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WO2004064852A1 - Melange de saponine steroidique normalise, procede de production et application correspondants - Google Patents

Melange de saponine steroidique normalise, procede de production et application correspondants Download PDF

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Publication number
WO2004064852A1
WO2004064852A1 PCT/BG2003/000043 BG0300043W WO2004064852A1 WO 2004064852 A1 WO2004064852 A1 WO 2004064852A1 BG 0300043 W BG0300043 W BG 0300043W WO 2004064852 A1 WO2004064852 A1 WO 2004064852A1
Authority
WO
WIPO (PCT)
Prior art keywords
standardised
extraction
butanol
water
per cent
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/BG2003/000043
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English (en)
Other versions
WO2004064852B1 (fr
Inventor
Roika GYULEMETOVA
Daniela Shopova
Valentin Dimov
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.)
SOPHARMA AD
Original Assignee
SOPHARMA AD
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 to UAA200508283A priority Critical patent/UA80182C2/uk
Application filed by SOPHARMA AD filed Critical SOPHARMA AD
Priority to HR20050614A priority patent/HRPK20050614B3/xx
Priority to AU2003286011A priority patent/AU2003286011A1/en
Priority to EA200501170A priority patent/EA008763B1/ru
Priority to GB0513893A priority patent/GB2412867B/en
Priority to EEP200500024A priority patent/EE05443B1/xx
Publication of WO2004064852A1 publication Critical patent/WO2004064852A1/fr
Publication of WO2004064852B1 publication Critical patent/WO2004064852B1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants

Definitions

  • the present invention relates to a standardised steroid saponin mixture obtained from the epigeous part of Tribulus terrestris L. for application in the synthesis of drugs exerting the already known aphrodisiac effect in addition to drugs with new indications.
  • the invention pertains also to the method of preparing of a standardised steroid saponin mixture obtained from the epigeous part of Tribulus terrestris L.
  • a method of isolating a standardised steroid saponin mixture obtained from the epigeous part of Tribulus terrestris L. (BG Patent 52085) is know to exist, the said method consisting in subjecting the plant material to extraction using an up to 70 per cent solution of low alcohol, ethanol in particular, then chloroform treatment and extraction from the water solution using water- saturated n-butanol, followed by concentration of the butanol extract up to 1/8 th of the volume, after which the residue thus obtained is separated and dried, while the residues from the mother liquors are water-dissolved and then added directly to the chloroform-treated water solution.
  • a standardised mixture is thus obtained, the said mixture containing 50 to 55 per cent of furostanol saponins, calculated on the basis of protodioscin.
  • Harvest is between 1.7 to 2 per cent depending on the saponin content in the plant material.
  • the problem that the present invention has solved is the extraction from the epigeous part of Tribulus terrestris L of a substance containing a high level of furostanol saponins, which can be used to prepare new drugs with new indications.
  • the problem has been solved by obtaining a standardised steroid saponin mixture containing 80 per cent of furostanol saponins.
  • the method of preparation consists in subjecting the ground plant material to extraction using aqueous methanol solvent with a water/methanol ratio ranging from 1 :1 to 1 :99 at a temperature from 52 to 55°C.
  • the extract is then treated with active carbon and after filtration is vacuum concentrated until methanol is fully removed.
  • the aqueous concentrate is subsequently subjected to extraction with methylene chloride. Methylene chloride is then distilled off and regenerated for further use in the method.
  • the purified aqueous solution is acidified with hydrochloric acid up to pH 4 and is subjected to extraction with water-saturated n-butanol by the known method. Butanol extracts are then washed with a sodium chloride solution and vacuum concentrated to obtain a dry residue which is dissolved in a low alcohol.
  • Harvest from air-dried plant material is about 3 per cent.
  • This new product containing more than 80 per cent of furostanol saponins can be used to prepare new drugs exerting an immunomodulating and/or immunostimulating effect.
  • One tonne of ground plant material is subjected to extraction using a 70- per cent methanol aqueous solution at 50° C until exhaustion.
  • the extract is drawn off, then active carbon is added thereto.
  • the resultant is passed through a filter press.
  • the aqueous concentrate thus obtained is subjected to a triple extraction with methylene chloride in a ratio of 1 :2, 1 :1 , and 1 :1 respectively.
  • the organic solvent is distilled of and regenerated, while cube residue is disposed of.
  • the purified aqueous extract is acidified with hydrochloric acid up to pH 4 and subjected to an eightfold extraction with water n-butanol in a ratio of 1 :1.
  • Butanol extracts are washed with a 5-per cent sodium chloride solution and the concentrated until a dry residue is obtained under vacuum at 60° C and then dissolved into methanol. The mixture is slowly dropped into acetone, left at a temperature of 10° C for 20 hours and finally Nutch-filtered, washed with acetone and dried.
  • a light yellow powder containing 85 percent of furostanol saponins is obtained as a result.
  • Harvest is 3 per cent from air-dried plant material.
  • the product analysis is performed on the basis of protodioscin. (R. Gyulemetova, M. Tomova, M. Simova, T. Pangarova, Pharmazie, 37, H.4 1982).
  • One tonne of ground plant material is subjected to extraction using a 70- per cent methanol aqueous solution at 50° C until exhaustion.
  • the extract is drawn off, then active carbon is added thereto.
  • the resultant is passed through a filter press.
  • the aqueous concentrate thus obtained is subjected to a triple extraction with methylene chloride in a ratio of 1 :2, 1 :1 , and 1 :1 respectively.
  • the organic solvent is distilled of and regenerated, while cube residue is disposed of.
  • the purified aqueous extract is acidified with hydrochloric acid up to pH 4 and subjected to an eightfold extraction with water saturated n-butanol in a ratio of 1 :1.
  • Butanol extracts are washed with a 1-per cent sodium hydroxide solution, the ratio of alkaline water to butanol extract being 1:1 and after separating the two layers, the butanol layer is washed with water up to pH 7. Butanol extracts are then vacuum concentrated until the organic solvent is fully removed, after which the aqueous solution is dried.
  • a light yellow powder containing 85 percent of furostanol saponins is obtained as a result.
  • Harvest is 3 per cent from air-dried plant material.
  • the product analysis is performed on the basis of protodioscin. (R. Gyulemetova, M. Tomova, M. Simova, T. Pangarova, Pharmazie, 37, H.4 1982).
  • FS furostanol saponins
  • mice Male ICR mice (average body weight from 18 to 20 g) were given various oral doses of FS, according to the description shown in Table 1.
  • Experimental infection was caused in a mouse by subcutaneous inoculation of 25 to 30 bacterial cells from an 18-hour agar Kl. Pneumonae culture (strain No 52145, Pasteur Institute, Paris). Contamination dose was chosen after running preliminary experiments aimed at obtaining a 50-per cent survival rate. The infection was followed up for eight days, taking account of the subject's general condition, mortality rate (percentage), survival rate and average survival time (AST 8 in days). The protective effect of FS was evaluated along the increase in survival rates and average survival times calculated as differences between experimental groups and controls.
  • Kl. Pneumoniae cell to FS was determined using an adapted version of the Bauer method (4).
  • Petri dishes (100 mm) containing agar were inoculated with 0.2 ml of bacterial suspension (10 cells/ml).
  • Wells (10 mm) were made and filled with 0.2 ml of a FS solution of various concentration. Inhibition areas were measured after incubation for 24 hours at 37°C.
  • Keflin was used as a positive control (Lilly, USA), in minimum inhibition concentrations of 0.150 mg/ml.
  • Alveolar Ma were obtained through in situ lung lavage by injecting and drawing a 0.1 - 1.0 ml TCM 199 solution containing 20 mM HEPES, 100 U/ml of penicillin and 0.1 mg/ml of streptomycin (Flaw Lab., UK) plus 3 U/ml of heparin (G. Richter, Hungary). The average number of washed aMa from each group was determined and the cells were then placed on incubation plates (BDSL, Scottland) in a concentration of 3 x 10 cells/ml to assess their phagocytic and microbicidal activity using a H 3 -thymidine radiometric method. (5)
  • the anti-infectious effect of FS varies according to dosage and administration schedules (Table 1).
  • the highest dose administrated (625.0 mg/kg) showed the strongest protective effect in all 10-day administration schedules, starting 35, 25 or 15 day before infection; the peak of the effect was observed where the last FS dose was administered on the 15 th day before infection.
  • FS do not exhibit in-vitro antibacterial activity.
  • a solution of FS in physiological serum at concentrations of 0.01 , 0.025, 0.05, 0.1 , 2.0, 5.0, 10.0, 25.0, 50.0, 100.0, 250.0 and 500.0 mg/ml did not suppress Kl.
  • Pneumoniae growth unlike the marked suppression observed in the Keflin group, within a mean area of 21.5 ⁇ 1.0 mm. Stimulation of aMa
  • FS do not exert a bactericide effect.
  • FS influence the main effector mechanisms of cell and humoral immunity thus granting a marked protection from infection.
  • the optimum dose of 625.0 mg/kg administered over a sequence of 10 days is very close to the schedule (6) applied in humans.
  • the strongest protective effect obtained with the schedule where the time gap between the last application of FS and infection is 15 days can be explained with the dynamics of aMa activation.
  • the maximum increase in their functional activity is observed by the 20 th day which coincides with the acute phase of the infection (day 3 to 5).
  • the great number of aMa with an increased phagocytic and microbicidal capacity prevent aggravation of the infection and reduce mortality rate, thus simultaneously increasing survival rate.
  • FS activate aMa which play a significant role in the antibacterial protection of the lung, in particular in managing infections caused by opportunistic pathogens such as Kl. Pneumonae (6).
  • the results represent average data from four independent experiments using 10 experimental animals for each group.

Landscapes

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

Abstract

L'invention concerne un mélange de saponine stéroïde normalisé, obtenu à partir de la partie épigée de Tribulus terrestris L., contenant plus de 80 pour cent de saponines de furostanol. L'invention concerne également un procédé permettant de produire ledit mélange et son application comme immunostimulateur et immunomodulateur.
PCT/BG2003/000043 2003-01-24 2003-12-11 Melange de saponine steroidique normalise, procede de production et application correspondants Ceased WO2004064852A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
UAA200508283A UA80182C2 (en) 2003-01-24 2003-11-12 Mixture of steroid saponins obtained from tribulus terrestris l. with immunomodulating properties, a method of its obtaining and application
HR20050614A HRPK20050614B3 (en) 2003-01-24 2003-12-11 Standardised steroid saponin mixture, a method of its obtaining and application
AU2003286011A AU2003286011A1 (en) 2003-01-24 2003-12-11 Standardised steroid saponin mixture, a method of its obtaining and application
EA200501170A EA008763B1 (ru) 2003-01-24 2003-12-11 Стандартизованная смесь стероидных сапонинов, способ ее получения и ее применение
GB0513893A GB2412867B (en) 2003-01-24 2003-12-11 Standardised steroid saponin mixture, a method of its obtaining and application
EEP200500024A EE05443B1 (et) 2003-01-24 2003-12-11 Standarditud steroidsete saponiinide segu, selle saamise meetod ja kasutamine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BG107499A BG65737B1 (bg) 2003-01-24 2003-01-24 Стандартизирана смес от стероидни сапонини, метод за нейното получаване и приложението й
BG107499 2003-01-24

Publications (2)

Publication Number Publication Date
WO2004064852A1 true WO2004064852A1 (fr) 2004-08-05
WO2004064852B1 WO2004064852B1 (fr) 2004-10-07

Family

ID=32739195

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/BG2003/000043 Ceased WO2004064852A1 (fr) 2003-01-24 2003-12-11 Melange de saponine steroidique normalise, procede de production et application correspondants

Country Status (10)

Country Link
AU (1) AU2003286011A1 (fr)
BG (1) BG65737B1 (fr)
EA (1) EA008763B1 (fr)
EE (1) EE05443B1 (fr)
GB (1) GB2412867B (fr)
HR (1) HRPK20050614B3 (fr)
LV (1) LV13366B (fr)
PL (1) PL377142A1 (fr)
UA (1) UA80182C2 (fr)
WO (1) WO2004064852A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7906493B2 (en) 2003-12-22 2011-03-15 Btg International Limited Core 2 GlcNAc-T inhibitors
US7998943B2 (en) 2005-07-06 2011-08-16 Btg International Limited Core 2 GlcNAc-T inhibitors III
US8197794B2 (en) 2003-12-22 2012-06-12 Ms Therapeutics Limited Core 2 GlcNAc-T inhibitors
CN103040880A (zh) * 2012-12-13 2013-04-17 大兴安岭林格贝有机食品有限责任公司 一种刺蒺藜皂苷的分离纯化方法
US8609633B2 (en) 2005-07-06 2013-12-17 Ms Therapeutics Limited Core 2 GlcNAc-T inhibitors
EP4509130A1 (fr) * 2023-08-14 2025-02-19 Vemo-99 Ood Procédé de purification d'alcaloïdes de pyrrolizidine d' un produit végétal biologiquement actif contenant des furostanol saponines dérivé de tribulus terestris

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020082780A1 (en) * 1999-08-13 2002-06-27 ALEXIS Brian Natural, anti-bacterial, anti-virus, anti-herpes cream

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BG52085B2 (en) * 1985-01-18 1996-06-28 Tomova Method for the isolation of standardized mixture of steroid saponins

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020082780A1 (en) * 1999-08-13 2002-06-27 ALEXIS Brian Natural, anti-bacterial, anti-virus, anti-herpes cream

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ACHENBACH H ET AL: "CARDIOACTIVE STEROID SAPONINS AND OTHER CONSTITUENTS FROM THE AERIAL PARTS OF TRIBULUS CISTOIDES", PHYTOCHEMISTRY, PERGAMON PRESS, GB, vol. 35, no. 6, 1 April 1994 (1994-04-01), pages 1527 - 1543, XP000576854, ISSN: 0031-9422 *
ADAIKAN P G ET AL: "HISTORY OF HERBAL MEDICINES WITH AN INSIGHT ON THE PHARMACOLOGICAL PROPERTIES OF TRIBULUS TERRESTRIS", AGING MALE, PARTHENON, LONDON, GB, vol. 4, no. 3, 2001, pages 163 - 169, XP009015949, ISSN: 1368-5538 *
GJULEMETOWA R ET AL: "UEBER DIE BESTIMMUNG VON FUROSTANOLSAPONINEN IM PRAEPARAT TRIBESTAN", PHARMAZIE, VEB VERLAG VOLK UND GESUNDHEIT. BERLIN, DD, vol. 37, no. 4, 1982, pages 296, XP001154500, ISSN: 0031-7144 *
MURAKAMI TOSHIYUKI ET AL: "Medicinal foodstuffs. XVII. Fenugreek seed. (3): Structures of new furostanol-type steroid saponins, trigoneosides Xa, Xb, XIb, XIIa, XIIb, and XIIIa, from the seeds of Egyptian Trigonella foenum-graecum L", CHEMICAL AND PHARMACEUTICAL BULLETIN (TOKYO), vol. 48, no. 7, July 2000 (2000-07-01), pages 994 - 1000, XP000180963, ISSN: 0009-2363 *
PETIT PIERRE R ET AL: "Steroid saponins from fenugreek seeds: Extraction, purification, and pharmacological investigation on feeding behavior and plasma cholesterol", STEROIDS, vol. 60, no. 10, 1995, pages 674 - 680, XP000876727, ISSN: 0039-128X *
YAN W ET AL: "Steroidal saponins from fruits of Tribulus terrestris", PHYTOCHEMISTRY, PERGAMON PRESS, GB, vol. 45, no. 4, June 1997 (1997-06-01), pages 811 - 817, XP004293208, ISSN: 0031-9422 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7906493B2 (en) 2003-12-22 2011-03-15 Btg International Limited Core 2 GlcNAc-T inhibitors
US8197794B2 (en) 2003-12-22 2012-06-12 Ms Therapeutics Limited Core 2 GlcNAc-T inhibitors
US7998943B2 (en) 2005-07-06 2011-08-16 Btg International Limited Core 2 GlcNAc-T inhibitors III
US8609633B2 (en) 2005-07-06 2013-12-17 Ms Therapeutics Limited Core 2 GlcNAc-T inhibitors
CN103040880A (zh) * 2012-12-13 2013-04-17 大兴安岭林格贝有机食品有限责任公司 一种刺蒺藜皂苷的分离纯化方法
EP4509130A1 (fr) * 2023-08-14 2025-02-19 Vemo-99 Ood Procédé de purification d'alcaloïdes de pyrrolizidine d' un produit végétal biologiquement actif contenant des furostanol saponines dérivé de tribulus terestris

Also Published As

Publication number Publication date
BG107499A (bg) 2004-08-31
HRP20050614A2 (en) 2006-06-30
HRPK20050614B3 (en) 2007-10-31
GB0513893D0 (en) 2005-08-10
PL377142A1 (pl) 2006-01-23
EE200500024A (et) 2005-10-17
EE05443B1 (et) 2011-08-15
EA200501170A1 (ru) 2005-12-29
UA80182C2 (en) 2007-08-27
WO2004064852B1 (fr) 2004-10-07
BG65737B1 (bg) 2009-09-30
EA008763B1 (ru) 2007-08-31
AU2003286011A1 (en) 2004-08-13
GB2412867B (en) 2007-07-04
LV13366B (en) 2006-03-20
GB2412867A (en) 2005-10-12

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