WO2008013362A1 - Composition de médicament de traitement ou de prévention de l'ulcère gastrique - Google Patents

Composition de médicament de traitement ou de prévention de l'ulcère gastrique Download PDF

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Publication number
WO2008013362A1
WO2008013362A1 PCT/KR2007/002693 KR2007002693W WO2008013362A1 WO 2008013362 A1 WO2008013362 A1 WO 2008013362A1 KR 2007002693 W KR2007002693 W KR 2007002693W WO 2008013362 A1 WO2008013362 A1 WO 2008013362A1
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WO
WIPO (PCT)
Prior art keywords
freeze
stomach
stomach ulcer
supernatant
earthworms
Prior art date
Application number
PCT/KR2007/002693
Other languages
English (en)
Inventor
Il Hwan Cho
Chul Kyu Lee
Jang Sik Shin
Byung Soo Kim
Original Assignee
Il Hwan Cho
Chul Kyu Lee
Jang Sik Shin
Byung Soo Kim
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 Il Hwan Cho, Chul Kyu Lee, Jang Sik Shin, Byung Soo Kim filed Critical Il Hwan Cho
Publication of WO2008013362A1 publication Critical patent/WO2008013362A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/62—Leeches; Worms, e.g. cestodes, tapeworms, nematodes, roundworms, earth worms, ascarids, filarias, hookworms, trichinella or taenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • 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
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to a composition for preventing or treating stomach ulcers. More specifically, the present invention relates to a composition efficacious in preventing or treating stomach ulcers comprising a freeze-dried earthworm powder or an earthworm-extracted supernatant, both of which contain lumbrokinase as an active ingredient, wherein the earthworm-extracted supernatant is prepared by wet-grinding living earthworms and centrifuging the grinded earthworms, and the freeze-dried earthworm powder is obtained by filtering the supernatant, followed by freeze-drying.
  • Dried earthworm powders or earthworm extracts have been used for antihyperlipemic, antidiabetic, blood pressure-controlling and antithrombosis drugs. Such use is based on their medical efficacies recorded in Oriental Medicine Literatures (Shinnongbonchogyeong, etc).
  • Oriental Medicine Literatures Shinnongbonchogyeong, etc.
  • the present inventors have demonstrated that lumbrokinase contained in earthworms is efficacious in treating stomach ulcers via repeated research and tests, taking into consideration the facts that earthworms contain a great amount of lumbrokinase, which is one of the proteases, and that a great deal of protease activated receptors (PARs) which have activities for lumbrokinase are present in a human's stomach.
  • PARs protease activated receptors
  • Lumbrokinase contained in earthworms is reported to be a serine-based protease, be considerably stable against heat or pH and exhibit a specific activity for fibrin, which is one of thrombus' ingredients. Lumbrokinase administered orally must be released through the intestines into blood so that it can exert its efficacy. Research associated with this release is considered to be recently conducted.
  • PARs protease activated receptors
  • the present invention has been made to solve the foregoing problems of the prior art and it is an aspect of the present invention to provide a composition for preventing and treating stomach ulcers comprising a freeze-dried earthworm powder or an earthworm-extracted supernatant, both of which contain lumbrokinase as an active ingredient, wherein the earthworm-extracted supernatant is prepared by wet-grinding living earthworms and centrifuging the grinded earthworms, and the freeze-dried earthworm powder is obtained by filtering the supernatant, followed by freeze-drying.
  • a composition for preventing and treating stomach ulcers comprising a freeze-dried earthworm powder or an earthworm-extracted supernatant, both of which contain lumbrokinase as an active ingredient, wherein the earthworm-extracted supernatant is prepared by wet-grinding living earthworms and centrifuging the grinded earthworms, and the freeze-dried earthworm powder is obtained by filtering the supernatant, followed by freeze-drying .
  • composition of the present invention is efficacious in preventing and treating stomach ulcers.
  • FIGs. 1 and 2 are photographs showing the gastrointestines of a control group in Example 4 according to the present invention
  • FIGs. 3 and 4 are photographs showing the gastrointestines of a white rat to which Omeprazole is administered in Example 4 according to the present invention
  • FIGs. 5 and 6 are photographs showing the gastrointestines of a white rat to which Stillene is administered in Example 4 according to the present invention.
  • FIGs . 7 and 8 are photographs showing the gastrointestines of a white rat to which a freeze-dried earthworm powder is administered in Example 4 according to the present invention. [Best Mode]
  • the anti-stomach ulcer composition according to the present invention comprises a freeze-dried earthworm powder or a supernatant extracted from earthworms (hereinafter, referred to simply as "earthworm supernatant”) .
  • the anti-stomach ulcer composition contains lumbrokinase , which is one of the proteases, as an active ingredient.
  • a method for preparing the anti-stomach ulcer composition of the present invention comprises: washing raw earthworms with distilled water; wet-grinding the earthworms; centrifuging the earthworms at 2,000 ⁇ g to 4,000*g for 20 to 40 min to obtain a supernatant; and preparing a supernatant-containing composition for preventing and treating stomach ulcers.
  • the method may further comprise filtering the supernatant through diatomaceous silica to remove water- insoluble materials.
  • the method may further comprise freeze-drying the supernatant to prepare a freeze-dried earthworm powder.
  • the preparation of the anti-stomach ulcer composition is carried out using the freeze-dried earthworm powder.
  • the supernatant was filtered through diatomaceous silica to separate water-insoluble materials therefrom.
  • the resulting residue was freeze-dried to prepare a freeze-dried earthworm powder.
  • the weight of the freeze-dried earthworm powder obtained from the raw earthworms (10 Kg) was 1.2 Kg and a titer of a casein digestion was 870 units /g.
  • Example 2 Effects of Stomach Ulcer Protection on Stomach Ulcer Model Induced by Stress 6 week-old white Wistar male rats were used as subjects.
  • Stomach ulcers were induced by a Water-Immersion Restraint Stress Model in which white rats are immersed in a bath. This model is to induce rats to have acute stomach ulcers by forcing the rats to be immersed in a stress cage containing water they hate for 6 hours.
  • a test drug (Stillene ® 60 mg/kg or freeze-dried earthworm powder 50 mg/kg) was administered to the rats at 30 minutes before water-immersion. The temperature of the bath was maintained at 21 ° C to 23 ° C.
  • the stomach of each specimen was enucleated and the pylorus of the stomach was then ligated. Then, 3 mL of a 2% formalin solution was injected through the cardiac orifice and the specimen was fixed for 10 min. After completion of the fixation, the greater curvature of the stomach was excised and washed with physiological saline. The resulting greater curvature was thoroughly spread, fixed on a fixing plate and taken as a photograph. The area of injured site in the photograph was measured with a bio-imaging analyzer.
  • Table 1 Effects of Freeze-dried Earthworm Powder on Stomach Ulcers Induced by Water-Immersion Restraint Stress
  • Stillene ® (Positive control drug): available from Dong-a pharmaceutical Co. , Ltd.
  • Stomach ulcer area is represented by "average ⁇ standard error”.
  • a stomach ulcer-inducing drug used herein was indomethacin, one of non-steroidal anti- inflammatory drugs.
  • the indomethacin was reported to inhibit activity of cyclooxygenase that participates in prostacyclin synthesis in gastric cells, causing gastric injury.
  • a test drug (Stillene * 60 mg/kg or freeze-dried earthworm powder 50 mg/kg) was administered to the Wistar rats, which had been fasted during the overnight prior to testing. After 30 minutes, 20 mg/kg of indomethacin was orally-administered to the rats to induce stomach ulcers. At 6 hours following the stomach ulcer-inducing drug administration, the rats were sacrificed.
  • the stomach of each specimen was enucleated and the pylorus of the stomach was then ligated. 3 mL of a 2% formalin solution was injected through the cardiac orifice and the specimen was fixed for 10 min. After completion of the fixation, the greater curvature of the stomach was excised and washed with physiological saline. The resulting greater curvature was thoroughly spread, fixed on a fixing plate and taken as a photograph. The length of injured site in the photograph was measured with a bio-imaging analyzer.
  • Stillene ® (Positive control drug) : available from Dong-a pharmaceutical Co. , Ltd.
  • Stomach ulcer area is represented by "average ⁇ standard error”. " * " represents statistical significance at 95% confidence level, in contrast with control groups.
  • Example 4 Stomach Ulcer Treatment Effects of Freeze-dried Earthworm Powder on Stomach Ulcer Model 6 week-old white Wistar male rats were used as subjects. Stomach ulcers were induced by a Water-Immersion Restraint Stress Model in the same manner as Example 2. Stomach ulcer-induction (water-immersion) was performed for three days, once per day, that is, three times in total. In the first day, after the rats were subjected to water- immersion for 3 hours, they were isolated from a bath and transferred into a breeding cage. At 3 hours following the water-immersion, a test drug (Omeprazole 10 mg/kg, Stillene ® 60 mg/kg or freeze-dried earthworm powder 50 mg/kg) was orally-administered to the rats.
  • a test drug Omeprazole 10 mg/kg, Stillene ® 60 mg/kg or freeze-dried earthworm powder 50 mg/kg
  • the water-immersion was carried out for 2 hours and the test drugs were administered to the rats in the same dosage as in the first day at one hour prior to water-immersion and at three hours after the completion of water-immersion.
  • water-immersion and drug administration were carried out in the same manner as in the second day.
  • the rats were sacrificed and the stomach thereof was enucleated.
  • the pylorus of the stomach was then ligated.
  • 3 mL of a 2% formalin solution was injected through the cardiac orifice and the specimen was fixed for 10 min.
  • the greater curvature of the stomach was excised and washed with physiological saline.
  • the resulting greater curvature was thoroughly spread, fixed on a fixing plate and taken as a photograph.
  • the area of injured site in the photograph was measured with a bio-imaging analyzer.
  • Table 3 Stomach Ulcer Treatment Effects of Freeze-dried Earthworm Powder on Stomach Ulcers Induced by Water- Immersion Restraint Stress
  • Stillene ® (Positive control drug) : available from Dong-a pharmaceutical Co., Ltd.
  • Omeprazole used in only Example 4, where a stomach ulcer treatment effect is tested, as ingredient of stomach ulcer drug available from Sigma Co., Ltd.
  • Stomach ulcer area is represented by "average ⁇ standard error”.
  • w * Ii represents statistical significance at 95% confidence level, in contrast with control groups.
  • Example 5 Tests with Earthworm-extracted Supernatant The tests were performed in the same manner as in Examples 2 to 4 , except that 8.5 kg of the earthworm- extracted supernatant prepared in Example 1 was used instead of the freeze-dried earthworm powder. Since the earthworm- extracted supernatant has a weight, about 7-fold higher than that of the freeze-dried earthworm powder, it was used in an amount corresponding to 7-fold of the weight of the freeze- dried earthworm powder used in Examples 2 to 4.
  • the anti-stomach ulcer composition of the present invention is efficacious in preventing and treating stomach ulcers, thus being industrially applicable.
  • w * " represents statistical significance at 95% confidence level, in contrast with control groups.
  • Example 5 Tests with Earthworm-extracted Supernatant The tests were performed in the same manner as in Examples 2 to 4 , except that 8.5 kg of the earthworm- extracted supernatant prepared in Example 1 was used instead of the freeze-dried earthworm powder. Since the earthworm- extracted supernatant has a weight, about 7-fold higher than that of the freeze-dried earthworm powder, it was used in an amount corresponding to 7-fold of the weight of the freeze- dried earthworm powder used in Examples 2 to 4.
  • the anti-stomach ulcer composition of the present invention is efficacious in preventing and treating stomach ulcers, thus being industrially applicable.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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Abstract

La présente invention concerne une composition pour prévenir et traiter les ulcères gastriques. Cette composition comprend une poudre de vers de terre lyophilisée ou un surnageant extrait des vers de terre. Dans les deux cas, le principe actif est la lumbrokinase. En l'occurrence, le surnageant se prépare par broyage à sec de vers de terre vivants, puis par centrifugation du broyat, la poudre lyophilisée se préparant par filtrage du surnageant, lequel filtrage est suivi de la lyophilisation. Cette composition convient particulièrement en prévention et traitement des ulcères gastriques.
PCT/KR2007/002693 2006-07-25 2007-06-04 Composition de médicament de traitement ou de prévention de l'ulcère gastrique WO2008013362A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020060069987A KR100814201B1 (ko) 2006-07-25 2006-07-25 항위궤양용 또는 위궤양치료용 약학조성물
KR10-2006-0069987 2006-07-25

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WO2008013362A1 true WO2008013362A1 (fr) 2008-01-31

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010029453A1 (fr) * 2008-09-10 2010-03-18 Pt.Dexa Medica Composition d'agent thrombolytique et anti-thrombotique ainsi que son procédé de production
CN106955355A (zh) * 2016-01-08 2017-07-18 北京百奥药业有限责任公司 他汀类药物与蚓激酶的药物组合物、制剂及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4568545A (en) * 1982-10-02 1986-02-04 Amano Seiyaku Kabushiki Kaisha Thrombolytic agent
EP0383533B1 (fr) * 1989-02-15 1994-08-24 Eimei Company Ltd Médicament contre la thrombose et sa méthode de préparation
KR20000003837A (ko) * 1998-06-29 2000-01-25 장용택 롬브리신을 유효성분으로 하는 면역증강제
KR20050107640A (ko) * 2004-05-10 2005-11-15 신풍제약주식회사 유기용매를 이용한 구인 단백질분해효소 분말의 제조방법

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4568545A (en) * 1982-10-02 1986-02-04 Amano Seiyaku Kabushiki Kaisha Thrombolytic agent
EP0383533B1 (fr) * 1989-02-15 1994-08-24 Eimei Company Ltd Médicament contre la thrombose et sa méthode de préparation
KR20000003837A (ko) * 1998-06-29 2000-01-25 장용택 롬브리신을 유효성분으로 하는 면역증강제
KR20050107640A (ko) * 2004-05-10 2005-11-15 신풍제약주식회사 유기용매를 이용한 구인 단백질분해효소 분말의 제조방법

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010029453A1 (fr) * 2008-09-10 2010-03-18 Pt.Dexa Medica Composition d'agent thrombolytique et anti-thrombotique ainsi que son procédé de production
CN106955355A (zh) * 2016-01-08 2017-07-18 北京百奥药业有限责任公司 他汀类药物与蚓激酶的药物组合物、制剂及其应用

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KR100814201B1 (ko) 2008-03-17
KR20080010040A (ko) 2008-01-30

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