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WO2017034389A1 - Composition probiotique destinée au traitement ou à la prévention d'hypercholestérolémie - Google Patents

Composition probiotique destinée au traitement ou à la prévention d'hypercholestérolémie Download PDF

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Publication number
WO2017034389A1
WO2017034389A1 PCT/MY2016/050015 MY2016050015W WO2017034389A1 WO 2017034389 A1 WO2017034389 A1 WO 2017034389A1 MY 2016050015 W MY2016050015 W MY 2016050015W WO 2017034389 A1 WO2017034389 A1 WO 2017034389A1
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WO
WIPO (PCT)
Prior art keywords
cholesterol
composition
ftdc
subject
effective amount
Prior art date
Application number
PCT/MY2016/050015
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English (en)
Inventor
Min Tze LIONG
Lee Ching LEW
Huey Shi LYE
Joo Ann EWE
Mohd Nazalan MOHD NAJIMUDIN
Kee Shin SIM
Li Oon Chuah
Sy Bing CHOI
Hiroshi Ohno
Original Assignee
Universiti Sains Malaysia
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 Universiti Sains Malaysia filed Critical Universiti Sains Malaysia
Publication of WO2017034389A1 publication Critical patent/WO2017034389A1/fr

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Classifications

    • 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
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61K2035/11—Medicinal preparations comprising living procariotic cells
    • A61K2035/115—Probiotics

Definitions

  • This present invention relates to a composition for treatment or management of high blood cholesterol. More particularly, the composition provided herein is capable of reducing total serum cholesterol in a subject.
  • Hypercholesterolemia is a condition characterized by high levels of cholesterol in the blood. Cholesterol is essential to the proper functioning of the body. It is required for the production of hormones, bile and vitamin D. Cholesterol travels through the blood in the form of lipoprotein, which is a combination of cholesterol and protein.
  • lipoprotein which is a combination of cholesterol and protein.
  • HDL high-density lipoprotein
  • LDL low- density lipoprotein
  • VLDL very low-density lipoprotein
  • a healthy person has a total cholesterol level of less than 200 mg cholesterol per deciliter of blood, and a LDL level of less than 100 mg/dL blood.
  • HDL functions to remove LDL which is responsible for the plaque buildup on the walls of arteries.
  • CAD coronary artery disease
  • Hypercholesterolemia is a chronic disease that remains asymptomatic for decades. People diagnosed with hypercholesterolemia may resort to cholesterol-lowering medications to bring LDL level back to normal. Drugs commonly used to treat high cholesterol include statins, niacin (nicotinic acid), bile acid sequestrants, cholesterol absorption inhibitors and fibric acid derivatives. However, many people may avert the use of cholesterol-lowering drug by practicing dietary control, such as avoiding diets which are high in fat, salt and free sugar and low in complex carbohydrate, fruits and vegetables. Besides, people affected with hypercholesterolemia are advised to maintain a healthy lifestyle through smoking cessation, reduced alcohol intake, increased physical activity and weight reduction.
  • An United States Patent No. 20070172468 provides a dietary supplement for reducing cholesterol levels comprising at least one phytosterol source, at least one soluble fiber source, at least one guggulsterone source and at least one policosanol source. Another United States Patent No.
  • 20060062862 describes a cholesterol- reducing agent made of dietary fiber and at least one cholesterol-reducing active ingredient selected from the group consisting of statin, inhibitor of bile acid resorption, bile acid sequestrant, fibrate, nicotinic acid derivative, phytosterol, plant stanol, cholesterol-reducing plant extract, gugulipid and soy protein-containing product.
  • dietary supplement containing phytosterol may not be suitaible for consumption for people with phytosterolemia, an inherited lipid disorder.
  • consumption of guggulipid by people with bleeding disorder is harmful as guggulipid can slow down blood clotting process and increase the chances of bruising and bleeding.
  • guggulipid might also stimulate thyroid activity, which can be problematic for people who are on thyroid replacement medication for hypothyroidism.
  • bile acid sequestrant may bind drug and fat-soluble vitamins, consequently preventing absorption of drugs or causing vitamin deficiency.
  • the primary object of the present invention is to provide a composition capable of reducing total serum cholesterol in a subject upon ingestion.
  • the composition is relatively safe for consumption as Lactobacillus fermentum spp. have low pathogenic potential and are one of the human microflora.
  • Another object of the present invention is to provide a composition capable of promoting bile salt deconjugation. In order to balance enterohepatic circulations, deconjugation of bile salt stimulates production of new bile acids, which eventually leads to reduction of cholesterol in the blood.
  • one object of the present invention is to provide a composition capable of lowering total serum cholesterol that is suitable for subjects with high blood cholesterol and abnormal red blood cell morphology.
  • one object of the present invention is to provide a method of reducing total serum cholesterol in a subject by providing the subject a oral composition comprising L. fermentum FTDC 8312 in a pharmaceutically effective amount.
  • At least one of the preceding objects is met, in whole or in part, by the present invention, in which the embodiment of the present invention describes a composition capable of reducing total serum cholesterol in a subject upon ingestion comprising Lactobacillus fermentum strain FTDC 8312 in a pharmaceutically effective amount.
  • the reducing of total serum cholesterol is achieved by way of promoting bile salt deconjugation in the subject.
  • the pharmaceutically effective amount of L. fermentum strain FTDC 8312 is 8 to 10 logio CFU/g (colony-forming units per gram).
  • the composition may further comprise a pharmaceutically acceptable carrier.
  • the carrier may be selected from the group consisting of dextrin, sugar alcohol, polysaccharides, prebiotics or any compound deemed necessary for production of hygroscopic powder.
  • composition may be formulated into capsule, emulsion or suspension.
  • the present invention features a method of reducing total serum cholesterol in a subject comprising administering orally the subject a composition comprising L. fermentum strain FTDC 8312 in a pharmaceutically effective amount.
  • composition comprising L. fermentum strain 8312 in the pharmaceutically effective amount reduces total serum cholesterol by way of promoting bile production as a result of enhanced bile salt deconjugation.
  • Figure 1 shows the total serum cholesterol of BALB/c mice after fed with high- fat diet for 2 weeks (p ⁇ 0.05).
  • FIG. 2 shows the total serum cholesterol (TC) of hypercholesterolemia induced-mice after 7 weeks of treatment with the composition described herein (p ⁇ 0.05).
  • Figure 3 shows the FIDL-cholesterol levels of hypercholesterolemia induced- mice after 7 weeks of treatment with the composition described herein (p ⁇ 0.05). shows the LDL-cholesterol levels of hypercholesterolemia induced- mice after 7 weeks of treatment with the composition described herein (p ⁇ 0.05). shows the atherogenic indexes of hypercholesterolemia induced-mice after 7 weeks of treatment with the composition described herein (p ⁇ 0.05). shows the serum apolipoprotein levels of hypercholesterolemia induced-mice after 7 weeks of treatment with the composition described herein (p ⁇ 0.05). shows the ratio of apoBlOO/apoAl of hypercholesterolemia induced- mice after 7 weeks of treatment with the composition described herein (p ⁇ 0.05).
  • FIG. 1 shows the fecal cholesterol levels of hypercholesterolemia induced- mice after 7 weeks of treatment with the composition described herein (p ⁇ 0.05). shows the fecal triglycerides levels of hypercholesterolemia induced- mice after 7 weeks of treatment with the composition described herein (p ⁇ 0.05). shows the fecal total bile acids levels of hypercholesterolemia induced- mice after 7 weeks of treatment with the composition described herein (p ⁇ 0.05).
  • Figure 11 shows the ratio of cholesterol :phospholipid (C:P) content in red blood cell membrane of hypercholesterolemia induced-mice after 7 weeks of treatment with the composition described herein (p ⁇ 0.05).
  • Figure 12 shows the morphology of red blood cell of control group for (A) 0 week and (B) 7 weeks of treatment with the composition described herein; Lactobacillus fermentum FTDC 8312 group for (A) 0 week and (B) 7 weeks of treatment with the composition described herein; and Lactobacillus fermentum JCM 1173 group for (A) 0 week and (B) 7 weeks of treatment with the composition described herein.
  • the present invention discloses a composition capable of reducing total serum cholesterol in a subject upon ingestion comprising Lactobacillus fermentum strain FTDC 8312 (referred hereinafter to as "FTDC 8312") in a pharmaceutically effective amount.
  • FTDC 8312 in the composition is alive upon consumption.
  • FTDC 8312 may be immobilized.
  • the composition confers a cholesterol-lowering effect to the subject. In more particular, intake of the composition results in reduction of serum/plasma total cholesterol, LDL-cholesterol and triglycerides as well as increment of HDL-cholesterol.
  • ingestion of FTDC 8312 leads to increase in serum HDL-cholesterol level, decrease in serum LDL-cholesterol level and decrease in atherogenic index (total cholesterol/HDL-cholesterol). More specifically, serum apolipoprotein A-l (apoAl) level is increased while serum apolipoprotein B-100 (apoB lOO) level is reduced owing to the consumption of FTDC 8312.
  • ApoAl is a major component of HDL in plasma. It promotes efflux of cholesterol from white blood cells within artery wall to liver for excretion.
  • ApoBlOO is the primary apolipoprotein for LDL in plasma which is responsible for carrying cholesterol around the body. High level of ApoBlOO in the body causes the formation of plaques on the artery walls. Accordingly intake of FTDC 8312 promotes excretion of cholesterol from the plasma and prevents hardening of the arteries.
  • the composition disclosed herein is capable of reducing total serum cholesterol. Specifically, reduction of total serum cholesterol is achieved by way of promoting bile acids synthesis in the subject as a result of enhanced bile salts deconjugation.
  • Bile salts are bile acids conjugated to amino acids such as taurine and glycine.
  • the terms 'bile salts' and 'conjugated bile acids' are used interchangeably unless otherwise indicated.
  • FTDC 8312 produces bile acid hydrolase which hydrolazes bile salts into free bile acids that are more hydrophobic and thus not able to be reabsorbed into the small intestines compared to conjugated bile acids.
  • Deconjugated bile salts that are not reabsorbed by the small intestines are excreted from the body, causing an increase in fecal total bile acids.
  • the liver is triggered to produce new bile acids to replenish the bile acids.
  • cholesterol is broken down to produce bile acids, such as cholic acid and chenodeoxycholic acid, resulting in a decrease in the total serum cholesterol level.
  • the pharmaceutically effective amount of FTDC 8312 is from 8 to 10 logio CFU/g (colony-forming unit per gram). More preferably, the pharmaceutically effective amount of FTDC 8312 is about 9 logio CFU/g.
  • the composition may be formulated into capsule, emulsion or suspension.
  • the composition is prepared in liquid form.
  • the composition comprising FTDC 8312 is formulated into microemulsion.
  • the composition disclosed herein can be used to produce a food or drink product containing FTDC 8312.
  • FTDC 8312 may present in the food or drink product at a range of from 8 to 10 logio CFU per gram of food or drink product.
  • the composition can be a dietary supplement containing the bacteria strain.
  • the composition may further comprise excipient selected from the group consisting of preservative, emulsifier, stabilizer, sweetener, flavoring agent, or the combination thereof. It is preferable to include dextrin, sugar alcohol, polysaccharides, prebiotics or any compound deemed necessary for production of hygroscopic powder.
  • the term 'prebiotics' as used herein refers to substances capable of promoting growth of L. fermentum strain FTDC 8312 in the composition when it is provided as dietary supplement.
  • the composition disclosed herein is especially suitable for subjects with high blood cholesterol.
  • the composition is suitable for subjects with both high blood cholesterol and abnormal red blood cell morphology problem.
  • the present invention features a method of reducing total serum cholesterol in a subject comprising administering orally the subject a composition as described in the foregoing description in a pharmaceutically effective amount.
  • the pharmaceutically effective amount of FTDC 8312 is from 8 to 10 logio CFU/g. More preferably, the pharmaceutically effective amount of FTDC 8312 is about 9 logio CFU/g.
  • the composition can be consumed regularly, for example, everyday
  • composition comprising L. fermentum strain 8312 in the pharmaceutically effective amount reduces total serum cholesterol by way of promoting bile salt deconjugation in the subject.
  • enhanced bile salt deconjugation eventually leads to increased production of new bile acids, which in turn will lead to reduction of total serum cholesterol.
  • Lactobacillus fermentum FTDC 8312 was isolated from human fecal samples. The cholesterol lowering effect of strain FTDC 8312 was compared using a strain obtained from the Japan Collection of Microorganisms, RIKEN, Japan, L. fermentum JCM 1173, in an experiment utilizing mice as model organism. The organisms were activated successively 3 times in sterile de Man, Rogosa, and Sharpe (MRS) broth (Hi-Media, Mumbai, India) before experimental use.
  • MRS Sharpe
  • PBS phosphate buffer saline
  • fermentum FTDC 8312 10 9 CFU/mL
  • JCM 1173 group HFD + 400 ⁇ .
  • Figure 11 shows that the cholesterol :phospholipids (C:P) ratio of red blood cells (RBC) from mice on the FTDC 8312 diet after 7 weeks was lower to those on the control and JCM 1173 diets.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

L'invention concerne une composition probiotique pour le traitement ou la prévention d'hypercholestérolémie, capable de réduire le cholestérol sérique total chez un sujet lors de l'ingestion, et comprenant une souche de Lactobacillus fermentum FTDC 8312 dans une quantité pharmaceutiquement efficace.
PCT/MY2016/050015 2015-08-25 2016-03-17 Composition probiotique destinée au traitement ou à la prévention d'hypercholestérolémie WO2017034389A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MYPI2015702828 2015-08-25
MYPI2015702828A MY193625A (en) 2015-08-25 2015-08-25 Probiotic composition for treatment or prevention of high blood cholesterol

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WO2017034389A1 true WO2017034389A1 (fr) 2017-03-02

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112877241A (zh) * 2021-02-02 2021-06-01 浙江大学 一株人源性发酵乳杆菌zjuids06及其应用
NL2038332A (en) * 2024-03-12 2024-08-29 Chongqing Tianyou Dairy Co Ltd Lactobacillus fermentum ty-m18 and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002034273A1 (fr) * 2000-10-25 2002-05-02 Atheromastat Pty Ltd. Compositions et methodes de diagnostic et de traitement de troubles cardio-vasculaires

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002034273A1 (fr) * 2000-10-25 2002-05-02 Atheromastat Pty Ltd. Compositions et methodes de diagnostic et de traitement de troubles cardio-vasculaires

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE GenBank 8 January 2014 (2014-01-08), Database accession no. ASXU00000000 *
LEW, LC ET AL.: "Dermal Bioactives from lactobacilli and bifidobacteria.", ANNALS OF MICROBIOLOGY, vol. 63, 2013, pages 1047 - 1055 *
LISTIOHADI, Y ET AL.: "Moisture sorption, compressibility and caking of lactose polymorphs.", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 359, 2008, pages 123 - 134, XP022707707, DOI: doi:10.1016/j.ijpharm.2008.03.044 *
LYE, HS ET AL.: "Removal of cholesterol by lactobacilli via incorporation and conversion to coprostanol.", JOURNAL OF DAIRY SCIENCE, vol. 93, 2010, pages 1383 - 1392, XP026982921 *
TAN, PL ET AL.: "Bioactive Dairy Ingredients For Food and Non-Food Applications.", ACTA ALIMENTARIA, vol. 43, 2014, pages 113 - 123 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112877241A (zh) * 2021-02-02 2021-06-01 浙江大学 一株人源性发酵乳杆菌zjuids06及其应用
NL2038332A (en) * 2024-03-12 2024-08-29 Chongqing Tianyou Dairy Co Ltd Lactobacillus fermentum ty-m18 and application thereof

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