• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Compositions of phytic acid, magnesium and polyphenols and their application for the prevention of oxalcalcic renal lithiasis. The present invention relates to a composition comprising phytic acid or a salt of phytate, magnesium in the form of a salt, hydroxide or oxide and optionally at least one polyphenol. These components can be in isolated form or form part of an enriched plant extract. The invention also relates to the use of this composition for the treatment of renal lithiasis, preferably calcium or oxocalcic, either in the form of a medicament, a nutraceutical or functional food or a food supplement. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2555166A1
    申请号:ES201430961
    申请日:2014-06-25
    公开日:2015-12-29
    发明作者:Félix Grases Freixedas；Antonia COSTA BAUZÀ；Rafael María PRIETO ALMIRALL；Adrián RODRÍGUEZ RODRÍGUEZ
    申请人:Universitat de les Illes Balears；
    IPC主号:
    专利说明:

    The present invention relates to a composition comprising phytic acid or any of its salts of phytate, magnesium and optionally polyphenols, which is useful for the treatment of renal lithiasis, mainly calcium calcium lithiasis, for the synergy between its components to inhibit the crystallization of calcium salts, the
    10 decrease in free oxalate and papillary lesions due to oxidative stress.
    Therefore, the present invention belongs to the field of pharmacology.
    STATE OF THE TECHNIQUE
    15 It is known that the ionic species of philic acid (phytates) have the capacity to inhibit the development of calcium salt deposits in biological fluids, thus reducing the risk of developing both calcium kidney stones and other pathological calcifications. It is also known that phytate, which is found in tissues and
    20 fluids of mammals, comes mainly from the diet. Recently, it has been shown that renal stones of calcium oxalate papillary monohydrate occur as a result of lesions that originate in the tissue of the renal papilla (F Grases, A Costa-Bauza, RM Prieto, A Cante, A Servera, BMe Uro /, 2013, 13:14, doi: 10.1186 / 1471-2490-13-14). These lesions give rise to processes of
    Tissue calcification in the form of hydroxyapatite in the intrapapillary tissue, which when increasing in size and crossing the epithelium that covers the papilla and coming into contact with the urine (which is permanently supersaturated in calcium oxalate) leads to the beginning of the development of stones papillae Crystallization inhibitors together with the immune system can reverse this process since by slowing down the process of
    Crystallization allows macrophages to destroy the nascently formed hydroxyapatite (F Grases, RM Prieto, P San chis, e Saus, T De Francisco, J Nephro /, 2008, 21 (5), 768-75). Obviously, the lower the number of injuries, the less likely the process of developing the papillary calculus will be less. Recent studies have shown that certain compounds with properties
    Antioxidants, such as polyphenols, significantly decrease the development of intrapapillary calcifications (F. Grases, RM Prieto, I Gomila, P Sanchis, A CostaBauza, Urol Res, 2009, 37 (1), 35-40), which is why They can present an important role in the prevention of renal lithiasis.
    Calcium oxalate stones represent approximately 70% of kidney stones, with the level of urinary oxalate being an important risk factor for its development. The control of free oxalate in urine is a very important aspect in the treatment against the development of calcium oxalate stones. Thus, magnesium, at
    The formation of soluble complexes with the oxalate ion significantly reduces the supersaturation of calcium oxalate, which translates into an increase in its difficulty in generating calcium oxalate crystals.
    DESCRIPTION OF THE INVENTION
    The present invention aims at presenting new formulas for the
    treatment of renal lithiasis, preferably calcium renal lithiasis, related to
    aspects described in the state of the art section and with discoveries
    Recent studies on the combination of phytic acid and / or its pharmaceutically acceptable titrates with polyphenols and magnesium salts. This combination can result
    very beneficial for the treatment of kidney stones, preferably stones
    renal calcium, and more preferably calcium oxalate, since the capacity
    Inhibit of the crystallization of calcium salts by titate adds to the effect
    The beneficial effects of polyphenols on papillary lesions from oxidative stress. These two effects combine with the capacity of magnesium
    to decrease concentrations of free oxalate in urine, by forming complexes
    soluble with it and thus reduce supersaturation with respect to calcium oxalate. He
    Magnesium also synergistically enhances the ability of phytate to inhibit
    crystallization of calcium oxalate. The present invention provides a method for the treatment and prevention of renal calcifications by the combined use of
    titate, polyphenols and / or salts, hydroxides or magnesium oxides.
    Therefore, a first aspect of the present invention relates to a composition comprising phytic acid or any of its salts, which may be in form
    isolated or in the form of an enriched vegetable extract, and magnesium in the form of hydroxide or oxide salt.
    The term "calcifications" or "calculations" includes all processes or conditions that involve / induce the formation of solid precipitates in the urine. Thus the conditions that induce renal calculi or calculi include, but are not limited to a high level of urinary oxalate, a high level of urinary excretion of calcium or a reduced presence or activity of nucleation and crystalline growth inhibitors.
    The term "urinary oxalate" refers to the excretion of oxalate in the urine. Normal levels between 8-30 mg / day are considered, while if these exceed 45mg / day it is considered a situation of hyperoxaluria. Urine oxalate levels can reach levels between 90 and 270mg / day in patients with primary hyperoxaluria.
    "Hypercalciuria" refers to a high urinary excretion of calcium which exceeds 300mg / day or 4mg / kg / day
    The "reduced presence or activity of inhibitors of nucleation and growth of crystalline solids" refers to all those compounds that can modulate said process, which include but are not limited to glycoproteins such as nephrocalcin or osteopontin and certain inorganic and organic polyphosphates. . These compounds interact with the crystals and inhibit their growth.
    In the present invention, "phytic acid" or "myo-inositol-hexaphosphate" means the molecule of formula:
    and "phytate" is the form of phytic acid in which at least one hydrogen has been lost so that the corresponding phosphate group interacts with a cation (K, Mg, Ca, Mn, Zn and Fe). The phytate salts of interest in the invention are mainly sodium, potassium, calcium, magnesium, zinc and calcium-magnesium salts.
    In a preferred embodiment, the composition of the invention comprises at least one polyphenol.
    In the present invention, polyphenols are understood as a group of chemical substances found in plants characterized by the presence of more than one phenolic group per molecule. These products have important antioxidant characteristics and are also suitable for human consumption. The polyphenols with special interest for the composition of the invention are those extracted from the seeds of red grape or white grape, although they can come from other plant species such as berries, tea, beer, olive oil, chocolate / cocoa, nuts, pomegranates etc. . Concrete examples of preferred polyphenols of the invention are epicatechin, catechin, gallocatechin, epigallocatechin, quercetin, resveratrol, tannic acid or gallic acid.
    Thus, it has been possible to verify in an "in vivo" model using experimental animals that with a composition comprising 1% phytate with a supplement of polyphenols extracted from the white grape seed, a reduction in renal calcification of the 50%, as explained in example 2.
    Other studies have shown that the presence of magnesium in artificial urine synergistically enhances the ability of phytate to inhibit the crystallization of calcium oxalate, as described in example 1.
    Magnesium, by forming salts more soluble than calcium with phytate, increases the absorption of phytate at the intestinal level, which results in an increase in phytate excreted in the urine and therefore in an increase in its inhibitory capacity against formation of kidney stones of calcium oxalate.
    These models demonstrate that a formulation comprising phytate in a form that also contains polyphenols and / or salts or magnesium oxide, can be used for the manufacture of medicaments or dietary supplements intended for the treatment or prophylaxis of renal lithiasis, preferably calcium, and more preferably oxaloccalcic.
    5 For the purposes of the present invention, phytic acid and / or its pharmaceutically acceptable salts may be used freely as pure substances, extracts of plant species containing them, such as for example white or brown rice extracts, or vehiculated in plant species that contain them, such as germs or external parts of the grains or fruits of wheat, oats, soybeans,
    10 almonds, garrofín, etc.
    Polyphenols can also be used freely as pure substances or
    as extracts of plant species that contain them or that are
    pharmaceutically acceptable.
    Magnesium can be supplied in the form of its pharmaceutically acceptable salts such as magnesium oxide, magnesium hydroxide, magnesium citrate, magnesium stearate, magnesium carbonate, magnesium chloride and magnesium sulfate.
    In a preferred embodiment, the composition of the invention comprises between 40 and 50% by weight of phylic acid or its salts.
    In a preferred embodiment, the composition of the invention comprises between 25 and 25% by weight of magnesium in the form of salt, hydroxide or oxide.
    In a preferred embodiment, the composition of the invention between 10-30% by weight of polyphenols.
    Another aspect of the invention relates to the use of the composition of the invention for the manufacture of a medicament.
    Another aspect of the invention relates to the use of the composition described for the manufacture of a medicament for the treatment of renal lithiasis. Preferably the renal lithiasis is calcium renal lithiasis.
    Another aspect of the invention relates to the use of the composition of the invention for the preparation of a medicament intended to reduce risks and improve the health status of patients with diseases related to the crystallization of calcium oxalate.
    A very important advantage of using the combination of phytate, polyphenols and magnesium is that the action of a calcium oxalate crystallization inhibitor is combined with the action of polyphenols that, by preventing or decreasing papillary tissue lesions, also decrease the number of heterogeneous nuclei of calcium oxalate, with the action of magnesium, which by forming soluble complexes with oxalate, decreases the urinary supersaturation of calcium oxalate.
    The combination of phytate, polyphenols and magnesium can be administered in solid form (including granules, powder or suppositories) or in liquid form (such as solutions, suspensions or emulsions). In turn, they can be administered as such
    or, after being subjected to operations such as sterilization, preservative addition, stabilizer addition or emulsifier addition.
    The co-administration of phytate, polyphenols and magnesium may be combined with one
    or more compounds that facilitate its absorption through the selected administration route. Thus, they can be administered with lactose, sucrose, talc, magnesium stearate, cellulose, calcium salts, gelatin, fatty acids, as well as with other pharmaceutically acceptable substances.
    Pharmaceutical compositions containing phytate, polyphenols and magnesium will include an amount of each active ingredient that effectively reduces urinary oxalate levels. The effective amounts for this purpose depend on factors such as the route of administration, the health of the individual or urinary levels of oxalate, although these factors do not limit the inclusion of others that help define the recommended amounts. In any case, it is understood that the amounts of each active ingredient that each individual will take will be determined by a specialist based on each individual circumstance. In a preferred embodiment, the composition is in a dose suitable for administration between 500 mg / day and 1,000 mg / day.
    The term "renal lithiasis", "urolithiasis" or "nephrolithiasis" refers to the disorder caused by the presence of stones or stones inside the kidneys or urinary tract (ureters, bladder). Kidney stones are made up of normal urine substances (calcium salts, uric acid, cystine etc.) that for different reasons have been
    10 concentrated and precipitated forming fragments of greater or lesser size.
    The term "uric acid crystals" or "uric acid stones" includes all those processes or conditions that involve / induce the formation of solid precipitates in the urine in which this substance is involved.
    In a preferred embodiment, the composition is a pharmaceutical composition or a nutraceutical or functional food.
    In the present invention it is understood as "nutraceutical" or "functional food", a
    20 food that has a beneficial effect on health. Similarly, the nutraceutical term can be applied to extracts or chemical compounds obtained from common foods. Examples of foods to which nutraceutical properties are attributed are olive oil, red wine, broccoli, soybeans, etc. Nutraceuticals are normally used in nutritional mixtures and in the industry
    25 pharmaceutical. Just as some foods can be classified as nutraceuticals, some nutritional supplements are also classified, such as fatty acids such as omega-3 derived from fish oil and some vegetables or antioxidants and vitamins.
    The pharmaceutically acceptable adjuvants and vehicles that can be used in said compositions are the adjuvants and vehicles known to those skilled in the art and commonly used in the elaboration of therapeutic compositions.
    Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the
    5 invention. The following examples and figure are provided by way of illustration, and are not intended to be limiting of the present invention.
    BRIEF DESCRIPTION OF THE FIGURES
    10 FIG. 1. It shows the graphical representation of the induction times of crystallization (in minutes) for a solution of 200 mg / L of calcium and 50 mg / L of oxalate, in synthetic urine, at different concentrations of magnesium and titate.
    EXAMPLES
    15 Example 1. Measurement of the crystallization of calcium oxalate in the presence of magnesium and phytate.
    From a solution of 200 mg / L of calcium and 50 mg / L of oxalate, in urine
    20 synthetic, induction times were calculated for the crystallization of calcium oxalate in the presence of different concentrations of titate and / or magnesium. Table 1 shows these induction times, which, as can be seen more clearly in Figure 1, increase with increasing magnesium and phytate levels. Thus, when there is neither magnesium nor phytate, calcium oxalate takes 1 minute to crystallize.
    25 This time is increased to 10 minutes by adding 100 mg / L of magnesium, and in turn is increased to 44 minutes if, in addition to 10 mg / L of magnesium, 1 mg / L of phytate is added.
    Table 1: Crystallization induction times (in minutes) for a solution of
    30 200 mg / L calcium and 50 mg / L oxalate, in synthetic urine, at different concentrations of magnesium and titate.
    mg / L fitalo omg / L Mg I (min)25 mg / L Mg t (min)75 mg / L Mg I (min)100 mg / L Mg I (min)
    OR one1.5610
    0.5 3612twenty
    0.75 471827
    one 6.59.53544
    Example 2. Effect of the composition of the invention on wistar rats subjected to a lithogenic diet.
    A group of wistar rats were pretreated with polyphenols extracted from white grape seeds (added to drinking water in concentrations of 200 mg / L) and phytate (1% of the solid diet supplied to animals, in the form of phytin, which is magnesium calcium salt). Subsequently, papillary renal lithiasis was induced by administration of ethylene glycol and the preventive treatment was continued. The antilithic activity of the polyphenol + phytate mixture was evaluated through the calcium content of the kidneys of the animals (extracted at the end of the experiment) and the corresponding histological studies of the renal tissue, by comparison with the corresponding control groups. It was observed that the applied prophylactic treatment reduced by 50% the 15 renal calcification.
    Example 3. Effect of the composition of the invention on patients with renal lithiasis problems.
    In this example, three pharmaceutical compositions of the present invention are illustrated.
    Composition 1
    Compound Quantity
    Calcium-magnesium phytate 300mg
    Magnesium citrate 250 mg
    I Epicatechin
    Composition 2
    Calcium-magnesium phytate 300mg
    Magnesium citrate 250mg
    Catechin 150 mg
    Composition 3
    Brown rice extract equivalent to a quantity of magnesium oxide phytate Black grape seed extract equivalent to a quantity polyphenols from250 mg 150 mg 150 mg
    Composition 4
    Garrofin germ extract and dry wheat extract equivalent to an amount of phytate 150 mg
    Magnesium oxide 100 mg
    White grape seed extract equivalent to a quantity of polyphenols of 90mg
    A patient is given orally 200 mg of calcium-magnesium phytate (phytin)
    together with 200 mg of magnesium citrate and 100 mg of quercitin, twice a day, at
    Breakfast and after dinner. After treatment, it was observed that the capacity
    inhibit the patient's urine against crystallization of calcium oxalate
    5 increased by 40% with reference to the patient's own urine before ingesting phytate.
    The antioxidant capacity of urine (potentiometrically evaluated by a
    platinum electrode) was increased by 15%. These variations may involve from
    a significant decrease in recurrences until a total elimination of the process of
    calculogenesis, since they eliminate and / or normalize key factors in the process of calculogenesis, such as urine inhibitory capacity, oxaluria and protection
    against oxidative stress.
    权利要求:
    Claims (13)
    [1]
    one. Composition comprising phytic acid or any of its salts and magnesium in the form of salt, hydroxide or oxide.
    [2]
    2. Composition according to claim 1 comprising at least one polyphene!
    [3]
    3. Composition according to claim 2 wherein the polyenol is selected from
    epicatechin, catechin, gallocatechin, epigallocatechin, quercetin, resveratrol, gallic acid and tannic acid.
    [4]
    Four. Composition according to any of claims 2 or 3 wherein the polyethenol is in the form of enriched vegetable extract from the grape seed.
    [5]
    5. Composition according to any one of claims 1 to 4 wherein the phytate salt is selected from sodium, potassium, calcium, magnesium, zinc or calcicomagnesic
    Composition according to any one of claims 1 to 5 wherein the phytate is in the form of an enriched vegetable extract from rice, garrofin, wheat, oats, soy or almond.
    [7]
    7. Composition according to any one of claims 1 to 6 wherein the magnesium is
    25 found in a form that is selected from magnesium oxide, magnesium hydroxide, magnesium citrate, magnesium stearate, magnesium carbonate, magnesium chloride and magnesium sulfate.
    [8]
    8. Composition according to any one of claims 1 to 7 comprising between 40-50% by weight of phytic acid or its salts.
    [9]
    9. Composition according to any one of claims 1 to 8 comprising between 25-40% by weight of magnesium in the form of a hydroxide or oxide salt.
    [10]
    10. Composition according to any of claims 2 to 9 comprising between 10-30% by weight of polyphenols.
    [11]
    eleven. Composition according to any of claims 1 to 10 which further
    5 comprises lactose, sucrose, talc, magnesium stearate, cellulose, calcium salts, gelatin or fatty acids.
    [12]
    12. Composition according to any of claims 1 to 11 presented in
    form of a pharmaceutical composition, functional food, a nutraceutical product or a nutritional supplement.
    [13]
    13. Composition according to any of claims 1 to 12 for the manufacture of a medicament.
    14. Use of the composition according to any of claims 1 to 12 for the manufacture of a medicament for the treatment of renal lithiasis.
    [15]
    15. Use according to claim 14 wherein the renal lithiasis is calcium renal lithiasis
    16. Use of the composition according to any of claims 1 to 12 for the preparation of a medicament intended to reduce risks and improve the health status of patients with diseases related to the crystallization of calcium oxalate.
    17. Use according to any of claims 14 to 16, wherein the composition is in a dose suitable for administration between 500 mg and
    1,000 mg
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    同族专利:
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    ES2058025A1|1992-12-04|1994-10-16|Univ De Las Islas Baleares|Application of phytic acid and/or its phytates in pathological and prepathological conditions derived from renal oxalocalcic idiopathic lithiasis|
    ES2068158B1|1993-09-08|1995-11-16|Univ De Las Islas Baleares|PHARMACEUTICAL COMPOSITIONS OF FITIC ACID OR ITS DERIVATIVES AND APPLICATIONS THEREOF.|
    CN1111958A|1994-05-16|1995-11-22|华南师范大学|Method for making spiral algae sheet|
    JPH1017447A|1996-06-28|1998-01-20|Lion Corp|Antiodontolithic agent and composition for oral cavity|
    US5219889A|1988-01-05|1993-06-15|The University Of Texas System|Dietary supplementation with potassium magnesium citrate|
    FR2826361B1|2001-06-26|2004-08-13|Guy Parc|NOVEL PLANT AND CELL CULTURE MEDIA, TISSUES AND PLANT ORGANS CONTAINING AN ORGANIC NITROGEN SOURCE AND A PHOSPHORIC ESTER SOURCE|
    CN101805236B|2010-05-11|2012-02-08|蔡瑞琳|Controlled-release zinc magnesium selenium phytate fertilizer and preparation method thereof|
    BRPI1003695A2|2010-10-25|2013-02-19|De Jesus Henrique Pereira|capillary tonic manufacturing process|
    JP5492121B2|2011-03-09|2014-05-14|日本化学工業株式会社|Metal surface treatment agent, metal surface treatment method and surface treated steel plate|DE102016013737A1|2016-11-17|2018-05-17|WindplusSonne GmbH|Hexahydroxycyclohexanhexaphosphorsäureestersalze for the treatment of calcinosis and diet foods with Hexahydroxycyclohexanhexaphosphorsäureestersalzen as additives|
    EP3556398A1|2018-04-16|2019-10-23|Croda Denmark A/S|Phytates for use as a biomolecules delivery or adsorption system|
    CN111418558B|2019-09-22|2021-09-28|山西大学|Construction method of ablation metabolic urinary calculus animal model|
    CN111116354A|2019-12-17|2020-05-08|天津大学|Application of gallic acid and its derivatives in controlling calcium oxalate crystallization process|
    法律状态:
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    ES201430961A|ES2555166B1|2014-06-25|2014-06-25|Compositions of phytic acid, magnesium and polyphenols and their application for the prevention of oxaloccalcic renal lithiasis|ES201430961A| ES2555166B1|2014-06-25|2014-06-25|Compositions of phytic acid, magnesium and polyphenols and their application for the prevention of oxaloccalcic renal lithiasis|
    CN201580033945.6A| CN106535906B|2014-06-25|2015-04-14|Composition containing phytic acid, magnesium and polyphenol for treating or preventing renal calculus|
    ES15721753T| ES2776402T3|2014-06-25|2015-04-14|Composition containing phytic acid, magnesium and polyphenols for the treatment or prevention of kidney stones|
    MX2016016995A| MX2016016995A|2014-06-25|2015-04-14|Composition containing phytic acid, magnesium and polyphenols for the treatment or prevention of renal lithiasis.|
    EP15721753.0A| EP3162376B1|2014-06-25|2015-04-14|Composition containing phytic acid, magnesium and polyphenols for the treatment or prevention of renal lithiasis|
    US15/319,546| US11213535B2|2014-06-25|2015-04-14|Composition containing phytic acid, magnesium and polyphenols for the treatment or prevention of renal lithiasis|
    PCT/ES2015/070296| WO2015197892A1|2014-06-25|2015-04-14|Composition containing phytic acid, magnesium and polyphenols for the treatment or prevention of renal lithiasis|
    KR1020167036615A| KR20170015360A|2014-06-25|2015-04-14|Composition containing phytic acid, magnesium and polyphenols for the treatment or prevention of renal lithiasis|
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