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    • 专利摘要:
    Oral therapeutic composition based on a complex of (+) - catechin and at least one basic amino acid or at least one basic amino acid or a derivative of a basic amino acid intended for mammals, used for the treatment and the cancer prevention.
    公开号:BE1023772B1
    申请号:E2013/0350
    申请日:2013-05-17
    公开日:2017-07-17
    发明作者:Paul Niebes；Bronislav Henric May；Saïd Rachidi；Julien Estager
    申请人:Valore；
    IPC主号:
    专利说明:

    Composition based on (+) - catechin and amino acid complex for the treatment and prevention of cancer
    The present invention relates to an oral therapeutic composition based on monomeric (+) - catechin complex and at least one basic amino acid or at least one derivative of a basic amino acid for mammals, and in particular to the human being.
    By monomeric (+) - catechin complex and at least one basic amino acid or at least one derivative of a basic amino acid is meant a molecular structure in which said monomeric (+) - catechin is linked to said minus one amino acid, or a derivative of a basic amino acid, by hydrogen bridge bonds.
    Such an oral composition is already known, for example, from US Pat. No. 4,285,964 in the context of the treatment of chronic degenerative diseases of connective tissues. Among these degenerative diseases, the most well known and widespread in humans are, for example, osteoarthritis, chondromalacia and periodontosis.
    According to US 4,285,964, said monomeric (+) - catechin complex and at least one basic amino acid or at least one derivative of a basic amino acid is a drug in which the active substance is (+) monomeric catechin.
    This document furthermore demonstrates that said solubility in an aqueous solution (such as water at physiological pH) of (+) - catechin is high (400 g / l) when the latter forms a complex with a basic amino acid such as L-arginine or L-lysine. This improved solubility in aqueous medium allows a better control of (+) - catechin concentrations and is therefore more interesting than the use of pure (+) - catechin, the solubility of which in water is limited to 1 g / L, for parenteral administration, hence the interest of a treatment based on injectable solutions of (+) - catechin complexes. Therefore, the composition comprising the complex of (+) - catechin and a basic amino acid or at least one derivative of a basic amino acid as disclosed in US 4,285,964 is therefore primarily intended to be administered by injection to mammals.
    In this regard, the composition according to US 4,285,964 has its pH adjusted to the physiological value (pH = 7.2 - 7.4) by adding a biocompatible acid.
    It is important to note that if US Pat. No. 4,285,964 suggests the oral or injectable use of a composition based on (+) - catechin complex and at least one basic amino acid or at least one a derivative of a basic amino acid, it gives no guarantee as to the effectiveness of this composition for the treatment of chronic degenerative diseases of the connective tissues.
    In view of the prior art, it is suggested an anti-degenerative activity of the connective tissues of the complex composition of (+) - catechin and at least one basic amino acid or at least one derivative of an acid basic amine (complex [C: AA]).
    However, no document discloses to date the particular use of said complex composition [C: AA] for the oral treatment of cancer in mammals. It is only by pure extrapolation that an oral composition is mentioned in passing.
    The present invention relates to the particular use of the oral composition based on (+) - catechin complex and at least one basic amino acid or at least one derivative of a basic amino acid for the treatment and cancer prevention.
    In the context of this particular new therapeutic use, said monomeric (+) - catechin complex and at least one basic amino acid or at least one derivative of a basic amino acid is a drug in which the active substance is (+) - monomeric catechin. The use of monomeric (+) - catechin for the treatment of cancer in mammals is known from the article by Weynant M.J., Carothers A.M., Dannenberg A.J., and Betragnolli Μ. M., published in 2001 in Cancer Research, Volume 61, page 118.
    This article describes the treatment of intestinal tumors in mice with monomeric (+) - catechin, thus not in the form of a complex with at least one basic amino acid or at least one derivative of a basic amino acid, administered by oral route. In particular, this article states that because of its high oral bioavailability, (+) - catechin is a promising active agent for the treatment of a wide variety of epithelial tumors in mammals, preferably in humans. human.
    Unfortunately, if this article stops promising conclusions, the latter remain hypothetical insofar as the study was conducted on a small sample of small mammals (mice) and therefore does not allow to assess certain therapeutic efficacy. (+) - catechin in the treatment and prevention of cancer.
    By oral bioavailability is meant the proportion of (+) - catechin that acts in the body in relation to the amount absorbed orally.
    In their article, the authors do not define what they mean by high bioavailability. From the results presented in the context of the present invention, it is observed that the high oral bioavailability of one gram of monomeric (+) - catechin reaches a value of at least 900 ng. h / ml in humans. On reading the above article and in view of the results of the present invention, therefore, high bioavailability in humans means a bioavailability of at least 900 ng. h / ml for oral administration of one gram.
    In the context of the present invention, it has been observed quite surprisingly that the monomeric (+) - catechin complex and at least one basic amino acid or at least one derivative of a basic amino acid , when administered orally, allows, in the same way as monomeric (+) - catechin in a form which is not a complex formed with at least one basic amino acid or at least one derivative of a basic amino acid, the treatment and prevention of cancer. The use of the [C: AA] complex in cancer treatment and prevention is made possible by the high oral bioavailability of (+) - catechin when complexed with at least one acid amino acid or at least one derivative of a basic amino acid, this property has not yet been disclosed.
    Indeed, the results obtained by the inventors of the present patent application show that the bioavailability measured in humans for one gram of (+) - catechin ingested in the form of (+) - catechin complex and at least a basic amino acid is at least 900 ng. h / ml.
    This high oral bioavailability for (+) - catechin in the form of (+) - catechin complex and at least one basic amino acid or at least one derivative of a basic amino acid is more surprising that it is not obvious from US Pat. No. 4,285,964 to emphasize this characteristic for the [C: AA] complex,
    Indeed, since (+) - catechin complexes are very soluble in water (400 g / L), it is expected that their ability to cross lipid tissues is low, but the results indicated in the context of the present invention demonstrate the opposite.
    Equally surprisingly, it is observed that the oral bioavailability of the (+) - catechin ingested in the form of monomeric (+) - catechin complex is much higher (1263 + 88 ng h / ml for 0.920 g (+) - monomeric catechin ingested as 1.5g of complex) to that of monomeric (+) - catechin ingested alone (832 + 150 ng.h / ml for an equivalent amount of 0.920 g of an oral intake (+) - pure monomeric catechin), ie + 52% increase in bioavailability thanks to the complex.
    The use of (+) - pure monomeric catechin means according to the invention the use of (+) - catechin in a form which is not a monomeric (+) - catechin complex with at least one basic amino acid or at least one derivative of a basic amino acid.
    This characteristic is all the more unexpected as pure monomeric (+) - catechin has a solubility in water 400 times lower than that measured when it is solubilized in a complex form formed with at least one basic amino acid or at least one derivative of a basic amino acid. The use of an oral [C: AA] complex for the treatment and prevention of cancer is particularly advantageous since it allows the use of (+) - catechin at a dosage equivalent to 61% of the dosage used for a pure monomeric (+) - catechin-based treatment to achieve the same bioavailability value. For example, an oral bioavailability of 904 ng. h / ml is reached by ingesting 1 g of a monomeric (+) - catechin complex and at least one amino acid comprising 0.61 g of monomeric (+) - catechin, whereas this bioavailability value is reached when ingestion of pure monomeric (+) - catechin at a dose of 1 g.
    An oral bioavailability of 1263 ng. h / ml is obtained with 1.5 g of complex. An oral bioavailability of 832 ng. h / ml (value for 0.92 g of catechin) is reached with 1.5 X 832, all divided by 1263, ie 0.99 g (1 g) of complex containing 0.61 g (0.616 g) of (+) - catechin.
    Two other important advantages are to be noted.
    Firstly, the use of (+) - catechin administered orally in the form of a complex [C: AA] gives a maximum plasma concentration c (max) more than doubled compared to that obtained with the same dose of (+) - catechin monomeric pure ingested under the same conditions: c (max) 571 ng for 1g of (+) - catechin ingested as a complex against 280 ng for 1 g of monomeric (+) - catechin ingested as such, an increase + 103%.
    Secondly, these peak plasma concentrations are more than doubled [T (max)] more than twice as fast when (+) - catechin is ingested as a [C: AA] complex rather than as (+) monomeric catechin alone: T (max) 30 min versus 80 min, an increase of + 166%.
    All these characteristics are serious advantages particularly in the case of a drug for the prevention and / or treatment of cancer. The doses to be administered being in this case often very high and to take in the long term it is interesting not only to be able to reduce them thanks to the complex. .. [C: AA] but also to obtain directly after taking this complex of blood levels more than doubled compared to those that one would obtain with the molecule alone.
    Since (+) - catechin is generally well tolerated, the only complaints at high doses are stomach heaviness, which could then be eliminated or at least reduced by the use of the [C: AA] complex in the context of long-term treatment.
    It has thus been demonstrated, according to the present invention, the high oral bioavailability of the [C: Lys / HCl] complex compared to that measured for pure monomeric (+) - catechin in humans.
    Furthermore, it is also demonstrated in the present invention, in addition to the known antioxidant properties, the stabilizing properties of membranes, protective properties of the connective tissue framework that surround mammalian organs and a direct protective action of the gastric mucosa reputed subject to carcinoid ulcers and tumors, all of these features making the monomeric (+) - catechin complex and a basic amino acid an especially active agent for preventing and treating cancers and cancerous proliferations.
    Furthermore, it is demonstrated in the present invention that the use of the monomeric (+) - catechin complex and at least one basic amino acid or oral basic amino acid derivative for the treatment and prevention of cancer is at least as effective as a use of said composition by injection. Since the oral treatment is at least as effective as the injectable treatment, this first will be preferred. However, the invention does not exclude the use of the complex for the manufacture of an injectable solution for the treatment and prevention of cancer.
    Advantageously, said monomeric (+) - catechin complex and at least one basic amino acid is a complex in which the ratio between said monomeric (+) - catechin and said at least one basic amino acid or its derivative is a ratio understood to be between 1: 0.25 and 1: 4, preferably between 1: 1 and 1: 4. Advantageously, said ratio is a 1: 1 or 1: 2 ratio.
    In particular, said at least one basic amino acid is lysine or arginine of natural or synthetic origin, or a mixture of both.
    Preferably, said at least one basic amino acid is lysine.
    In a preferred embodiment of the present invention, said complex is a complex comprising a lysine molecule for a monomeric (+) - catechin molecule.
    In an advantageous embodiment of the present invention, said complex is a complex comprising an arginine molecule for a monomeric (+) - catechin molecule.
    In a particular embodiment of the present invention, said complex is a complex comprising two lysine molecules for a monomeric (+) - catechin molecule.
    In another particular embodiment of the present invention, said complex is a complex comprising two arginine molecules for a monomeric (+) - catechin molecule.
    In another preferred form, said complex is a complex comprising a lysine molecule and an arginine molecule for a monomeric (+) - catechin molecule.
    The oral composition is characterized in that it further comprises at least one acid, preferably present in equimolar amount relative to that of basic amino acid or derivative of a basic amino acid.
    Advantageously, said at least one acid is preferably chosen from ascorbic acid, acetic acid, citric acid and hydrochloric acid. Very advantageously, said acid is ascorbic acid.
    The role of ascorbic acid is that of a vitamin supplement, this molecule being deficient in mammals suffering from cancer. In addition, ascorbic acid, itself an antioxidant, plays a synergistic antioxidant role compared to that of (+) - catechin.
    In a particular embodiment, said composition is characterized in that it further comprises one or more biocompatible excipients.
    Preferably, the content of (+) - catechin complex with said basic amino acid or said at least one derivative of a basic amino acid is between 15 and 95% by weight relative to the total weight of said composition, preferably between 60 and 90%, advantageously 65 to 85%.
    Advantageously, the composition is characterized by a pH equal to or greater than 7, preferably between 7 and 11, advantageously between 7.2 and 9.
    A composition whose pH is greater than 7 is for example obtained when the latter has not been neutralized and, in this particular case, during the production of said composition, thus eliminates a step of adding This acid is expensive and can be restrictive, especially when corrosive mineral acids are used.
    Preferably, said oral composition is characterized in that it is used for the prevention and the treatment of a variety of forms of cancer including chronic or non-chronic leukemias, cancers of the prostate, breast, uterus, testes, bladder, kidneys, lungs, bronchi, bones, mouth, esophagus, stomach, liver, pancreas, colon-rectal, lymphoma, myeloma but not exclusively. Indeed, it has been demonstrated in the context of the present invention that said oral or injectable (parenteral) composition prevents tumors from spreading, helps the body to heal after surgical removal of cancers and reduces the toxic effect of others. drugs used in chemotherapy. It is further demonstrated here that said composition also reduces the destruction of connective tissue and in particular that of collagen fibers during radiotherapy. Other embodiments of the composition according to the invention are indicated in the appended claims.
    The present invention also relates to the use of an oral therapeutic composition based on monomeric (+) - catechin complex and at least one basic amino acid or at least one derivative of a basic amino acid for mammals for the treatment and prevention of cancer.
    The present invention also relates to the use of a monomeric (+) - catechin complex and at least one basic amino acid or at least one derivative of a basic amino acid for the manufacture of an oral composition for the treatment and prevention of cancer in the mammal. Other features and advantages of the invention will emerge from the description given below, by way of non-limiting example and with reference to the comparative examples described below.
    Figure 1 illustrates the NMR spectra of the monomeric (+) - catechin complex and lysine for a 1: 2 equivalence ratio (a) and a 1: 1 equivalence ratio (b).
    Figure 2 illustrates the NMR spectra of the monomeric (+) - catechin complex and arginine for a 1: 2 equivalence ratio (a) and a 1: 1 equivalence ratio (b).
    FIG. 3 illustrates the evolution of plasma concentrations (cc) measured in ng / ml over time T (hour) after the assimilation of (+) - catechin hydrochlorrolysinate (monomeric (+) - catechin-rich at 61% by weight, group A) and one gram of pure monomeric (+) - catechin (group B).
    Example 1: Preparation of a monomeric (+) - catechin complex and lysine 1a. Complex (+) - monomeric catechin and lysine in a 1: 2 equivalence ratio
    Monomeric (+) - catechin, extracted from Uncaria Gambir, is milled and then dried at 50 ° C under vacuum for 30 minutes.
    After this drying step, the (+) - catechin extracted comprises at least trace water.
    Two equivalents of lysine are added successively with stirring until dissolved in distilled water in which helium is bubbled therein. The solution is then heated to 40 ° C and stirred for about one hour until complete dissolution of the two equivalents of lysine and is then put in the fridge 16h.
    The solution is then filtered on a beaker and washed with 50 ml of distilled water and then dried with evaporation of the water first at the rotavapor and then at the vacuum ramp (for 4 hours at a temperature of 50 ° C.).
    The product obtained is not soluble in deuterated methanol but in deuterated water (D20, solvent used for NMR analysis). The NMR spectrum obtained is illustrated in FIG. Upon reading the NMR spectrum, it is observed that the complex is formed of two moles of lysine per mole of monomeric (+) - catechin.
    Moreover, the presence of the three peaks A, B and C on the spectrum shows that lysine is well linked to catechin. Indeed, there is a strong modification of the aromatic peaks of (+) - catechin with a disappearance of the peaks at 5.95-5.87 ppm and a poor integration of the peaks at the level of 6.50-7.00 ppm. This indicates that there is an interaction between lysine and aromatic rings of (+) - catechin, at the level of phenolic groups, these interactions involving bonds of hydrogen bridge type. 1b. Complex (+) - monomeric catechin and lysine in a 1: 1 equivalence ratio
    The monomeric (+) - catechin complex with lysine in a ratio of 1: 1 equivalence was synthesized according to the same protocol as that used for the synthesis of the lysine complex of Example 1a but decreasing by a factor of 2 the amount of lysine such that there is an excess of (+) - catechin which promotes the formation of said complex at a 1: 1 equivalence ratio due to the lysine deficiency.
    The NMR spectrum drawn in deuterated water is illustrated in FIG. 1b. On reading the NMR spectrum, it is observed that the complex is formed of one mole of lysine per mole of monomeric (+) - catechin
    EXAMPLE 2 Preparation of a complex of monomeric (+ 1-catechin and arginine 2a) Complex of monomeric (+) - catechin and arginine in a 1: 2 equivalence ratio
    The monomeric (+) - catechin complex with arginine was synthesized according to the same protocol used for the synthesis of the lysine complex of Example 1a. On reading the NMR spectrum illustrated in FIG. 2a, it is observed that the complex is formed of two moles of arginine per one mole of monomeric (+) - catechin. 2b. Complex (+) - monomeric catechin and arginine in a 1: 1 equivalence ratio
    The monomeric (+) - catechin complex with arginine was synthesized according to the same protocol used for the synthesis of the lysine complex of Example 1b. On reading the NMR spectrum of said complex illustrated in FIG. 2b, it is observed that the complex is formed of one mole of arginine per one mole of monomeric (+) - catechin.
    Example 3 Measurement of the Oral Bioavailability of Monomeric (+) - Catechin Chlorhydrolysinate (TC Complex: Lys ƒ HCM 1.5 g of a monomeric (+) - catechin complex and at least one basic amino acid monomeric (+) - catechin chlorhydrolysinate The monomeric (+) - catechin hydrochloride is present in a proportion of 61% by weight relative to the total weight of said complex (ie 0.92 g for 1.5 g). (+) - monomeric catechin is obtained by neutralization of said complex [C: Lys] with HCl added in an equimolar amount to that of said complex, is administered to a group A of 5 healthy volunteers.
    The (+) - catechin content in the blood was measured for group A volunteers over time after taking 1.5g monomeric (+) - catechin hydrochlorrolysate containing 0.92 g of (+) - catechin monomeric (Table 1).
    Table 1: Plasma concentration (cc) of monomeric (+) - catechin (in nq / ml) for group A as a function of time T (hour)
    Table 2: Oral bioavailability assessment parameters calculated from the plasma concentration (cc) curves of monomeric (+) - catechin (in nq / ml) for group A as a function of time T (hour)
    FIG. 3 illustrates the evolution of plasma concentrations (cc) measured in ng / ml over time T (hour) after oral administration of (+) - catechin hydrochlorrolysinate (curve A), this curve is extrapolated from the data listed in Table 1. The area measured under the curve indicates the total (and) concentration of (+) - catechin assimilated in the plasma measured over a period of six hours after ingestion of (+) - catechin as a complex formed with chlorhydrolysinate. This parameter makes it possible to calculate, from the data of Table 1, the bioavailability of (+) - catechin expressed in ng. h / ml. The and is 1263 + 88 ng. h / ml for (+) - catechin hydrochlorrolysinate.
    In FIG. 3, the maximum concentration c (max) corresponds to the peak of the curve. For the group that received the complex [C: Lys / HCl], the c (max) reached 525 ng / ml. This maximum concentration is reached at a time T (max) of 0.5 h for group A having received the monomeric (+) - catechin complex.
    Comparative Example 1: Measurement of the Oral Bioavailability of Pure Monomeric (+) - Catechin
    A dose of 1 g of pure monomeric (+) - catechin is administered to a group B of 5 healthy volunteers.
    Blood (+) - catechin content was measured for group B volunteers over time after (+) - catechin intake. The results are shown in Table 3.
    Table 3: Plasma concentration (cc) of monomeric (+) - catechin (in ng / ml) for group B as a function of time T (hour)
    Table 4: Oral bioavailability assessment parameters calculated from the plasma concentration (cc) curves of monomeric (+) - catechin (in nq / ml) for group B as a function of time T (hour)
    Figure 3 illustrates the evolution of plasma concentrations (cc) measured in ng / ml over time T (hour) after oral administration of pure (+) - catechin (curve B). This curve is extrapolated from the data listed in Table 3. The area measured under the curve indicates the total concentration (and) of (+) - catechin assimilated in the plasma measured over a period of ► six hours from the ingestion of pure (+) - catechin. This parameter is used to calculate, from the data in Tables 1 and 3, the bioavailability of (+) - catechin expressed in ng. h / ml. And is calculated at 1263 + 88 ng. h / ml for 1.5g of (+) - catechin hydrohydrolysinate containing 0.92g of pure (+) - catechin. It is calculated at 904 + 163 ng. h / ml for 1 g pure (+) - catechin, ie 832 +150 ng. h / ml for 0.92 g pure (+) - catechin, corresponding to the dose ingested with the complex [C: Lys / HCl] (see Example 2 according to the invention), an improvement in the bioavailability of at least 52%.
    In FIG. 3, the maximum concentrations c (max) correspond to the peaks of the curves. For the group which has received 1 g of pure monomeric (+) - catechin, the c (max) is calculated at 280 ng / ml, ie 258 ng / ml for 0.92 g of pure (+) - catechin corresponding to the dose of +) - catechin ingested with the [C: Lys / HCI] complex. For the group receiving [C: Lys / HCl] complex, c (max) reached 525 ng / ml, which corresponds to a 103% increase over pure (+) - catechin. These maximum concentrations are reached respectively at a time T (max) of 1.20 h for group B and 0.5 h for the group which has been treated with the monomeric (+) - catechin complex.
    From this first comparative example, the (+) - catechin complex, and in particular (+) - catechin hydrohydrolysinate, is shown to significantly (+ 52%) improve the oral bioavailability of (+) - catechin. monomeric compared to its pure form. The rate of passage of monomeric (+) - catechin in the blood, measured by the parameter T (max), as well as the maximum concentration, c (max), are also very significantly increased: respectively + 166% and + 103%, relative to the intake of monomeric (/ +) - catechin in its pure form.
    Example 4 Measurement of the Effect of Monomeric (+) - Catechin Chlorhydrolysinate and of Monomeric (+) - Catechin Ascorbolysinate on the Total and Collagen Involvement of 3H-Proline in the Skin
    The stabilization of lysosome membranes prevents the release of proteolytic enzymes responsible for the degradation of the conjunctive matrix, including collagen. This degradation is responsible for the spread of metastatic cancer cells regardless of the type of cancer (Cell Communication and Signaling 2010, 8:22).
    The skin is a tissue particularly rich in connective matrix and collagen fibers, which gives it all its elasticity. The efficacy of (+) - catechin hydrochlorrolysinate and monomeric (+) - catechin ascorbolysinate administered orally, on the one hand on the total incorporation (on the whole skin) and on the other hand in the collagen of it, 3H-proline is demonstrated here.
    To do this, a study was conducted in vivo on a batch of 24 female Wistar rats weighing 95 to 115 g, divided into two groups C and D, each of 12 rats. For each group, the radioactive 3H-hydroxyproline, whose specific activity is 13.6 Ci / 10 -3 mol, was administered to all the animals by intraperitoneal injection of proline-L- (5-3H) to a dose relative to the weight of the individuals of 1 mCi / kg, which represents a radioactive 3H-proline activity of 100 pCi / individual 6 rats from each group received a treatment based on monomeric (+) - catechin by gavage at 100 mg / kg for 5 days before sacrifice The remaining 6 rats not receiving monomeric (+) - catechin treatment were a control subgroup (Ctrl). monomeric (+) - catechin hydrohydrolysinate while group D received monomeric (+) - catechin ascorbolysinate.
    Table 5: action of monomeric (+) - catechin in its complex forms (100 mq / kq) on the level (in dpm / mq) of total incorporation (IT) and in the collagen (IC) of 3H-hydroxyproline in the rat's skin
    In Table 5, the rate of incorporation is measured by the disintegration number of radioactive 3H-hydroxyproline per minute (dpm) per mg dry mass. The higher the number, the higher the concentration of 3H-hydroxyproline.
    The results in Table 5 show that catechol and the (+) - catechin hydrochlorrolysinate complex stimulate the biosynthesis of connective tissue and particularly that of collagen.
    In addition, this example, according to the invention, confirms the protection of the connective tissue in vivo by the oral absorption of complexes of (+) - monomeric catechin orally and therefore the protection of this frame, in particular against intrusion. of cancer cells.
    Comparative Example 2: Measurement of the Effect of Pure Monomeric (+) - Catechin on the Total Inclusion and Collagen of 3H-Proline in the Skin
    In this comparative example, a group E of 12 Wistar rats weighing 95 to 115 g to which radioactive 3H-hydroxyproline, whose specific activity is 13.6 Ci / 10'3 mol, was administered to all individuals by intraperitoneal injection of proline-L- (5-3H) at a dose relative to the weight of the individuals of 1mCi / kg, which represents a radioactive 3H-proline activity of 100 pCi / individual. Six rats from each group received pure monomeric (+) - catechin treatment by gavage at 100 mg / kg for 5 days before sacrifice. The other 6 rats not receiving monomeric (+) - catechin treatment are a control subgroup (ctr1).
    Table 6: action of pure monomeric (+) - catechin (100 mq / kq) on the rate (in dpm / mq) of total incorporation (IT) and in the collagen (IC) of 3H-hydroxyproline in the skin of rat
    In Table 6, the incorporation rate is measured by the disintegration number of radioactive 3H-hydroxyproline per minute (dpm) per mg dry weight. The higher the number, the higher the concentration of 3H-hydroxyproline.
    The results of Tables 5 and 6 show that the increase in the incorporation rate for monomeric (+) - catechin chlorhydrolysinate (+ 15%) and monomeric (+) - catechin ascorbolysinate (+ 14% ) is equivalent to that measured when the rats are gaved with pure monomeric (+) - catechin (+ 16%).
    This comparative example confirms the protection of the connective tissue in vivo by the oral absorption of monomeric (+) - catechin complexes orally and therefore the protection of this weft, in particular against the intrusion of cancer cells, and this, at lower de facto monomeric catechin (+) - catechin levels (61 mg of (+) - catechin per 100 mg of complex) than that encountered when taking pure (+) - catechin (100 mg of (+) - catechin ).
    Example 5: Measurement of the action of monomeric (+) - catechin chlorhydrolysinate (fc: Lys / HCl complex on the incidence of gastric ulcers and on the level of histamine in the gastric mucosa in rats Mastomvs
    In this example, the efficacy of monomeric (+) - catechin chlorhydrolysinate in vivo in an African rat, the Mastomys which is known to spontaneously cause gastric lesions and in particular gastric carcinomas is demonstrated.
    The Mastomys have a special system of cells storing histamine in the gastric mucosa, these cells can give rise to carcinoid tumors.
    In this example, a sample of n = 48 Mastomys is sensitized a first time by an intraperitoneal injection of 3 μg of ovalbumin dissolved in 0.2 ml of saline containing 1 mg of aluminum hydroxide ovalbumin which causes antibodies. anti-immunoglobulin E (IgE) and G (IgG). After 7 days, a second injection of 1 mg of ovalbumin in 0.01 ml of saline solution is performed in the gastric mucosa in the corpus of anesthetized animals, which causes ulcerous lesion at the level of the injection.
    The 48 rats are divided into three groups: one of 24 and two of 12 individuals. The first group of 24 individuals (G1) received a placebo (NaCl solution concentrated at 0.15 M).
    The second group (G2) of 12 individuals was treated with monomeric (+) - catechin hydrochlorrolysinate administered orally twice daily (2 χ 300 mg), two days before injection and three days after injection. . The third group (G3) of 12 individuals received, under the same conditions as that of the G2 group, monomeric (+) - catechin hydrochlorrolysinate at the rate of 100 mg but intraperitoneally.
    As shown by the results in Table 7, administration of (+) - catechin chlorhydrolysiniate orally results in a very significant (-72%) decrease in the number of animals with gastric ulcer (NU) and significant decrease (-18%) of the histamine (TH) level, this level being expressed in 10'6 mg / kg of protein, in the gastric mucosa. The histamine level is measured for groups G1, G2 and G3 based on a sample of n = 12 individuals.
    The decrease in the level of histamine accumulated in the gastric mucosa results directly from the action of monomeric (+) - catechin on the cell wall that stores histamine. By contributing to the strengthening of the cell wall, the monomeric (+) - catechin makes it possible to reduce the level of histamine assimilated at the level of the gastric mucosa and thus to reduce the number of ulcers.
    It is interesting to note from this experiment that in particular in many types of leukemia, chronic or acute, there is an increase in mast cells with concomitant increase in histamine levels and an increase in immunoglobulin levels (Blood Cells Mol Dis 35 (3), 370-383, 2005).
    Table 7: Effect of (+) - catechin hydrochlorrolysinate on the incidence of gastric ulcers and histamine levels in gastric mucosa in Mastomvs
    Example 6 Measurement of the action of monomeric (+) - catechin chlorhydrolysinate (fC: Lys-HCI1 complex in the treatment of cancer patients
    In this example, the results of the test for the effect of monomeric (+) - catechin chlorhydrolysinate in two cancer patients treated for more than one year on a tablet of 500 mg complex [C: Lys / HCl ] per day are presented.
    In the first patient, a 67-year-old man with lymphoplasmocytic lymphoma (Waldenstöm's macroglobulinemia type) was detected in a postoperative blood test on day 0. The diagnosis is based on the electrophoretic detection of a monoclonal immunoglobulin (IgM) peak. This diagnosis was reconfirmed and the peak assayed in a second analysis using the same electrophoresis detection.
    Immunoglobulins play a vital role in the body's defense against aggression and are normally secreted by B cells.
    In multiple myeloma or, for example, in the case of Waldenstöm disease, secretion of a single type of immunoglobulin or monoclonal immunoglobulin by plasma cells present in the bone marrow and which proliferate in an uncontrolled manner is observed.
    These immunoglobulins are found at a high concentration in the blood and in the urine. They therefore constitute true tumor markers. Their dosage accounts for the number of diseased cells, the extension of the disease and therefore allows to follow its evolution under treatment.
    Successive blood tests gave the following data for the IgM assay (in mg per 100 ml of plasma):
    Table 8: Changes in the level of IqM (in mq / 100 ml) in the blood over time
    The results in Table 8 show that, since taking monomeric (+) - catechin hydrochloride for one and a half years, there is a stabilization below the maximum detected on the day that the treatment was administered.
    The infiltration rate remained low and despite IgM values greater than 2000 mg / 100 ml. The patient has also not undergone chemotherapeutic treatment. It is therefore considered that it is stabilized.
    In the second patient, left subclavicular cervical lymphadenopathy was first detected on day D0. Then, 2 weeks later, a left renal adenocarcinoma was detected for this patient, followed by nephrectomy of the left kidney 3 days after detection of adenocarcinoma in this kidney.
    Afterwards, on day D + 3 months, a left cervical lymph node dissection was applied to the patient. After this intervention, a series of 15 radiotherapy sessions followed. From the day D0 + 15 months (either day or day), the patient was administered orally a 500mg tablet of (+) - catechin hydrochlorrolysinate per day.
    At day JT + 15 months, the appearance of a pathological mediastinal lymphadenopathy (a volume of 45 cm3) was observed and required mediastinal lymph node dissection followed by pulmonary exploration at day 17 +. This examination revealed the involution of a small micronodular opacity of 5mm in the left lung and the absence of secondary lesions in the parenchyma of the lung and the abdominal stage. At JT + 19 months, the consultation report concluded that renal cell carcinoma with clear cells was in complete remission. This diagnosis was reconfirmed during the control examinations performed at Jt + 23 months. Clearly, it appears that taking (+) - catechin hydrochloricysinate for one year has stabilized the condition of the patient.
    权利要求:
    Claims (21)
    [1]
    An oral therapeutic composition based on monomeric (+) - catechin complex and at least one basic amino acid or at least one basic amino acid derivative for mammals, said composition being characterized in that it is used for the treatment and prevention of cancer.
    [2]
    An oral composition according to claim 1, wherein said monomeric (+) - catechin complex and at least one basic amino acid, or at least one derivative of a basic amino acid, is a complex in which the ratio between said monomeric (+) - catechin and said at least one basic amino acid or its derivative is a ratio of between 1: 1 and 1: 4.
    [3]
    An oral composition according to claim 1 or 2, wherein said at least one basic amino acid is lysine or arginine of natural or synthetic origin, or a mixture of both.
    [4]
    An oral composition according to any one of the preceding claims, wherein said at least one basic amino acid is lysine.
    [5]
    5. oral composition according to any one of the preceding claims, characterized in that it further comprises at least one acid, preferably present in equimolar amount relative to that of basic amino acid or derivative of a basic amino acid .
    [6]
    An oral composition according to claim 5, wherein said at least one acid is selected from ascorbic acid, acetic acid, citric acid and hydrochloric acid.
    [7]
    An oral composition according to claims 5 or 6, wherein said acid is ascorbic acid.
    [8]
    8. oral composition according to any one of the preceding claims, characterized in that it further comprises one or more biocompatible excipients.
    [9]
    An oral composition according to any one of the preceding claims, wherein the content of (+) - catechin complex with said at least one basic amino acid or said at least one derived from a basic amino acid is between 15 and 95. % by weight relative to the total weight of said composition, preferably between 60 and 90%, advantageously from 65 to 85%.
    [10]
    10. An oral composition according to any one of the preceding claims, characterized by a pH equal to or greater than 7, preferably between 7 and 11, advantageously between 7.2 and 9.
    [11]
    11. Use of said composition according to any one of the preceding claims for the treatment and prevention of cancer.
    [12]
    12. Use of a monomeric (+) - catechin complex and at least one basic amino acid or at least one derivative of a basic amino acid for the manufacture of an oral composition for treatment and prevention cancer in mammals and in particular in humans.
    [13]
    The use according to claim 12, wherein said monomeric (+) - catechin complex and at least one basic amino acid or at least one derivative of a basic amino acid, is a complex in which the ratio between said monomeric (+) - catechin and said at least one basic amino acid or its derivative is a ratio of between 1: 1 and 1: 4.
    [14]
    The use according to any one of claims 12 to 13, wherein said at least one basic amino acid is lysine or arginine of natural or synthetic origin or a mixture of both.
    [15]
    15. Use according to any one of claims 12 to 14, wherein said basic amino acid is lysine.
    [16]
    16. Use according to any one of claims 12 to 15, wherein said composition further comprises at least one acid, preferably present in equimolar amount relative to that basic amino acid or derivative of a basic amino acid.
    [17]
    17. Use according to any one of claims 12 to 16, wherein said at least one acid is selected from ascorbic acid, acetic acid, citric acid and hydrochloric acid.
    [18]
    18. Use according to any one of claims 12 to 17, wherein said acid is ascorbic acid.
    [19]
    19. Use according to any one of claims 12 to 18, wherein said composition further comprises one or more biocompatible excipients.
    [20]
    20. Use according to any one of claims 12 to 19, wherein said composition comprises a content of (+) - catechin complex with said at least one basic amino acid or said at least derived from a basic amino acid which is between 15 and 95% by weight relative to the total weight of said composition, preferably between 60 and 90%, advantageously from 65 to 85%.
    [21]
    21. Use according to any one of claims 12 to 20, wherein said composition is characterized by a pH equal to or greater than 7, preferably between 7 and 11, advantageously between 7.2 and 9.
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    同族专利:
    公开号 | 公开日
    CA2912128A1|2014-11-20|
    JP2016518422A|2016-06-23|
    US9844595B2|2017-12-19|
    US20160089358A1|2016-03-31|
    CN105392479A|2016-03-09|
    WO2014184197A1|2014-11-20|
    MX2015015667A|2016-07-20|
    AU2014267398B2|2019-02-21|
    SG11201509433RA|2015-12-30|
    WO2014184198A1|2014-11-20|
    EP2996688A1|2016-03-23|
    ES2730947T3|2019-11-13|
    BR112015028661A2|2017-07-25|
    JP2016518423A|2016-06-23|
    BE1023772B9|2017-08-02|
    EP2996686B1|2019-04-03|
    AU2014267398A1|2015-11-19|
    US20160095923A1|2016-04-07|
    EP2996686A1|2016-03-23|
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    法律状态:
    2017-10-30| FG| Patent granted|Effective date: 20170717 |
    优先权:
    申请号 | 申请日 | 专利标题
    BE20130350A|BE1023772B9|2013-05-17|2013-05-17|COMPOSITION BASED ON A- CATECHIN AND AMINO ACID COMPLEX FOR THE TREATMENT AND PREVENTION OF CANCER|BE20130350A| BE1023772B9|2013-05-17|2013-05-17|COMPOSITION BASED ON A- CATECHIN AND AMINO ACID COMPLEX FOR THE TREATMENT AND PREVENTION OF CANCER|
    MX2015015667A| MX2015015667A|2013-05-17|2014-05-13|Composition comprising a complex of -catechin and amino acid for the treatment and prevention of cancer.|
    US14/889,470| US9844595B2|2013-05-17|2014-05-13|Composition comprising a complex of -catechin and amino acid for the treatment and prevention of cancer|
    ES14727731T| ES2730947T3|2013-05-17|2014-05-13|Oral composition based on- catechin|
    BR112015028661A| BR112015028661A2|2013-05-17|2014-05-13|composition comprising a- catechin and amino acid complex for cancer treatment and prevention|
    JP2016513335A| JP2016518423A|2013-05-17|2014-05-13|Oral composition comprising -catechin|
    JP2016513334A| JP2016518422A|2013-05-17|2014-05-13|Composition comprising -catechin and amino acid complex for the treatment and prevention of cancer|
    AU2014267398A| AU2014267398B2|2013-05-17|2014-05-13|Composition comprising a complex of -catechin and amino acid for the treatment and prevention of cancer|
    EP14726103.6A| EP2996688A1|2013-05-17|2014-05-13|Composition comprising a complex of -catechin and amino acid for the treatment and prevention of cancer|
    US14/889,512| US20160095923A1|2013-05-17|2014-05-13|Oral composition comprisng -catechin|
    EP14727731.3A| EP2996686B1|2013-05-17|2014-05-13|Oral composition comprising -catechin|
    SG11201509433RA| SG11201509433RA|2013-05-17|2014-05-13|Composition comprising a complex of -catechin and amino acid for the treatment and prevention of cancer|
    PCT/EP2014/059781| WO2014184198A1|2013-05-17|2014-05-13|Oral composition comprising -catechin|
    CN201480039349.4A| CN105392479A|2013-05-17|2014-05-13|Composition comprising a complex of -catechin and amino acid for the treatment and prevention of cancer|
    CA2912128A| CA2912128A1|2013-05-17|2014-05-13|Composition a base d'un complexe de -catechine et d'acide amine pour le traitement et la prevention du cancer|
    PCT/EP2014/059780| WO2014184197A1|2013-05-17|2014-05-13|Composition comprising a complex of -catechin and amino acid for the treatment and prevention of cancer|
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