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• • 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
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
• • 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
• • 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
  • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
  • C12N1/20—Bacteria; Culture media therefor
  • C12N1/205—Bacterial isolates
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
  • C12R2001/00—Microorganisms ; Processes using microorganisms
  • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
  • C12R2001/225—Lactobacillus
  • C12R2001/25—Lactobacillus plantarum

Definitions

• the invention relates to compositions comprising Lactobacillus plantarum 2830 (ECGC 131 10402) for use in the treatment, prevention or control of cholesterol.
• CVD cardiovascular disease
• WHO World Health Organization
• LDL-C low density lipoprotein cholesterol
• CAD coronary artery disease
• statins have a range of intolerance and safety concerns which affect compliance and they are expensive. Plant sterols and stanols have been explored as possible alternatives to statins. However large amounts of these substances, 3-4 tea spoons, need to be taken to achieve an average reduction in LDL-C of between 7 and 10.5 %. This is an issue as plant sterols and stanols are expensive.
• Bile Salt Hydrolase (BSH) active probiotics have been shown to increase intraluminal bile acid deconjugation, resulting in increased levels of circulating deconjugated bile salts in humans and animal studies.
• Lactobacillus plantarum strains have been suggested as BSH active probiotics with high upper gastrointestinal survival characteristics.
• a composition comprising Lactobacillus plantarum 2830 (ECGC 131 10402), or mutant strain or strains thereof, for use in the reduction or modulation of total cholesterol (TC) and low density lipoprotein cholesterol (LDL- C) levels in an individual.
• TC total cholesterol
• LDL- C low density lipoprotein cholesterol
• a composition comprising Lactobacillus plantarum 2830 (ECGC 131 10402), or mutant strain or strains thereof, for use in the management, treatment or prevention of elevated total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels in an individual.
• TC total cholesterol
• LDL-C low density lipoprotein cholesterol
• composition comprising Lactobacillus plantarum 2830 (ECGC 131 10402), or mutant strain or strains thereof, for use in the management, treatment or prevention of hypercholesterolemia in an individual.
• Lactobacillus plantarum 2830 (ECGC 131 10402) for use in the manufacture of a medicament for the treatment or prevention of hypercholesterolemia.
• Lactobacillus plantarum 2830 (ECGC 131 10402) in a method of treatment or prevention of hypercholesterolemia.
• Lactobacillus plantarum 2830 (ECGC 131 10402) for use in the manufacture of a food supplement or foodstuff for management, treatment or prevention of hypercholesterolaemia
• the hypercholesterolaemia is mild hypercholesterolaemia.
• Lactobacillus plantarum 2830 (ECGC 131 10402) will be administered to an individual in an amount in the range of 10 5 cfu to 10 12 cfu. More preferably, Lactobacillus plantarum 2830 (ECGC 131 10402) may be in an amount in the range of 10 8 cfu to 10 10 cfu. Although it will be appreciated that different dosages may be administered depending upon the individuals' condition. Most preferably, the Lactobacillus plantarum is in an amount of about 120mg of the active strain providing about 1 .8 x 10 9 cfu.
• the composition may comprise further excipients necessary for the manufacture of a dosage form and its breakdown following ingestion.
• the composition may further comprise disintegrants, binders, lubricants and glidants.
• composition may further comprise one or more disintegrants selected from: polyvinylpyrollidone, sodium starch glycolate and carboxymethylcellulose.
• composition may further comprise one or more binders selected from; starches, saccharides, cellulose, sugar alcohols, gelatin, polyvinylpyrollidone and polyethylene glycol.
• binders selected from; starches, saccharides, cellulose, sugar alcohols, gelatin, polyvinylpyrollidone and polyethylene glycol.
• the composition further comprises corn starch.
• the composition may further comprise one or more glidants selected from talc, magnesium carbonate, fumed silica and silicon dioxide.
• glidants selected from talc, magnesium carbonate, fumed silica and silicon dioxide.
• the composition further comprises silicon dioxide.
• the composition may further comprise one or more lubricants selected from stearic acid, vegetable stearin and magnesium stearate.
• lubricants selected from stearic acid, vegetable stearin and magnesium stearate.
• the composition further comprises magnesium stearate.
• Administration frequency would also be dependent upon an individuals' condition but preferably the composition would be administered twice daily.
• the composition may be administered at any time of day. However, preferably the composition is adminstered before meals.
• the composition may be in any easily administered form, for example in the form of a powder, tablet, or capsule.
• the composition may be in the form of a food stuff or food additive.
• the composition may be in the form of a drinkable liquid, a spread and/or powder which can be mixed with a solid or liquid food stuff.
• the composition could be used as a dietary supplement - for example to be blended with foods/drinks or consumed alongside foods/drinks.
• composition may further comprise an excipient or carrier compound to modify the release profile of one or more of the components through the intestinal environment. Release should occur at the most appropriate time for reducing cholesterol absorption. Typically, the culture must survive relatively intact until it reaches the intestinal enterocytes of the small intestine.
• composition may be encapsulated. Many encapsulation techniques will be apparent to the skilled addressee and the one employed will be tailored to the required stability of Lactobacillus plantarum 2830 (ECGC 131 10402) during digestive transit.
• Lactobacillus plantarum 2830 (ECGC 131 10402) may be concentrated and/or freeze dried.
• Advantageously Lactobacillus plantarum 2830 (ECGC 131 10402) has demonstrated excellent freeze drying survival in pilot scale manufacturing trials.
• composition may further comprise one or more active ingredients selected from: vitamins, minerals, phytochemicals, antioxidants, and combinations thereof.
• Vitamins may include fat soluble vitamins such as vitamin A, vitamin D, vitamin E, and vitamin and combinations thereof.
• vitamins can include water soluble vitamins such as vitamin C (ascorbic acid), the B vitamins (thiamine or B 1 , riboflavoin or B25 niacin or B3, pyridoxine or B6, folic acid or B9, cyanocobalimin or B12, pantothenic acid, biotin), and combinations thereof.
• Minerals may include, but are not limited to, sodium, magnesium, chromium, iodine, iron, manganese, calcium, copper, fluoride, potassium, phosphorous, molybdenum, selenium, zinc, and combinations thereof.
• Antioxidants may include but are not limited to ascorbic acid, citric acid, rosemary oil, vitamin A, vitamin E, vitamin E phosphate, tocopherols, di-alpha-tocopheryl phosphate, tocotrienols, alpha lipoic acid, dihydrolipoic acid, xanthophylls, beta cryptoxanthin, lycopene, lutein, zeaxanthin, astaxanthin, beta-carotene, carotenes, mixed carotenoids, polyphenols, fiavonoids, and combinations thereof.
• Phytochemicals may include but are not limited to cartotenoids, chlorophyll, chlorophyllin, fiber, flavanoids, anthocyamns, cyaniding, delphinidin, malvidin, pelargonidin, peonidin, petunidin, flavanols, catechin, epicatechin, epigallocatechin, epigailocatechingallate, theaflavins, thearubigins, proanthocyanins, flavonols, quercetin, kaempferol, myricetin, isorhamnetin, flavononeshesperetin, naringenin, eriodictyol, tangeretin, flavones, apigenin, luteolin, lignans, phytoestrogens, resveratrol, isoflavones, daidzein, genistein, glycitein, soy isoflavones, and combinations thereof.
• the composition may comprise a prebiotic specifically tailored to Lactobacillus plantarum 2830 (ECGC 131 10402).
• the prebiotic may selectively accentuate the growth and survivability of Lactobacillus plantarum 2830 (ECGC 131 10402).
• the composition may further comprise one or more fillers.
• the composition may further comprise one or more fillers selected from the following: maltodextrin, sucrose or fillers with cholesterol reducing ability.
• the composition further comprises beta glucans which can reduce cholesterol thus cooperatively enhancing the cholesterol reducing/controlling functions of the other excipients in the composition.
• the composition may be administered with one or more statins, sterols and/or stanols.
• Advantageously co-administration with known cholesterol lowering therapeutics can provide enhanced cholesterol reduction and/or control.
• Plant sterols ahve been shown to increase levels of serum plant sterols which have been found part of atherosclerotic plaques and in the retina of long-term plant sterol and stanol users.
• BSH-active probiotic bacteria have been shown to reduce circulating cholesterol and plant sterols.
• a combination of plant sterols and BSH-active probiotics can therefore reduce/control cholesterol levels and reduce plant sterol serum levels advantageously improving the safety profile of sterol products.
• BSH-active bacteria should work in a complementary fashion with statins to amplify LDL receptor activity and the clearance of serum cholesterol, as they increase bile salt deconjugation and reduce sterol absorption. Therefore co-administration of BSH-active probiotics and statins can potentially result in a greater reduction in serum LDL-C enabling a reduction in statin dosage thus reducing costs and side effects and improving patient compliance.
• the composition is stored at 4 °C or below. Bacterial growth is stabilised in this temperature range thus ensuring the stability of the composition.
• the composition may further comprise a prebiotic growth medium which is specific to the growth of the Lactobacillus plantarum strain.
• the prebiotic growth medium will preferably be capable of being producing by the Lactobacillus plantarum strain by reverse enzyme reaction.
• the enzyme may comprise a saccharolytic or glycosidase enzymes. These saccharolytic or glycosidase enzymes may be derived from bacteria or fungi.
• the prebiotic growth medium may comprise oligosaccharides such as galacto- oligosacharides, (GOS), gluco-oligosacharides, or fructo- oligosaccharides (FOS) in varying concentrations. It is preferred that the oligosaccharide form is substantially the same as the form produced by ⁇ -galactosidases, a-galactosidases, a- and ⁇ -glucosidases, a-mannosidases and ⁇ - xylosidases reverse reactions of the strain.
• oligosaccharides such as galacto- oligosacharides, (GOS), gluco-oligosacharides, or fructo- oligosaccharides (FOS) in varying concentrations. It is preferred that the oligosaccharide form is substantially the same as the form produced by ⁇ -galactosidases, a-galactosid
• the prebiotic growth medium may be present in an amount which provides optimal growth and survival of the strain within the gut without impacting on safety, tolerance, and shelf life.
• Lactobacillus plantarum 2830 (ECGC 131 10402), or mutant strain or strains thereof, for use in a method of preventing, treating or modulating hypercholesterolaemia, wherein the Lactobacillus plantarum is administered in an amount in the range of 1 x 10 5 to 10 12 cells twice a day. More preferably, the Lactobacillus plantarum may be administered in an amount in the range of 1 x 10 8 to 1 x 10 10 cells. Most preferably, the Lactobacillus plantarum is administered in an amount about 1 .8 x 10 9 cells. Also preferably, the Lactobacillus plantarum is administered in an amount of about 120mg of the active strains.
• the Lactobacillus plantarum may be administered shortly before, during or after morning and evening meals. Preferably, the Lactobacillus plantarum is administered shortly before breakfast and the evening meal.
• the Lactobacillus plantarum may be administered as a medicine or as a dietary supplement.
• the Lactobacillus plantarum may be in a freeze dried form.
• the Lactobacillus plantarum may be administered with one or more additional cholesterol lowering components. Such components may comprises: statins, sterols and/or stands. Furthermore, the Lactobacillus plantarum may be administered with one or more probiotics and/or prebiotics.
• the Lactobacillus plantarum may be administered in combination with a prebiotic growth medium which is specific to the growth of the Lactobacillus plantarum strain.
• the prebiotic growth medium will preferably be capable of being producing by the Lactobacillus plantarum strain by reverse enzyme reaction.
• the prebiotic growth medium may comprise oligosaccharides, which will preferably comprise galacto-oligosaccharide (GOS).
• the Lactobacillus plantarum is stored at 4 ⁇ or below before administration.
• a method of producing Lactobacillus plantarum 2830 (ECGC 131 10402), or mutant strain or strains thereof, for use in the preparation of a medicament or food supplement, comprising:
• the survival rates for freeze drying the Lactobacillus plantarum cells by such a method is over 70%. Furthermore, the method has been advantageously found that the method produces the Lactobacillus plantarum cells in amounts of up to 8 x 10 11 cfu/g.
• the method will of course be suitable for producing Lactobacillus plantarum 2830 (ECGC 131 10402), or mutant strain or strains thereof, for a composition as herein above described, or indeed the Lactobacillus plantarum 2830 (ECGC 131 10402) as herein above described.
• a human volunteer study was conducted to establish the safety, compliance and extent of cholesterol reduction and control by administering formulations comprising Lactobacillus plantarum ECGC 131 10402 to 49 mildly hypercholesterolaemic adults.
• the study was carried out independently by the Department of Food and Nutritional Sciences at the University of Reading, UK.
• the study was carried out according to the Helsinki declaration and written informed consent was obtained from all volunteers.
• the study protocol was approved by the Research Ethics committee of the University of Reading.
• Subjects were male or female, aged 30 - 65 years. Subjects were excluded if they had had a previous cardiovascular event within the last 6 months, if secondary dyslipemias related to thyroid dysfunction were present, if they had used any drug affecting lipid metabolism in the previous 3 months, if they had a history of alcohol abuse, if they had taken antibiotics in the previous 6 months or if they had taken prebiotics/probiotic preparations in the last month.
• TC total cholesterol
• LDL-C low density lipoprotein cholesterol
• HDL-C high density lipoprotein cholesterol
• TAG fasting triacylglycerol
• Urine, blood and faeces were collected for bile acid and metagenomic and metabolomics studies.
• the first set of analyses considered all study participants and different patient subgroups. These subgroups were based on baseline total cholesterol ( ⁇ 5mmol/l, 5-5.9 mmol/l and ⁇ 6.0 mmol/l), gender and age ( ⁇ 50 yrs, 50-59 yrs, ⁇ 60 yrs).
• Tables 5-7 show the mean and standard deviation at baseline and the end of treatment at 12 weeks.
• TC, LDL-C, HDL-C and TAG concentrations are expressed in mmol/l.
• the baseline adjusted value for TC levels in all subjects was 0.12mmol/l lower in the active group compared to the placebo group, a 2.3% decrease.
• Stratification according to baseline TC concentrations revealed variations between the higher TC and medium to low subgroups.
• the change between baseline and end of treatment was 4.2% lower in the active compared to the placebo group (0.19mmol/l lower).
• the baseline adjusted end of treatment TC concentrations were 0.23mmol/l lower in the active group, corresponding to a 4.17% reduction.
• HDL-C increased slightly between baseline and 12 weeks for both placebo and active groups.
• the HDL-C concentrations for the all subject and TC ⁇ 5mmol/lgroup were 0.06 mmol/l (4.5%) and 0.09mmol/l (7.4%) higher in the active group when compared to the placebo.
• the all subject and TC ⁇ 5mmol/l groups in this period showed average increases in HDL cholesterol levels of 0.09mmol/l (6.5%) and 0.10mmol/l (7.8%) respectively when compared to the placebo group.
• Stratification according to baseline TC concentrations and gender revealed no significant treatment effect on HDL levels.
• LDL-C cholesterol reduced between baseline and 12 weeks in all the active treatment groups. This effect was not observed in the placebo group.
• LDL-C concentrations for the all subject groups were on average 0.24mmol/l (7.2%) lower when compared to placebo.
• LDL-C showed an average 0.47mmol/l decrease (13.1 %), but this did not reach statistical significance.
• the LDL reducing effect appeared to occur consistently across both the 0-6 and 6-12 week periods. The results suggest patients with higher initial levels of LDL cholesterol may benefit from higher reductions in LDL-C than others.
• Lactobacillus plantarum ECGC 131 10402 has the potential to lower blood TC and LDL-C in hypercholesterolaemic and mildly hypercholesterolaemic subjects.
• Active Lactobacillus plantarum ECGC 131 10402 and placebo capsules were stored at 4°C throughout the study duration. Product stability was checked at baseline, 6 weeks and 12 weeks (end of treatment) of the study and no significant change was observed in bacterial numbers. No bacterial growth was detected in the placebo capsules.
• Lactobacillus plantarum is a widely used probiotic which is considered Generally Regarded as Safe (GRAS) by the US Food and Drug Administration (FDA) and has a Qualified Presumption of Safety (QPS) designation by the European Food Standard Agency. This would suggest that Lactobacillus plantarum ECGC 131 10402 has the potential to be a safe and effective treatment for the treatment of hypercholesterolemia.
• GRAS Generally Regarded as Safe
• FDA US Food and Drug Administration
• QPS Qualified Presumption of Safety
• the application refers to the following indications of deposited biological material:

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