EP3592340A1 - Compositions for the treatment of cardiovascular disease - Google Patents

Compositions for the treatment of cardiovascular disease

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Publication number
EP3592340A1
EP3592340A1 EP18714842.4A EP18714842A EP3592340A1 EP 3592340 A1 EP3592340 A1 EP 3592340A1 EP 18714842 A EP18714842 A EP 18714842A EP 3592340 A1 EP3592340 A1 EP 3592340A1
Authority
EP
European Patent Office
Prior art keywords
composition according
monacolin
concentration
extract
present
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.)
Withdrawn
Application number
EP18714842.4A
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German (de)
French (fr)
Inventor
Umberto DI MAIO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Neilos SRL
Original Assignee
Neilos SRL
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Filing date
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Publication of EP3592340A1 publication Critical patent/EP3592340A1/en
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    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/009—Sachets, pouches characterised by the material or function of the envelope
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
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    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
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    • A61K36/062—Ascomycota
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    • A61K36/13—Coniferophyta (gymnosperms)
    • A61K36/15—Pinaceae (Pine family), e.g. pine or cedar
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/32—Burseraceae (Frankincense family)
    • A61K36/328—Commiphora, e.g. mecca myrrh or balm of Gilead
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/67—Piperaceae (Pepper family), e.g. Jamaican pepper or kava
    • 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)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • 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)
    • A61K36/87—Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A—HUMAN NECESSITIES
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    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • 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
    • A61K47/06—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
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    • 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
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
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    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
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    • 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

Definitions

  • the present invention relates to a composition of substances, preferably obtained from nat- ural sources, which is effective in the treatment of hypercholesterolemia and in the prevention of atherosclerosis plaque formation and cardiovascular disease.
  • Hypercholesterolemia a form of dyslipidemia, is a condition characterized by high blood cholesterol concentration. Since cholesterol is not water-soluble, it is transported in the blood by lipoproteins. Lipoproteins are classified on the basis of their density into Very Low Density Lipoproteins (VLDLs), Low Density Lipoproteins (LDLs), Intermediate Density Lipoproteins (IDLs) and High Density Lipoproteins (HDLs). High plasma levels of cholesterol transported by non-HDL lipoproteins, in particular LDL lipoproteins, are associated with increased risk of atherosclerosis and cardiovascular disease. In contrast, in- creased levels of HDL cholesterol are considered as protective.
  • VLDLs Very Low Density Lipoproteins
  • LDLs Low Density Lipoproteins
  • IDLs Intermediate Density Lipoproteins
  • HDLs High Density Lipoproteins
  • Cardiovascular disease is the leading cause of mortality in developed and developing countries.
  • cardiovascular diseases account for 4 million deaths every year, and even though a certain reduction in the number of deaths has been recently observed, these dis- eases are still the main cause of mortality.
  • coronary heart disease alone accounts for at least 1.8 million deaths per year, representing 20% of the total.
  • cardiovascular risk factors including hypertension, hypercholesterolemia, hypertriglyceridemia and hyperglycaemia.
  • Hyperlipidemias and reduced HDL levels depend on various interrelated factors, which can be of the behavioural, environmental, genetic (for example the presence of mutations in genes encoding for lipoproteins) or metabolic (e.g. diabetes mellitus) type.
  • Hypercholesterolemia, hypertriglyceridemia and low blood HDL concentration are the leading cause of atherosclerosis and diseases associated therewith, such as angina pectoris, myocardial infarction, cerebrovascular disease and peripheral vascular diseases (venous and arterial occlusion).
  • LDL low density lipoprotein
  • a first class of drugs consists of ion exchange resins (cholestyramine and colestipol), whose mechanism of action is based on the interaction with bile acids, which are sequestered by the resins through the formation of ion bonds. This causes an increase in the synthesis of bile acids and a consequent increase in the expression of LDL receptors on liver cells, due to a decrease in hepatic cholesterol concentration.
  • the side effects of ion exchange resins are mainly dyspepsia, swelling and increased plasma triglyceride concentration.
  • a second class of drugs consists of statins. They inhibit the enzyme HMG-CoA (3- hydroxy-3-methylglutaryl coenzyme A reductase), involved in the synthesis of mevalo- nate, which in turn is essential in the biosynthesis of cholesterol. The inhibition of this physiological process leads to an increase in the expression of LDL receptors at the hepatic level, with a consequent reduction in the plasma concentration of these lipoproteins.
  • statins are the most widely used drugs for reducing cholesterolemia.
  • the side effects, which have a very high incidence, are mainly hepatotoxicity and especially myopathy and rhabdomyolysis.
  • a third class of drugs consists of ezetimibe, which interacts with the PC1L1 (Niemann- Pick CI -like- 1 protein) transporter, thereby inhibiting dietary cholesterol absorption.
  • the main side effects of ezetimibe are abdominal pain, flatulence, diarrhoea, fatigue. This medication may be used in combination with statins.
  • a fourth class of drugs consists of nicotinic acid and structurally related compounds, which interact with the HM74A protein, a Gi protein-coupled receptor, thus causing inhibition of the activity of the hormone-sensitive lipase (HSL), which reduces triglyceride lipolysis and fatty acid excretion.
  • HSL hormone-sensitive lipase
  • nicotinic acid is a vitamin, at the dosages at which it is used (>1000 mg/day) it exhibits several side effects, including itching and redness of the skin and dyspepsia, which limit the therapeutic application thereof.
  • a fifth class of drugs consists of fibrates, which interact with PPARa (peroxisome proliferator activated protein-a) receptors, thereby causing increased lipoprotein lipase expression and decreased apoC-III expression, which leads to an increase in fatty acid clearance.
  • fibrates are able to stimulate the expression of apoA-I and apoA-II, thus increasing blood HDL levels.
  • side effects including myopathy, gastrointestinal disorders, rash, urticaria, headache, impotence and anaemia.
  • the present invention provides a composition comprising a synergistic combination of active substances, obtained from natural sources, which has proved particularly effective in the treatment of hypercholesterolemia, and in the prevention of atherosclerosis plaque formation and related cardiovascular disease.
  • composition of the invention is as defined in appended claim 1. Further features and advantages of the invention are defined in the dependent claims. The claims form an integral part of the present specification.
  • the present invention relates to a synergistic combination of active substances, which can be obtained from natural sources or by organic synthesis, which has proved to be particularly effective in the treatment of hypercholesterolemia and conse- quently in the prevention of atherosclerosis plaque formation and hypercholesterolemia- related cardiovascular diseases.
  • the synergistic composition of the invention comprises one or more monacolins, curcumin, procyanidins, piperine and optionally coenzyme Qio and/or plant sterols or stanols, as the active substances.
  • compositions of the invention are resveratrol, policosanols, including, for example, octacosanol, folic acid and chromium, in particular chromium picolinate.
  • Monacolins are naturally occurring substances that can be obtained, for example, from the fermentation of red rice by the yeast Monascus purpureus. Among these, it is worth mentioning in particular monacolin K, which has the same chemical structure as lovastatin.
  • Monacolin K is a competitive inhibitor of the enzyme 3 -hydroxy-3 -methyl glutaryl coenzyme A reductase (HMG- CoA reductase), which interferes with the production of mevalonate, necessary for cholesterol biosynthesis. Inhibition of HMG-CoA reductase is due to the structural homology between the ⁇ - hydroxy acid form of monacolin K and 3 -hydroxy-3 -methyl glutaryl coenzyme A.
  • monacolin K In addition to monacolin K, also other monacolins are present in the red Monascus purpureus fermented rice, namely monacolins J, L and M, which inhibit 3 -hydroxy-3 -methyl glutaryl coenzyme A reductase and therefore can be used in the synergistic composition of the present invention as an alternative or in association with monacolin K.
  • monacolins K, J, L and/or M are present in the composition of the invention at a concentration within the range of from 0.01% w/w to 10% w/w, more preferably within the range of from 0.05% w/w to 2% w/w, still more preferably within the range of from 0.5%) w/w to 1%) w/w based on the total weight of the active substances of the composition.
  • Curcumin is endowed with numerous pharmacological activities, including antiinflammatory, antioxidant, immunomodulatory, anti-tumour and neuro-protective activities. This substance is one of the most powerful, naturally occurring anti-inflammatory drugs and is extracted from Curcuma longa.
  • Curcumin has been shown to be effective in reducing lipid peroxidation and plasma cholesterol levels in many studies in humans and rodents.
  • curcumin is capable of acting on LXRa receptor, which enables an in- creased gene expression of cytochrome CYP7A1, which is involved in the biosynthesis of bile acids from cholesterol.
  • This effect has been demonstrated in an in vivo study in rats: the administration of a diet containing 0.1%> w/w curcumin to rats is associated with a significant increase (p ⁇ 0.05) in CYP7A1 expression and with a 68%> reduction in plasma LDL cholesterol levels.
  • Guggulsterone a compound extracted from the Commiphora mukul plant, has also the ability to induce CYP7A1 expression and therefore to increase the synthesis of bile acids. Guggulsterone competes with bile acids for FXR receptor binding, preventing the negative feedback mechanism and leading, in fact, to an increase in bile acid synthesis. While acting with a different mechanism from that of curcumin, guggulsterone still leads to the same effect of increasing the expression of CYP7A1, and thus can be used alternatively or in addition to curcumin in the synergistic composition of the present invention.
  • curcumin and/or guggulsterone is/are present in the synergistic composition of the invention at a total weight concentration within the range of from 1%> w/w to 90%) w/w, more preferably within the range of from 10%> w/w to 30%> w/w, based on the total weight of the active substances of the composition.
  • Pipeline is a chemical compound belonging to the vanilloid group, equipped with a molecular portion superimposable to that of vanillin. This substance is the main alkaloid of black pepper ⁇ Piper nigrum L.) and other plants belonging to the Piperaceae family, such as for example Piper longum L.
  • Piperine has shown an important inhibitory activity against two isoforms of the Acyl- CoA: cholesterol acyltransf erase enzyme (AC ATI and ACAT2), which act by esterifying cholesterol.
  • AC ATI and ACAT2 cholesterol acyltransf erase enzyme
  • AC ATI and ACAT2 inhibition activity is very interesting since esterification of cholester- ol by ACAT1 and ACAT2 is a fundamental process for its insertion in chylomicrons and consequently for its intestinal absorption.
  • inhibition of AC ATI and ACAT2 can prevent lipid accumulation in macrophages, with consequent inhibition of foam cell formation and atherosclerosis plaque formation.
  • Piperine also has an important inhibitory activity against enzymes involved in the metabolism of xenobiotics. In particular, piperine administration has been shown to lead to increased bioavailability of coenzyme Qio. Co-administration of curcumin and piperine has also been shown to lead to increased oral bioavailability of curcumin.
  • piperine and/or guineensine is/are present in the synergistic composition of the present invention at a total weight concentration within the range of from 0.10% w/w to 20% w/w, more preferably within the range of from 0.10% w/w to 5% w/w, based on the total weight of the active substances of the composition.
  • Procyanidins are phenolic molecules belonging to the class of tannins and have cholesterol-lowering properties. Tannins are phenolic compounds that are widespread in nature, and able to precipitate proteins. In general, tannins are high molecular weight (MW > 500 Da) compounds and have numerous hydroxyl groups in their structure. Tannins are structurally very heterogeneous. Structurally, they can be divided into 3 groups:
  • Procyanidins are part of the larger group of condensed tannins, also known as proanthocyanidins. From a chemical point of view, they are derived from flavan-3-ol compounds, in particular catechin and epicatechin, and may have an oligomeric or polymeric structure.
  • Procyanidins have the following general structure:
  • n 0-5, while in polymeric procyanidins, n > 5.
  • the procyanidins object of the present invention, have the structure shown in the figure, with n comprised between 0 and 15. These substances are found in great abundance in plants of the genus Malus, e.g. Malus domestica Borkh., Malus pumila Mill, or Malus pu- mila Mill, cv Annurca, but also in many other plant species, such as Pinus pinaster and Wilis Vinifera.
  • the Annurca apple (Malus pumila Miller cv Annurca) is an apple cultivar, which is native to southern Italy and widespread in Campania, where 60% of the apples produced belong to this cultivar. Numerous studies have shown that this variety of apples has the highest content of polyphenols compared to other cultivars, such as Red Delicious, Pink Lady, Fuji and Golden Delicious.
  • the polyphenols contained in the apple extract have been shown to be able to reduce the activity of CETP (Colesteryl Ester Transfer Protein), which has the function of transferring cholesterol esters from HDL to LDL lipoproteins.
  • CETP Coldestryl Ester Transfer Protein
  • apple polyphenols can increase HDL plasma concentrations and reduce the value of the non-HDL/HDL cholesterol ratio.
  • procyanidins are also known to be poorly absorbed in the intestine and to have the ability to form inclusion compounds with cholesterol. This is the main mechanism through which procyanidins lead to inhibition of dietary cholesterol absorption.
  • Phlorizin a dihydrochalcone found exclusively in apples, may be useful in the maintenance of normal plasma glucose levels, being able to reduce glucose uptake by the liver and intestinal cells.
  • procyanidins are present in the synergistic composition of the present invention at a total weight concentration within the range of from 1% w/w to 50% w/w, more preferably within the range of from 2.0%) w/w to 20% w/w, based on the total weight of the active substances of the composition.
  • Coenzyme Qio (also known as ubiquinone and ubidecarenone) is a benzoquinone belonging to the ubiquinone group, which consists of liposoluble molecules involved in electron transport processes at the mitochondrial level, with a fundamental role in the oxidative phosphorylation process.
  • Coenzyme Qio is known to be capable of inhibiting low density lipoprotein peroxidation.
  • the mechanism of action more than in the direct reaction with peroxyl radicals, consists in the reduction of the a-tocopheroxyl radical into a-tocopherol. Supplementation with coenzyme Qio has been found to lead to an increase in ubiquinol concentration in LDLs, and a reduction in their peroxidability.
  • coenzyme Qio could have a direct antiatherogenic activity.
  • Another interesting pharmacological effect of coenzyme Qio administration consists in the reduction of the systolic and diastolic pressures.
  • the synergistic composition of the present invention also comprises coenzyme Qio, whose levels are reduced by the extended use of monacolin k or other monacolins.
  • coenzyme Qio is present in the synergistic composition of the present invention at a concentration by weight within the range of from 0.10% w/w to 20% w/w, more preferably within the range of from 0.5% w/w to 2% w/w, based on the total weight of the active substances of the composition.
  • Phytosterols are an integral part of plant cell membranes. They are structurally similar to cholesterol, but with some structural differences.
  • the term "phytosterols" is commonly used to describe both plant sterols, which have a double bond in position 5 of the ring, and plant stanols, in which the double bond is reduced.
  • Phytosterols are extracted from vegetable oils, such as corn oil, canola oil, soybean oil, sunflower oil, olive oil. There are also present to a lesser extent in nuts, seeds, fruit and vegetables. The most abundant sterols are sitosterol, campesterol and stigmasterol. They represent approximately 65%, 30%, and 3%, respectively, of plant sterol consumption in the diet. Stanols, on the other hand, are less abundant in nature but can be synthesized by hydrogenation of plant sterols. Thanks to the structural similarity with cholesterol, plant sterols and stanols act by blocking cholesterol absorption in the small intestine and decreasing blood levels of low density lipoproteins (LDLs).
  • LDLs low density lipoproteins
  • plant sterols and/or stanols are present in the synergistic composition of the invention at a concentration by weight within the range of from 10% w/w to 90% w/w, more preferably within the range of from 20% w/w to 70% w/w, still more preferably within the range of from 50% w/w to 65% w/w, based on the total weight of the ac- tive substances of the composition.
  • the synergistic composition of the invention is manufactured as a pharmaceutical formulation or as a dietary supplement, preferably in a solid, liquid or semi-solid oral dosage form.
  • Preferred oral dosage forms are tablets, capsules, sachets, powders, granules, pellets, gels, syrups, elixirs, oral solutions, suspensions or emulsions. Those most preferred are sachets and capsules.
  • the synergistic composition of the invention is manufactured as an oral dosage form designed to administer from 1 to 50 mg/day of monacolins, from 10 to 2000 mg/day of curcumin and/or guggulsterone, from 50 to 4000 mg/day of procyanidins, optionally in combination with phlorizin, from 1 to 50 mg/day of piperine and/or guineensine, and optionally from 5 to 200 mg/day of coenzyme Qio and from 100 to 3000 mg/day of plant sterols and/or stanols.
  • the synergistic composition object of the present invention is particularly advantageous for use in the treatment of hypercholesterolemia as it simultaneously achieves different effects, in particular the reduction of plasma LDL levels and the increase of HDL levels, the inhibition of intestinal cholesterol absorption, and the anti -atherogenic effect. All of this, on the whole, leads to a reduction in the risk of cardiovascular disease, in particular coro- nary artery disease, heart attack, angina pectoris and strokes.
  • monacolin K and monacolins in general, are able to inhibit the enzyme 3- hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), a key enzyme in cholesterol biosynthetic pathway.
  • HMG-CoA reductase 3- hydroxy-3-methylglutaryl-coenzyme A reductase
  • curcumin and/or guggulsterone by acting on the LXRa receptor and the FXR receptor, respectively, increase the expression of cytochrome CYP7A1, with a consequent increase in the synthesis of bile acids from cholesterol.
  • LDL-R LDL receptors
  • procyanidins can complex bile acids in the intestine, thereby preventing their re- absorption. Since more than 95% of synthesized bile acids are normally reabsorbed at the intestinal level, the disruption of this mechanism causes increased synthesis thereof, with further depletion of liver cholesterol levels, increase in LDL receptor expression, and decrease in plasma LDL lipoprotein levels.
  • a second effect of the composition of the present invention is the ability to increase plasma HDL concentration.
  • the action results from the synergy of actions of the following com- ponents of the formulation:
  • procyanidins have the ability to inhibit the activity of CETP (colesteryl ester transfer protein), involved in the transfer of cholesterol esters from HDL to LDL. In this way, they are able to increase HDL cholesterol levels and reduce the non-HDL cholesterol/HDL cholesterol concentration ratio;
  • curcumin has the ability to increase the expression of the ABCAl transporter in macrophages and peripheral tissues. In this way, it increases the outflow of cholesterol from peripheral tissues, which is delivered to the plasma by HDLs, with a consequent in- crease in the plasma concentration of these lipoproteins.
  • a third effect of the composition of the present invention is the ability to reduce cholesterol absorption at the intestinal level, with a consequent reduction in the plasma concentra- tion of total cholesterol.
  • the action results from the synergy of the following active substances:
  • procyanidins by forming complexes with cholesterol, reduce the intestinal absorption of the latter;
  • phytosterols compete with cholesterol for binding to the PC1L1 (Niemann-Pick Cl-like-1 protein) transporter, which allows its absorption into the enterocyte. In this way, they reduce the amount of cholesterol absorbed at the intestinal level;
  • piperine and guineensine have the ability to inhibit the enzyme ACAT2 (sterol O-acyltransferase), which is fundamental for cholesterol absorption in the gut.
  • ACAT2 sterol O-acyltransferase
  • piper- ine by blocking this process, limits the intestinal absorption of cholesterol, which is thereafter excreted by the enterocyte via the ABCG5 and ABCG8 transporters.
  • composition of the present invention has the ability to inhibit atherosclerosis plaque formation, through the following mechanisms:
  • curcumin by acting on the LXRa receptor, increases the expression of the ABCAl transporter, with consequent greater outflow of cholesterol from foam cells. Moreover, thanks to its antioxidant action, it inhibits LDL oxidation. Lastly, the anti- inflammatory action of this compound contributes to the reduction of the atherosclerosis process;
  • procyanidins thanks to their antioxidant activity, further contribute to preventing atherosclerosis plaque formation.
  • the cholesterol-lowering, anti- atherogenic, anti-inflammatory and antioxidant effects of a composition falling within the scope of the present invention have been assessed in comparison with the cholesterol- lowering, anti-atherogenic, anti-inflammatory and antioxidant effects of the individual constituents separately. This allowed the presence of a synergistic effect to be confirmed.
  • Curcuma longa d.e. 95% curcuminoids 150.000
  • Vitis vinifera d.e. 95% polyphenols, 30% procyanidins 133.500
  • Silicon dioxide q.s.
  • Curcuma longa d.e. 95% curcuminoids 150.000
  • Vitis vinifera d.e. 95% polyphenols, 30% procyanidins 133.500
  • Silicon dioxide q.s.
  • composition of the present invention and its synergistic effect can be assessed by experimentally determining the cholesterol-lowering and anti-atherogenic effects (by assessing the concentration of total cholesterol, LDL, HDL and triglycerides in blood) in a murine hypercholesterolemia model, before and after treatment with the complete composition or with separate components thereof.
  • antioxidant and antiinflammatory activities can be assessed with reference to the complete composition and its separate components.

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Abstract

The invention relates to a synergistic composition of naturally occurring substances, which is particularly effective in the treatment of hypercholesterolemia. The composition of the invention comprises at least one substance having 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitory activity, a substance having cytochrome CYP7A1 expression increasing activity, a substance having inhibitory activity against the enzyme Acyl-CoA: cholesterol acyltransferase ACAT1 and ACAT2 isoforms, procyanidins, and optionally, coenzyme Q10 and phytosterols.

Description

COMPOSITIONS FOR THE TREATMENT OF CARDIOVASCULAR DISEASE
The present invention relates to a composition of substances, preferably obtained from nat- ural sources, which is effective in the treatment of hypercholesterolemia and in the prevention of atherosclerosis plaque formation and cardiovascular disease.
Hypercholesterolemia, a form of dyslipidemia, is a condition characterized by high blood cholesterol concentration. Since cholesterol is not water-soluble, it is transported in the blood by lipoproteins. Lipoproteins are classified on the basis of their density into Very Low Density Lipoproteins (VLDLs), Low Density Lipoproteins (LDLs), Intermediate Density Lipoproteins (IDLs) and High Density Lipoproteins (HDLs). High plasma levels of cholesterol transported by non-HDL lipoproteins, in particular LDL lipoproteins, are associated with increased risk of atherosclerosis and cardiovascular disease. In contrast, in- creased levels of HDL cholesterol are considered as protective.
Cardiovascular disease is the leading cause of mortality in developed and developing countries. In Europe, cardiovascular diseases account for 4 million deaths every year, and even though a certain reduction in the number of deaths has been recently observed, these dis- eases are still the main cause of mortality. In Europe, coronary heart disease alone accounts for at least 1.8 million deaths per year, representing 20% of the total.
Epidemiological studies have identified several cardiovascular risk factors, including hypertension, hypercholesterolemia, hypertriglyceridemia and hyperglycaemia.
Hyperlipidemias and reduced HDL levels depend on various interrelated factors, which can be of the behavioural, environmental, genetic (for example the presence of mutations in genes encoding for lipoproteins) or metabolic (e.g. diabetes mellitus) type. Hypercholesterolemia, hypertriglyceridemia and low blood HDL concentration are the leading cause of atherosclerosis and diseases associated therewith, such as angina pectoris, myocardial infarction, cerebrovascular disease and peripheral vascular diseases (venous and arterial occlusion).
The use of drugs capable of controlling blood cholesterol levels, and in particular low density lipoprotein (LDL) levels, has led to a reduction in mortality.
There are several classes of drugs for the treatment of diseases which can be associated with cardiovascular risk, however the administration of these active principles is often associated with a number of side effects. A first class of drugs consists of ion exchange resins (cholestyramine and colestipol), whose mechanism of action is based on the interaction with bile acids, which are sequestered by the resins through the formation of ion bonds. This causes an increase in the synthesis of bile acids and a consequent increase in the expression of LDL receptors on liver cells, due to a decrease in hepatic cholesterol concentration.
The side effects of ion exchange resins are mainly dyspepsia, swelling and increased plasma triglyceride concentration.
A second class of drugs consists of statins. They inhibit the enzyme HMG-CoA (3- hydroxy-3-methylglutaryl coenzyme A reductase), involved in the synthesis of mevalo- nate, which in turn is essential in the biosynthesis of cholesterol. The inhibition of this physiological process leads to an increase in the expression of LDL receptors at the hepatic level, with a consequent reduction in the plasma concentration of these lipoproteins. Currently, statins are the most widely used drugs for reducing cholesterolemia. The side effects, which have a very high incidence, are mainly hepatotoxicity and especially myopathy and rhabdomyolysis.
A third class of drugs consists of ezetimibe, which interacts with the PC1L1 (Niemann- Pick CI -like- 1 protein) transporter, thereby inhibiting dietary cholesterol absorption. The main side effects of ezetimibe are abdominal pain, flatulence, diarrhoea, fatigue. This medication may be used in combination with statins. A fourth class of drugs consists of nicotinic acid and structurally related compounds, which interact with the HM74A protein, a Gi protein-coupled receptor, thus causing inhibition of the activity of the hormone-sensitive lipase (HSL), which reduces triglyceride lipolysis and fatty acid excretion. In addition, these compounds inhibit a key enzyme in the biosynthesis of triglycerides, i.e. diacylglycerol acetyl transferase-2. Although nicotinic acid is a vitamin, at the dosages at which it is used (>1000 mg/day) it exhibits several side effects, including itching and redness of the skin and dyspepsia, which limit the therapeutic application thereof.
Lastly, a fifth class of drugs consists of fibrates, which interact with PPARa (peroxisome proliferator activated protein-a) receptors, thereby causing increased lipoprotein lipase expression and decreased apoC-III expression, which leads to an increase in fatty acid clearance. Moreover, fibrates are able to stimulate the expression of apoA-I and apoA-II, thus increasing blood HDL levels. In this case too, there are various side effects, including myopathy, gastrointestinal disorders, rash, urticaria, headache, impotence and anaemia.
Therefore, there is a continuing need to provide alternative treatments that are effective against hypercholesterolemia, which do not have the above side effects or have reduced side effects.
These and other needs are met by the present invention, which provides a composition comprising a synergistic combination of active substances, obtained from natural sources, which has proved particularly effective in the treatment of hypercholesterolemia, and in the prevention of atherosclerosis plaque formation and related cardiovascular disease.
The composition of the invention is as defined in appended claim 1. Further features and advantages of the invention are defined in the dependent claims. The claims form an integral part of the present specification.
A detailed description of some preferred embodiments of the invention is provided hereinafter. As previously mentioned, the present invention relates to a synergistic combination of active substances, which can be obtained from natural sources or by organic synthesis, which has proved to be particularly effective in the treatment of hypercholesterolemia and conse- quently in the prevention of atherosclerosis plaque formation and hypercholesterolemia- related cardiovascular diseases.
In a preferred embodiment, the synergistic composition of the invention comprises one or more monacolins, curcumin, procyanidins, piperine and optionally coenzyme Qio and/or plant sterols or stanols, as the active substances.
Further active substances which may be used in the compositions of the invention are resveratrol, policosanols, including, for example, octacosanol, folic acid and chromium, in particular chromium picolinate.
Monacolins are naturally occurring substances that can be obtained, for example, from the fermentation of red rice by the yeast Monascus purpureus. Among these, it is worth mentioning in particular monacolin K, which has the same chemical structure as lovastatin. Monacolin K is a competitive inhibitor of the enzyme 3 -hydroxy-3 -methyl glutaryl coenzyme A reductase (HMG- CoA reductase), which interferes with the production of mevalonate, necessary for cholesterol biosynthesis. Inhibition of HMG-CoA reductase is due to the structural homology between the β- hydroxy acid form of monacolin K and 3 -hydroxy-3 -methyl glutaryl coenzyme A.
A number of studies have shown that the administration of red yeast rice leads to a reduc- tion in total cholesterol and LDL cholesterol, with an increase in HDL cholesterol levels. Other studies have shown the cholesterol lowering effect of monacolin K.
In addition to monacolin K, also other monacolins are present in the red Monascus purpureus fermented rice, namely monacolins J, L and M, which inhibit 3 -hydroxy-3 -methyl glutaryl coenzyme A reductase and therefore can be used in the synergistic composition of the present invention as an alternative or in association with monacolin K. In a preferred embodiment, monacolins K, J, L and/or M are present in the composition of the invention at a concentration within the range of from 0.01% w/w to 10% w/w, more preferably within the range of from 0.05% w/w to 2% w/w, still more preferably within the range of from 0.5%) w/w to 1%) w/w based on the total weight of the active substances of the composition.
Curcumin is endowed with numerous pharmacological activities, including antiinflammatory, antioxidant, immunomodulatory, anti-tumour and neuro-protective activities. This substance is one of the most powerful, naturally occurring anti-inflammatory drugs and is extracted from Curcuma longa.
Curcumin has been shown to be effective in reducing lipid peroxidation and plasma cholesterol levels in many studies in humans and rodents.
Among others, curcumin is capable of acting on LXRa receptor, which enables an in- creased gene expression of cytochrome CYP7A1, which is involved in the biosynthesis of bile acids from cholesterol. This effect has been demonstrated in an in vivo study in rats: the administration of a diet containing 0.1%> w/w curcumin to rats is associated with a significant increase (p<0.05) in CYP7A1 expression and with a 68%> reduction in plasma LDL cholesterol levels.
Guggulsterone, a compound extracted from the Commiphora mukul plant, has also the ability to induce CYP7A1 expression and therefore to increase the synthesis of bile acids. Guggulsterone competes with bile acids for FXR receptor binding, preventing the negative feedback mechanism and leading, in fact, to an increase in bile acid synthesis. While acting with a different mechanism from that of curcumin, guggulsterone still leads to the same effect of increasing the expression of CYP7A1, and thus can be used alternatively or in addition to curcumin in the synergistic composition of the present invention.
In a preferred embodiment, curcumin and/or guggulsterone is/are present in the synergistic composition of the invention at a total weight concentration within the range of from 1%> w/w to 90%) w/w, more preferably within the range of from 10%> w/w to 30%> w/w, based on the total weight of the active substances of the composition. Pipeline is a chemical compound belonging to the vanilloid group, equipped with a molecular portion superimposable to that of vanillin. This substance is the main alkaloid of black pepper {Piper nigrum L.) and other plants belonging to the Piperaceae family, such as for example Piper longum L.
Piperine has shown an important inhibitory activity against two isoforms of the Acyl- CoA: cholesterol acyltransf erase enzyme (AC ATI and ACAT2), which act by esterifying cholesterol.
Other chemical compounds contained in the extract of plants belonging to the Piperaceae family, such as guineensine, also have the same action.
AC ATI and ACAT2 inhibition activity is very interesting since esterification of cholester- ol by ACAT1 and ACAT2 is a fundamental process for its insertion in chylomicrons and consequently for its intestinal absorption. In addition, inhibition of AC ATI and ACAT2 can prevent lipid accumulation in macrophages, with consequent inhibition of foam cell formation and atherosclerosis plaque formation. Piperine also has an important inhibitory activity against enzymes involved in the metabolism of xenobiotics. In particular, piperine administration has been shown to lead to increased bioavailability of coenzyme Qio. Co-administration of curcumin and piperine has also been shown to lead to increased oral bioavailability of curcumin. In a preferred embodiment, piperine and/or guineensine is/are present in the synergistic composition of the present invention at a total weight concentration within the range of from 0.10% w/w to 20% w/w, more preferably within the range of from 0.10% w/w to 5% w/w, based on the total weight of the active substances of the composition. Procyanidins are phenolic molecules belonging to the class of tannins and have cholesterol-lowering properties. Tannins are phenolic compounds that are widespread in nature, and able to precipitate proteins. In general, tannins are high molecular weight (MW > 500 Da) compounds and have numerous hydroxyl groups in their structure. Tannins are structurally very heterogeneous. Structurally, they can be divided into 3 groups:
1. Condensed tannins (or proanthocyanidins);
2. Hydrolyzable tannins;
3. Phlorotannins.
Procyanidins are part of the larger group of condensed tannins, also known as proanthocyanidins. From a chemical point of view, they are derived from flavan-3-ol compounds, in particular catechin and epicatechin, and may have an oligomeric or polymeric structure.
Procyanidins have the following general structure:
In oligomeric procyanidins, n = 0-5, while in polymeric procyanidins, n > 5.
The procyanidins, object of the present invention, have the structure shown in the figure, with n comprised between 0 and 15. These substances are found in great abundance in plants of the genus Malus, e.g. Malus domestica Borkh., Malus pumila Mill, or Malus pu- mila Mill, cv Annurca, but also in many other plant species, such as Pinus pinaster and Wilis Vinifera. The Annurca apple (Malus pumila Miller cv Annurca) is an apple cultivar, which is native to southern Italy and widespread in Campania, where 60% of the apples produced belong to this cultivar. Numerous studies have shown that this variety of apples has the highest content of polyphenols compared to other cultivars, such as Red Delicious, Pink Lady, Fuji and Golden Delicious.
The polyphenols contained in the apple extract, in particular the low molecular weight procyanidins, have been shown to be able to reduce the activity of CETP (Colesteryl Ester Transfer Protein), which has the function of transferring cholesterol esters from HDL to LDL lipoproteins. In this way, apple polyphenols can increase HDL plasma concentrations and reduce the value of the non-HDL/HDL cholesterol ratio.
High molecular weight procyanidins are also known to be poorly absorbed in the intestine and to have the ability to form inclusion compounds with cholesterol. This is the main mechanism through which procyanidins lead to inhibition of dietary cholesterol absorption.
Phlorizin, a dihydrochalcone found exclusively in apples, may be useful in the maintenance of normal plasma glucose levels, being able to reduce glucose uptake by the liver and intestinal cells.
In a preferred embodiment, procyanidins, optionally in combination with phlorizin, are present in the synergistic composition of the present invention at a total weight concentration within the range of from 1% w/w to 50% w/w, more preferably within the range of from 2.0%) w/w to 20% w/w, based on the total weight of the active substances of the composition.
Coenzyme Qio (also known as ubiquinone and ubidecarenone) is a benzoquinone belonging to the ubiquinone group, which consists of liposoluble molecules involved in electron transport processes at the mitochondrial level, with a fundamental role in the oxidative phosphorylation process. Coenzyme Qio is known to be capable of inhibiting low density lipoprotein peroxidation. The mechanism of action, more than in the direct reaction with peroxyl radicals, consists in the reduction of the a-tocopheroxyl radical into a-tocopherol. Supplementation with coenzyme Qio has been found to lead to an increase in ubiquinol concentration in LDLs, and a reduction in their peroxidability.
In addition to its important antioxidant properties, coenzyme Qio could have a direct antiatherogenic activity. Another interesting pharmacological effect of coenzyme Qio administration consists in the reduction of the systolic and diastolic pressures.
Monacolin K, which inhibits the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, allows a decrease in the biosynthesis of cholesterol as well as of mevalonate-derived isoprenoid compounds, such as ubiquinone and dolichol. For this reason, it may be useful that the synergistic composition of the present invention also comprises coenzyme Qio, whose levels are reduced by the extended use of monacolin k or other monacolins.
In a preferred embodiment, coenzyme Qio is present in the synergistic composition of the present invention at a concentration by weight within the range of from 0.10% w/w to 20% w/w, more preferably within the range of from 0.5% w/w to 2% w/w, based on the total weight of the active substances of the composition.
Phytosterols are an integral part of plant cell membranes. They are structurally similar to cholesterol, but with some structural differences. The term "phytosterols" is commonly used to describe both plant sterols, which have a double bond in position 5 of the ring, and plant stanols, in which the double bond is reduced.
Phytosterols are extracted from vegetable oils, such as corn oil, canola oil, soybean oil, sunflower oil, olive oil. There are also present to a lesser extent in nuts, seeds, fruit and vegetables. The most abundant sterols are sitosterol, campesterol and stigmasterol. They represent approximately 65%, 30%, and 3%, respectively, of plant sterol consumption in the diet. Stanols, on the other hand, are less abundant in nature but can be synthesized by hydrogenation of plant sterols. Thanks to the structural similarity with cholesterol, plant sterols and stanols act by blocking cholesterol absorption in the small intestine and decreasing blood levels of low density lipoproteins (LDLs).
In a preferred embodiment, plant sterols and/or stanols are present in the synergistic composition of the invention at a concentration by weight within the range of from 10% w/w to 90% w/w, more preferably within the range of from 20% w/w to 70% w/w, still more preferably within the range of from 50% w/w to 65% w/w, based on the total weight of the ac- tive substances of the composition.
The synergistic composition of the invention is manufactured as a pharmaceutical formulation or as a dietary supplement, preferably in a solid, liquid or semi-solid oral dosage form. Preferred oral dosage forms are tablets, capsules, sachets, powders, granules, pellets, gels, syrups, elixirs, oral solutions, suspensions or emulsions. Those most preferred are sachets and capsules.
Preferably, the synergistic composition of the invention is manufactured as an oral dosage form designed to administer from 1 to 50 mg/day of monacolins, from 10 to 2000 mg/day of curcumin and/or guggulsterone, from 50 to 4000 mg/day of procyanidins, optionally in combination with phlorizin, from 1 to 50 mg/day of piperine and/or guineensine, and optionally from 5 to 200 mg/day of coenzyme Qio and from 100 to 3000 mg/day of plant sterols and/or stanols. The synergistic composition object of the present invention is particularly advantageous for use in the treatment of hypercholesterolemia as it simultaneously achieves different effects, in particular the reduction of plasma LDL levels and the increase of HDL levels, the inhibition of intestinal cholesterol absorption, and the anti -atherogenic effect. All of this, on the whole, leads to a reduction in the risk of cardiovascular disease, in particular coro- nary artery disease, heart attack, angina pectoris and strokes.
The ability of the formulation to reduce the plasma levels of low-density lipoprotein de- pends on the following synergistic actions of the components of the composition:
(i) monacolin K, and monacolins in general, are able to inhibit the enzyme 3- hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), a key enzyme in cholesterol biosynthetic pathway. This leads to a reduction in cholesterol synthesis, fol- lowed by an increase in the expression of LDL-R receptors at the hepatic level and a lowering of blood LDL concentration;
(ii) curcumin and/or guggulsterone, by acting on the LXRa receptor and the FXR receptor, respectively, increase the expression of cytochrome CYP7A1, with a consequent increase in the synthesis of bile acids from cholesterol. This results in higher expression of LDL receptors (LDL-R), due to a reduced hepatocyte cholesterol concentration. The greater number of LDL-Rs on the hepatocyte membrane allows the plasma LDL concentration to be reduced;
(iii) procyanidins can complex bile acids in the intestine, thereby preventing their re- absorption. Since more than 95% of synthesized bile acids are normally reabsorbed at the intestinal level, the disruption of this mechanism causes increased synthesis thereof, with further depletion of liver cholesterol levels, increase in LDL receptor expression, and decrease in plasma LDL lipoprotein levels.
The above-mentioned active substances all lead to an increase in LDL receptor expression at the hepatic level, but since the action is based on different mechanisms, they can exert a synergy of action.
A second effect of the composition of the present invention is the ability to increase plasma HDL concentration. The action results from the synergy of actions of the following com- ponents of the formulation:
(i) procyanidins have the ability to inhibit the activity of CETP (colesteryl ester transfer protein), involved in the transfer of cholesterol esters from HDL to LDL. In this way, they are able to increase HDL cholesterol levels and reduce the non-HDL cholesterol/HDL cholesterol concentration ratio;
(ii) curcumin has the ability to increase the expression of the ABCAl transporter in macrophages and peripheral tissues. In this way, it increases the outflow of cholesterol from peripheral tissues, which is delivered to the plasma by HDLs, with a consequent in- crease in the plasma concentration of these lipoproteins.
A third effect of the composition of the present invention is the ability to reduce cholesterol absorption at the intestinal level, with a consequent reduction in the plasma concentra- tion of total cholesterol. The action results from the synergy of the following active substances:
(i) procyanidins, by forming complexes with cholesterol, reduce the intestinal absorption of the latter;
(ii) phytosterols compete with cholesterol for binding to the PC1L1 (Niemann-Pick Cl-like-1 protein) transporter, which allows its absorption into the enterocyte. In this way, they reduce the amount of cholesterol absorbed at the intestinal level;
(iii) piperine and guineensine have the ability to inhibit the enzyme ACAT2 (sterol O-acyltransferase), which is fundamental for cholesterol absorption in the gut. In fact, cholesterol must be esterified by this enzyme to be able to be inserted in chylomicrons. Piper- ine, by blocking this process, limits the intestinal absorption of cholesterol, which is thereafter excreted by the enterocyte via the ABCG5 and ABCG8 transporters.
Lastly, the composition of the present invention has the ability to inhibit atherosclerosis plaque formation, through the following mechanisms:
(i) the cholesterol-lowering activity, resulting from the pharmacological actions mentioned above, is very important for the reduction of the atherosclerosis process;
(ii) curcumin, by acting on the LXRa receptor, increases the expression of the ABCAl transporter, with consequent greater outflow of cholesterol from foam cells. Moreover, thanks to its antioxidant action, it inhibits LDL oxidation. Lastly, the anti- inflammatory action of this compound contributes to the reduction of the atherosclerosis process;
(iii) coenzyme Qio has an anti-atherogenic effect mainly related to its antioxidant and radical-scavenging activities;
(iv) procyanidins, thanks to their antioxidant activity, further contribute to preventing atherosclerosis plaque formation.
As described in the experimental section that follows, the cholesterol-lowering, anti- atherogenic, anti-inflammatory and antioxidant effects of a composition falling within the scope of the present invention have been assessed in comparison with the cholesterol- lowering, anti-atherogenic, anti-inflammatory and antioxidant effects of the individual constituents separately. This allowed the presence of a synergistic effect to be confirmed.
The examples that follow are provided for illustration purposes only and do not limit the scope of the invention as defined in the appended claims.
EXAMPLES
Below are some examples of formulation, with the daily doses of the relevant active substances.
FORMULATION EXAMPLES
EXAMPLE 1
Active ingredient Quantity Concentration by weight
(based on the total formulation)
Phytosterols 800 mg 20.00%
Curcumin 100 mg 2.50%
Procyanidins 80 mg 2.00%
Piperine 20 mg 0.50%
Monacolin K 10 mg 0.25%
Coenzyme Qio 10 mg 0.25%
TOTAL WEIGHT 4000 mg
SACHET
EXAMPLE 2
Active ingredient Quantity Concentration by weight
(based on the total formulation) Curcumin 100 mg 16.67%
Procyanidins 80 mg 13.33%
Piperine 20 mg 3.33%
Monacolin K 10 mg 1.67%
Coenzyme Qio 10 mg 1.67%
TOTAL WEIGHT 600 mg
CAPSULE
EXAMPLE 3
Active ingredient Daily Dose
Phytosterols 800 mg
Malus pumila Miller cv Annurca d.e. 200 mg
Curcuma longa L. d.e. 150 mg
Piper nigrum d.e. 20 mg
Monacolin K 10 mg
Coenzyme Qio 10 mg
EXAMPLE 4
Active ingredient Daily Dose
Phytosterols 800 mg
Pinus pinaster Aiton d.e. 200 mg
Curcuma longa L. d.e. 150 mg
Piper nigrum d.e. 20 mg
Monacolin K 10 mg
Coenzyme Qio 10 mg
EXAMPLE 5
Active ingredient Daily Dose
Phytosterols 800 mg
Vitis vinifera d.e. 200 mg
Curcuma longa L. d.e. 150 mg Piper nigrum d.e. 20 mg
Monacolin K 10 mg
Coenzyme Qio 10 mg
EXAMPLE 6
Active ingredient Daily Dose
Phytosterols 800 mg
Commiphora mukul Hook d.e. 500 mg
Malus pumila Miller cv Annurca d.e. 200 mg
Piper nigrum d.e. 20 mg
Monacolin K 10 mg
Coenzyme Qio 10 mg
EXAMPLE 7
Active ingredient Daily Dose
Phytosterols 800 mg
Malus domestica d.e. 200 mg
Curcuma longa L. d.e. 100 mg
Piper nigrum d.e. 20 mg
Monacolin K 10 mg
Coenzyme Qio 10 mg
EXAMPLE 8
Active ingredient Daily Dose
Phytosterols 800 mg
Commiphora mukul Hook d.e. 500 mg
Malus pumila Miller cv Annurca d.e. 200 mg
Piper nigrum d.e. 20 mg
Monacolin K 10 mg
Coenzyme Qio 10 mg
EXAMPLE 9 (tablets) INGREDIENTS QUANTITY (mg)
Red fermented rice, d.e. 3% Monacolin K 166.700
Curcuma longa, d.e. 95% curcuminoids 150.000
Vitis vinifera, d.e. 95% polyphenols, 30% procyanidins 133.500
Polygonum cuspidatum, d.e. 98% resveratrol 51.020
Saccharum ojficinarum, d.e. 98% policosanols, 60% 15.000 octacosanol
Piper nigrum, d.e. 95% piperine 1.580
Folic Acid 0.440
Chromium picolinate 0.370
Microcrystalline cellulose q.s.
Dibasic calcium phosphate q.s.
Sodium croscarmellose q.s.
Glycerol behenate q.s.
Magnesium stearate q.s.
Silicon dioxide q.s.
EXAMPLE 10 (sachets)
INGREDIENTS QUANTITY (mg)
Phytosterols 890.000
Red fermented rice, d.e. 3% Monacolin K 166.700
Curcuma longa, d.e. 95% curcuminoids 150.000
Vitis vinifera, d.e. 95% polyphenols, 30% procyanidins 133.500
Coenzyme Qio 10.000
Piper nigrum, d.e. 95% piperine 1.580
Folic Acid 0.440 Chromium picolinate 0.370
Sucrester q.s.
Dietary maltodextrin q.s.
Flavour q.s.
Maltodextrin-coated citric acid q.s.
Sucralose q.s.
Silicon dioxide q.s.
In all the above tables, d.e. stands for dry extract.
The effectiveness of the composition of the present invention and its synergistic effect can be assessed by experimentally determining the cholesterol-lowering and anti-atherogenic effects (by assessing the concentration of total cholesterol, LDL, HDL and triglycerides in blood) in a murine hypercholesterolemia model, before and after treatment with the complete composition or with separate components thereof. Similarly, the antioxidant and antiinflammatory activities can be assessed with reference to the complete composition and its separate components.

Claims

1. A composition comprising the combination of the following active substances:
- at least one monacolin selected from the group consisting of monacolin K, monacolin J, monacolin L, monacolin M and any combination thereof;
- curcumin and/or guggul sterone;
- pipeline and/or guineensine; and
- at least one procyanidin, optionally in combination with phlorizin.
2. The composition according to claim 1, comprising the at least one monacolin at a concentration by weight comprised within the range of from 0.01% w/w to 10% w/w based on the total weight of the active substances.
3. The composition according to claim 1 or 2, comprising curcumin and/or guggul- sterone at a concentration by weight comprised within the range of from 1% to 90% w/w based on the total weight of the active substances.
4. The composition according to any one of claims 1 to 3, comprising the at least one procyanidin at a concentration by weight comprised within the range of from 1% to 50% w/w based on the total weight of the active substances.
5. The composition according to any one of claims 1 to 4, comprising piperine at a concentration by weight comprised within the range of from 0.10% to 20% w/w based on the total weight of the active substances.
6. The composition according to any one of claims 1 to 5, further comprising coenzyme Q10, preferably at a concentration by weight comprised within the range of from 0.10% to 20%) w/w based on the total weight of the active substances.
7. The composition according to any one of claims 1 to 6, further comprising at least one plant sterol and/or at least one plant stanol, preferably at a concentration by weight comprised within the range of from 10% to 90% w/w based on the total weight of the ac- tive substances.
8. The composition according to any one of claims 1 to 7, wherein the said monacolins are present as a red Monascus purpureas fermented rice extract.
9. The composition according to any one of claims 1 to 8, wherein said curcumin is present as a Curcuma longa L. extract and/or said guggulsterone is present as a Commiphora mukul extract.
10. The composition according to any one of claims 1 to 9, wherein said at least one procyanidin and optionally phlorizin are present as an extract from a plant of the genus Malus, preferably Malus domestica Borkh., Malus pumila Mill, or Malus pumila Mill, cv Annurca, or said at least one procyanidin is present as a Pinus pinaster extract or as a Vitis vinifera extract.
11. The composition according to any one of claims 1 to 10, wherein said piperine and/or guineensine are present as an extract from a plant of the genus Piper, preferably Piper nigrum L. or Piper longum L.
12. The composition according to any one of claims 1 to 11, which is a pharmaceutical composition or a nutritional supplement in an oral dosage form.
13. The composition according to any one of claims 1 to 12, for use in the treatment of hypercholesterolemia, and/or in the inhibition of atherosclerosis plaque formation, and/or in the prevention of cardiovascular disease.
EP18714842.4A 2017-03-08 2018-03-08 Compositions for the treatment of cardiovascular disease Withdrawn EP3592340A1 (en)

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