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WO2018142328A1 - Composition de traitement d'une hyperuricémie - Google Patents

Composition de traitement d'une hyperuricémie Download PDF

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Publication number
WO2018142328A1
WO2018142328A1 PCT/IB2018/050654 IB2018050654W WO2018142328A1 WO 2018142328 A1 WO2018142328 A1 WO 2018142328A1 IB 2018050654 W IB2018050654 W IB 2018050654W WO 2018142328 A1 WO2018142328 A1 WO 2018142328A1
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Prior art keywords
composition
weight
vitamin
quercetin
dry extract
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PCT/IB2018/050654
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English (en)
Inventor
Giorgio MAGGIANI
Original Assignee
Aisal Sa
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Publication of WO2018142328A1 publication Critical patent/WO2018142328A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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 
    • 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
    • A61K36/736—Prunus, e.g. plum, cherry, peach, apricot or almond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • composition for hyperuricemia treatment Composition for hyperuricemia treatment
  • the present invention relates to a composition comprising quercetin, prunus cerasus and vitamin C.
  • the invention further relates to the use of said composition in maintaining the levels of uric acid and/or in the prevention and/or treatment of hyperuricemia, in particular in the prevention and/or treatment of idiopathic or primary hyperuricemia.
  • hyperuricemia refers to a condition that, in the absence of any symptoms, is characterized by levels of uric acid in the blood such as to induce a risk of urates being deposited in the joints or in tissues: the optimal threshold value is set at 7 mg/dl in men and 6.5 mg/dl in women, values above which there is a possibility of saturation of uric acid in the blood and thus its precipitation in the form of crystals.
  • miscible pool the total amount of uric acid present in a diffusible, rapidly exchangeable form in plasma and in interstitial fluids (the so-called miscible pool) is about 1000 mg, with fluctuations ranging between 500 and 1300 mg.
  • This pool is maintained in a balance between "inputs” and “outputs”: the former (inputs) are represented by the introduction, into circulation, of uric acid originating mostly from the endogenous production of purines (equal to 600-700 mg) and to a lesser extent from exogenous food intake (200 mg) and from the resulting catabolism of tissue nucleic acids (100 mg); the latter (outputs) are largely represented by urinary excretion (400-600 mg) and to a lesser extent by elimination via the intestinal route (100-200 mg).
  • an increase in levels of uric acid can fundamentally reflect two causes, namely, an increase in the synthesis of uric acid or a reduced urinary elimination thereof.
  • Intake through food does not constitute a major cause of hyperuricemia, since the maximum increase of uric acid obtainable with a diet rich in purines, as well as the maximum reduction of levels of uric acid resulting from a dietary restriction of purines, is about 1 mg/dl.
  • Hyperuricemia is an independent cardiovascular risk factor, increasingly recognized by the medical and scientific communities. Recent data suggest that hyperuricemia is also a risk factor for the development of kidney failure, type 2 diabetes and dementia. Hyperuricemia is considered a risk factor for mortality especially in women, the elderly and individuals with a high cardiovascular risk or pre-existing cardiovascular diseases (Grassi D et al., High Blood Pressure & Cardiovascular Prevention (2014), 21 (4), 235-242). Some experimental studies have demonstrated that cell damage determines an increase in cytoplasmic uric acid, and this appears to stimulate the inflammatory response both by activating the maturation of dendritic cells and by promoting the immune response mediated by CD8+ T lymphocytes.
  • uric acid causes endothelin levels to increase and stimulates the innate immune response, which seems to have a fundamental role in determining hypertension and cardiovascular diseases (C. Ruggiero C, et al., Eur Hearth J (2006), 27(10), 1 174-1 181 ).
  • the prevalence of hyperuricemia in western countries is between 8-10% of the adult population, with peaks of up to 25-30% of people who are overweight or suffer from metabolic syndrome. Hyperuricemia is the cause of gout.
  • the drugs known for treating chronic hyperuricemia include nonspecific xanthine- oxidase inhibitors, for example, allopurinol and febuxostat, which act by inhibiting the synthesis of uric acid from purines.
  • Allopurinol is generally administered for 2-3 weeks after treatment for the acute stage of gout and administration is extended for an indefinite period, established by the physician based on the severity of the disease and patient response. Initially, 100 mg are taken per day, on a full stomach; the dose is subsequently adjusted based on the plasma concentrations of uric acid. In the case of mild forms of gout, the maintenance dose is 100-200 mg of the drug per day; this is increased up to 300-600 mg/die and 700 mg/die in forms of medium and high severity, respectively. In the event of kidney failure, the dosage needs to be reduced.
  • allopurinol consist in diarrhea, a general sense of malaise, stomachache (less frequent if it is taken on a full stomach); headache, dizziness, drowsiness; a metallic taste in the mouth; tingling or numbness in the hands and feet; itching, hives, scaling, sore throat or inexplicable fever, and yellowing of the skin or eyes.
  • Febuxostat is available in 80 and 120 mg tablets, is more effective and better tolerated than allopurinol, but also much more expensive.
  • uricosurics such as, for example, probenecid and sulfinpyrazone, which lead to a lowering of the blood uric acid concentration by increasing urinary excretion.
  • probenecid is a renal tubular transport blocking agent that must initially be taken in 250 mg oral doses every 12 hours for 7 days.
  • the maintenance dose is 500 mg orally every 12 hours.
  • the dose can be modified on the basis of blood levels of uric acid.
  • Sulfinpyrazone is a uricosuric generally used as a replacement for allopurinol and in the event of relapses of gout that are particularly difficult to treat.
  • the therapy begins with 100-200 mg per day, on a full stomach. Every 2-3 weeks it is possible to modify the dose: 600-800 mg per day. In this case as well, the dosage is modulated so as to control the levels of uric acid.
  • the most common side effects of the sulfinpyrazone are dyspnea or breathlessness, wheezing, constriction, fever or sore throat, bed sores, ulcers or white patches in the mouth or on the lips, swollen or painful glands, unusual bleeding or wounds.
  • Colchicine a toxic alkaloid with antifungal action, is useful for favoring the elimination of uric acid; the effectiveness of this drug is comparable to that of non-steroidal anti-inflammatory drugs (NSAIDs).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Colchicine is preferable to NSAIDs in patients with cardiac disease, given that it does not generate water retention. Colchicine must be taken in an attack dose of 500 meg every 4 hours, until the prodromes are reduced. Do not exceed 6 mg per cycle. Also useful for the prevention of relapses: the maintenance dose is 1 mg per day.
  • the most frequent side effects, especially in the treatment of acute gout attacks, include the onset of gastrointestinal conditions such as nausea, abdominal pain and diarrhea.
  • Prolonged administration of this active ingredient in light of its biological activity, could give rise to agranulocytosis, thrombocytopenia, aplastic anemia, neuritis and a vitamin B12 deficiency.
  • the presence of gastrointestinal hemorrhaging, liver and kidney damage and myopathies has only rarely been observed.
  • quercetin is a flavonol that exerts a protective effect against atherosclerosis by interfering with the proatherogenic activity of macrophages and the pro-oxidant/pro-inflammatory response (Lara-Guzman OJ, et al., J Pharmacol Exp Ther (2012), 343(2), 296-306); quercetin increases the macrophage cholesterol efflux and therefore the consumption of quercetin can decrease the risk of atherosclerosis (Sun L, et al., Int J Clin Exp Pathol (2015), 8(9), 10854-60); furthermore, quercetin protects cardiomyocytes from oxidative stress (Ozbek N, et., Gen Physiol Biophys (2015), 34(4), 407-14).
  • quercetin has demonstrated to reduce the expression of C-reactive protein and cardiovascular risk factors (SAA, fibrinogen); such systemic effects together with local anti-proliferative and anti-inflammatory activity at the level of the aorta may contribute to attenuating atherosclerosis (Kleemann R, et al., Atherosclerosis (201 1 ), 218(1 ), 44-52).
  • SAA cardiovascular risk factors
  • Flavonols are the most abundant flavonoids in foods and are mostly present in a glycosylated form and at relatively low concentrations, about 15-30 mg/Kg. The foods richest in them are onions, Savoy cabbage, leeks, broccoli and bilberries. Red wine and tea are also sources of flavonols and contain up to 45 mg/Kg of flavonols.
  • quercetin is well tolerated also at high doses and this makes it possible to overcome the problem of the low bioavailability of these compounds and reach the blood concentrations necessary to ensure clinical action (Hoek-van den Hil et al., Genes Nutr (2015), 10(4), 469).
  • the amount of quercetin taken in daily through the diet (25-30 milligrams) is very far from being able to perform any biological activity. Even after a meal rich in foods containing the molecule, therefore, the blood concentrations are too low to justify the activity that is associable, by contrast, with the intake of pharmacological doses.
  • Quercetin is a xanthine-oxidase inhibitor and therefore acts by inhibiting the synthesis of uric acid from purines (Bindoli A et al., Pharmacol Res Commun. (1985); 17(9):831 -9).
  • quercetin was administered at a dose of 500 mg/die for 4 weeks. The primary objective of the study was to reduce uric acid after 2 and 4 weeks respectively. Treatment with quercetin reduced the plasma concentrations of uric acid on average by 26.5 micromol/L (p ⁇ 0.0008) (Shi Y, et al., Br J Nutr (2016), 1 15(5), 800-6).
  • quercetin showed to possess a high anti-inflammatory action that could be particularly useful in treating acute gout attacks.
  • Diabetic nephropathy is one of the main causes of terminal kidney failure in diabetic patients; the oxidative stress determined by hyperglycemia represents the main cause thereof (Zahedi M et al., Int J Prev Med (2013), 4(7), 777-85).
  • the renoprotective, anti-oxidative and anti-apoptotic effects of a low oral dose of quercetin were studied in a rat model of diabetic nephropathy.
  • quercetin caused a reduction in polyuria (-45%) and glycemia (-35%), reduced hypertriglyceridemia and exerted a significant effect on kidney function by decreasing proteinuria and the high levels of uric acid, urea and creatinine; this was accompanied by an improvement in the glomerulosclerosis of the kidney (Gomes I, et al., Lipids in Health and Disease (2014), 13, 84).
  • Cherries also, contain flavonoids, in particular anthocyanins and catechins, and possess antioxidant activity.
  • 2 doses of concentrated cherry juice were administered to 12 healthy volunteers (mean age 26 years): about 1 ounce (30 ml) of concentrated juice mixed with 100 ml of water (equivalent to 90 whole cherries) or 2 ounces (60 ml) of concentrated juice mixed with 100 ml of water.
  • Vitamin C is the most potent water-soluble antioxidant present in blood plasma and also acts as a regenerator of vitamin E and of carotenoid radical cationic species. Plants and some animal organisms are capable of synthesizing it from glucides, whereas humans are not capable of synthesizing it and must take it in through food. Vitamins E and C and ⁇ -carotene are known to have a synergistic effect as "scavengers" of reactive nitrogen species.
  • vitamin C reduced the risk of gout in a dose- dependent manner.
  • vitamin C was confirmed to significantly reduce the risk of occurrence of gout (Choi H, et al., Arch Intern Med (2009), 169 (5), 502-507).
  • women with the highest levels of ascorbic acid showed a decrease of about 4.6 mm Hg in systolic pressure and slightly more than 6 mm Hg in diastolic pressure, compared to women with the lowest levels of ascorbic acid. This result contributes to confirming the protective effect of vitamin C in patients with cardiovascular risks.
  • Patent application WO0064472 describes a fruit-based polyphenolic antioxidant complex comprising cherry extract, quercetin and vitamin C.
  • Patent application US 201 1262595 describes an antioxidant composition comprising cherry juice powder, quercetin and sodium ascorbate.
  • Patent application CN 105495258 describes a beverage comprising freeze-dried cherry powder, dried hawthorn powder, freeze-dried tomato powder, dried mulberry leaf powder and vitamin C; these ingredients act by suppressing the synthesis of uric acid, promoting its excretion and/or favoring diuresis. Therefore, the administration of a beverage comprising a combination of all these ingredients produces the effect of reducing the levels of uric acid.
  • the present inventors have addressed the problem of providing a pharmaceutical composition useful in the treatment of subjects with hyperuricemia.
  • the present inventors have addressed the problem of treating borderline hyperuricemia without relying on drugs having considerable side effects and/or which are very costly.
  • the present inventors have studied therapies based on natural substances with the aim of controlling the serum levels of uric acid in subjects with asymptomatic hyperuricemia.
  • a composition comprising quercetin, prunus cerasus dry extract and vitamin C, particularly a composition in which the ingredients are present in specific amounts and/or reciprocal weight ratios, is effective in reducing the levels of uric acid. Furthermore, the present inventors have found that said composition is effective in significantly reducing the values of systolic arterial pressure (SAP) and diastolic arterial pressure (DAP) and, in the subgroup of patients who showed signs of metabolic syndrome associated with hyperuricemia, the composition is effective in significantly reducing the levels of the pro-inflammatory cytokines IL-6 and TNF- alpha. Finally, the present inventors have found that the treatment with the composition does not alter the glycemia of patients.
  • SAP systolic arterial pressure
  • DAP diastolic arterial pressure
  • composition of the invention comprising quercetin, prunus cerasus dry extract and vitamin C is more active in reducing the levels of uric acid, pressure values and the levels of pro-inflammatory cytokines, in a statistically significant and therefore unexpected manner compared to a reference composition comprising only prunus cerasus dry extract and vitamin C.
  • a first object of the present invention is a composition comprising
  • quercetin in a percentage by weight ranging from 1 % to 30%, preferably from 2% to 25%
  • prunus cerasus dry extract in a percentage by weight ranging from 2% to 40%, preferably from 2.5% to 35%
  • vitamin C in a percentage by weight ranging from 5% to 60%, preferably from 4.5% to 55%; said percentages by weight being calculated relative to the total weight of the composition
  • quercetin is present in an amount ranging from 100 mg to 300 mg
  • prunus cerasus dry extract is present in an amount ranging from 200 mg to 400 mg
  • vitamin C is present in an amount ranging from 400 mg to 600 mg.
  • a second object of the present invention is a method for preparing the composition in accordance with the first object of the invention.
  • a third object of the present invention is the composition in accordance with the first object of the invention, for use as a medicament.
  • a fourth object of the present invention is a composition in accordance with the first object of the invention, for use in the prevention and/or treatment of hyperuricemia.
  • a fifth object of the present invention is the use of a composition in accordance with the first object of the invention in the preparation of a medicament for the prevention and/or treatment of hyperuricemia.
  • a sixth object of the present invention is a method for the prevention and/or treatment of hyperuricemia comprising the step of administering, to a subject who needs it, an effective amount of a composition in accordance with the first object of the invention.
  • a seventh object of the present invention is the use of a composition in accordance with the first object of the invention, as a dietary supplement for maintaining the levels of uric acid.
  • Prunus cerasus is a fruit tree belonging to the Rosaceae family and the genus prunus. In Italy, a distinction is made mainly among three varieties of sour cherry, with fruits (cherries) of a different color and different acidity: "Amareno” (the most widespread variety), with light red-colored fruits having a bitterish, slightly acidic flavor (amarena cherries); “Visciolo”, with bright red-colored fruits having a relatively sweet, slightly acidic flavor (visciola cherries); “Marasco”, with small blackish-red colored fruits having a very bitter, acidic flavor (marasca cherries). In English-speaking countries, mainly two sour cherry varieties are grown: Montmorency, a type of amarena, with light red-colored fruits; and Morello, with dark red-colored fruits.
  • the term “maintain” or “maintaining” means preserving a physiological condition or capacity, in this case physiological levels of uric acid.
  • the optimal threshold value of uric acid is fixed at a value equal to or less than 7 mg/dl in men and a value equal to or less than 6.5 mg/dl in women.
  • the term “prevent” or “prevention” means reducing the incidence of the pathology concerned.
  • the term "treat” or “treatment” means slowing down, stopping or reversing its progression.
  • the treatment of a subject affected by a pathology means reversing its progression, ideally to such a point as to eliminate the pathology itself.
  • administer in reference to the composition, means that the composition has been orally introduced into the subject to be treated.
  • the term "effective amount” is the amount of composition which, when administered to a subject, is effective in maintaining a physiological condition or capacity, and/or reducing the incidence of a pathology, and/or slowing down, stopping or reversing the progression of a pathology.
  • Figure 1 shows the values of uric acid in the whole sample, expressed in mg/dL, measured at time TO and time T1.
  • Figure 2 shows the systolic arterial pressure (SAP) and diastolic arterial pressure (DAP) values of the whole sample, expressed in mm/hg, measured at time TO and time T1 .
  • SAP systolic arterial pressure
  • DAP diastolic arterial pressure
  • the first object of the present invention is a composition
  • a composition comprising (i) quercetin in a percentage by weight ranging from 1 % to 30%, preferably from 2% to 25%; (ii) prunus cerasus dry extract in a percentage by weight ranging from 2% to 40%, preferably from 2.5% to 35%; and (iii) vitamin C in a percentage by weight ranging from 5% to 60%, preferably from 4.5% to 55%; said percentages by weight being calculated relative to the total weight of the composition;
  • the prunus cerasus (sour cherry) dry extract may be obtained from the fruit (cherry) or peduncle of the fruit; preferably it is obtained from the peduncle of the fruit.
  • the prunus cerasus (sour cherry) dry extract may be obtained from any variety; preferably it is obtained from Amareno, Visciolo, Marasco, Montmorency and Morello.
  • the dry extract is obtained from the peduncle of the fruit and the variety of prunus cerasus is selected indistinctly from among Amareno, Visciolo, Marasco, Montmorency and Morello.
  • the prunus cerasus dry extract can be prepared with methods known to the person skilled in the art.
  • the prunus cerasus dry extract was prepared by means of a process comprising: grinding of cherry peduncles, extraction with a 25% v/v ethanol solution in water and filtration; the product obtained (cake) was concentrated/desolvated with a 25% v/v ethanol solution in water; the extract obtained was spray dried and finally sieved.
  • the composition preferably comprises (i) quercetin in a percentage by weight ranging from 2.5% to 15%, preferably from 3% to 10%; and/or (ii) prunus cerasus dry extract in a percentage by weight ranging from 3% to 25%, preferably from 3.5% to 20%; and/or (iii) vitamin C in a percentage by weight ranging from 5% to 45%, preferably from 5.5% to 40%; said percentages by weight being calculated relative to the total weight of the composition.
  • the composition comprises (i) quercetin in a percentage by weight ranging from 2.5% to 15%, preferably from 3% to 10%; (ii) prunus cerasus dry extract in a percentage by weight ranging from 3% to 25%, preferably from 3.5% to 20%, more preferably from 3.5% to 15%; and (iii) vitamin C in a percentage by weight ranging from 5% to 45%, preferably from 5.5% to 40%, more preferably ranging from 5.5% to 20%; said percentages by weight being calculated relative to the total weight of the composition.
  • the composition comprises (i) 4.4% quercetin; (ii) 6, 7 % prunus cerasus dry extract ; (iii) 11 .1 % vitamin C; said percentages by weight being calculated relative to the total weight of the composition.
  • the composition comprises
  • the ratio, by weight, of (i) quercetin, (ii) prunus cerasus dry extract and (iii) vitamin C is 1 :1 .4-1 .6:2.2-4; preferably it is 1 : 1.5: 2.5.
  • the composition comprises
  • composition in accordance with the first object of the invention preferably comprises no other active pharmaceutical ingredients, in particular it comprises no other ingredients that suppress the synthesis of uric acid, promote its excretion or favor diuresis.
  • composition in accordance with the first object of the invention preferably comprises at least one pharmaceutically acceptable vehicle.
  • composition consists of
  • At least one pharmaceutically acceptable vehicle at least one pharmaceutically acceptable vehicle.
  • Acceptable vehicles for oral compositions are those commonly employed and known to the person skilled in the art, e.g. carriers, diluents, excipients, suspending agents, caking agents, lubricants, adjuvants, vehicles, release systems, emulsifiers, disintegrating agents, adsorbents, preservatives, surfactants, colorants, flavorings and sweeteners.
  • the composition as described above is suitable for oral administration in the form of a powder to be dissolved in water, a tablet, a soft gelatin capsule, a hard gelatin capsule or any other dosage form known to the person skilled in the art.
  • the composition of the present invention is preferably in the form of a powder to be dissolved in water.
  • a second object of the present invention is a method for preparing the composition in accordance with the first object of the invention.
  • composition of the present invention can be prepared according to conventional methods known to the person skilled in the art, for example by mechanically mixing the powders of the active ingredients and, where present, the pharmaceutically acceptable excipients, using a mixer; the resulting mixture can be stirred until obtaining uniformity.
  • the obtained mixture can be compacted to obtain a tablet and, optionally, a coating can be applied to the tablet.
  • the obtained mixture can be introduced into a soft or hard gelatin capsule, or in another dosage form known to the person skilled in the art.
  • a third object of the present invention is the composition in accordance with the first object of the invention for use as a medicament.
  • a fourth object of the present invention is a composition for use in the prevention and/or treatment of hyperuricemia; preferably in the prevention and/or treatment of idiopathic or primary hyperuricemia, comprising (i) quercetin in a percentage by weight ranging from 1 % to 30%, preferably from 2% to 25%, (ii) prunus cerasus dry extract in a percentage by weight ranging from 2% to 40%, preferably from 2.5% to 35%, and (iii) vitamin C in a percentage by weight ranging from 5% to 60%, preferably from 4.5% to 55%, said percentages by weight being calculated relative to the total weight of the composition,
  • quercetin is present in an amount ranging from 100 mg to 300 mg
  • prunus cerasus dry extract is present in an amount ranging from 200 mg to 400 mg
  • vitamin C is present in an amount ranging from 400 mg to 600 mg.
  • a fifth object of the present invention is the use, in the preparation of a medicament for the prevention and/or treatment of hyperuricemia, preferably in the prevention and/or treatment of idiopathic or primary hyperuricemia, of a composition
  • a composition comprising (i) quercetin in a percentage by weight ranging from 1 % to 30%, preferably from 2% to 25%, (ii) prunus cerasus dry extract in a percentage by weight ranging from 2% to 40%, preferably from 2.5% to 35%, and (iii) vitamin C in a percentage by weight ranging from 5% to 60%, preferably from 4.5% to 55%, said percentages by weight being calculated relative to the total weight of the composition,
  • quercetin is present in an amount ranging from 100 mg to 300 mg
  • prunus cerasus dry extract is present in an amount ranging from 200 mg to 400 mg
  • vitamin C is present in an amount ranging from 400 mg to 600 mg.
  • a sixth object of the present invention is a method for the prevention and/or treatment of hyperuricemia, preferably for the prevention and/or treatment of idiopathic or primary hyperuricemia, comprising the step of administering, to a subject who needs it, an effective amount of a composition comprising (i) quercetin in a percentage by weight ranging from 1 % to 30%, preferably from 2% to 25%, (ii) prunus cerasus dry extract in a percentage by weight ranging from 2% to 40%, preferably from 2.5% to 35%, and (iii) vitamin C in a percentage by weight ranging from 5% to 60%, preferably from 4.5% to 55%, said percentages by weight being calculated relative to the total weight of the composition,
  • quercetin is present in an amount ranging from 100 mg to 300 mg
  • prunus cerasus dry extract is present in an amount ranging from 200 mg to 400 mg
  • vitamin C is present in an amount ranging from 400 mg to 600 mg.
  • a seventh object of the present invention is the use, as a dietary supplement for maintaining the levels of uric acid, of a composition
  • a composition comprising (i) quercetin in a percentage by weight ranging from 1 % to 30%, preferably from 2% to 25%, (ii) prunus cerasus dry extract in a percentage by weight ranging from 2% to 40%, preferably from 2.5% to 35%, and (iii) vitamin C in a percentage by weight ranging from 5% to 60%, preferably from 4.5% to 55%, said percentages by weight being calculated relative to the total weight of the composition,
  • the prunus cerasus (sour cherry) dry extract can be obtained from the fruit (cherry) or peduncle of the fruit; preferably it is obtained from the peduncle of the fruit.
  • the prunus cerasus (sour cherry) dry extract can be obtained from any variety; preferably it is obtained from Amareno, Visciolo, Marasco, Montmorency and Morello.
  • the dry extract is preferably obtained from the peduncle of the fruit and the variety of prunus cerasus is selected indistinctly from among Amareno, Visciolo, Marasco, Montmorency and Morello.
  • the composition preferably comprises (i) quercetin in a percentage by weight ranging from 2.5% to 15%, preferably from 3% to 10%; (ii) prunus cerasus dry extract in a percentage by weight ranging from 3% to 25%, preferably from 3.5% to 20%, and even more preferably from 3.5% to 15%; and (iii) vitamin C in a percentage by weight ranging from 5% to 45%, preferably from 5.5% to 40%, and even more preferably from 5.5% to 20%; said percentages by weight being calculated relative to the total weight of the composition.
  • the composition comprises (i) 4.4% quercetin; (ii) 6.7% prunus cerasus dry extract; and (iii) 1 1 .1 % vitamin C; said percentages by weight being calculated relative to the total weight of the composition.
  • the composition comprises
  • the ratio, by weight, of (i) quercetin, (ii) prunus cerasus dry extract and (iii) vitamin C is 1 : 1 .4-1 .6:2.2-4; preferably it is 1 : 1 .5: 2.5.
  • the composition comprises
  • the composition preferably comprises no other active pharmaceutical ingredients, in particular it comprises no other ingredients that suppress the synthesis of uric acid, promote its excretion or favor diuresis.
  • the composition preferably comprises at least one pharmaceutically acceptable vehicle.
  • the composition consists of
  • At least one pharmaceutically acceptable vehicle at least one pharmaceutically acceptable vehicle.
  • the composition is preferably for oral use; it is more preferably in the form of a homogeneous mixture of powders to be dissolved in water.
  • the composition is preferably administered once daily.
  • compositions (1 ) representative of the invention were prepared in the form of a homogeneous mixture of powders comprising: (i) 200 mg of quercetin; (ii) 300 mg of prunus cerasus dry extract (prepared as described above); (iii) 500 mg of vitamin C; pharmaceutically acceptable excipients, q.s. to 4500 mg.
  • BMI Body Mass Index
  • Borderline levels of arterial pressure or grade 1 hypertension SAP greater than or equal to 140 mm/Hg and less than 150mm/Hg and/or DAP greater than or equal to 90 mm/Hg and less than 95 mm/Hg.
  • the baseline characteristics of the subjects (at TO) after the period of dietary stabilization and prior to treatment are shown in table 1 .
  • Table 1 baseline characteristics of the sample of subjects (at TO)
  • composition (1 ) representative of the invention in the form of a homogeneous mixture of powders to be dissolved in water, 4500 mg/die for a period of 4 weeks, at the end of which (T1 ) the baseline parameters analyzed were re-evaluated for all patients. Furthermore, in a subgroup of subjects who also showed signs of metabolic syndrome, an assessment was made of the effects of the treatment on pro-inflammatory cytokines (IL-6 and TNF-alpha), measured in plasma using the validated ELISA method and spectrophotometric analysis.
  • pro-inflammatory cytokines IL-6 and TNF-alpha
  • the data have been expressed as means.
  • the parameters analyzed were compared using ANCOVA followed by Tukey's post-hoc test.
  • the significance threshold was set at p ⁇ 0.05.
  • Fig. 1 in the total sample the levels of uric acid went from 7.9 mg/dL (TO, baseline) to 6.9 mg/dL (T1 ) (p ⁇ 0.02 vs. TO, baseline).
  • the treatment with the composition (1 ) representative of the invention at 4500 mg/die for one month further brought about a statistically significant decrease in the systolic arterial pressure (SAP, p ⁇ 0.04 vs. TO, baseline) and diastolic arterial pressure (DAP, p ⁇ 0.05 vs. TO, baseline) values (see Fig.2).
  • composition (1 ) in accordance with the invention in which (i) quercetin, (ii) prunus cerasus dry extract and (iii) vitamin C are present in specific amounts and/or reciprocal weight ratios, is able to reduce plasma levels of uric acid in hyperuricemic subjects, is effective in reducing the SAP/DAP pressure values and, in the subgroup of patients who showed signs of metabolic syndrome associated with hyperuricemia, is effective in significantly reducing the levels of the pro-inflammatory cytokines IL-6 and TNF-alpha.
  • composition (1 ) representative of the invention comprising (i) quercetin, (ii) prunus cerasus dry extract and (iii) vitamin C, was prepared as described in example 1 .
  • a comparative composition (2) comprising (ii) prunus cerasus dry extract and (iii) vitamin C, was prepared as follows:
  • a comparative composition (2) were prepared, according to conventional methods known to the person skilled in the art, in the form of a homogeneous mixture of powders comprising: 300 mg of prunus cerasus dry extract (prepared as described above), 500 mg of vitamin C and pharmaceutically acceptable excipients, q.s. to 4500 mg.
  • BMI Body Mass Index
  • Pregnancy or suspected pregnancy 60 subjects aged between 25 and 65 were enrolled; they had idiopathic or primary hyperuricemia, were overweight and had suboptimal pressure levels. The subjects, divided into two groups of 30 subjects each, A1 and B1 , underwent a 4- week stabilization diet, aimed at standardizing dietary habits and correcting excesses. Arterial pressure was evaluated, according to guidelines, as the mean of 3 consecutive measurements taken two minutes apart, in a seated position. Uric acid was measured in peripheral blood after 12 hours fasting using the standard method.
  • Table 4 baseline characteristics (at TO) of the sample of subjects divided into groups A1 and B1
  • the 30 subjects in group A1 took the composition (1 ) representative of the invention in the form of a homogeneous mixture of powders to be dissolved in water, 4500 mg/die for a 30-day period; the 30 subjects in group B1 took the comparative composition (2) in the form of a homogeneous mixture of powders to be dissolved in water, 4500 mg/die for a 30-day period.
  • the baseline parameters analyzed were re-evaluated for all 60 subjects.
  • the data have been expressed as means.
  • the parameters analyzed were compared by means of the Kruskall-Wallis test (also known by the name non- parametric one-way ANOVA).
  • the significance threshold was set at p ⁇ 0.0001 .
  • the data analysis was performed using the software SPSS v.21 (IBM).
  • Table 5 characteristics of the sample of subjects divided into groups A1 and B1 at time T1
  • the mean levels of uric acid were reduced from 8.2 mg/dL (TO, baseline) to 6.5 mg/dL (T1 ) and in group B1 subjects, the mean levels of uric acid were reduced from 8.1 mg/dL (TO, baseline) to 7.9 mg/dL (T1 ).
  • the Kruskal-Wallis test revealed the existence of a statistically significant difference between the levels of uric acid at TO and T1 , both in group A1 and in group B1 , with a p-value ⁇ 0.0001 .
  • the subjects who underwent a larger decrease are the ones belonging to group A1 , treated with the composition (1 ) representative of the invention; the reduction in the levels of uric acid in group A1 was statistically significant versus the reduction in the levels of uric acid in group B1 ( p ⁇ 0.0001 ).
  • SAP/DAP was reduced from 146/93 mmHg (TO, baseline) to 137/85 mmHg (T1 ) and in the group B1 subjects, SAP/DAP was reduced from 144/94 mmHg (TO, baseline) to 140/88 mmHg (T1 ).
  • the Kruskal-Wallis test revealed the existence of a statistically significant difference between the pressure levels at TO and T1 , both in group A1 and in group B1 , with a p-value ⁇ 0.0001 .
  • the subjects who underwent a larger decrease in SAP/DAP are the ones belonging to group A1 , treated with the composition (1 ) representative of the invention; the reduction in the SAP/DAP levels in the group A1 was statistically significant versus the reduction of the levels SAP/DAP in the Group B1 ( p ⁇ 0.0001 ).
  • Table 6 baseline characteristics of the sample of subjects in subgroup A1 and subgroup B1 (at TO)
  • the values of the pro-inflammatory cytokines IL-6 and TNF-alpha decreased from 6.39 pg/ml (TO, baseline) to 4.26 pg/ml (T1 ) and from 7.98 pg/ml (TO, baseline) to 3.79 pg/ml (T1 ), respectively; in the subgroup B1 subjects, the values of the pro-inflammatory cytokines IL-6 and TNF-alpha decreased from 6.94 pg/ml (TO, baseline) to 5.60 pg/ml (T1 ) and from 7.97 pg/ml (TO, baseline) to 4.90 pg/ml (T1 ), respectively.
  • the Kruskal-Wallis test revealed the existence of a statistically significant difference in the levels in the pro-inflammatory cytokines IL-6 and TNF-alpha at times TO and T1 , both in subgroup A1 and in subgroup B1 , with a p-value ⁇ 0.0001 .
  • the subjects who underwent a larger decrease in the levels of the pro-inflammatory cytokines IL-6 and TNF-alpha are the ones belonging to subgroup A1 , treated with the composition (1 ) representative of the invention; the reduction in the levels of the pro-inflammatory cytokines in subgroup A1 was statistically significant versus the reduction in the corresponding values in subgroup B1 ( p ⁇ 0.0001 ).
  • compositions (1 ) and (2) showed to be similar. Therefore, the data reported in example 1 demonstrate that the administration of the composition (1 ) in accordance with the invention to patients with idiopathic or primary hyperuricemia represents a valid alternative to traditional therapy with drugs, also in the presence of comorbidities, such as a borderline rise in systolic/diastolic pressure or the concomitance of an aspecific inflammatory substrate, since it demonstrates to be effective and at the same time is free of the side effects that occur with traditional therapy with drugs.
  • comorbidities such as a borderline rise in systolic/diastolic pressure or the concomitance of an aspecific inflammatory substrate
  • the data reported in example 2 demonstrate that the administration of the composition (1 ) in accordance with the invention, in which quercetin is present in addition to prunus cerasus dry extract and vitamin C, produces a statistically significant reduction in the levels of uric acid, systolic pressure (SAP), diastolic pressure (DAP) and pro-inflammatory cytokines compared to the reduction produced as a result of the administration of the comparative composition (2), comprising solely prunus cerasus dry extract and vitamin C.
  • SAP systolic pressure
  • DAP diastolic pressure
  • pro-inflammatory cytokines compared to the reduction produced as a result of the administration of the comparative composition (2), comprising solely prunus cerasus dry extract and vitamin C.

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Abstract

La présente invention concerne une composition comprenant de la quercétine, un extrait sec de prunus cerasus et de la vitamine C. L'invention concerne également l'utilisation de la composition pour maintenir les taux d'acide urique et/ou pour prévenir et/ou traiter une hyperuricémie, en particulier pour prévenir et/ou traiter une hyperuricémie idiopathique ou primaire.
PCT/IB2018/050654 2017-02-03 2018-02-02 Composition de traitement d'une hyperuricémie WO2018142328A1 (fr)

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CN105495258B (zh) * 2015-12-07 2018-05-18 广东盛元中天生物科技有限公司 一种有助降尿酸的水果饮料

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11541094B2 (en) 2019-08-06 2023-01-03 Healthrite Partners, LLC Formulations for treating metabolic syndrome and increasing energy levels
CN110651939A (zh) * 2019-09-09 2020-01-07 宁波萃元科技有限公司 一种适用于痛风人群的组合物

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