FR2972327A1 - Oral nutraceutical composition, useful for preventing and/or treating glutathione deficiencies, comprises combination of antioxidants comprising glutathione and hydrolyzable tannin and mucoadhesive and matrix vehicle and regulating agent - Google Patents

Abstract

Oral nutraceutical composition (I) comprises: (a) a combination of antioxidants comprising a glutathione or its derivative and at least one hydrolyzable tannin; and (b) mucoadhesive and matrix vehicle comprising (i) mucoadhesive compound, (ii) matrix compound and (iii) a regulating agent for the matrix effect, where (I) is such that the ratio between the weight of the combination of antioxidants and the sum of the weight of the mucoadhesive compound and matrix compound is 0.5-1.5. An independent claim is included for use of the mucoadhesive and matrix vehicle compound for the preparation of solid unit nutraceutical composition further comprising one or more active agents to release oral active agents. ACTIVITY : Anabolic. MECHANISM OF ACTION : None given.

Description

2972327

The present invention relates to the field of food supplements and, more particularly, nutraceutical compositions; it is a combination of glutathione and at least one antioxidant co-factor, formulated in a composition for the administration and absorption of antioxidant compounds in the oral mucosa. Glutathione (GSH) is a tripeptide composed of glycine, cysteine and glutamic acid; it is considered the most potent antioxidant, also called the "Antioxidant Master" (Dr. John T Pinto of the Sloan Kettering Cancer Center of New York, http://www.glutathionediseasecure.com/what-is-glutathione.html ). Virtually all cells contain a high concentration. Naturally present in our body, it protects cells from oxidative stress by neutralizing and destroying free radicals, highly reactive and unstable molecules, and participates in the good metabolism of toxins and the stimulation of the immune system. In our lifetime, glutathione plays an important protective role. Indeed, it is known, that high levels of glutathione can fight the oxidation of fatty acids in the bloodstream, including cholesterol, delaying the process of plaque formation in the arteries, the underlying cause of the most heart disorders. Interestingly, high levels of GSH have been shown to be associated with good health and longevity (Pr Jean Carper, "Stop Aging Now", Ed Harper Paperbacks, first edition June 1996). Conversely, a glutathione deficiency contributes to the oxidative stress involved in aging and in the development of diseases. On the other hand, the role of glutathione in the development of the fetus and placenta is described in the literature. It acts in the placenta to neutralize the pollutants before they reach the fetus during its development. 2 2972327

Several complications during pregnancy have been linked to low levels of glutathione. Indeed, the publication of Hamon et al. (a Gender Differences in the Glutathione Metabolism (GSH) of the Very Preterm "Pediatric Archives (Jan 2011) confirms the role that glutathione appears to play in oxidative stress 5 during pregnancy:" right after birth, if the level of GSH is similar in the large premature baby boy or girl, the enzymes involved in its synthesis (GPX) and its regeneration (GR) are significantly higher in girls. This difference may explain, in part, the better resistance to oxidative stress observed in girls. Glutathione thus helps to effectively protect the body against the development of diseases and helps preserve cells from aging. According to Earl Mindell, author of "What we should know about the super antioxidant miracle", without it we could literally not survive and other major antioxidants like vitamins C and E would be unable to act and effectively protect our disease organism. However, with age, the cellular level of glutathione decreases; in fact, as early as 40 years, the glutathione losses are of the order of 30% and these pass to. 40% from 50 years old. This decrease can be accentuated by a number of factors including exposure to tobacco or pollution, an unbalanced diet 20 and the practice of endurance exercises. It is therefore necessary to strengthen the GSH cell levels using adapted nutritional supplements providing glutathione and possibly other co-factors. Supplementation with glutathione by nutritional supplements adapted to the oral route is however not satisfactory because, thus administered, glutathione has a very low bioavailability in humans; it is largely destroyed during the process of digestion by the pH variations as well as the different gastric and intestinal digestive enzymes. Thus, administering a single 3000 mg glutathione dose to healthy subjects does not lead to an increase in the level of blood glutathione (Witschi A et al., The systemic availability of oral glutathione.) Eur J Clin. 1992, 43: 667-9). Glutathione-based compositions are currently marketed in the dietary supplement market; some are aimed at 3 2972327

to provide precursors of glutathione such as cysteine, glutamate, glycine and N-acetylcysteine (for example, the product NAC® comprising, inter alia, N-acetylcysteine, marketed by Nutrilife and the product Immunocal® comprising a milk protein isolate as well as cysteine and glycine marketed by Immunotech research). These solutions completely obscure certain factors which very strongly limit the effectiveness of such a supplementation on the restoration of a satisfactory level of endogenous glutathione: the bioavailability of each of these precursors which must be absorbed by the intestine; The GSH reconstitution yield from these precursors (yield which decreases with age); some adverse effects reported with certain precursors (eg, some gastrointestinal disorders have been reported with significant intake of N-acetylcysteine products). Certain supplements seek to improve the absorption of glutathione at the gastrointestinal level by the addition of antioxidant compounds which are preferentially degraded in contact with digestive enzymes, thus limiting the gastrointestinal metabolism of glutathione (for example the product Immunocal®). . It is known that the oral cavity has interesting absorption properties, thus allowing certain small molecules to be absorbed directly at their site of administration. This route then offers the advantage of avoiding the effects of the first hepatic passage, where metabolization of the active compounds takes place, and limiting the degradation of the active ingredients by the gastrointestinal enzymes. Thus, compositions formulated as orodispersible tablets or chewing gums for oral and non-intestinal GSH release have also been placed on the market; this is particularly the case of the "Perlingual Glutathione" tablets marketed by Smartcity® and which combine reduced glutathione and vitamin C and the reduced L-glutathione product Sublingual® from VIT AU +, a tablet to be sucked up comprising 100 mg of L-Glutathione (marketed 30 France by EXODIET). Unfortunately, all of these forms release glutathione into the oral cavity and do not prevent the swallowing of the latter; its bioavailability is little or not increased, it is difficult to conclude to a real effectiveness of these compositions yet promising because of their practicality of use. 4 2972327

Indeed, even if the pH of the mouth and the enzymes present in the saliva (amylase and salivary peptidase) lead to a slower glutathione degradation than in the stomach and intestine, there is no less than the release of glutathione in the mouth is not sufficient to substantially improve its absorption, especially because of its dissolution in saliva and swallowing. Thus, the solutions proposed to date for oral glutathione supplementation only lead to a low absorption of glutathione in the digestive tract and it remains necessary to develop a formulation for satisfactory glutathione uptake. The Applicant has developed a nutraceutical composition in solid form whose administration in the mouth leads to improved absorption of glutathione. More specifically, the Applicant has found that when glutathione and hydrolysable tannins are administered together at the level of the oral mucosa, their oral absorption is mutually increased. In fact, when combined, these antioxidants have complementary antioxidant properties: glutathione acts as an antioxidant active intercellularly, and hydrolysable tannin blocks the enzymes responsible for the metabolism of glutathione. The present invention thus relates to an oral nutraceutical composition comprising: a) an antioxidant combination composed of glutathione or a derivative thereof and at least one hydrolysable tannin; and b) a mucoadhesive and matrix vehicle comprising: i. a mucoadhesive compound, ii. a matrix compound, a regulator of the matrix effect, said composition is such as to ensure the oral release of glutathione and hydrolysable tannin over a period of between 30 minutes and 120 minutes after administration of said composition and that the ratio the weight of said antioxidant combination and the sum of the weights of said mucoadhesive compound and said matrix compound is between 0.5 and 1.5. By glutathione derivative is meant in particular the thiol derivatives such as those described in International Application WO 89/00427. Glutathione also refers to glutathione presented in its reduced form (GSH) and glutathione presented in its oxidized form (GSS). 5 2972327

Glutathione or its derivatives is present in the compositions according to the invention at a dose of between 5 mg and 300 mg per unit dose of composition whose total mass of said composition is between 40 mg and 3 g; more particularly, between 5 mg and 200 mg per unit dose of composition and preferably between 100 mg and 200 mg per unit dose of composition. The hydrolyzable tannins are antioxidant compounds of natural origin which have the advantage of being able to degrade preferentially in contact with the digestive enzymes; they comprise: gallotannins, or gallic tannins, formed from galloyl units or their meta-depsidic derivatives linked to various polyol-, flavanol- or triterpenoids units represented in particular and not limited by acidic compounds such as gallic acid, digallic acid, vanillic acid, divanilloylquinic acid derivative (Burkinabin A, B or C), the compound corillagin ([3,5-dihydroxy-2- (3,4,5-trihydroxybenzo yl ) oxy-6 - [(3,4,5-trihydroxybenzoyl) oxymethyl] oxan-4-yl] 3,4,5-trihydroxybenzoate), glucogallin derivatives, polygalloyl glucose derivatives ...; ellagrtamns, or ellagic tannins, formed from at least two galloyl units which are coupled together and without a glycosidic linkage with flavanol units, such as for example and not limited to ellagic acid, gallagic acid, derivatives of punicalagin the punicalin compound, the roburin A compound, the pentagalloyl glucose derivatives such as the tellimagrandin II compound ...; - Tannic flavonoids such as for example quercetin, cutin, hesperidin ...; anthocyanidins such as, for example, cyanidin, delphinidine, etc. These compounds are also known for their antioxidant properties, which are superior to those of conventional polyphenols, vitamin C and vitamin E. These compounds are especially abundant in berries (raspberries, blackberries), strawberry, walnuts, pecans, pomegranate, cranberry, plums, blueberry, grapes, cherries ... Thus, the hydrolysable tannins present in the composition according to the invention can come from a plant extract rich in flavonoids and tannins. More particularly, plants rich in gallotanin and / or ellagitannin will be selected; said plant extracts being preferably fruit extracts. Preferably, these extracts are derived from the plant "Punita Granatum", pomegranate, marketed under the name of pomegranate extract, particularly rich in hydrolyzable tannins, especially ellagitannins represented mainly by ellagic acid. These extracts are generally obtained after an alcoholic or hydroalcoholic extraction. Preferably, the pomegranate extract is obtained after an alcoholic extraction. In a wide range of clinical studies conducted for almost twenty years, researchers have found that the most potent of hydrolysable tannins is ellagic acid; this antioxidant is abundantly present in the pomegranate.

Other studies have also shown that when a pomegranate extract rich in ellagic acid is administered to patients with significant oxidative stress, for example following radiotherapy, or heavy alcohol consumption, the acid ellagic blocked the enzymes responsible for glutathione consumption during stress, namely glutathione reductase and glutathione peroxidase, and thus maintain a circulating glutathione level close to that of normal. The publication "Enhancement of radiation-induced oxidative stress and cytotoxicity in tumor cells by ellagic acid." - Clin Chim Acta. 2005 Sep; 359 (1-2): 89-100 Bhosle SM et al. shows that, during radiotherapeutic treatment of a tumor, the joint administration of ellagic acid makes it possible to protect against oxidative stress. This effect has been demonstrated by the measurement of antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase (GSH-Px) and glutathione reductase (GR) enzymes whose levels decrease after the administration of ellagic acid. The dose of hydrolysable tannin in the compositions according to the invention is chosen to be sufficient to protect the glutathione from its metabolism. Preferably, the hydrolysable tannin is selected from ellagic acid, gallic acid, their mixture or a plant extract which contains ellagic acid and / or gallic acid. Indeed, the oral absorption of glutathione is improved when it is combined with an extract containing at least 20% gallic acid or ellagic acid. When the hydrolysable tannin is in the form of a pomegranate extract, an extract which contains at least 20% by weight of ellagic acid with respect to the total extract will be selected; preferably, the extract contains at least 30% ellagic acid; more preferably, at least 40% ellagic acid. Then the compositions according to the invention may comprise a dose of between 0.5 and 50 mg of pomegranate extract per unit dose of composition; preferably, 0.5 and 40 mg of pomegranate extract per unit dose of composition; preferably, between 10 and 30 mg of pomegranate extract per unit dose of composition. Thus, according to one preferred variant, the compositions according to the present invention are such that the glutathione or its derivatives and the hydrolysable tannin (s) are present in a hydrolyzable glutathione / tannin weight ratio of 0.1 at 10; preferably from 1 to 10; preferably between 4 and 8. According to a preferred variant, the composition according to the invention contains glutathione and pomegranate extract respectively at doses of 150 mg and 20 mg. In general, the composition according to the invention allows an intake of antioxidants in amounts ranging from 10 to 300 mg of antioxidants per unit of setting. The composition according to the invention is in a form suitable for oral administration such that it remains in contact with the mucous membrane of the mouth to allow oral absorption of glutathione; preferably, it is a tablet capable of adhering to the oral mucosa and gradually releasing glutathione and the hydrolysable tannin (s) for one to several hours. More specifically, the compositions according to the invention are such that they comprise a mucoadhesive and matrix vehicle composed of (i) at least one mucoadhesive compound, (ii) at least one matrix compound, and (iii) at least one regulating agent of the matrix effect. Said vehicle may further contain other excipients authorized by the pharmacopoeia and without effects on the mucoadhesive and matrix properties of the composition, such as sweetening agents, flavoring agents, stabilizing agents, lubricating agents and dyestuffs. By "carrier" is meant an association of excipients into which the combination of antioxidants is introduced, said excipients being physiologically and especially pharmaceutically acceptable for oral administration. Mucoadhesive vehicle means a vehicle capable of sticking to the mucous membrane of the mouth. 8 2972327

The term "matrix vehicle" means a vehicle capable of swelling in the presence of a liquid and eroding slowly, without ever disintegrating. Said matrix property thus making it possible to regulate the release of the antioxidant compounds. The mucoadhesive compounds which can be used according to the invention are preferably compounds of natural origin. Their use in the composition according to the invention makes it capable of adhering to the surface of the oral mucosa in less than five minutes once the tablet is deposited at the sublingual level. Another feature of said mucoadhesive compounds is that they are capable of forming in the presence of a biological fluid whose temperature is maintained between 30 ° C and 37 ° C, such as saliva, an adhesive matrix, when they are put directly in contact with a mucous membrane. Said adhesive matrix having the particularity of being formed in less than 5 minutes. By matrix, it is necessary to understand a set of excipient (s) which constitutes a support for the formulation of active compounds and intended to prolong and control the release of the active compounds; the excipients being most often polymeric and resistant to disintegration. Said mucoadhesive compound (s) are advantageously chosen from water-soluble compounds such as derivatives of sodium alginate, carrageenan, xanthan gum, guar gum, locust bean gum, gum arabic, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose. The mucoadhesive compound being advantageously a cellulose derivative; preferably hydroxypropyl methylcellulose. The mucoadhesive compound is present in the composition according to the invention in mass doses of between 10 and 60% relative to the total weight of the composition, preferably in mass doses of between 20 and 40% relative to the total weight of the composition. the composition. The matrix compound which can be used in the compositions according to the invention is a derivative capable of swelling in contact with the water forming a matrix which, in contact with saliva, hydrates instantly and erodes slowly while gradually releasing the combination of antioxidants; the matrix compound is preferably a hydrocolloid. 9 2972327

According to one particular variant, the compositions according to the invention are such that the mucoadhesive compound and the matrix compound are identical. Preferably, the matrix compound is a hydrocolloid chosen from nonionic polysaccharide derivatives having a viscosity of between 5 and 10,000 cps in a 2% solution in water, more particularly the viscosity of the derivative is between 50 and 5,000. cps, more particularly between 50 and 500 cps, preferably the viscosity of the matrix compound is between 50 and 150 cps. Preferably, but not limited to, the hydrocolloid is sodium alginate, xanthan gum, guar gum, carrageenan, pectin, hydroxypropylcellulose, hydroxyethylcellulose hydroxymethylcellulose, hydroxypropylmetylcellulose. According to a particular variant, the matrix compound is a nonionic cellulose (hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmetylcellulose); preferably it is hydroxypropylmethylcellulose. The matrix compound is present in the composition according to the invention in mass doses of between 10 and 60% relative to the total weight of the composition, preferably in mass doses of between 20 and 40% relative to the total weight of the composition. the composition. In particular, the ratio between the weight of said combination of antioxidants and the sum of the weights of said mucoadhesive compound and said matrix compound is between 0.5 and 1.5; more particularly between 0.7 and 1.25. The matrix mucoadhesive vehicle also comprises one or more compounds that regulate mucoadhesive and matrix effects. Said compound (s) makes it possible to advantageously regulate the release of the combination of antioxidants. Said regulating compound (s) have the particularity of being soluble in water or body fluids such as saliva in amounts greater than 50 g / 100 ml; preferably in amounts greater than 100g / 100m1. As a regulatable compound (s) usable (s), it is possible to use soluble solid diluents, said (s) compound (s) regulator (s) being present (s) in said composition in a total mass fraction ranging from 20 to 90% relative to the total weight of the composition and preferably ranging from 30 to 45% relative to the total weight of the composition. 20 25 30 10 2972327

Thus, the regulator compound is chosen from polyols, such as mannitol, sorbitol, xylitol, maltitol, lactose, sucrose, isomaltulose, polyoloside compounds, such as fructooligosaccharide and inulin, dextrin, malto-dextrin, fructose, maltose, erythritol ... the polyol is preferentially maltitol. One of the advantages obtained by using the compositions according to the invention is that they are capable of forming a matrix in contact with biological liquids, controlling the release of the combination of antioxidants for a minimum of 30 minutes and a maximum of 300 minutes. Preferably, the release time will be between 30 minutes and 120 minutes, more preferably between 45 minutes and 60 minutes. The Applicant has demonstrated that by using the matrix mucoadhesive compositions according to the invention, the antioxidants had a residence time in the oral mucosa greater than that obtained with any other conventional forms of tablets or oral delivery form. such as an oral gel, a syrup, a solution, a tablet to be sucked or an orodispersible tablet ... The Applicant has found that by placing said composition at the sublingual level, the amount of absorbed glutathione is significantly greater than that obtained with the conventional forms cited above. Indeed, the use of a mucoadhesive and matrix vehicle controlling the release of antioxidants exhibiting mucoadhesive properties has made it possible to concentrate the absorption of glutathione as well as that of the antioxidant co-factor, in particular the pomegranate extract. at the sublingual level, and thus limit the amount of antioxidants swallowed.

The Applicant has also found that when the glutathione is associated with a hydrolysable tannin, preferably a gallotanin and / or an ellagitain, for example, a pomegranate extract, and that the whole is presented in the form of a mucoadhesive tablet matrix, saliva production is reduced. An astringency appears as soon as the tablet is deposited at the sublingual level.

The Applicant has also found that the absence of saliva production reduces the swallowing process and thus reduces the amounts of glutathione and hydrolyzable tannins swallowed. 11 2972327

The compositions of the present invention may further include enzyme inhibitors for enhancing the bioavailability of glutathione. According to a particular aspect of the present invention, the mucoadhesive matrix composition does not contain a chitin derivative, more particularly chitosan or its salts. Indeed, the Applicant has found that when a chitosan derivative was incorporated into the composition of the mucoadhesive matrix tablet, the taste of it was not compatible with its sublingual administration. On the other hand, although their presence creates an oral acidic environment favorable for maintaining the non-ionized form of glutathione which exhibits improved bioavailability, the compositions of the present invention do not include pH regulating agents. Indeed, the presence of such acidifying agents stimulates the secretion of saliva, which would lead to the dissolution of glutathione and other antioxidants but also to accentuate the loss of active ingredients due to involuntary swallowing from a high production of saliva under the effect of the acid compound. Still for the purpose of avoiding such asset loss by swallowing and according to another aspect of the present invention, the composition does not include any acid compound other than any glutathione derivatives or hydrolyzable tannins which would exhibit an acid function. . By acid compound is meant any compound having at least one free acid function; by way of example, it may be citric acid, tartaric acid, fumaric acid, phosphoric acid, etc. According to yet another aspect of the present invention, the composition does not include of insoluble compound in water, and more particularly in saliva, such as insoluble solid diluents, solid powdery binders. Mention may be made more particularly of microcrystalline cellulose, cellulose powder, calcium carbonate, calcium bicarbonate, dicalcium phosphate, tricalcium phosphate, magnesium silicate, kaolin, bentonite, talc, However, in the case where the composition according to the invention is a tablet, it may include a water-insoluble compound consisting of a lubricating agent. Among the lubricating agents commonly used in a compressed form, may be mentioned by way of example, magnesium stearate, zinc stearate, 12

sodium stearyl fumarate, sucroester derivatives, derivatives of glycerol behenate in proportions ranging from 0.1% to 2% by weight relative to the total weight of the tablet. Indeed, the Applicant has found that when an insoluble compound was introduced into the composition of the mucoadhesive matrix tablet comprising the antioxidant combination, the matrix and mucoadhesive effects were short-lived and did not make it possible to obtain mucoadhesion and controlled release of antioxidants. More particularly, the presence of insoluble compound in the composition of the tablet, led the tablet to disintegrate in less than 10 minutes and this regardless of the doses of use of said compounds. The present invention relates more particularly to compositions as described above in a dosage form which, once introduced into the mouth, to adhere to the oral mucosa; preferably, the dosage form is an uncoated (uncoated) tablet which consists of said nutraceutical composition according to the invention. In general, the present invention thus relates to a solid unit nutraceutical composition for human use; preferably, the unitary solid form is a tablet. According to a preferred variant, the tablet is in a slightly rounded round shape, making it possible to espouse the sublingual space and to maximize the area of contact of the tablet with the mucosa. According to a further preferred variant, the diameter of the tablet is between 7 mm and 13 mm, preferably between 8 mm and 12 mm, more particularly, the diameter of the tablet is 10 mm with a radius of curvature of 25. Thus, the unitary solid nutraceutical composition is intended to be administered at the oral level by application directly in contact with the oral mucosa; preferably, it is deposited under the tongue. The solid unit nutraceutical composition, preferably the tablet, is manufactured by a method conventionally used for the manufacture of tablets (direct compression, wet granulation or compaction); preferably, direct compression and wet granulation will be used for their manufacture. 13 2972327

During the manufacture of said tablets, and before the compression step, the composition according to the invention can be in various forms: powder, granules or pellets. The physical characteristics of the solid unit nutraceutical composition, preferably a mucoadhesive matrix tablet, enabling it to control the release of the combination of antioxidants are as follows: a hardness or resistance to rupture, measured according to the European Pharmacopoeia, which is greater than 25N and preferably greater than 40N; an ability to release antioxidants in vitro in more than 10 minutes. Preferably, these physical characteristics are as follows: a hardness or tensile strength, measured according to the European Pharmacopoeia, which is greater than 40 N, preferably greater than 60 N and less than 100 N; An ability to reduce saliva production in less than 10 minutes, preferably less than 5; an ability to release the antioxidants over a period of from 30 minutes to 120 minutes, preferably from 30 minutes to 60 minutes after administration of the solid unit nutraceutical composition. The present invention further relates to the use of a mucoadhesive and matrix vehicle composed of (i) at least one mucoadhesive compound, (ii) at least one matrix compound, and (iii) at least one regulating agent for the matrix effect, the compounds being as defined above, for the preparation of a solid unit nutraceutical composition comprising, in addition, one or more active agents and such that the oral release of said active agents is progressive, it is that is spread over a period of between 30 minutes to 120 minutes, preferably 30 minutes to 60 minutes, after administration of said solid unit nutraceutical composition. The present invention further relates to a method for administering active agents, such as antioxidants, to the oral mucosa. The method according to the invention is preferably intended to be administered together at the oral level of glutathione and an extract of pomegranate; said 14 2972327

This method is perfectly suited to the administration of antioxidants to children, adolescents and adults. The advantages of this method is that it allows sublingual, oral and perlingual antioxidants to be administered, thereby improving their absorption; in particular, it makes it possible to limit the degradation or the metabolism of glutathione. Other advantages of this method are that it reduces saliva production and the swallowing process. The method according to the invention consists in: administering a solid unitary nutraceutical composition to an individual who places it in the mouth, under the tongue; said composition must thus be maintained for a period of time greater than 30 minutes; preferably greater than 45 minutes without being swallowed or chewed. The present invention finally relates to the use of a composition according to the invention for preventing and / or treating glutathione deficiencies and the resulting pathologies; Glutathione plays an important role in cell function, including their differentiation, proliferation and apoptosis. Glutathione is involved in the etiology and proliferation of many human pathologies, such as cancer, Page-related diseases, cardiovascular pathologies, inflammation, diseases affecting immunity or metabolism, and pathologies. neurodegenerative diseases (Parkinson's disease, Alzheimer's disease) as described by N. Ballatori et al. in "Glutathione dysregulation and the etiology and progression of human diseases" Biol Chem. 2009 25 March; 390 (3): 191-214. More particularly, this use may for example be intended to increase and / or strengthen the immune defenses, to slow the development of cardiovascular diseases such as atherosclerosis, to slow the progression of Alzheimer's and Parkinson's diseases, as mentioned. in the article cited above and 30 repeated in articles published in the journal Nutranews Numbers of November 2002, from January and March 2006. 15 2972327

EXAMPLES Protocols for preparing tablets based on a composition according to the invention and for characterizing the adhesive properties of said tablets - preparation protocol A method of manufacturing the compositions according to the invention of said nutraceutical composition as defined above comprises the steps following: the mixture for direct compression is prepared according to the manufacturing method by wet granulation corresponding to the addition to the mixture of all the excipients of a demineralized water solution. Once the granule obtained, it is dried and then calibrated. The grain thus obtained is then lubricated to form the compression mixture. a) preparing all the raw materials used in the composition of the matrix mucoadhesive tablet: that is to say the antioxidant compounds, the mucoadhesive compound, the matrix compound, the matrix and adhesive effects regulating agents; b) all the compounds according to the invention are mixed using a conventional mixing device to guarantee the homogeneity of the product in the end; C) demineralized water is sprayed onto the moving mixture; d) the grain thus formed is then calibrated on a grid of 630 microns. e) once calibrated, the grain is introduced into a tumble mixer to which may optionally be added, flavoring agents and sweeteners; the lubricant is then added; the mixture is then ready to be compressed. In carrying out the present method of manufacture, the combination of antioxidants is granulated with the mucoadhesive, matrix and effect-regulating compounds for the purpose of forming the compression mixture prior to being compressed. Another peculiarity of the present invention is that the mucoadhesive and matrix compounds must be granulated beforehand by the addition of demineralized water or by the addition of an aqueous or hydroalcoholic solution of 0 g) 16 2972327

polyvinylpyrrolidone (PVP), then calibrated on 630μm to induce the mucoadhesive and matrix effect instantaneously and prolonged. In order to judge the adhesive aspect of the tablets, an in vitro adhesion test on "plate" was set up. The aim of the following study protocol is to mimic the behavior of the matrix mucoadhesive tablet in vivo. the tablet is placed on a paper filter previously moistened with 500 μl of pH 7.4 buffer solution, thermostated at 37 ° C. (defined in the European Pharmacopoeia). - The adhesion of the tablet on the filter is made by a slight pressure exerted on the surface of the tablet. - Once the adhesion is done, 5001.1L of buffer solution are again deposited. 3 minutes after adhesion of the tablet to the filter, 500 μL of buffer solution is again deposited on the tablet surface. - After 10 minutes, the filter is returned to evaluate the adhesiveness of the tablet and the duration of adhesion. - Every 5 minutes, 2001, rL of buffer solution are deposited on the filter, to mimic the continuous production of saliva at the sublingual level. The membership time is determined as the time from when the filter is returned to when the tablet falls. It is nevertheless important to note that in the context of this test, mechanical wear due to friction of the tongue on the floor of the mouth is ignored. This test does not reflect the time of adhesion in the mouth but allows to have an in vitro tool to classify the different formulas according to their adhesive power. Examples of compositions according to the invention The examples below describe nutraceutical compositions according to the invention and are not limiting in nature. 5 10 17 2972327

Example 1: A matrix mucoadhesive composition comprising, as a matrix and mucoadhesive agent, hydroxypropylmethylcellulose and, as a regulating agent, maltitol. Phase Raw materials Percent composition Glutathione 30.0% Pomegranate extract 4.0% Internal phase 28.0% low viscosity hydroxypropylmethylcellulose (Methocel K100LV) Directly compressible Maltitol 37.0% Outer phase Magnesium stearate 1.0% The pharmacotechnical characteristics of the matrix mucoadhesive tablets of composition described in Example 1 manufactured according to the manufacturing protocol as described in the invention are shown in the table below: Parameters analyzed Results Tablet dimension Diameter 10mmR10 Average mass of tablets 513mg Average hardness of tablets 72N Average thickness 6.9mm Adhesiveness time to the filter 59 minutes Evaluation of the matrix effect by measuring 2 hours of the disintegration time Example 2: matrix mucoadhesive composition comprising, as matrix agent, hydroxypropylmethylcellulose, as mucoadhesive agent, carrageenan and, as a regulating agent, maltitol . Phase Raw materials Percent composition Internal phase Glutathione 30.0% Pomegranate extract 4.0% 18 2972327 Carrageenan 2% Hydroxypropylmethyl cellulose 20.0% K100LV Maltitol 43.0% External phase Magnesium stearate 1.0% The pharmacotechnical characteristics of the matrix mucoadhesive tablets of composition described in Example 2 Manufactured according to the manufacturing protocol as described in the invention are shown in the table below: Parameters analyzed Results Size of the tablet Diameter 10mmR10 Average mass of the tablets 509mg Average hardness of the tablets 90N Average thickness 7.19mm Adhesion time at filter 72 minutes Evaluation of the matrix effect by measuring 3 hours of the disintegration time Example 3: matrix mucoadhesive composition comprising, as a matrix and mucoadhesive agent, hydroxypropylmethylcellulose and, as regulating agent, maltitol. Phases Raw materials Percent composition Glutathione 30.0% Pomegranate extract 4.0% Internal phase Hydroxypropylmethyl cellulose 20.0% K100 LV Carboxymethyl cellulose 10.0% sodium Maltitol 35.9% External phase Magnesium stearate 1% Colloidal silica anhydrous 0.1 10 19 2972327

The pharmacotechnical characteristics of the matrix mucoadhesive tablets of the composition described in Example 3 manufactured according to the manufacturing protocol as described in the invention are shown in the table below: Parameters analyzed Results Tablet dimension Diameter l OmmR10 Average mass of the tablets 500.6mg Average hardness of the tablets 80.8N Average thickness 7.44mm Filter adhesion time 90 minutes Evaluation of the matrix effect by measuring the 3 hours of the disintegration time Example 4: matrix mucoadhesive composition comprising, as a matrix agent, hydroxypropylmethylcellulose, as a mucoadhesive agent, carrageenan and, as a regulating agent, maltitol. Phase Raw material Percent composition Glutathione 30.0% Pomegranate extract 4.0% Internal phase Hydroxypropylmethyl cellulose 20.0% K100LV Carrageenan 10.0% Maltitol 35.0% External phase Magnesium stearate 1.0% The pharmacotechnical characteristics of the matrix mucoadhesive tablets of the composition described in Example 4 manufactured according to The manufacturing protocol as described in the invention is shown in the table below: 2972327 Parameters analyzed Results Tablet size Diameter 10mmR10 Average mass of tablets 514.5mg Average hardness of tablets 68.6N Average thickness 6.30mm Time Example 5: Mucoadhesive matrix composition comprising, as a matrix agent, sodium alginate, as a mucoadhesive agent, hydroxypropylmethylcellulose and, as a regulating agent, maltitol. Phase Raw material Percent composition Glutathione 30.0% Pomegranate extract 4.0% Internal phase Hydroxypropylmethylcellulose 20.0% low viscosity (Methocel K100LV) Sodium alginate LF 120 10.0% Maltitol directly compressible 35.0% Outer phase Magnesium stearate 1.0% Pharmacotechnical characteristics of Matrix mucoadhesive tablets of composition described in Example 5 manufactured according to the manufacturing protocol as described in the invention are shown in the table below: Parameters analyzed Results Size of the tablet Diameter 10mmR10 Average mass of the tablets 507.3mg Average hardness of the tablets tablets 65.8N Average thickness 6.13mm Adhesive time 150 minutes 10 5 21 2972327

Example 6: Mucoadhesive matrix composition comprising, as matrix and mucoadhesive agent, hydroxypropylmethylcellulose and, as a regulating agent, maltitol Phase Raw materials Percent composition Glutathione 30.0% Grenade extract 4.0% Internal phase Hydroxypropylmethylcellulose low 28.0% viscosity (Methocel K100LV ) Maltitol directly compressible 31.5% Magnesium stearate 1.0% Outer phase Vanilla aroma 5.0% Natural sweetener: Stevia extract 0.5% Example 7: Matrix mucoadhesive composition comprising, as co-antioxidant factor, a black tea extract and, as matrix and mucoadhesive agent, hydroxypropylmethylcellulose. Phase Raw materials Percent composition Glutathione 30.0% Black tea extract rich in Theaflavin 6.0% Internal phase Hydroxypropylmethylcellulose low 28.0% viscosity (Methocel K100LV) Maltitol directly compressible 29.5% Magnesium stearate 1.0% Outer phase Vanilla aroma 5.0% Natural sweetener: stevia extract 0.5% 22 2972327

Example 8: Mucoadhesive matrix composition comprising an extract of green tea as co-antioxidant factor. Phase Raw material Percent composition Glutathione 30.0% Green tea extract "Teavigo®" 5.0% Internal phase Low hydroxypropylmethylcellulose 29.0% viscosity Maltitol directly compressible 29.5% Magnesium stearate 1.0% Outer phase Lemon aroma 5.0% Natural sweetener: stevia extract 0.5% Example 9: Matrix mucoadhesive composition comprising an extract of witch hazel and glutathione as antioxidants. Phase Raw materials Percent composition Glutathione 30.0% Witch hazel extract 3.0% Internal phase Hydroxypropylmethylcellulose low 29.0% viscosity K100LV Maltitol directly compressible 31.5% Magnesium stearate 1.0% Outer phase Lemon aroma 5.0% Natural sweetener: stevia extract 0.5 %

Claims (20)

1. An oral nutraceutical composition comprising: a) a combination of antioxidants composed of glutathione or a derivative thereof and at least one hydrolysable tannin; and b) a mucoadhesive and matrix vehicle comprising: i. a mucoadhesive compound, ii. a matrix compound, iii. a matrix effect controlling agent, said composition is such that the ratio between the weight of said combination of antioxidants and the sum of the weights of said mucoadhesive compound and said matrix compound is between 0.5 and 1.5. 2. The oral nutraceutical composition according to claim 1, characterized in that the hydrolysable tannin is a gallotanin or an ellagitanin, preferably an ellagitannin. 15 3. oral nutraceutical composition according to claim 1 or claim 2, characterized in that the ratio between the glutathione and the hydrolysable tannin is between 1 and 10. 4. The oral nutraceutical composition according to any one of the preceding claims, characterized in that the amount of glutathione or its derivative is between 5 and 300 mg per unit dose of composition. 5. oral nutraceutical composition according to any one of the preceding claims, characterized in that the hydrolysable tannin is an extract of pomegranate. 6. The oral nutraceutical composition according to any one of the preceding claims, characterized in that the amount of pomegranate extract is between 0.5 and 50 mg per unit dose of composition and contains at least 20% by weight of ellagic acid. 7. The oral nutraceutical composition according to any one of the preceding claims, characterized in that the matrix compound is a hydrocolloid. 8. oral nutraceutical composition according to claim 7, characterized in that said hydrocolloid is a nonionic polysaccharide. 9. oral nutraceutical composition according to claim 8, characterized in that the nonionic polysaccharide has a viscosity at 2% in water of between 50 and 5000 cps. 10. oral nutraceutical composition according to claim 9, characterized in that the nonionic polysaccharide compound is hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose. 11. oral nutraceutical composition according to any one of the preceding claims, characterized in that the regulating agent is a solid diluent compound soluble in water, whose solubility is greater than 50g / 100ml. 12. oral nutraceutical composition according to claim 11, characterized in that the regulating agent is a soluble diluent compound belonging to the family of polyols. 13. oral nutraceutical composition according to claim 11 or claim 12, characterized in that the regulating agent is present in the composition in a total mass fraction ranging from 20 to 90%. 14. oral nutraceutical composition according to any one of the preceding claims, characterized in that it ensures the oral release of glutathione and hydrolysable tannin over a period of between 45 minutes and 60 minutes. 15. oral nutraceutical composition according to any one of the preceding claims, characterized in that it contains no acid compound other than any glutathione derivatives or hydrolyzable tannins which have an acid function. 25 16. oral nutraceutical composition according to any one of the preceding claims, characterized in that it does not comprise any insoluble compound with the exception of a lubricating agent when said composition is a tablet. 17. The oral nutraceutical composition according to any one of the preceding claims, characterized in that it is in solid unitary form for human use, preferably a tablet. 18. oral nutraceutical composition according to claim 17, characterized in that said tablet has an average hardness greater than 40 N. 19. Use of a mucoadhesive and matrix vehicle composed of (i) at least one mucoadhesive compound, (ii) at least one matrix compound, and (iii) at least one matrix effect regulating agent, for the preparation of a solid unit nutraceutical composition further comprising one or more active oral release agents of said active agents. 20. Use of a composition according to any one of the preceding claims for preventing and / or treating glutathione deficiencies.