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WO1998042350A1 - Cholesterol lowering pharmaceutical composition - Google Patents

Cholesterol lowering pharmaceutical composition Download PDF

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Publication number
WO1998042350A1
WO1998042350A1 PCT/KR1997/000127 KR9700127W WO9842350A1 WO 1998042350 A1 WO1998042350 A1 WO 1998042350A1 KR 9700127 W KR9700127 W KR 9700127W WO 9842350 A1 WO9842350 A1 WO 9842350A1
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Prior art keywords
cholesterol
compound
pharmaceutical composition
pentagalloylglucose
solution
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/KR1997/000127
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French (fr)
Inventor
Jong Koo Park
Hong Suk Kye
Hi Jae Cho
Chul Hoon Lee
Young Hoon Kim
Jae Kyu Shin
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CJ Corp
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CJ Corp
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Priority to AU31923/97A priority Critical patent/AU3192397A/en
Publication of WO1998042350A1 publication Critical patent/WO1998042350A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024—Esters of saccharides
    • 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)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony

Definitions

  • the present invention relates to a novel pharmaceutical composition useful in preventing or treating hypercholesterolemia or atherosclerosis or promoting lipid metabolism in mamr ⁇ als.
  • Cholesterol is a component of animal cell membrane and an important lipid as precusors of bile acid, steroid hormone, vitamin D, etc.
  • Cholesterol level in body is defined as the combination of exogenous cholesterol taken in from outside, endogenous cholesterol biosynthesized in the body, and bile acids discharged into the stool and urine.
  • the ratio of exogenous holesterol to endogenous cholesterol is about 3: 1. That is, the quantity of cholesterol synthesized in the body is even greater than that of cholesterol taken in from outside and much of such endogenous cholesterol is biosynthesized in the liver.
  • the drug for the treatment of hypercholesterolemia or atherosclerosis includes internal uptake inhibitor (Cholestyramin), lipid metabolism promotor (Heparin) and cholesterol biosynthesis inhibitor (Lovastatin).
  • internal uptake inhibitor Choestyramin
  • Heparin lipid metabolism promotor
  • Lovastatin cholesterol biosynthesis inhibitor
  • the 1,2,3,4,6-O-pentagalloylglucose compound of the present invention is isolated from Paeonia m ⁇ irfan SIM., Paeoniaceae.
  • This medicinal plant is known to exhibit pharmacological actions such as antiinflammation, thrombocyte agglutinati, anti hemorrhage, analgesia, antiparalysis, gastric secretion, antibacterial action, etc, but there are no reports suggesting cholesterol lowering action thereof.
  • the present pentagalloylglucose compound can be orally administered, injected or infused in single or, preferably, in combination with conventional pharmaceutically acceptable carriers, adjuvants or additives.
  • the present compound may be formulated into tablet, solution, capsule, granule, particle, powder, injection, etc.
  • the carrier for oral formulation includes, for example, starch, mannitol, crystalline cellulose, CMC Na, water, ethanol, etc.
  • the carrier for injection includes water, physiological saline solution, glucose solution, and other conventionally used solutions.
  • the dry powder of Paeonia woulan SIM. was extracted in 80% methanol solution at the temperature of 70 °C for 3 hours.
  • the methanol was removed from the resulting extracts under reduced pressure and the further extraction was carried out using n-butanol.
  • the resulting extracts was chromatographed on silica gel, eluting with n-hexane and ethanol to yield active fraction which was then run on high performance liquid chromatography column to isolate the 1,2,3,4,6-O-pentagalloylglucose compound (C ) H 32 O 26 , MW 940.70).
  • test compound was added to 0.1 mM potassium phosphate buffer, pH 7.4, comprising rat liver microsome fraction (containing 0.1 mg of proteins), rat liver cytosol fraction (containing 0.1 mg of proteins), 1 mM
  • a control was also prepared and measured with the same manner as described above but not using any test compounds.
  • test compound was added to 0 1 M potassium phosphate buffer, pH 7.4, comprising rat liver microsome fraction (containing 0.05 mg of proteins), 5 mM potassium chloride, 10 mM potassium fluoride, 1 mM
  • NADPH 30 mM nicotinamide, 001 mM tolnaftate and 0.01 mM [1-1H] ammonium farnesylpyrophosphate to prepare 100 ⁇ l of reaction mixture.
  • the reaction mixture was incubated at 37 °C for 2 hours, the reaction was stopped by the addition of 400 ⁇ l of 20% sodium hydroxide (95% ethanol solution).
  • the reaction mixture was saponified at 75 °C for 30 minutes and 200 ⁇ l of distilled water and 500 ⁇ l of petroleum ether were then added to extract the squalene.
  • the extracted squalene was concentrated and dried to obtain a residue.
  • a control was also prepared and measured in the same manner as described above but not using any test compounds.
  • group A was supplied with conventional solid rat feeds for ten days and was orally administered with 0.2% aqueous methylcellulose solution once each day.
  • Group B was supplied with high cholesterol level solid feeds and was orally administered with 0.2% aqueous methylcellulose solution once each day
  • group C was supplied with high cholesterol level solid feeds and orally administered with a solution of pentagalloylglucose compound (100 mg/kg of rat weight/5ml) in 0.2% methylcellulose
  • group D was supplied with high cholesterol level solid feeds and orally administered with a solution of pentagalloylglucose compound (300 mg kg of rat weight/5ml) in 0.2% methylcellulose.
  • day 1 the feeding was stopped and the rats were killed. After bloods were collected from the dead rats and serum was separated, levels of triglyceride (TG), cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) were measured using Blood
  • LDL-C low density lipoprotein cholesterol
  • LDL-C Total TC - (TG/5 + HDL-C)
  • groups A, B and C were supplied with conventional solid rat feeds for ten days. Once each day during that period, group A was orally administered with 0.2% aqueous methylcellulose solution, group B was orally administered with a solution of pentagalloyl glucose compound (30 mg/kg of rat weight 5ml) in 0.2% methylcellulose, and group C was orally administered with a solution of lobastatin (30 mg/kg of rat weight/5ml) in 0.2% methylcellulose. On day 1 1 the feeding was stopped and the rats were killed. After bloods were collected from the dead rats and serum was separated, levels of triglyceride (TG), cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) were measured using
  • LDL-C Total TC - (TG/5 + HDL-C)

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Biotechnology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Steroid Compounds (AREA)

Abstract

The present invention discloses a novel pharmaceutical composition useful in preventing or treating hypercholesterolemia or atherosclerosis or promoting lipid metabolism in mammals which comprises an effective amount of 1,2,3,4,6-O-pentagalloylglucose having the structure (I).

Description

CHOLESTEROL LOWERING PHARMACEUTICAL COMPOSITION
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to a novel pharmaceutical composition useful in preventing or treating hypercholesterolemia or atherosclerosis or promoting lipid metabolism in mamrηals.
Description of the Prior Art
Cholesterol is a component of animal cell membrane and an important lipid as precusors of bile acid, steroid hormone, vitamin D, etc.
However, excessive cholesterol in blood causes sclerosis of the arteries in which cholesterol forms a deposit of plaque on the inner lining of arteries.
As blood cholesterol levels become higher, the incidence of coronary atherosclerosis also rises and, due to this, the potential for diseases such as myocardial infarction or cerebral apoplexy is increased.
Cholesterol level in body is defined as the combination of exogenous cholesterol taken in from outside, endogenous cholesterol biosynthesized in the body, and bile acids discharged into the stool and urine. The ratio of exogenous holesterol to endogenous cholesterol is about 3: 1. That is, the quantity of cholesterol synthesized in the body is even greater than that of cholesterol taken in from outside and much of such endogenous cholesterol is biosynthesized in the liver.
The drug for the treatment of hypercholesterolemia or atherosclerosis includes internal uptake inhibitor (Cholestyramin), lipid metabolism promotor (Heparin) and cholesterol biosynthesis inhibitor (Lovastatin). However, it has been known that such dnigs have side effects, such as liver or kidney disturbance, cholelithiasis, dyspepsia, etc.
Therefore, there is always a need to develop new drugs useful in treating or preventing hypercholesterolemia or atherosclerosis in mammals.
SUMMARY OF THE INVENTION
The present invention provides a novel pharmaceutical composition useful in preventing or treating hypercholesterolemia or atherosclerosis or promoting lipid metabolism in mammals which comprises an effective amount of a pentagalloylglucose compound having the following structure:
Figure imgf000004_0001
DETAILED DESCRIPTION OF THE INVENTION
The 1,2,3,4,6-O-pentagalloylglucose compound of the present invention is isolated from Paeonia mσirfan SIM., Paeoniaceae. This medicinal plant is known to exhibit pharmacological actions such as antiinflammation, thrombocyte agglutinati, anti hemorrhage, analgesia, antiparalysis, gastric secretion, antibacterial action, etc, but there are no reports suggesting cholesterol lowering action thereof.
The present pentagalloylglucose compound can be orally administered, injected or infused in single or, preferably, in combination with conventional pharmaceutically acceptable carriers, adjuvants or additives. For example, the present compound may be formulated into tablet, solution, capsule, granule, particle, powder, injection, etc.
The carrier for oral formulation includes, for example, starch, mannitol, crystalline cellulose, CMC Na, water, ethanol, etc. The carrier for injection includes water, physiological saline solution, glucose solution, and other conventionally used solutions.
The method for isolating the pentagalloylglucose compound of the present invention and the cholesterol lowering actions thereof will be described in detail below.
Isolation of the present pentagalloylglucose compound
The dry powder of Paeonia woulan SIM. was extracted in 80% methanol solution at the temperature of 70 °C for 3 hours. The methanol was removed from the resulting extracts under reduced pressure and the further extraction was carried out using n-butanol. The resulting extracts was chromatographed on silica gel, eluting with n-hexane and ethanol to yield active fraction which was then run on high performance liquid chromatography column to isolate the 1,2,3,4,6-O-pentagalloylglucose compound (C )H32O26, MW 940.70).
Inhibitory Action on Choi esterol Biosynthesis
Inhibition of cholesterol biosynthesis by varied concentrations of the test pentagalloylglucose compounds as shown in Table I below was measured by a liquid scintillation method.
The test compound was added to 0.1 mM potassium phosphate buffer, pH 7.4, comprising rat liver microsome fraction (containing 0.1 mg of proteins), rat liver cytosol fraction (containing 0.1 mg of proteins), 1 mM
ATP, 6 mM glutathione, M glucose- 1 -phosphate, 0.04 mM CoA, 0.25 M NAD, 0.25 M NADP and 0.2 M [1-I4C] sodium acetate to prepare 100 μl of reaction mixture. After the reaction mixture was incubated at 37T for 2 hours, the reaction was stopped by the addition of 250 μl of 15% potassium hydroxide (95% ethanol solution). The reaction mixture was saponified at 75 °C for 1 hour and 250 μl of distilled water and 500 μl of petroleum ether were then added to extract the cholesterol. The extracted cholesterol was concentrated and dried to obtain a residue whose radiation activity was then measured using a liquid scintillation counter.
A control was also prepared and measured with the same manner as described above but not using any test compounds.
The cholesterol biosynthesis inhibiting effect of the test compound was determined as inhibition percentage using the following equation: Inhibition percentage
Radiation activity of control — Radiation activity of test compound
X 100
Radiation activity of control
The results are indicated in Table I below.
Table I Inhibitory action of the pentagalloylglucose compound on cholesterol biosynthesis
Figure imgf000007_0001
Inhibitory Action on Squalene J3iosynthesis
The test compound was added to 0 1 M potassium phosphate buffer, pH 7.4, comprising rat liver microsome fraction (containing 0.05 mg of proteins), 5 mM potassium chloride, 10 mM potassium fluoride, 1 mM
NADPH, 30 mM nicotinamide, 001 mM tolnaftate and 0.01 mM [1-1H] ammonium farnesylpyrophosphate to prepare 100 μl of reaction mixture. After the reaction mixture was incubated at 37 °C for 2 hours, the reaction was stopped by the addition of 400 μl of 20% sodium hydroxide (95% ethanol solution). The reaction mixture was saponified at 75 °C for 30 minutes and 200 μl of distilled water and 500 μl of petroleum ether were then added to extract the squalene. The extracted squalene was concentrated and dried to obtain a residue. The residue was dissolved in a small amount of chloroform and the resulting solution was thin layer chromatographed over silica gel, developing with chloroform, to isolate the squalene whose radiation activity was then measured using a liquid scintillation counter.
A control was also prepared and measured in the same manner as described above but not using any test compounds.
The squalene biosynthesis inhibiting effect of the test compound was determined as inhibition percentage using the following equation:
Inhibition percentage =
Radiation activity of control - Radiation activity of test compound X 100
Radiation activity of control
The results are indicated in Table I below.
Table I
Inhibitory effect of pentagalloylglucose compound on squalene biosynthesis
Figure imgf000008_0001
Action to lower serum cholesterol level In hypercholesterolemic hamster
Four groups of male hamster (syrian golden), weighing 120 ± 5g and 10 to 12 weeks old, each group consisting of six hamsters, were raised for a period of two weeks, light of 12 hours and darkness of 12 hours everyday, in a rat house with temperature of 25 ! 1 °C and humidity of 55 ± 5%. Water and feed were supplied unlimitedly during that period.
After the preliminary raising period of 12 weeks, group A was supplied with conventional solid rat feeds for ten days and was orally administered with 0.2% aqueous methylcellulose solution once each day. Group B was supplied with high cholesterol level solid feeds and was orally administered with 0.2% aqueous methylcellulose solution once each day, group C was supplied with high cholesterol level solid feeds and orally administered with a solution of pentagalloylglucose compound (100 mg/kg of rat weight/5ml) in 0.2% methylcellulose, and group D was supplied with high cholesterol level solid feeds and orally administered with a solution of pentagalloylglucose compound (300 mg kg of rat weight/5ml) in 0.2% methylcellulose. On day 1 1 the feeding was stopped and the rats were killed. After bloods were collected from the dead rats and serum was separated, levels of triglyceride (TG), cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) were measured using Blood
Biochemistry Autoanalyzer (manufactured by Ciba-corning). The serum 2 low density lipoprotein cholesterol (LDL-C) level was calculated by the following equation:
LDL-C = Total TC - (TG/5 + HDL-C)
The results are indicated in Table II below.
Table II Inhibitory action of pentagalloylglucose compound on blood cholesterol levels in hypercholesterolemic hamster
Figure imgf000010_0001
* The values in parenthesis indicate percentages of Group B.
Action to Lower Serum Cholesterol Level in Healthy Hamster
Three groups of male hamster (syrian golden), weighing 120 ± 5 g and 10 to 12 weeks old, each group consisting of six individuals, were raised for a period of two weeks, 12 hours of day and 12 hours of night everyday, in spearate rat houses with temperature of 25 ± 1 "C and humidity of 55 ± 5%. Water and feed were supplied unlimitedly during that period.
After the preliminary raising period of 12 weeks, groups A, B and C were supplied with conventional solid rat feeds for ten days. Once each day during that period, group A was orally administered with 0.2% aqueous methylcellulose solution, group B was orally administered with a solution of pentagalloyl glucose compound (30 mg/kg of rat weight 5ml) in 0.2% methylcellulose, and group C was orally administered with a solution of lobastatin (30 mg/kg of rat weight/5ml) in 0.2% methylcellulose. On day 1 1 the feeding was stopped and the rats were killed. After bloods were collected from the dead rats and serum was separated, levels of triglyceride (TG), cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) were measured using
Blood Biochemistry Autoanalyzer (manufactured by Ciba-corning). The serum low density lipoprotein cholesterol (LDL-C) level was calculated by the following equation: LDL-C = Total TC - (TG/5 + HDL-C)
The results are indicated in Table HI below.
Table III
Inhibitory action of pentagalloyl glucose compound on blood cholesterol levels of healthy hamster
Figure imgf000011_0001
The values in parenthesis indicate percentages of Group B.

Claims

WHAT IS CLAIMED IS:
1. A pharmaceutical composition for the prevention or treatment of hypercholesterolemia or atherosclerosis or the promotion of lipid metabolism in mammals which comprises an effective amount of a pentagalloylglucose compound having the following structure:
Figure imgf000012_0001
2. The composition according to claim 1 which inhibits the squalene biosynthesis.
PCT/KR1997/000127 1997-03-21 1997-06-27 Cholesterol lowering pharmaceutical composition Ceased WO1998042350A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004009094A1 (en) * 2002-07-24 2004-01-29 Ohio University Methods and compositions for treating diabetes mellitis
WO2005070943A1 (en) * 2004-01-23 2005-08-04 Ohio University Pgg separation and purification
CN120695018A (en) * 2025-08-26 2025-09-26 山东第一医科大学附属省立医院(山东省立医院) Application of 1,2,3,4,6-O-pentagalloylglucose in the preparation of anti-cholestatic liver disease drugs

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20030075947A (en) * 2002-03-19 2003-09-26 제네티카 주식회사 Angiogenesis inhibitor

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004009094A1 (en) * 2002-07-24 2004-01-29 Ohio University Methods and compositions for treating diabetes mellitis
WO2005070943A1 (en) * 2004-01-23 2005-08-04 Ohio University Pgg separation and purification
CN1930178B (en) * 2004-01-23 2010-06-23 俄亥俄州立大学 PGG separation and purification
US8357796B2 (en) 2004-01-23 2013-01-22 Ohio University PGG separation and purification
CN120695018A (en) * 2025-08-26 2025-09-26 山东第一医科大学附属省立医院(山东省立医院) Application of 1,2,3,4,6-O-pentagalloylglucose in the preparation of anti-cholestatic liver disease drugs

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