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
• • 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
  • A61P9/12—Antihypertensives

Definitions

• the invention relates to a composition comprising Lactobacillus plantarum 2830 (ECGC 131 10402) which has been shown to be useful in the treatment, prevention and/or management of hypertension.
• Hypertension otherwise known as high blood pressure, is a major health problem and is a risk factor for cardiovascular disease (CVD).
• CVD cardiovascular disease
• WHO World Health Organization
• High cholesterol is often linked to hypertension due to a build up of cholesterol plaque in blood vessels.
• Treatments for hypertension include angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, diuretics and beta-blockers. However, all of these treatments are not without their side effects and therefore alternative or more natural treatments would be preferable.
• ACE angiotensin-converting enzyme
• 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.
• BSH Bile Salt Hydrolase
• bile acids are deconjugated in the intestines, dietary and biliary cholesterol absorption is reduced and the recirculation of bile is altered, resulting in better control of low density lipoprotein cholesterol (LDL-C) levels in blood.
• LDL-C low density lipoprotein cholesterol
• composition comprising Lactobacillus plantarum 2830 (ECGC 131 10402), or mutant strain or strains thereof, for use in the treatment, control or prevention of hypertension.
• composition comprising Lactobacillus plantarum 2830 (ECGC 131 10402), or mutant strain or strains thereof, for use in the treatment, control or prevention of hypertension.
• composition comprising Lactobacillus plantarum 2830 (ECGC 131 10402), or mutant strain or strains thereof, for use in the manufacture of a medicament for the treatment, control or prevention of hypertension.
• compositions in the treatment or prevention of hypertension are in an individual having at least mild hypercholesterolemia.
• a foodstuff or food supplement composition comprising Lactobacillus plantarum 2830 (ECGC 131 10402), or mutant strain or strains thereof, for use in the reduction, prevention and/or control or hypertension.
• a composition comprising Lactobacillus plantarum 2830 (ECGC 131 10402), or mutant strain or strains thereof, for use in the manufacture of a food supplement or foodstuff for the treatment, control or prevention of hypertension.
• the Lactobacillus plantarum 2830 (ECGC 131 10402), or mutant strain or strains thereof will preferably be present in the composition in an effective amount so as to reduce, prevent or control hypertension.
• the Lactobacillus plantarum will be administered to an individual in an amount in the range of 10 5 cfu/g to 10 12 cfu/g.
• the Lactobacillus plantarum may be administered to an individual in an amount in the range of 1 x 10 5 cfu to 1 x 10 12 cfu. More preferably, will be administered in an amount in the range of 1 x 10 8 cfu to 1 x 10 10 cfu. Most preferably, the Lactobacillus plantarum is in an amount of about 120mg of the active strain providing about 1 .8 x 10 9 cfu. Although it will be appreciated that different dosages may be administered depending upon the individuals' condition and degree of hypertension and other medical considerations.
• 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, but preferably the composition is adminstered after meals. Administration after a meal advantageously accentuates the deconjugation effect of the BSH active Lactobacillus plantarum. Most bile acid secretion occurs after the consumption of a meal and the amount of bile acid secreted is proportionally related to the amount and type of food consumed.
• 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 in for reducing cholesterol absorption and thus control hypertension. Typically, the culture must survive relatively intact until it reaches the intestinal enterocytes of the small intestine.
• the 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 the Lactobacillus plantarum during digestive transit.
• the encapsulate may comprise a prebiotic specifically tailored to the Lactobacillus plantarum.
• the Lactobacillus plantarum 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 further comprise one or more cholesterol reducing agents.
• the composition may comprise beta glucans.
• the composition may be administered with one or more statins, sterols and/or stanols.
• the composition may be co-administration with other hypertension active ingrements or used in as part of a combination therapy with such active ingredients to reduce the quanity of ingredients administered and therefore limit side effects.
• 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.
• a method of treating an individual with or at risk of elevated hypertension by administering a composition having an effective amount of the Lactobacillus plantarum.
• Lactobacillus plantarum 2830 (ECGC 131 10402), or mutant strain or strains thereof, for use in a method of preventing, treating or modulating hypertension, wherein the Lactobacillus plantarum is administered in an amount in the range of 1 x 10 5 to 10 12 cells twice a day.
• 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 hypertension active ingredient components.
• Such components may comprises: angiotensin- converting enzyme (ACE) inhibitors, calcium channel blockers, diuretics or beta-blockers.
• ACE angiotensin- converting enzyme
• 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).
• GOS galacto-oligosaccharide
• the Lactobacillus plantarum is stored at 4°C 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: a) fermenting Lactobacillus plantarum under conditions sufficient to produce a culture broth;
• 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 hypertension control by administering compositions 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.
• Lactobacillus plantarum ECGC 131 10402 has the potential to lower systolic blood pressure in at least 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 hypertension.
• 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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• 2015
  • 2015-11-02 GB GBGB1519327.9A patent/GB201519327D0/en not_active Ceased
• 2016
  • 2016-11-02 JP JP2018517278A patent/JP6867378B2/ja active Active
  • 2016-11-02 WO PCT/GB2016/053390 patent/WO2017077286A1/en not_active Ceased
  • 2016-11-02 CA CA3001539A patent/CA3001539A1/en active Pending
  • 2016-11-02 EP EP16794395.0A patent/EP3370747B1/en active Active
  • 2016-11-02 AU AU2016348841A patent/AU2016348841B2/en active Active
  • 2016-11-02 US US15/764,994 patent/US11413317B2/en active Active
• 2022
  • 2022-07-20 US US17/869,433 patent/US11903979B2/en active Active

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