WO2009132807A1 - Extrait polyphénolique - Google Patents

Extrait polyphénolique Download PDF

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Publication number
WO2009132807A1
WO2009132807A1 PCT/EP2009/003012 EP2009003012W WO2009132807A1 WO 2009132807 A1 WO2009132807 A1 WO 2009132807A1 EP 2009003012 W EP2009003012 W EP 2009003012W WO 2009132807 A1 WO2009132807 A1 WO 2009132807A1
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WIPO (PCT)
Prior art keywords
polyphenols
hydrolysed
composition
oleuropein
composition according
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PCT/EP2009/003012
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English (en)
Inventor
Herman Van Mellaert
Arne Heyerick
Antonie Van Der Saag
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Bio-Actor Bvba
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Publication of WO2009132807A1 publication Critical patent/WO2009132807A1/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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin

Definitions

  • the present invention is on particular compositions comprising certain combinations of the main olive polyphenols, such as for instance oleuropein and/or ligstroside in combination with hydroxytyrosol and/or tyrosol characterized in that the ratio of non-hydrolysed polyphenols (oleuropein and/or ligstroside) to hydrolysed polyphenols (hydroxytyrosol and/or tyrosol) is within certain thresholds which unexpectedly provide certain health benefits as compared to other compositions of olive polyphenols already known in the art.
  • non-hydrolyzed (olive) polyphenols are deemed to comprise one or more of the polyphenols selected from the group consisting of oleuropein, oleuropein aglycon, ligstroside and ligstroside aglycon; and the "hydrolyzed polyphenols" are deemed to comprise hydroxytyrosol and/or tyrosol.
  • the compositions contain standardized quantities for at least two of said olive polyphenols.
  • compositions as well as the use of said compositions in the prevention and/or treatment of inflammatory conditions.
  • inflammatory conditions including bone loss induced or exacerbated by estrogen deficiency, oxidative stress and/or chronic inflammation.
  • Bone is not a static tissue. Bone experiences a constant remodelling resulting from a tightly regulated balance between bone resorption and de novo synthesis of bone tissue involving two main cell types, respectively the osteoblasts that provide the new bone tissue and the osteoclasts that destroy the bone substances.
  • osteoblasts and osteoclasts For humans or animals in adulthood, the balanced action of osteoblasts and osteoclasts makes it possible to maintain the bone mass in the long term and simultaneously ensures bone tissue remodelling by bone resorption and de novo bone synthesis. Nevertheless with ageing or disease, the bone remodelling process becomes unbalanced, resulting in bone loss that is referred to as osteopenia or, once bone loss is more severe, as osteoporosis.
  • osteopenia bone loss that is referred to as osteopenia or, once bone loss is more severe, as osteoporosis.
  • osteopenia bone loss that is referred to as osteopenia
  • osteoporosis is seen in general as a disorder associated with an increased bone resorption or inhibition of de novo bone synthesis, i.e. it is not restricted to age related imbalance between osteoblast and osteoclast activity.
  • osteoporosis The most common disorder associated with bone density reduction is osteoporosis, the occurrence of which appears most frequently in women, after the beginning of the menopause.
  • Osteoporosis is a systemic skeletal disease characterized by a bone mass reduction and bone tissue microarchitecture degradation, associated with increased bone fragility and with fracture sensitivity thereof.
  • osteoporosis includes in addition to the foregoing also other pathological disorders associated with an imbalanced bone metabolism are Paget's disease, bone loss or osteolysis observed in the vicinity of a prothesis, metastatic bone disease, cancer induced hypocalcemia, multiple myeloma, and periodontal diseases such as for example gingivitis and periodontitis.
  • osteopenia-induced bone loss and more in particular osteopenia and osteoporosis, including bone loss induced or exacerbated by estrogen deficiency, oxidative stress and/or chronic inflammation.
  • inflammatory conditions shall include any health condition or disease that is associated with or accompanied by an increase in inflammation related markers, and may include diseases such as Crohn's disease, inflammatory/irritable bowel disease, ulcerative colitis, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, osteopenia, osteoporosis, Paget's disease, hypertension, atherosclerosis, vasculitis, psoriasis, lupus, sleroderma, Sjogren's syndrome, polymyositis, dermatomyositis, mixed connective tissue disease, asthma, chronic obstructive pulmonary disease, chronic prostatitis, pelvic inflammatory disease.
  • diseases such as Crohn's disease, inflammatory/irritable bowel disease, ulcerative colitis, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, osteopenia, osteoporosis, Paget's disease, hypertension, atherosclerosis, vascu
  • the non hydrolysed polyphenols in particular oleuropein and/or ligstroside, on the other hand are not only more slowly absorbed, but also slowly hydrolysed in vivo into hydroxytyrosol and tyrosol respectively. It was surprisingly found that the combination of a hydrolysed and a non-hydrolysed polyphenol (e.g. hydroxytyrosol and oleuropein), characterized in that the ratio of oleuropein to hydroxytyrosol is within certain treshholds, provides for an optimal pharmacokinetics profile whereby a rapid and longer term sustained effect is obtained.
  • a hydrolysed and a non-hydrolysed polyphenol e.g. hydroxytyrosol and oleuropein
  • the currently available extracts such as the olive leaf extracts or the olive waste water extracts, either contain only one standardized quantity of one of the polyphenols, and/or to the extent they do contain standardized quantities of more than one polyphenol they do not contain oleuropein and hydroxytyrosol in a ratio consistent with what is described in the present invention.
  • concentration of polyphenols present in said extracts is such that the amount of extract needed to obtain the desired anti-inflammatory effect or bone protective effect, is too high.
  • This invention relates to methods and compositions for treating and preventing inflammatory conditions, notably osteopenia and osteoporosis, and is based on the finding that particular ratios of non-hydrolysed to hydrolysed polyphenols bring about a considerable improvement with regard to bone mineral density in an animal model for osteoporosis.
  • non-hydrolised polyphenols are generally represented by the compounds of formula (I) wherein
  • R 1 represents H or OH
  • R 2 represents H or OH
  • R 3 is selected from OH, H, halogen, cyano, amino, nitro, nitroso, Ci -6 alkyl, Ci -6 alkoxy, and Ci -6 alkyloxycarbonyl; wherein each of said alkyl, alkoxy or alkyloxycarbonyl group is linear or branched;
  • R 4 is selected from H, OH, aryl, halogen, amino, Ci -6 alkyl, C2-e alkenyl, C ⁇ alkyny ⁇ and Ci -6 alkyloxy; wherein each of said alkyl, alkenyl, alkynyl or alkyloxy group is linear or branched; and
  • R 5 is selected from H, OH, aryl, halogen, amino, glucose, ⁇ -D-glucopyranose, Ci -6 alkyl, C2-6 alkenyl, Ca -6 alkynyl, and Ci -6 alkyloxy; wherein each of said alkyl, alkenyl, alkynyl or alkyloxy group is linear or branched, including solvates and pharmaceutically acceptable addition salts thereof.
  • the non-hydrolised polyphenols are those compounds of formula (I) wherein; R 1 represents H or OH; R 2 represents H or OH; R 3 represents Ci -6 alkyloxycarbonyl, more in particular methoxycarbonyl; R 4 represents Ci -6 alkyl, more in particular methyl; and R 5 represents hydrogen or ⁇ -D-glucopyranose, including solvates and pharmaceutically acceptable addition salts thereof.
  • the non-hydrolysed polyphenol consists of ligstroside (CAS Registry N° 35897-92-8).
  • hydroolised polyphenols are generally represented by the compounds of formula (II)
  • R 1 represents H or OH
  • R 2 represents H or OH, including solvates and pharmaceutically acceptable addition salts thereof.
  • the non-hydrolised polyphenols are selected from hydroxy-tyrosol (CAS Registry N° 10597-60-1 ), and tyrosol (CAS Registry N° 501-94-0).
  • compositions according to the present invention for use in the treatment or prevention of osteopenia and osteoporosis, including bone loss induced or exacerbated by estrogen deficiency, oxidative stress and/or chronic inflammation. It further provides the use of said compositions in the treatment or prevention of inflammatory conditions and more in particular the treatment or prevention of osteopenia and osteoporosis, including bone loss induced or exacerbated by estrogen deficiency, oxidative stress and/or chronic inflammation. It is also an object of the present invention to describe how such compositions can be obtained, either as an extract, a combination of extracts, a combination of an extract with a synthetic compound or as a mixture of synthetic compounds.
  • the present invention provides a composition for use in the treatment or prevention of osteopenia and osteoporosis, said composition comprising non-hydrolysed polyphenols of formula (I) as defined hereinbefore and hydrolysed polyphenols of formula (II) as defined hereinbefore, and characterized in that the weight ratio of non-hydrolysed polyphenols to hydrolysed polyphenols is equal to or greater than 1 to 4 (1 :4); in particular the weight ratio of non-hydrolysed polyphenols to hydrolysed polyphenols is between about 1:2 and about 100:1 ; more in particular between about 1:1 and about 50:1; even more in particular between about 3:2 and about 10:1.
  • the present invention provides a composition comprising non-hydrolysed polyphenols of formula (I) as defined hereinbefore and hydrolysed polyphenols of formula (II) as defined hereinbefore, characterized in that the weight ratio of non-hydrolysed polyphenols to hydrolysed polyphenols is equal to or greater than 2:1 and up to about 100:1; in particular between about 3:2 and about 50:1 ; more in particular between about 3:2 and about 10:1 ; even more in particular greater than 2:1 and smaller than 4:1; in particular a ratio of 3:1.
  • said compositions comprising an excess of non-hydrolysed polyphenols to hydrolysed polyphenols of at least 2:1 are particularly useful in the treatment or prevention osteopenia and osteoporosis. It is thus an object of the present to provide said compositions for use in the treatment of osteopenia and osteoporosis, including bone loss induced or exacerbated by estrogen deficiency, oxidative stress and/or chronic inflammation.
  • the non-hydrolized polyphenol essentially consists of oleuropein, i.e. some percentages of other norv hydrolyzed polyphenols may be present, wherein said other non-hydrolyzed polyphenols have no material effect in the characteristics of the compositions of the present invention, and the hydrolyzed polyphenol essentially consists of hydroxytyrosol, i.e.
  • compositions of the present invention comprise oleuropein as the non-hydrolysed polyphenol and hydroxytyrosol as the hydrolysed polyphenol.
  • compositions as defined hereinbefore are in further aspect of the invention, obtainable from the stems, the leaves, the fruits or the stones of plants belonging to the Oleaceae family.
  • Plants belonging to the Oleaceae family include a plant of genus Olea europaea (olive tree), a plant of genus Ligustrum, a plant of genus Syringa, a plant of genus Fraximus, a plant of genus Jasminum and a plant of genus Osmanthus.
  • the extracts are obtained from a plant of genus Olea europaea (olive tree) and come in a liquid form or in a powder.
  • compositions are prepared from extracts of immature or semi-mature olives. These olives are known to be rich in polyphenolics, notably oleuropein and hydroxytyrosol.
  • aqueous extract olive pulp from the immature or semi-mature olives is first pressed to obtain a liquid-phase mixture including olive oil, vegetation water, and solid by- products. Thereafter, the vegetation water is separated from the rest of the liquid phase mixture and collected. Exemplary methods of obtaining vegetation water are described in U.S. Patent Nos. 6,165, 475 and 6,197, 308, both to R. Crea, each of which are expressly incorporated herein by reference in their entirety.
  • Finch et al. teach an apparatus for recovering olive oil from olives. Initially, olives are fed to a pulper that separates the olive pits from the olives to obtain a pitless olive meat. The meat is then taken up by an extraction screw that subjects the meat to an extraction pressure sufficient to withdraw a liquid phase, comprising oil, water and a minor proportion of olive pulp.
  • the liquid phase is collected in a bin and then sent to a clarifying centrifuge that separates the pulp from the liquid phase to obtain a mixture comprising olive oil and vegetation water.
  • a purifying centrifuge then separates the vegetation water and a small proportion of solid matter from the mixture to obtain an olive oil, substantially free of vegetation water, that is collected in a tank.
  • the main olive polyphenols can be obtained directly from the vegetation water, or the vegetation water may be fractionated and/or purified to obtain the aforementioned polyphenols.
  • Exemplary methods for fractionating include partitioning with an organic solvent, high pressure liquid chromatography (HPLC) or the use of supercritical fluids.
  • Exemplary methods for preparing phenolic extracts derived from immature or semi- mature olives in accordance with the invention may be found in U. S. Patent Nos. 6,165, 475, and 6,197, 308, each of which is expressly incorporated by reference herein.
  • An exemplary method for preparing hydroxytyrosokich compositions from olive vegetation water is found in U. S. Patent Application No.09/944,744, which is expressly incorporated by reference herein.
  • Extracts of olives and olive leafs contain mainly non- hydrolysed olive polyphenols. Extracts of olive or olive leaf are therefore suitable sources of non-hydrolysed polyphenols (but the use of olives for extraction purposed would be expensive).
  • hydrolysis of the non-hydrolysed polyphenols present in the primary extracts is required.
  • Different procedures to obtain hydrolysed olive polyphenols from olive processing water or leaf extracts are known.
  • the hydrolysed olive polyphenols are obtained by biotransforming the water of leaf extracts with a non-homogeneous hyperthermophilic ⁇ -glycosidase immobilised on chitosan (Briante R. et al., J.Biotechnol. 2004 JuI 1 ;111(1):67-77).
  • compositions according to the present invention consist of a composition that is made up of a combination of oive leaf extract (primarily as a source of oleuropein) and of a polyphenol preparation obtained from olive processing water (primarily as a source of hydroxytyrosol).
  • an extract consisting mainly of oleuropein and to apply conditions that are suitable to obtain a partial hydrolysis of the oleuropein with a view to obtain a ration between oleuropein and hydroxytyrosol as required to practice the present invention.
  • compositions according to the invention in the treatment and/or prevention of inflammatory conditions; in particular for the treatment and/or prevention of osteopenia and osteoporosis, including osteoporosis induced or exacerbated by estrogen deficiency, oxidative stress and chronic inflammation; and more in particular for the treatment and/or prevention of osteopenia.
  • the composition comprises the extracts as defined hereinbefore.
  • a method for the treatment of an animal for example, a mammal including humans, suffering from inflammatory conditions, more in particular osteopenia and osteoporosis; and even more in particular osteopenia, which comprises administering an effective amount of a composition according to the present invention.
  • Said method comprising the systemic or topical administration of an effective amount of a composition according to the invention, to animals, including humans.
  • the effective amount of a composition, according to the present invention, which is required to achieve a therapeutical effect will, of course, vary with the particular composition, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.
  • a daily dosage of about 0,5 to 15 mg/kg; in particular 0,5 to 3 mg/kg of the non-hydrolysed polyphenols of formula (I) and the hydrolysed polyphenols of formula (II) should be applied.
  • compositions according to the invention would comprise between and about 5mg to 1g of each of the non-hydrolysed polyphenols of formula (I) and the hydrolysed polyphenols of formula (II) as defined hereinbefore; in particular comprising between and about 25mg to 500mg of each of the non-hydrolysed polyphenols of formula (I) and the hydrolysed polyphenols of formula (II) ; more in particular comprising between 50mg to 150mg of each of the non-hydrolysed polyphenols of formula (I) and the hydrolysed polyphenols of formula (II); even more in particular comprising between 30mg to 100mg of each of the non- hydrolysed polyphenols of formula (I) and the hydrolysed polyphenols of formula (II).
  • compositions would comprise between and about 15mg to 1 g of one or more of the polyphenols selected from the group consisting of hydroxytyrosol, tyrosol, ligstroside and oleuropein; in particular comprising between and about 50mg to 500mg of one or more of the polyphenols selected from the group consisting of hydroxytyrosol, tyrosol, ligstroside and oleuropein; more in particular comprising between 10Omg to 250mg of one or more of the polyphenols selected from the group consisting of hydroxytyrosol, tyrosol, ligstroside and oleuropein.
  • compositions would comprise between and about 15mg to 1g of the polyphenols hydroxytyrosol and oleuropein; in particular comprising between and about 50mg to 500mg of the polyphenols hydroxytyrosol and oleuropein; more in particular comprising between 100mg to 250mg of the polyphenols hydroxytyrosol and oleuropein.
  • compositions would comprise between and about 15mg to 1g of each of the polyphenols hydroxytyrosol and oleuropein; in particular comprising between and about 25mg to 500mg of each of the polyphenols hydroxytyrosol and oleuropein; more in particular comprising between 50 mg to 150mg of each of the polyphenols hydroxytyrosol and oleuropein; even more in particular comprising about 50 mg of hydroxytyrosol and about 100mg of oleuropein.
  • a method of treatment may also include administering the compositions according to the invention, on a regimen of between one and four intakes per day.
  • compositions according to the invention may further comprise a combination of extracts with a standardized amount of oleuropein.
  • One extract would be standardized for hydroxytyrosol and the second extract would be standardized for oleuropein.
  • Such second extract is typically a leaf extract; in particular a leaf extract obtainable from the leaves of a plant belonging to the Oleaceae family; more in particlar from the leaves of plants belonging to the genus of Olea europaea (olive tree).
  • the standardized amount of oleuropein in said second extract is ⁇ 5% (w/v); in particular > 20% (w/v); more in particular > 40% (w/v).
  • oleuropein rich leaf extracts are prepared using a method comprising the following steps: a) immersing Olea europaea leaves with an extraction solution essentially made of an alcoholic solution comprising at least 25% alcohol by weight, for example ethanol, for a period of time of at least 4 hours; b) recovering the resultant extraction solution from end of step a); c) immersing de novo Olea europaea leaves from step a) with a new extraction solution, which composition is similar to that defined hereabove, for a period of time of at least 4 hours; d) recovering the extraction solution from end of step c); e) collecting the resultant extraction solutions respectively from step b) and step c); f) vacuum distillating the resultant solution from
  • a combination of a composition as defined herein, with another agent used in the treatment of osteopenia is envisaged.
  • the extracts/compositions of the present invention may advantageously be employed in combination with other agents used in the treatment of osteopenia.
  • Examples of other agents used in the treatment of osteopenia are; the polyphosphonate class, such as etidronate or alendronate (European patent EP 210 728, American patent application published- under serial number 2001/0046977); - the thioamide oxazolidinones (American patent application published under serial number 2002/0010341); the isoflavone compounds (American patent application published under serial number 2002/0035074); or a Lycopersicon genus plant extract has also been proposed (American patent application published under serial number 2002/0009510).
  • the polyphosphonate class such as etidronate or alendronate
  • European patent EP 210 728 American patent application published- under serial number 2001/0046977
  • thioamide oxazolidinones American patent application published under serial number 2002/0010341
  • the isoflavone compounds American patent application published under serial number 2002/0035074
  • a Lycopersicon genus plant extract has also been proposed (American patent application published
  • the extracts While it is possible for the extracts to be administered alone, it is preferable to present them as a composition.
  • compositions of the present invention for use in the methods of the present invention, can be prepared in any known or otherwise effective dosage or product form suitable for use in providing topical or systemic delivery of the main olive polyphenols to the site of inflammation or the affected bone, which would include both pharmaceutical dosage forms as well as nutritional product forms suitable for use in the methods described herein.
  • compositions are preferably administered as oral dosage forms.
  • Preferred dosage or product forms include oral tablets; capsules, including encapsulation in microcapsules or liposomes such as for example described in US 5827531 ; oral liquids as well as bakery matrices such as bread, cookies and biscuits; and diary products such as butter, cheese, milk and yoghurt.
  • a nutritional composition according to the present invention comes as any form described in the present description, and in particular fat-base food products (butter, oil, margarine), bread, cookies, or oil kept food products, such as cheese, fish, meat, vegetables, or salads) or as seasoning products, such as condiments.
  • fat-base food products such as cheese, fish, meat, vegetables, or salads
  • seasoning products such as condiments.
  • compositions of the present invention come as liquid nutritional embodiments for oral or enteral administration that comprise one or more nutrients such as fats, carbohydrates, proteins, vitamins, and minerals.
  • Oral liquid nutritionals are preferred, in particular as a beverage, for example a flavored beverage.
  • These nutritional liquids are preferably formulated with sufficient viscosity, flow, or other physical or chemical characteristics to provide a more effective and soothing coating of the affected mucosa while drinking or administering the nutritional liquid.
  • These nutritional embodiments also preferably represent a balanced nutritional source suitable for meeting the sole, primary, or supplemental nutrition needs of the individual.
  • Non-limiting examples of suitable nutritional liquids within which the extracts can be formulated, and thus form selected nutritional liquid embodiments of the present invention are diary products such as milk and yoghurt; or a flavoured beverage.
  • Proteins suitable for use herein can be hydrolyzed, partially hydrolyzed or non- hydrolyzed, and can be derived from any known or otherwise suitable source such as milk (e. g. , casein, whey), animal (e. g. , meat, fish), cereal (e. g. , rice.corn), vegetable (e. g. , soy), or combinations thereof.
  • milk e. g. , casein, whey
  • animal e. g. , meat, fish
  • cereal e. g. , rice.corn
  • vegetable e. g. , soy
  • Fats or lipids suitable for use in the nutritional compositions include, but are not limited to, coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, MCT oil (medium chain triglycerides), sunflower oil, high oleic sunflower oil, structured triglycerides, palm and palm kernel oils, palm olein, canola oil, marine oils, cottonseed oils, and combinations thereof.
  • Carbohydrates suitable for use in the nutritional compositions may be simple or complex, lactose- containing or lactose-free, or combinations thereof.
  • suitable carbohydrates include hydrolyzed corn starch, maltodextrin, glucose polymers, sucrose, corn syrup, corn syrup solids, rice-derived carbohydrate, glucose, fructose, lactose, high fructose corn syrup and indigestible oligosaccharides such as fructooligosaccharides (FOS), and combinations thereof.
  • the nutritional compositions may further comprise any of a variety of vitamins, non- limiting examples of which include vitamin A, vitamin D, vitamin E 1 vitamin K, thiamine, riboflavin, pyridoxine, vitamin B12, niacin, folic acid, pantothenic acid, biotin, vitamin C, choline, inositol, salts and derivatives thereof, and combinations thereof.
  • vitamins non- limiting examples of which include vitamin A, vitamin D, vitamin E 1 vitamin K, thiamine, riboflavin, pyridoxine, vitamin B12, niacin, folic acid, pantothenic acid, biotin, vitamin C, choline, inositol, salts and derivatives thereof, and combinations thereof.
  • the nutritional compositions may further comprise any of a variety of minerals known or otherwise suitable for us in patients at risk of or suffering from osteopenia or osteoporosis, non-limiting examples of which include a calcium source, for example as an organic or inorganic physiologically acceptable compound, such as calcium inorganic salts (calcium chloride, calcium phosphate, calcium sulfate, calcium oxide, calcium hydroxide or calcium carbonate) or calcium comprising organic components such as powdered skim milk, calcium caseinate or calcium organic salts (calcium citrate, maleate or mixtures thereof).
  • a calcium source for example as an organic or inorganic physiologically acceptable compound, such as calcium inorganic salts (calcium chloride, calcium phosphate, calcium sulfate, calcium oxide, calcium hydroxide or calcium carbonate) or calcium comprising organic components such as powdered skim milk, calcium caseinate or calcium organic salts (calcium citrate, maleate or mixtures thereof).
  • the calcium amount comprised in a nutritional composition according to the present invention is suitable for a daily administration provided by said composition, ranging from 100 mg to 1000 mg, preferably from 200 mg to 700 mg and most preferably from 300 mg to 600 mg calcium.
  • a nutritional composition according to the present invention may further comprise minerals and trace elements such as sodium, potassium, phosphorus, magnesium, copper, zinc, iron, selenium, chromium and molybdenum.
  • compositions of the present invention can be prepared by any known or otherwise effective method for formulating or manufacturing the selected product form. Methods for preparing the pharmaceutical compositions according to the present invention can be found in "Remington ' s Pharmaceutical Sciences", Mid.Publishing Co., Easton, Pa., USA.
  • the extracts can be formulated along with common excipients, diluents, or carriers, and formed into oral tablets, capsules, sprays, mouth washes, lozenges, treated substrates (e. g. , oral or topical swabs, pads, or disposable, non-digestible substrate treated with the compositions of the present invention) ; oral liquids (e. g. , suspensions, solutions, emulsions), powders, or any other suitable dosage form.
  • treated substrates e. g. , oral or topical swabs, pads, or disposable, non-digestible substrate treated with the compositions of the present invention
  • oral liquids e. g. , suspensions, solutions, emulsions
  • powders e. g. , or any other suitable dosage form.
  • Non-limiting examples of suitable excipients, diluents, and carriers can be found in "Handbook of Pharmaceutical Excipients", Second edition, American Pharmaceutical Association, 1994 and include: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as acetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite ; carriers such as propylene glycol and ethyl alcohol, and lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols.
  • fillers and extenders such as star
  • the extracts described herein can also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes.
  • the main olive polyphenols are also well suited for formulation as a sustained or prolonged release dosage forms, including dosage forms that release active ingredient only or preferably in a particular part of the intestinal tract, preferably over an extended or prolonged period of time to further enhance effectiveness.
  • the coatings, envelopes, and protective matrices in such dosage forms may be made, for example, from polymeric substances or waxes well known in the pharmaceutical arts.
  • a polyphenol ⁇ extract rich in olive polyphenols can be obtained by pressing immature or semi immature olives rich in oleuropein and hydroxytyrosol.251 of the resulting olive pressing water, has to be filtered through 25 ⁇ filters and then concentrated to dryness in a rotary evaporator. The residue has to be diluted in 5 I of MeOH and extracted with 51 of c-Hexane in order to remove the remaining olive oil.
  • the MeOH extract (first extract) has to be evaporated and subjected to reverse phase medium pressure liquid chromatography with decreasing polarity mixtures of H 2 O-MeOH. Evaporation of the obtained water fraction should give approximately 15 g of an oily residue, which can be identified by NMR spectroscopy as a mixture of mainly Oleuropein and hydroxytyrosol (3:1).
  • Hydroxytyrosol Substantially purified Hydroxytyrosol (99.3%) was purchased from Sigma (St. Louis, USA)
  • SH controls
  • OVX surgically ovariectomized
  • the animals were fed with a semi-purified diet and were randomly assigned to groups (20 per group) as follows: 1) sham-operated controls (SH), 2) ovarietomized controls (OVX). The others were given the same standard diet supplemented with either 3) 0.015% Oleuropein (Oleu), 4) 0.015% hydroxytyrosol (OHT), 5) 0.15% Tyrosol, or 6) 0.09% Olive Polyphenol ⁇ Extract (OPE). During the whole experimental period (84 days), each compound/extract was mixed with the semi-purifed diet and given orally. Food was humidified (1ml/g). The rats had free access to water.
  • BMD Bone mineral density
  • BMD was assessed by dual-energy X-ray absorptiometry (DEXA), using a Hologic QDR-4500 A X-ray bone densitometer (Hologic, Massy, France).
  • DEXA dual-energy X-ray absorptiometry
  • M-BMD distal femur metaphyseal zone
  • D-BMD diaphysis
  • the OPE -extract prevented the inflammation-induced bone loss in OVX rats (fig. 1 ) to a larger extent than the individual polyphenols in comparable doses.
  • This extract seemed to act thanks to its combined antioxidant and anti-inflammatory properties, because urinary excretion of isoprostane was improved, bone formation was enhanced (as shown by increase of osteocalcinemia) and the extract seemed to reduce both inflammation (decreased granulocyte levels) and oxidative stress (low isoprostane concentration).
  • the bioavailability of the polyphenols was increased over a longer period of time due to the complementary pharmacokinetics of Oleuropein and Hydroxytyrosol.
  • Dairy products Dairy trails will be carried out to obtain food products with physiologically relevant levels of the extracts according to the invention, demonstrating a sensory appreciated end product with comparable or superior shelf life when compared to the non-formulated extracts.
  • Physiologically relevant levels are expected to be between and about at least 50% (w/v) of the extracts as provided hereinbefore; in particular comprising at least 10% (w/v) of the extracts as provided hereinbefore; more in particular comprising from 0.5% (w/v) to 5% (w/v) of the extracts as provided hereinbefore; even more in particular comprising ⁇ 1% (w/v) of the extracts as provided hereinbefore.
  • Diary products are milk and products made from milk, including cheese, butter and yoghurt.
  • the dairy composition will be based on yoghurt where the olive extracts of the present invention will be added at the different levels mentioned hereinbefore and at different steps during the production process.
  • the polyphenol ⁇ extracts will be added at different levels during dough mixing and is before proofing. For each recipe 20 breads and three batches of biscuits will be baked. The resulting breads will be assessed for their loaf volume, crumb structure, taste and staling stability. The biscuits will be assessed for their oxidation stability (rancimat test) and sensory attributes.
  • bakery compositions are expected to comprise between and about at least 20% (w/v) of the extracts as provided hereinbefore; in particular comprising at least 10% (w/v) of the extracts as provided hereinbefore; more in particular comprising from 0.5% (w/v) to 5% (w/v) of the extracts as provided hereinbefore; even more in particular comprising ⁇ 1 % (w/v) of5 the extracts as provided hereinbefore.

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  • Life Sciences & Earth Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne des compositions particulières comprenant certaines combinaisons des principaux polyphénols d’olive, tels que, par exemple, l’oleuropéine et/ou le ligstroside en combinaison avec l’hydroxytyrosol et/ou le tyrosol caractérisées en ce que le rapport des polyphénols non hydrolysés (oleuropéine et/ou ligstroside) aux polyphénols hydrolysés (hydroxytyrosol et/ou tyrosol) est dans certaines limites, qui présentent certains bénéfices inattendus pour la santé par rapport à d’autres compositions de polyphénols d’olive déjà connues dans l’art. Dans un mode de réalisation particulier de la présente invention, les compositions contiennent des quantités standardisées pour au moins deux desdits polyphénols d’olive.
PCT/EP2009/003012 2008-04-28 2009-04-24 Extrait polyphénolique WO2009132807A1 (fr)

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GB0807673.9 2008-04-28

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ITMI20131815A1 (it) * 2013-10-31 2015-05-01 Fattoria La Vialla Di Gianni Anton Io E Bandino L Uso antinfiammatorio di fitocomplessi liquidi da olive
US20160045519A1 (en) * 2013-04-05 2016-02-18 Nestec S.A. Compositions for use in stimulating bone growth
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US10226498B2 (en) 2013-10-31 2019-03-12 Fattoria La Vialla Di Gianni, Antonio E Bandido Lo Franco —Societa' Agricola Semplice Antiangiogenic use of liquid phytocomplexes from olive
CN110269849A (zh) * 2019-05-22 2019-09-24 温州医科大学附属口腔医院 羟基酪醇在制备治疗或预防牙周炎药物中的应用
CN111315386A (zh) * 2017-11-08 2020-06-19 雀巢产品有限公司 橄榄苦苷的生物转化
CN111343992A (zh) * 2017-11-08 2020-06-26 雀巢产品有限公司 橄榄苦苷的生物转化
IT202000010969A1 (it) * 2020-05-14 2021-11-14 Tecnologica S R L Nuovo biomateriale per la rigenerazione del tessuto osseo costituito dal polifenolo naturale oleuropeina, plasma autologo del paziente e vitamina c
WO2024079251A1 (fr) 2022-10-12 2024-04-18 Bioactor Bv Utilisation non thérapeutique d'une composition comprenant de l'oleuropéine

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US11166965B2 (en) 2013-04-05 2021-11-09 Societe Des Produits Nestle S.A. Compositions for use in stimulating bone growth
US20160045519A1 (en) * 2013-04-05 2016-02-18 Nestec S.A. Compositions for use in stimulating bone growth
US10675290B2 (en) * 2013-04-05 2020-06-09 Societe Des Produits Nestle S.A. Compositions for use in stimulating bone growth
AU2014273185B2 (en) * 2013-05-29 2019-04-18 Société des Produits Nestlé S.A. Compositions for use in cartilage breakdown
WO2014191447A1 (fr) * 2013-05-29 2014-12-04 Nestec S.A. Compositions utilisées en relation avec la dégradation cartilagineuse
EP4218743A3 (fr) * 2013-05-29 2023-12-20 Société des Produits Nestlé S.A. Compositions pour utilisation dans la décomposition du cartilage
US10226498B2 (en) 2013-10-31 2019-03-12 Fattoria La Vialla Di Gianni, Antonio E Bandido Lo Franco —Societa' Agricola Semplice Antiangiogenic use of liquid phytocomplexes from olive
CN105705156B (zh) * 2013-10-31 2020-10-23 吉安尼,安东尼奥和班迪诺弗朗哥的维亚拉农场-农业基础公司 橄榄的液体植物混杂物的抗炎应用
CN105705156A (zh) * 2013-10-31 2016-06-22 吉安尼,安东尼奥和班迪诺弗朗哥的维亚拉农场-农业基础公司 橄榄的液体植物混杂物的抗炎应用
US10653742B2 (en) 2013-10-31 2020-05-19 Fattoria La Vialla Di Gianni, Antonio E Bandino Lo Franco—Societa′ Agricola Semplice Anti-inflammatory use of liquid phytocomplexes from olive
WO2015063737A1 (fr) * 2013-10-31 2015-05-07 Fattoria La Vialla Di Gianni, Antonio E Bandino Lo Franco - Societa' Agricola Semplice Utilisation anti-inflammatoire de phytocomplexes liquides d'olive
ITMI20131815A1 (it) * 2013-10-31 2015-05-01 Fattoria La Vialla Di Gianni Anton Io E Bandino L Uso antinfiammatorio di fitocomplessi liquidi da olive
WO2016083525A1 (fr) * 2014-11-26 2016-06-02 Creta Farm Societe Anonyme Industrial And Commercial Trading As Creta Farm S.A. Extrait d'olive aqueux présentant des propriétés métaboliques et cardioprotectrices
CN111343992A (zh) * 2017-11-08 2020-06-26 雀巢产品有限公司 橄榄苦苷的生物转化
CN111315386A (zh) * 2017-11-08 2020-06-19 雀巢产品有限公司 橄榄苦苷的生物转化
CN110269849A (zh) * 2019-05-22 2019-09-24 温州医科大学附属口腔医院 羟基酪醇在制备治疗或预防牙周炎药物中的应用
IT202000010969A1 (it) * 2020-05-14 2021-11-14 Tecnologica S R L Nuovo biomateriale per la rigenerazione del tessuto osseo costituito dal polifenolo naturale oleuropeina, plasma autologo del paziente e vitamina c
WO2024079251A1 (fr) 2022-10-12 2024-04-18 Bioactor Bv Utilisation non thérapeutique d'une composition comprenant de l'oleuropéine

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