelletted HBV particles were suspended in 5mi of an aqueous solution which contained 1.24g of cesium chloride and centrifuged at 96,000xg for 42 hours.
  • PBS phosphate buffered saline
  • PBS phosphate buffered saline
  • Fig. 1 reproduces the image of HBV particles observed with an electron microscope.
  • HBV DNA positive-serum containing a large amount of HBV particles was added to the cultured liver cell medium obtained in step (1) in a volume ratio of 1:1 and cultured at 37°C for 120 hours under a 5% C0- atmosphere to obtain HBV infected cells.
  • step (3) The procedure of step (3) was repeated, except that corilagin preparated in Preparation Example was added to the medium containing cultured liver cell to a concentration of 20 ⁇ g/m , lO ⁇ g/mi, 5 ⁇ g/m or 2 ⁇ g/mi to infect HBV DNA positive-serum.
  • Figs. 2a and 2b wherein Fig. 2A is the photograph of the liver tissue cultured in the presence of 20 ⁇ g/m corilagin while Fig. 2B is represents the control cultured in the absence of corilagin.
  • Fig 2B an abundance of dyed HBsAg was found in the control, and some HBsAg was also detected in the liver tissues cultured in the presence of 10 ⁇ g/mi, 5 ⁇ g/mi and 2 ⁇ g/mi of added corilagin.
  • the liver tissue cultured in 20 ⁇ g/m£ corilagin exhibits no sign of HBsAg (Fig. 2A) . Accordingly, corilagin effect on the infection of HBV at a concentration of 20 ⁇ g/mi or more.
  • step (4) The procedure of step (4) was repeated except that brevifolin carboxylic acid preparated in Preparation Example was used at a concentration of 100 ⁇ g/m , 50 ⁇ g/ ⁇ u?, 25 ⁇ g/m 12 ⁇ g/m or 6 ⁇ g/m .
  • FIG. 3A is the photograph of the liver tissue cultured in the presence of 50 ⁇ g/m of added brevifolin carboxylic acid of the present invention
  • Fig. 3B the control.
  • an abundance of dyed HBsAg was found in the control, and some HBsAg was also detected in the liver tissues cultured in the presence of 25 ⁇ g/m , 12 ⁇ g/m and 6 ⁇ g/m-. of added brevifolin carboxylic acid.
  • brevifolin carboxylic acid exerts an inhibitory effect on the infection of HBV at a concentration of 50 ⁇ g/m or more.
  • Test Example 2 Inhibitory Activity of Corilagin or Brevifolin Carboxylic Acid on the
  • Corilagin prepared in the Preparation Example was dissolved in distilled water to final concentrations of 20 ⁇ g/m , 10 ⁇ g/rri, 5 ⁇ g/m and 2 ⁇ g/mi, respectively, the resulting solutions were reacted with HBV particles (Dane particles) , and then the degree of inhibition of DNA polymerase was determined as follows.
  • 0.2 ml of serum containing HBV particles was mixed with 2.3 ml of solution 1(0.01 M Tris-HCl (pH 7.4), 0.15 M NaCl) and then centrifuged at 4°C, 10,000 rpm for 10 min. The resulting supernatant was placed on 2.5 ml of solution 2(30 % (w/v) sucrose, 0.01 M Tris-HCl (pH 7.4), 0.15 M NaCl, 0.001 M EDTA, 0.1 % 2-mercaptoethanol, 1 mg bovine serum albumin (BSA) ) and then centrifuged at 4°C, 50,000 rpm for 4 hours.
  • BSA bovine serum albumin
  • the resulting pellets were suspended in 25 ⁇ l of solution 3(0.01 M Tris-HCl (pH 7.4), 0.15 M NaCl, 1 % NP-40, 0.1 % 2-mercaptoethanol) .
  • To the suspension were added 25 ⁇ l of corilagin solutions prepared above and 25 ⁇ l of polymerase mixture (0.2 M Tris-HCl (pH 7.4), 0.08 M MgCl 2 , 0.24 M NH 4 Cl, 1 M dATP, 1 mM dTTP, 0.0025 nM 3 H-dCTP and 0.0025 nM 3 H-dGTP(both of them are inactive and 21 Ci/mM) ) .
  • the mixture was reacted at 37°C for 3 hours and then spotted on a Watman 3 mm filter. The filter was washed with 15 % trichloroacetic acid and 90 % ethanol and then air-dried.
  • the amount of radioactivity of each spot was determined by using a liquid scintillation counter (Packand Inc., U.S.A.), and the degree of inhibition (%) of the DNA polymerase activity was determined based on the activity of DNA polymerase measured in the absence of corilagin, as 100%. The result is shown in Table 1.
  • Table 1 shows that the activity of HBV DNA polymerase decreases in proportion with increasing concentration of corilagin at 10 ⁇ g/m and more.
  • step (1) The procedure of step (1) was repeated except that brevifolin carboxylic acid preparated in Preparation Example was used at concentration of 100 ⁇ g/m!, 50 ⁇ g/m£, 25 ⁇ g/mi 12 ⁇ g/rru? and 6 ⁇ g/ml .
  • concentration of 100 ⁇ g/m!, 50 ⁇ g/m£, 25 ⁇ g/mi 12 ⁇ g/rru? and 6 ⁇ g/ml The result is shown in Table 2.
  • Table 2 shows that the activity of HBV DNA polymerase decreases in proportion with increasing concentration of brevifolin carboxylic acid at 25 ⁇ g/ml and more .
  • mice Twenty white mice were divided into two groups, each consisting of ten mice.
  • the mice of the first group were administered 0.1% aqueous solution of corilagin ( Experimental group) and the mice of the second group were administered physiological saline solution (Control group) , for 12 weeks, respectively.
  • sGOT serum glutamic oxaloacetic transaminase
  • sGPT serum glutamic pyruvic transaminase
  • serum alkaline phosphatase ALP
  • serum bilirubin activities were determined by using AST/GOT, ALT/GPT, ALP, and serum bilirubin diagnostic kits (Sigma Chemicals Co., U.S.A.) in accordance with the manufacturer's protocols.
  • step (1) The procedure of step (1) was repeated except that 0.1% aqueous solution of brevifolin carboxylic acid preparated in Preparation Example was used. The results of the above tests are shown in Table 4.
  • mice 15 4-week-old male mice each weighing from 15.9 to 22.9g and 15 4-week-old female mice each weighing 14.8 to 18.5g (Animal room, School of Medicine, Kyungpook National University, Korea) were divided into three groups.
  • mice of the first and second groups were intraperitoneally administered physiological saline solution containing 250mg/kg and 500mg/kg of corilagin (Experimental groups 1 and 2), respectively.
  • the mice of the third group were intraperitoneally administered physiological saline solution (Control group) . Lethality of mice and abnormalities of the internal organs thereof were observed 14 days from the administration and the result is shown in Table 5.
  • corilagin exhibited no toxicity when it was intraperitoneally administered.
  • step (1) The procedure of step (1) was repeated except that brevifolin carboxylic acid preparated in Preparation Example was used at concentration of 300 mg/kg and 600 mg/kg.
  • concentration of 300 mg/kg and 600 mg/kg The results of the above tests are shown in Table 6.
  • corilagin and brevifolin carboxylic acid were investigated employing a chronic active hepatitis B patient and a HBV carrier with chronic hepatitis as test subjects, as follows.
  • a patient who was presumed to suffer a chronic active hepatitis on the basis of the result of HBsAg ( + ) HBsAb(-) HBeAg(+) HBeAb(-) anti-HBc(+) in a hepatic function test and showed GOT of 124 and GPT of 221, which fall in the warning ranges, was administered with corilagin at a dose of 4 mg/kg body weight/day for 6 months .
  • HBeAb and serum HBV DNA were detected as positive and negative, respectively, after 3 months treatment with corilagin and the transaminase values were significantly improved. Further, HBeAg was detected as negative after 6 months treatment with corilagin.
  • step (1) The procedure of step (1) was repeated except that brevifolin carboxylic acid preparated in Preparation Example was used.
  • the alteration of the serological idices during the treatment is shown in Table 8.
  • HBeAb was detected as positive, after 3 months treatment with brevifolin carboxylic acid. Further, HBeAg and serum HBV DNA were detected as negative, respectively, after 6 months treatment with brevifolin carboxylic acid and the transaminase values were significantly improved.
  • corilagin and brevifolin carboxylic acid may be used as an effective HBV treating agent which have little toxicity and causes no adverse effect.

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Abstract

L'invention concerne une composition pharmaceutique comprenant de la corilagine ou un acide carboxylique de brévifoline, efficace pour la traitement de l'hépatite B.
PCT/KR1999/000190 1998-11-11 1999-04-22 Composition pharmaceutique pour le traitement de l'hepatite c comprenant de la corilagine ou de l'acide carboxylique de brevifoline WO2000027413A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR1019980048244A KR20000031970A (ko) 1998-11-11 1998-11-11 코릴라진을 포함하는 항 비형 간염 바이러스 조성물
KR1998/48244 1998-11-11
KR1998/48245 1998-11-11
KR1019980048245A KR20000031971A (ko) 1998-11-11 1998-11-11 브레비폴린 카르복실산을 포함하는 항 비형 간염 바이러스조성물

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2116253A1 (fr) * 2008-05-07 2009-11-11 Phytrix JV, LLC Nouvel extrait de Phyllanthus
WO2017210559A1 (fr) * 2016-06-02 2017-12-07 The Regents Of The University Of California Composés et méthodes de traitement de la fibrose ou du cancer

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0436239A (ja) * 1990-05-31 1992-02-06 Fujirebio Inc 抗ｈｂｖ剤
JPH04169527A (ja) * 1990-10-31 1992-06-17 Fujirebio Inc 抗ｈｂｖ剤
WO1998007437A1 (fr) * 1996-08-16 1998-02-26 Hepaguard Co., Ltd. COMPOSITION PHARMACEUTIQUE POUR LE TRAITEMENT DE L'HEPATITE B A BASE D'EXTRAIT DE Phyllanthus ussuriensis ET/OU DE $i(Phyllanthus urinaria)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0436239A (ja) * 1990-05-31 1992-02-06 Fujirebio Inc 抗ｈｂｖ剤
JPH04169527A (ja) * 1990-10-31 1992-06-17 Fujirebio Inc 抗ｈｂｖ剤
WO1998007437A1 (fr) * 1996-08-16 1998-02-26 Hepaguard Co., Ltd. COMPOSITION PHARMACEUTIQUE POUR LE TRAITEMENT DE L'HEPATITE B A BASE D'EXTRAIT DE Phyllanthus ussuriensis ET/OU DE $i(Phyllanthus urinaria)

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Chemical Abstract, Vol. 129, No. 14, 05 October 1998 (Columbus, Ohio, USA), page 10, abstract No. 169989X, CALIXTO et al., "A review of the plants of the genus Phyllanthus: their chemistry, pharmacology and therapeutic potential"; & Med. Res. Rev. 1998, Vol. 18, No. 4, pages 225 - 258 (Eng). *
Database WPI on EPOQUE, DW9212, London: Derwent Publications Ltd., AN:1992-092934; & JP-A-4 036 239 (FUJI REBIO KK), 06 February 1992 *
Patent Abstract of Japan; & JP-A-4 169 527 (FUJIREBIO INC.), 17 June 1992 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2116253A1 (fr) * 2008-05-07 2009-11-11 Phytrix JV, LLC Nouvel extrait de Phyllanthus
WO2017210559A1 (fr) * 2016-06-02 2017-12-07 The Regents Of The University Of California Composés et méthodes de traitement de la fibrose ou du cancer

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