MXPA99003240A

MXPA99003240A - A PROCESS FOR STABIlIZING LEVOGYRE ASCORBIC ACID (LAA) AND STABLE LAA COMPOSITIONS

Info

Publication number: MXPA99003240A
Application number: MXPA/A/1999/003240A
Authority: MX
Inventors: Joseph Pommez Philippe; Alcantara Martins Zucchetti Roberto; Chitarra Souza Simoni; De Souza Araujo Karla
Original assignee: Industria E Comercio De Cosmeticos Natura Ltda
Priority date: 1997-08-08
Filing date: 1999-04-07
Publication date: 2000-02-02

Abstract

The present invention refers to a process for stabilyzing LAA in an aqueous medium, which comprises the step of contacting the LAA with at least one compound capable of forming hydrogen bridges with the LAA. In another aspect, the invention relates to a stable aqueous LAA composition which comprises, in addition to said ascorbic acid, at least one compound which is linked to the LAA by hydrogen bridges, and to a process for preparing it. The present invention further relates to an emulsion including, in its aqueous phase, at least one compound linked to levogyre ascorbic acid (LAA) by hydrogen bridges. Further according to the present invention, a vitamin product is provided, in which a stable LAA composition as described above is contained in organic envelopes which enable a gradual and prolonged release of said LAA into the organism. Said vitamin product may further comprise a compound capable of stimulating the metabolism of the fibroblasts. The present invention further relates to a method for cosmetic, therapeutic or nutritional treatment, which comprises the administration of a composition as described above.

Description

A PROCESS TO STABILIZE ASCORBIC ACID LEVÓGIRO (AAL) AND STABLE AAL COMPOSITIONS FIELD OF THE INVENTION The present invention relates to a process for stabilizing levorotatory ascorbic acid, also known as AAL or, in more popular form, "Vitamin C" and to cosmetic, pharmaceutical, or nutritional, aqueous -or water-containing- compositions, stable, containing AAL.

BACKGROUND OF THE INVENTION Levorotatory ascorbic acid, hereinafter referred to as AAL, has the following form: and it is a long-known element in the pharmacopoeia, in medicine and in the REF. : 29935 cosmetics industry. Its application focuses on the most varied benefits, from the treatment of stomach problems, regeneration of the signs of the skin to the hygienic action and attenuation of the marks on the skin. The term "signs of the skin" as used herein, signifies the signs of aging of the skin such as wrinkles resulting from the action of time and external factors such as climatic actions (sun, wind and temperature). Examples of the use of AAL in medicine are described in US Pat. No. 2, 132, 662 issued in November 1938 to the Abbott laboratories, the inventors of which are Ernst H. Volwiler and others, in this case as an antiscorbutic agent. , and in U.S. Patent No. 2,721,161 issued in 1955 to the inventor Maise et al., who describe the use of AAL plus a nonionic surfactant, in the preparation of oral compositions or intulas ravas is to restore the level of AAL in the blood. The same is true of the cosmetics industry where AAL, in molecular form, whether or not associated with its salts and esters, has been used to combat the cutaneous aging process. In large part, in the cosmetics segment, the salts and esters of AAl alone are used more frequently than the AAL in its molecular form, since the precedents are chemically more stable, which has resulted in less effective products than if the AAL would have been used in its molecular form. Regarding the form of action sought by the cosmetics industry to combat skin aging, whether using the AAL or its derivatives, the studies carried out by the applicant and the literature show that skin aging comprises a phase regressive of the life cycle, with anatomical and physiological alterations, and with the degradation of certain organs and tissues. Some literature references that incorporate the studies made by the applicant include: 1-DARR, D.; COMBS, S .; PINNEL, S. Ascorbic acid and collagen synthesis: Rethinking a role for lipid pe roxi dat i on.

Archives of Biochemistry and Biophysics, 307, 331-5, 1993; 2- PINNEL, S.; MURAD, S. Vitamin C and collagen metabolism. In: KLIGMAN, A. M.; TAKASE, Y., Cutaneous aging Duke University Medical Center, 275-92, 1988; 3- PINNEL S. Topical Vitamin C. Magazine of Cosmiatria and Aesthetic Medicine. 31-6, 4th trim 1995; 4- DARR, D .; COMBS, S .; DUNSTON, S .; MANNNING, T .; PINNEL, S. Topical Vitamin C protecs porcine skin from ultraviolet radiation-induced damage. British Journal of Dermatology. 127, 247-53, 1992; 5- PINNEL, S. Regulation of collagen biosynthesis by ascorbic acid acid: a review. The Yale Journal of Biology and Medicine, 58, 553-9, 1985. Aging is manifested in the skin by the loss of elasticity, turgor loss, wrinkle formation and the appearance of spots. Among the physiological alterations that contribute actively to this process we can mention the decrease of the immunological functions, the decline of the basal metabolism, the alterations in the structure of the conjunctive tissue, the decrease in the capacity of renewal of the cutaneous lipids and in the components hygroscopic, which leads to a lower power of water retention, and consequently, to dehydration of the skin. All these alterations are the reflection of a series of internal and external factors that together contribute to the aging process. As internal factors, controlled internally by the genetic patterns of the individual, we can mention the following: the chronological factor, defined by aging, influenced by the genetic information contained in the cells; the immunological factor given by the decrease of the Langerhans cells, responsible for the surveillance of immunity, of the skin; the hormonal factor, given by the decrease of the hormonal activity, especially of the androgenic hormones, deteriorating the water retention capacity of the epidermis. Interactions with internal factors, a series of external factors also modulate cutaneous aging, such as the photoenvironment, caused by UV-A and UV-B radiation. The ultraviolet radiation acts at intercellular levels inducing alterations in the DNA capable of forming incorrect proteins and enzymes, accelerating and altering the activities of the cells. At the extracellular level, it can cause structural alterations in the collagen and elastin fibers and proteoglycans, which are fundamental in maintaining the turgor and the structure of the dermal layer. These alterations form groups of amorphous mass that cause a reduction in the external surface of the skin, also known as wrinkle formation. In addition to these damages, UV radiation also promotes molecular oxygen reactions with the lipids and proteins of cell membranes (1 ipoperodixation) forming free radicals which are extremely harmful molecules for cells. In addition, the so-called Environmental Factors can be indicated as external factors, for example, excessively high or low temperatures, wind, relatively low humidity and pollution, which in turn attack the hydro layer or mantle. , leading to transepidermal water loss, with consequent dehydration of the skin. There are also the Emotional Factors and the Habits of Life, generally the tension that is lived in the big cities and characterized by a poor diet, smoking and drinking alcoholic beverages, which causes, either, alterations or imbalances in the metabolism of the lipids and proteins of the dermal layer. These factors affect the skin in some way and can intensify with the age of the individual or with the biological cycle. The biological cycles of an individual are constituted by a set of alterations that result from these external and internal factors already described. The way in which each individual has lived each cycle will result in a certain degree of alterations. Cutaneous aging can be divided into 3 main cycles: the first begins at the age of 30 years, the second comprises the interval from 45 to 60 years and the third from 60 years onwards. In the age group of 30 to 45 the skin, in general, does not show visible signs. The action of free radicals decreases the activity of the cells involved in the immunological responses. every 10 years the skin loses 10% of its defense mechanism. Collagen and elastin, damaged by UV radiation, have decreased their capacity for restoration. Natural aging and the action of free radicals are also responsible for this reduction. Between 45 and 60 years of age there is a decrease in the production of sebum by the sebaceous glands, due to the lower concentration of androgenic hormones. The signs of weakening of the circulatory system become more evident. The damages caused by the free radicals intensify and the deficiencies of the immune system are accentuated more, in addition to that there is a decrease in the efficiency of the fibroblasts, damaging the restoration of the collagen. There is also a decrease in the reaction of elastic fibers and aminoglycosides, leading to the loss of lift.

From 60 years on, the signs that began in the previous cycle are accentuated more. The sebaceous glands are virtually destroyed because they receive less androgenic stimulation and because the deficient circulatory pattern is accentuated, thus decreasing the nutritional contribution and the elimination of toxins. An increase in immune deficiency is observed especially in areas that are exposed to UV radiation, and wrinkles begin to accentuate seriously with respect to the previously described picture, due to the fall in the production of collagen, elastin and glycos amino acids . The technologies for the treatment of the skin have proven to treat not only the visible signs of aging but also act more and more deeply in the causes of them, preventing potential risks that could contribute to the aging process. Based on this, the active principles are developed to act in specific sites of action, to act directly where required, that is, in deeper layers of the skin and directly in aspects that ensure skin support. The AAL has been one of the most researched elements for this purpose, and the main focus has been obtaining its stabilization, since it is one of the main antioxidants that exist in our blood and other tissue fluids. Like the body, the skin also ages. Many of the unwanted effects of skin aging (such as the formation of wrinkles) can be attributed to the loss of connective tissue. With aging the dermis becomes thinner and is lost up to more than 20% of its thickness. AA1 plays a vital role in the growth and repair of connective tissue. Many studies have proven their action in the process of cell regeneration and skin protection, through a series of mechanisms. The AAL is directly involved in the stimulation of collagen biosynthesis, a macromolecule that is essential to maintain skin tone. As an anti- oxidant substance, it directly combats free radicals, which are elements related to skin aging (an action proven by in vitro studies). In addition, the AAL is able to protect the skin against of UV radiation and its subsequent damages. Scientific reports show that the skin, especially with aging, becomes deficient in AAL. The amount of AAL, supplied by the feed, is not enough to act on the skin, effectively, and to combat the damage of the aging process. The AAL, through the ingestion of food or through oral supplements, is distributed throughout the body and, depending on the needs of the latter, may not reach the skin in sufficient quantities to stimulate the synthesis of collagen, and to combat the free radicals. In this form, under limit conditions of ascorbic acid, the latter can be absorbed and used preferably to maintain the most vital needs of the organism, with the detriment in the supply of the cutaneous tissue. Higher levels of AAL in the skin can not be obtained only orally. Studies with topical applications of AAL indicate that they reach much higher pharmacological levels than those found in normal skin. In this way, through topical use, it is possible to reach ideal concentrations of ALA in such a way that they can act efficiently and directly as an antioxidant, antifungal and regenerative agent. Collagen, the most abundant protein in the skin and essential to maintain skin tone, is regulated at each step of its synthesis. AAL is essential in the biosynthesis of collagen, acting as an important cofactor of its fundamental enzymes: prolyl hydroxylase and 1 is ilhydroxy lasa, which act by converting proline to hydroxyproline (an amino acid that is essential for the stability of the triple helix of procollagen ) and in the conversion of lysine to hydroxy 1 is ina (another amino acid that is fundamental for the stabilization of the collagen structure, participating in the formation of intermolecular bonds and imparting mechanical stability to the fiber). Regardless of its participation in the hydroxyl ation of lysine and proline, ALA can have an additional effect on collagen biosynthesis through genetic regulation, promoting an induction effect in the synthesis of collagen with the stimulation of the genetic transcription for type I and type III collagens. Studies "in vitro" with human fibroblasts show an increase in the synthesis of mRNA of 2 to 3 times higher, when in the presence of AAL. These mRNAs also prove to be approximately 2 times efficient in the translation of the collagen chains of the collagen, without causing any alteration in the synthesis process of the non-collagenic proteins. There is also the action of AAL in the production of aminoglycosides, components of the extracellular matrix of the dermis, closely related to the collagen fibers. In the presence of AAL its synthesis can be increased from 30 to 90% with a 50% increase in its deposition in the extracellular matrix. The AAL is also one of the main biological antioxidants, by virtue of its reducing properties, being able to neutralize these highly reactive species, important figures in the aging process. It can also act as an antioxidant in the peroxidative process of fat metabolism and formation of free radicals, also contributing to maintain vitamin E in the body, also an important antioxidant, in its reduced form, helping to protect against it. ipoperoxi daci ón and, consequently, avoiding damage to cell membranes. It should be emphasized that, qualitatively, the antiradical action of AAL is superior to that of Vitamin E and glutathione, even if they are associated. Damage to the skin, caused by ultraviolet radiation, is due, in part, to the generation of certain reactive oxygen varieties, such as superoxide anion, oxygen singlet and hydroxyl radical. Oxidant aggression promoted by radiation with generation of free radicals, results in widespread damage to the constituents of the skin. As a result of exposure to sunlight, the dermis undergoes major alterations accentuating the normal process of skin aging. In this case we have the degeneration of the elastic material, the degeneration of the collagen and the accumulation of aminoglycosides. Fibroblasts, exposed to UV radiation, reduce or even lose their ability to synthesize support macromolecules. The AAL in topical use is able to protect the skin against UVA and UVB radiation. However, it does not act as a solar filter since it is not capable of absorbing the radiation in this spectrum. Its protective effect is directly related to its anti-radical action. Its role as an antioxidant is essential to protect the skin against oxidative damage caused by exposure to radiation and the inflammatory reaction associated with it. The AAL can not be synthesized by the human body but it is available in vegetables and mainly in citrus fruits. Pure AAL, whether extracted from fruit or chemically synthesized, is a white or slightly yellowish powder, which has a relative stability when dissolved in an aqueous medium. This compound can easily be oxidized in the presence of atmospheric air, changing to dehydro ascorbic acid in addition to switching to other products that result from oxidation. This transformation diminishes its physiological properties, mainly in the conditions of use in which the exposure of the compound to atmospheric air occurs, such as, for example, when a topical solution is used. In a simplified way, the instability is manifested by the fact that, when it dissolves in an aqueous medium, it is ionized forming AAL anions "and releasing H + ions. Due to this instability, although it shows greater efficiency when it is in its original form, that is, in its molecular formula, the AAL is used in the form of its salts or esters, in such a way that the resulting compositions have greater stability for prolonged periods, thus preventing degradation due to contact with oxygen dissolved in water and absorbed from the air However, many works have been carried out with the main purpose of achieving the stability of the AAL in its molecular form, to allow its use in medicines and cosmetic compositions.An example of this approach can be found in the North American patent No. 4,983,382 of January 8, 1991. According to this patent, a solution containing AAL would become stable by adding an organic solution containing a first co-solvent, water up to 12% by weight and a second co-solvent at a concentration of up to 90%, based on the total weight of the solution, and also containing, obligatorily, ethanol at a concentration of at least 40% in weight of the solution. The disadvantage of this type of organic solution for the cosmetics industry and for the pharmaceutical industry, or for the food industry, consists in the fact that, although the AAL can exhibit an acceptable stability, the addition of ethanol in the mentioned contents It causes the skin to become irritated and become very dry, which can make the permeation of the AAL by the corneal extract difficult, besides causing, of course, an unpleasant sensation to the user. Another use of the AAL in its molecular form is described in the Brazilian patent application Pl 9008018, filed in the name of Bioderm, Inc. This document relates to a composition for reducing the depth or intensity of fine wrinkles in a skin affected by aging. intrinsic ofot oinduc gone. Although he does not make detailed comments about the stability of the AAL, the patent application referred to describes a series of actions that are beneficial for reducing the depth or intensity of fine wrinkles, by using a topical formulation which comprises, in combination with the AAL, tyrosine and a zinc salt such as zinc sulfate, and can be formulated, either as an ointment or as a hydrophilic cream. The mandatory inclusion of tyrosine and a zinc salt, makes the solution more expensive for the consumer, due to the large number of ingredients necessary for its production, and its effective action to combat skin aging has not yet been fully tested. In more recent works to achieve the stability of the AAL in its molecular form, the objective was to avoid the degradation of the acid by keeping the pH at low levels. In these works the appearance of ascorbates to the detriment of the maintenance of the molecular AAL in the solution, was credited to the ionization of the AAL and its degradation due to the contact of the anion of AAL with oxygen (either atmospheric air or pure oxygen present in the solution.) Indeed, the ionization of the AAL causes the formation of an ascorbate (AAL ") which is a metastable structure in water, due to the electronic resonance between carbons 1, 2, and 3 of the AAL, and the release of H + ions.

+ H3CT This reaction is governed by the spontaneity (free energy or "? G < 0") of the AAL to ionize, until a dynamic equilibrium is reached between the reactants (AAL) and the products (AAL "+ H +), and can be represented as follows : AAL OR AAL "4- H +.

For the minimum amount of ascorbate to be formed, as an ionization product and, therefore, for the maximum amount of AAL to remain stable, it was thought that the pH of the solution should be as low as possible. For this purpose the common practice for several previous solutions was to add any acid such as citric acid, for example, or increase the initial concentration of ALA. The pH of that solution containing AAL was related to the concentration of the AAL, by the following equation: pH = pK1 + l or g ([AAL] / [AAL]) where pH indicates the degree of acidity of the solution; pK1 is the first ionization constant of the AAL, equal to 4.2; [AAL] is the concentration of the AAL in its molecular form, contained in the solution; and (AAL ") is the concentration of ascorbate contained in the solution.

Thus, by means of the above equation, read according to the knowledge of the previous technique, in order not to ionize as much as possible of AAL (greater stability), the pH value of the solution should be less than pK1, a fact which has probably guided most of the solutions known in the prior art. Graphically, this assertion can be confirmed by analyzing Figure 1, which represents a pH curve versus the molar fraction of AAL. "In this Figure, we can see that for low pH values, we would have high concentrations of AAL and low concentrations of AAL " U.S. Patent No. 5,140,043, issued August 8, 1992, describes, for example, that the stabilization of AAL in amounts greater than 1% by volume of water can be achieved in an aqueous medium, when a carrier for topical application , in a ratio of water: carrier, of at least 1: 1, is associated with the AAL, the pH of the solution is less than 3.5. Although this is a mutual association between the AAL content, the ratio between the water and the carrier and a low pH (lower than 3.5), the inventors give great importance to the pH value in the stability of the AAL, the latter being considered a element that guarantees that at least 82% of the AAL will remain in its unmodified molecular form, as can be seen from the description found in column 4, lines 7-9, of that document. One of the disadvantages that are widely discussed by the inventors of that patent is the fact that carbons 2 and 3 contain acidic hydrogens that can be ionized in water, by virtue of a physical and chemical characteristic of the AAL, that is, their constant of ionization (pK) equal to 4.2.

Despite the technical advance provided by that patent, the topical use of a solution such as that described therein can irritate the more sensitive parts of the skin such as, for example, the contours of the eyes. Since the pH of the human skin is about 4 to 5, this sensation or irritation can be easily attributed to what the inventors consider in the patent as the "important factor that guarantees the stabilization of the AAL in its molecular form", ie , the low pH value of the solution, which is lower than 3.5, preferably lower than 2.5. In addition, another great disadvantage of the solution discussed in US Patent No. 5, 140, 043 is that, although the tests or stability analysis discussed therein are exhaustive, it takes into account conditions that are far removed from reality or the use of a product intended for topical application and to be handled for a long time. Regarding the time in which the test or analysis was carried out, it took only 12 weeks (84 days) and the low temperatures and luminosity to which the topical solution was exposed are hardly found in a consumer's home or even in the home. doctor's office. With good luck, the conditions established by these tests, keep the topical solution only against the most severe actions that would cause the destabilization and degradation of the AAL. More recently, the patent application publication EP 670,157, filed in the name of L'Oreal, describes the formation of a topical emulsion comprising an aqueous phase dispersed in an oil phase with the aid of an emulsifier, tell me concopo 1 io 1, which contains AAL at an acidic pH of at most 3.5. As in the case of U.S. Patent No. 5,140,043, the emulsion described in the European patent application, to which reference was made, shows a profile that irritates the skin due to a low pH which is intensified by the inclusion mandatory of an artificial emulsifier, which in turn is also irritating. Therefore, an objective of the present invention is to provide an effective process for stabilizing the AAL in an aqueous medium, which will allow the use of AAL in its molecular form, particularly in cosmetic, pharmaceutical or nutritional, aqueous compositions, which are sufficiently stable to guarantee the desired results in the storage and handling of these compositions during cosmetic or therapeutic treatments, without causing damage to the organism of the individuals subjected to these treatments.

BRIEF DESCRIPTION OF THE INVENTION In a first principal aspect, the invention relates to a process for stabilizing levorotatory ascorbic acid (ALA) in a medium containing water, characterized in that it comprises the step of contacting the ALA with at least one compound capable of forming hydrogen bonds with the AAL. In another principal aspect, the invention relates to a stable AAL composition in a medium containing water, which comprises at least one compound that is linked to the AAL by hydrogen bonds. Further, in accordance with the present invention, there is provided a Vitamin product, in which a stable AAL composition, such as that described above, is contained in organic bags or casings that allow the gradual and prolonged release of the AAL , to which reference was made, to the organism. This invention also relates to a Vitamin product characterized in that it comprises a stable AAL composition, such as that described above, inserted into an organic bag or envelope, and in that it additionally comprises at least one compound capable of stimulating the metabolism of fibroblasts. The present invention also relates to an emulsion characterized in that it includes, in its gaseous phase, at least one compound bound to levorotatory ascorbic acid (AAL) by means of hydrogen bonds. Also, in accordance with the present invention, there is provided a process for preparing a stable AAL solution, characterized in that it comprises the steps of: (a) heating a quantity of water; (b) add to this amount of heated water a compound capable of forming hydrogen bonds with the AAL, in an amount ranging from 1 to 5% m / v, and the amount of water heated should be at a temperature capable of promoting the dissolution of the compound that forms the hydrogen bonds, besides guaranteeing simultaneously the substantial elimination of any quantity of oxygen present; (c) homogenizing the product obtained in subsection (b); (d) cooling the resulting product to a temperature in the range of 10 ° to 40 °; (e) adding to the mixture obtained in part (d) from 5% to 20% m / v of AAL; and (f) homogenize the resulting solution.

The present invention further provides a method for the cosmetic, therapeutic or nutritional treatment, based on AAL, of an individual in need of such treatment, which comprises incorporating AAL into the organism of the individual through the administration of an AAL composition, stable, that includes, in addition to the ascorbic acid, at least one compound that is linked to the AAL through hydrogen bonds.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 represents a pH curve versus the molar fraction of AAL. "In this Figure, it can be seen that high concentrations of ALA and low concentrations of ALA" correspond to low pH values.

Figure 2 shows the stability of an aqueous composition of AAL in accordance with the present invention, when exposed to conditions of ambient temperature and artificial clarity.

Figures 3 and 4 represent graphs comparing the stability of AAL compositions, these being ilized, in accordance with the present invention and those of other known compositions.

DESCRIPTION OF ALLADA OF THE INVENTION After detailed studies, the present inventors found that the physical and chemical interaction of the hydrogen bonds formed with at least one of the hydroxyl and carboxyl groups of the AAL allows the prolonged stabilization of this compound, even in frequently used aqueous compositions, keeping all the beneficial characteristics of the compound preserved when it is used for cosmetic, pharmaceutical or nutritional purposes. The substantially physical or chemical interaction of AAL with a compound that forms hydrogen bonds eliminates or at least disinu, and significantly the ionization reaction and, consequently, the degradation of the AAL. The interaction of the compound that forms hydrogen bonds prevents the formation of AAL ions, thus ensuring the maintenance of the AAL in its molecular form The expression "a compound capable of forming hydrogen bonds", as used herein, is intended to include any chemical compound that, when present in an aqueous medium together with AAL, interacts substantially in a physical and chemical form with the latter, without altering, therefore, its original molecular form.This physical and chemical interaction may be represented using the scheme that is provided below: where UM means 1 to monomeric unit of a generic compound.

For the purposes of the present invention it has been found that, in a general form, any compound compatible with the AAL and capable of forming the hydrogen bonds referred to, can be employed to promote proper stabilization thereof. However, according to a preferred embodiment of the invention it has been considered appropriate to use polymers that carry a small monomeric unit with great compatibility and low molecular weight, which leaves a large number of groups capable of interacting physically and chemically with at least one of the OH groups of carbons 2 or 3 and carboxyl (C = 0) of carbon 1 of the AAL, thus effecting the physical and chemical interaction to which reference was made (hydrogen bridges) with the AAL, keeping it stable in its form molecular. In addition to the large number of groups that can interact with the AAL, these groups must have some link intensity (link strength) in the hydrogen bridges formed. "Linking power" is the value in Kcal / mol which defines the occurrence or non-occurrence of a hydrogen bridge, and for it to be defined as a bridge, the link should exhibit approximately 4.5 to 5.5 Kcal / mol, preferably an approximate value of 5 Kcal / mol. An example of a compound useful for the present invention is a polymer comprising a plurality of equal monomer units with a molecular weight of less than 100 g / mol and with a heterogeneous group in an amount greater than about 70% the relationship between the molecular mass of the polymer and the molecular weight of its monomer unit. The atomic ether groups referred to in the monomeric units of the polymer described above are preferably hydroxyl (OH) or hydrogen sulfide (SH) groups, and the molecular weight of each monomer unit is preferably less than or equal to 60 g / mol. For polymers with molecular masses that are in the order of less than the range of 70,000 g / mol to 200,000 g / mol, it is preferable that the number of groups to be toxic is approximately 0.9. molecular mass of the polymer and the molecular weight of its monomer unit. For example, for polymers with a molecular mass of less than 70,000 g / mol, it is preferred that the amount of the heterogeneous groups be about 0.9 the ratio between the molecular mass of the polymer and the molecular weight of its monomer unit. However, in the case of polymers with a molecular mass of approximately 150,000 g / mol, it is preferred that the amount of the heterogenous groups be equal to the ratio between the molecular mass of the polymer and the molecular weight of its monomer unit. In another example, when the polymer has a molecular mass of approximately 200,000 g / mol, it is preferable that the number of heteroatom groups be equal to 0.9 the ratio between the molecular mass of the polymer and the molecular weight of its monomer unit. A polymer that is particularly suitable for the purposes of the present invention is polyvinyl alcohol or, to a lesser extent, polyvinyl thio alcohol, and in this case the physical and chemical interaction can be represented as follows: The parameters and conditions for carrying out the stabilization process of the AAL, in accordance with the present invention, will depend on the hydrogen bond-forming compound, used, and on the end products that are specifically desired. Therefore, these parameters are not determinative of the invention and can be easily determined by any person skilled in the art in accordance with the objectives of each particular situation. Experiments carried out in accordance with the process of the invention show that it is possible to obtain a greater stability of the AAL than 90%, for a prolonged period of time and under adverse external conditions. In this way, it is possible to form, in some way, an amount of less than 10% of secondary compounds that could damage the efficiency of the resulting aqueous compositions. Therefore, the invention also provides a stable AAL composition, comprising, in addition to the ascorbic acid to which reference was made, at least one compound that is linked to the AAL through hydrogen bonds. An aqueous composition with these stability characteristics can show excellent results when used for cosmetic, pharmaceutical or nutritional purposes. It has been found, for example, that an aqueous composition according to the invention provides surprising results to reduce the signs of skin aging, when applied topically. When ingested or otherwise administered, for a pharmaceutical purpose, it raises the level of AAL in the body, which may pretend, for example, a better synthesis of collagen in the body, an antiscorbute action or an antioxidant action and a predictable destructive action of free radicals. For these specific purposes, the aqueous composition of the invention preferably has an AAL content ranging from about 5 to about 20% m / v, more preferably about 10% m / v, and a content of a compound forming a hydrogen bridges ranging from about 1% to about 5% m / v, preferably about 1% m / v. The aqueous composition of the invention may also advantageously comprise other additives or even other active ingredients that do not interfere with the stability of the AAL, and these components depend, of course, on the intended end use for the composition. For example, it can advantageously include a drinkable deoxygenator that aids in the decrease of the solubility of the oxygen in the solution, expelling it, thus intensifying the stabilization of the AAL. In the case of a composition for the cosmetic or pharmaceutical purpose, for example, a particularly suitable deoxygenator is a glycol, preferably propylene glycol, which may be present in a proportion of about 25% v / v, based on the total volume of the composition. In addition, a composition according to the invention, when formulated as a pharmaceutical composition, may contain other ingredients or compounds having curative properties such as for example other vitamins such as Vitamin A, B and mineral salts, in addition to necessary ingredients for the metabolism, in the case of a composition that is going to be ingested by a human being or an animal. Alternative glycerin alternatives may include glycerin or vegetable oils. The topical compositions, in turn, may contain moisturizing agents, preservatives, and thickeners such as sodium hyaluronate, nipagin / nipa z or 1 and polyacrylates, respectively. In another aspect of the invention, the association of an aqueous AAL composition according to the invention with compounds capable of stimulating the metabolism of fibroblasts is particularly advantageous, since the latter accentuate the stimulus for the synthesis of collagen with a view to prevent and correct the structure of the skin support, thus acting against wrinkles. An example of such compounds includes retinol and its derivatives, such as retinyl palmitate. Formulations containing an aqueous, stable AAL composition, together with the compound capable of stimulating the metabolism of fibroblasts, may also be included in a hydrophilic base or in a lipophilic base, or otherwise, in an emulsion. Although some emulsions are capable of intensifying skin irritations, when applied topically, that disadvantage can be minimized or even eliminated, by selecting less irritating surfactants and / or including compounds that attenuate the sensation of irritation. Either way, it has been found that the aqueous compositions of the invention, when prepared in the form of a solution, ie, with a water content greater than 50% m / v, do not present micelles, the presence of which indicates a of emulsion. Although it is possible to minimize or eliminate the potential irritation of the topically applicable emulsions, the absence of micelles in the aqueous, topical compositions obtained according to the invention can be considered as an additional advantage, since this eliminates, even in a more substantial way , the irritation resulting from the use. Another advantage of the stable, aqueous compositions of the invention is that the presence of the compound bound to the AAL by hydrogen bonds makes the stability of the composition independent of the definition of a low pH value. In fact, even if the composition reaches higher pH values, for example, greater than 3.0, a high stability of the AAL is obtained. This feature is fundamental for cosmetic or pharmaceutical compositions. Another important advantage, mainly for topical applications, is that the invention provides a favorable permeability of the composition by the corneal extract.

Another advantageous aspect of the invention lies in the ease and economy of the process for preparing that composition, which dispenses complex and expensive techniques, since it can be prepared, packaged, stored and transported at room temperature and in the presence of oxygen without losing the stability of the AAL. In a general form, an aqueous composition according to the invention can be prepared through a process that includes the step of dissolving at least one compound capable of forming hydrogen bonds with the AAL, in water, and adding the AAL to the resulting solution. According to a preferred embodiment of the invention, the aqueous composition is formulated as a stable AAL solution, comprising a polymer as described above, linked to the AAL by hydrogen bonds, for example, polyvinyl alcohol, and in addition a drinkable deoxygenator that is cosmetically and pharmaceutically acceptable, such as propylene glycol. Such a solution can be prepared through a process for preparing a stable AAL solution, characterized in that it comprises the steps of: (a) heating a quantity of water; (b) add to this amount of heated water a compound capable of forming hydrogen bonds with the AAL, in an amount of water that varies from 1 to 5% m / v, and the amount of water heated must be at a temperature capable to promote the dissolution of the hydrogen bonding compound, in addition to simultaneously guaranteeing a substantial elimination of any amount of oxygen present; (c) homogenizing the product obtained in subsection (b); (d) cooling the resulting product to a temperature ranging from 10 ° to 40 °; (e) adding to the mixture obtained in part (d) from 5% to 20% m / v of AAL; and (f) homogenize the resulting solution.

The illustrative examples presented below will serve to describe the present invention in a better way. However, the data and procedures illustrated refer only to some embodiments of the invention and should not be considered as illustrative of the scope thereof. To prepare all the analyzes, the AAL (Vitamin C) supplied by ROCHE MR in the form of a white powder Example 1: Stability of the AAL in an Aqueous Composition in accordance with ... (the invention).

A solution was prepared comprising 66.11% water, 16.53% polypropylene glycol, 16.53% AAL and 0.83% polyvinyl alcohol (APV) with the following characteristics: The above composition was subjected to ambient temperature and artificial clarity, and the data obtained is shown in Figure 2.

As can be seen from the graph, the AAL content of the previous sample, even after 160 days of storage at room temperature and exposed to artificial clarity, presents a stability greater than 90%.

Example 2: Comparative Example between a Stable Aqueous Composition according to the invention and other proposed compositions for the stabilization of the AAL.

A solution according to the invention was prepared, which contained 72.7% water. 17.44% polypropylene glycol, 9.0 AAL and 0.9% polyvinyl alcohol, described in Example 1, where all concentrations are defined by mass by mass (Solution 1). Additionally, a solution was prepared that contained the same components and the same proportions as those of solution 1, except for polyvinyl alcohol, which was replaced by hydroxyl ether 1 cell, in the same amount (Solution 2). A commercially available product (Solution 3) was also used which consists of a solution presented in the form of a serum containing approximately 10% of AAL, essences, zinc salts, bioferovorides, moisturizing agent and a preservative agent, and that it is indicated for topical use in order to provide a photoprotective effect by virtue of its ability to control the inflammatory response of the skin, associated with exposure to sunlight. The three solutions were exposed to artificial clarity and at room temperature. The comparative data are presented in Figure 3, where it can be seen that the stability of Solution 1 (of the invention) remains above 90%, while on the contrary, in the other solutions a decrease occurs.

Example 3: Comparative Example of the Stability of AAL in Solutions Exposed to Direct UV Radiation.

Five solutions of the ingredients indicated in Table II were compared with one another, wherein Solution 1 consisted of a solution according to the invention; Solution 2 consisted of a solution analogous to that of the invention but replacing the APV with hydroxyethylcellulose; Solutions 3 and 4 were the same as Solutions 2 and 1, respectively, but additionally contained citric acid to evaluate the effect of the pH decrease on the stability of the Solution. Solution 5 is an existing product on the market, such as the one described in the preceding example. (*) - unknown After the appropriate dilution to perform the readings in the spectrophotometer, in visible UV, the spectra were obtained with determined periods, without removing the cell (?) of sample in the sampling compartment, to in order to receive visible UV radiation, constantly inducing degradation of the AAL. Figure 4 shows the kinetics of AAL degradation with the time of exposure to visible UV radiation. It can be seen that, in an advantageous and surprising manner, the stability of the Solution 1 (the invention) presents only a slight decrease after 20 minutes of exposure to UV radiation, being also above Solution 5, representative of a product on the market. The AAL content of solutions 3 and 4, which include a citric acid with the function of decreasing the respective pH values and thus maintaining the stability, show that the inclusion of the acid did not fulfill its expected role, having been found a fall in the remaining amount of AAL or a loss of stability, while Solution 5 • presents acceptable stability under UV radiation. In a particularly preferred embodiment, an aqueous, stable AAL composition, as described above, is used in organic bags or shells, permeable to AAL, which allows its gradual and prolonged release into the body. The advantage of using these bags or wraps lies mainly in the fact that these provide additional protection for the composition of AAL, aqueous, "against the effects of the environment, in addition to improving its action in the body of an individual, especially when they are for a topical application, because by allowing a prolonged release of the AAL the bags or casings also provide for the preservation of target or target cells, unlike what used to happen with massive doses of AAL, which could cause death of the Said bags or casings for this purpose are described in U.S. Patent No. 5,395,620 (Huc et al) and refer to microcapsules containing a crosslinked polymer wall For the purposes of the invention these microcapsules they have a substantially globular shape, with a statistical distribution of sizes of less than 800 microns. This statistical distribution of sizes is smaller than 100 microns, more preferably from 0.2 to 100 microns, and even more preferably from 3 to 60 microns. The organic bags or casings are advantageously prepared from a matrix containing molecules selected from the group consisting of protein molecules, glycosaminoglycan molecules, polysaccharide molecules and mixtures thereof. The protein molecules and the aminoglycoside molecules can be of marine origin or they can come from terrestrial mammals, while the useful polysaccharide molecules are of vegetable origin. Preferably the protein molecules are collagen molecules and the aminoglycan glyco molecules are chondroitin sulfate molecules. But the polysaccharide molecules are preferably omanganic gal molecules. The analyzes carried out showed the greater efficiency of the AAL when it is inserted in those bags or organic casings and applied in a single layer of fibroblasts, as illustrated in the following graph, in which system 1 represents the AAL associated to organic wraps, while system 2 represents free AAL without being inserted into these organic wraps: The maintenance of an intense metabolic activity of the production of collagen proteins of the fibroblasts can be observed, even after 4 days. On the other hand, the fear that the composition of AAL, aqueous, stable, according to the invention, can not be adequately retained within those organic casings, did not prove to be true, since it was found that, surprisingly, the compositions of AAL, aqueous, stable, including hydrogen-forming polymers with a molecular mass as described herein, that is, less than the range of 70,000 g / mol to 200,000 g / mol, drained in a minimal form out of these organic envelopes, as the analyzes show, the result of which is represented by the following graph: As can be seen, an aqueous composition that includes a polymer with a molecular mass of 67,000 g / mol (indicated by the symbol B) is retained in a more advantageous form within the organic casings than in the case of the aqueous compositions including a polymer with a molecular mass of 31,000 g / mol (indicated by the symbol). In view of the above considerations, about the advantages of associating an aqueous, stable AAL composition, according to the invention, with the compounds capable of stimulating the metabolism of the fibroblasts, on the one hand, as well as of inserting the aqueous composition within organic casings such as those described in U.S. Patent No. 5,395,620, on the other hand, an especially preferred embodiment of the invention will be represented by a synthesis of these associations, ie, an AAL, aqueous composition, combined with a compound capable of stimulating the metabolism of fibroblasts and presented within an organic envelope, as described above. It should be borne in mind that the processes, methods, compositions and products described above represent only preferred embodiments of the present invention, the scope of which is defined by the accompanying rei indications.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims

1. A process for stabilizing levorotatory ascorbic acid (AAL) in a medium containing water, characterized in that it comprises the step of contacting the AAL with at least one compound capable of forming hydrogen bonds with the AAL.

2. A process according to claim 1, characterized in that the AAL is predominantly dissolved in the medium containing water.

3. A process according to claim 1 or 2, characterized in that the compound capable of forming hydrogen bonds with the AAL comprises a plurality of equal monomer units with a molecular weight of less than 100 g / mol and with a heterogeneous group. in an amount greater than about 70% of the ratio between the molecular mass of the compound and the molecular weight of its monomer unit.

4. A process in accordance with the rei indication 3, characterized in that the atomic methoxy group is selected from the hydroxyl (OH) or hydrogen sulfide (SH) groups.

5. A process according to any of claims 3 or 4, characterized in that the molecular weight of the monomer unit of the polymer is less than or equal to 60 g / m or 1.

6. A process according to any one of claims 1 to 5, characterized in that the compound has a molecular mass that is in the order of less than 70,000 and the amount of atheroic hetero groups is about 0.9 the ratio between the molecular mass of the compound and the molecular weight of its monomer unit.

7. A process according to any one of claims 1 to 5, characterized in that the compound has a molecular mass of approximately 150,000 g / mol, the amount of hetero groups is equal to the ratio between the mass molecular weight of the compound and the molecular weight of its monomep unit.

8. A process according to any one of claims 1 to 5, characterized in that the compound has a molecular mass of about 200,000 g / mol and the amount of heterogeneous groups is equal to 0.9 the ratio between the mass molecular weight of the compound and the molecular weight of its molecular unit.

9. A process according to any of the preceding claims, characterized in that the compound capable of forming hydrogen bonds is a polymer.

10. A process in accordance with the rei indication 9, characterized in that the polymer is a polyvinyl alcohol.

11. A process according to claim 9, characterized in that the polymer is a polyvinyl thio alcohol.

12. A stabilized levorotatory ascorbic acid (AAL) composition in a medium containing water, characterized in that it comprises at least one compound that is linked to the AAL by hydrogen bonds.

13. A composition according to claim 12, characterized in that the AAL is predominantly dissolved in the medium containing water.

14. A composition according to claim 12 or 13, characterized in that the compound linked by hydrogen bonding to the AAL comprises a plurality of equal monomer units, of molecular weight less than 100 g / mol and with a heterocyclic group in one amount greater than about 70% of the ratio between the molecular mass of the compound and the molecular weight of its monomeric unit.

15. A composition in accordance with the rei indication 14, characterized in that the toxic group is selected from the hydroxyl (OH) and hydrogen sulfide (SH) groups.

16. A composition according to any of claims 14 or 15, characterized in that the molecular weight of the monomer unit of the compound is less than or equal to 60 g / mol.

17. A composition according to any of claims 14 to 16, characterized in that the compound has a molecular mass that is in the order of less than 70,000, and the number of atomic hetero groups is approximately 0.9 of the mass ratio. molecular weight of the compound and the molecular weight of its monomer unit.

18. A composition according to any of claims 14 to 16, characterized in that the compound has a molecular mass of approximately 150,000 g / mol, and the number of heteroatomical groups is equal to the ratio between the molecular mass of the compound and the molecular weight of its monomer unit.

19. A composition according to any one of claims 14 to 16, characterized in that the compound has a molecular mass of about 200,000 g / mol, and the amount of toxic theotropic groups is equal to 0.9 the ratio between the mass molecular weight of the compound and the molecular weight of its monomer unit.

20. A composition according to any of the rei indications from 12 to 19, characterized in that it comprises from about 5 to about 20% m / v of AAL and from about 1 to 5% m / v of the compound bound to the AAL by bridges of hydrogen, based on the total composition.

21. A composition according to claim 20, characterized in that it comprises about 10% m / v of AAL and about 1% m / v of the compound bound to the AAL by hydrogen bonds, based on the total composition.

22. A composition according to any of claims 12 to 21, characterized in that the compound capable of forming hydrogen bonds is a polymer.

23. A composition according to claim 22, characterized in that the polymer is polyvinyl alcohol.

24. A composition according to claim 22, characterized in that the polymer is the polyvinyl thioalcohol.

25. A composition according to any of claims 12 to 14, characterized in that it also comprises a drinkable deoxygenator.

26. A composition according to the indication 25, characterized in that the drinkable deoxygenator is glycol.

27. A composition according to the rei indication 26, characterized in that the glycol is propylene glycol.

28. A composition according to any of claims 25 to 27, characterized in that the deoxygenator is present in a proportion of approximately 25% v / v, based on the total volume of the composition.

29. A composition according to any of claims 12 to 28, characterized in that it is a cohesive composition.

30. A composition according to any of claims 12 to 28, characterized in that it is a pharmaceutical composition.

31. A composition according to any of claims 12 to 28, characterized in that it is a nut ri cional composition.

32. A composition according to claim 29 or 30, characterized in that it is a topical solution.

33. A composition according to claim 32, characterized in that it is a topical solution for the purpose of diminishing the signs of the skin.

34. A composition according to rei indication 12, characterized in that it additionally contains at least one compound capable of stimulating the metabolism of fibroblasts.

35. A composition according to claim 34, characterized in that the compound capable of stimulating the metabolism of fibroblasts is retinol.

36. A composition according to claim 34, characterized in that the compound capable of stimulating the metabolism of fibroblasts is a derivative of ret ino 1.

37. A composition according to claim 36, characterized in that the compound capable of stimulating the metabolism of fibroblasts is retinyl palmitate.

38. A composition according to any of claims 34 to 37, characterized in that it is included in a hydrophilic base.

39. A composition according to any of claims 34 to 37, characterized in that it is included in a lipophilic base.

40. An emulsion characterized in that it includes, in its aqueous phase, at least one compound bound to the levorotatory ascorbic acid (AAL) by hydrogen bonds.

41. A vitamin product characterized in that it comprises an aqueous AAL composition according to any of claims 12 to 39, inserted in an organic bag or shell, and in addition it comprises at least one compound capable of stimulating the metabolism of the fibroblasts.

42. A process for preparing a stable AAL solution, characterized in that it comprises the steps of: (a) heating a quantity of water; (b) adding to this amount of heated water a compound capable of forming hydrogen bonds with the AAL, in an amount ranging from 1 to 5% m / v, the amount of water heated should be at a temperature capable of promoting the dissolution of the hydrogen bridge-forming compound, in addition to simultaneously guaranteeing the substantial elimination of any amount of oxygen present; (c) homogenizing the product obtained in subsection (b); (d) cooling the resulting product to a temperature ranging from 10 ° C to 40 ° C; (e) adding to the mixture obtained in part (d) from 5% to 20% m / v of AAL; and (f) homogenize the solution result ant e.

43. A process according to claim 40, characterized in that it additionally comprises the step of associating a drinkable deoxygenator with the quantity of water before the heating step.

44. A process according to claim 40 or 41, characterized in that, in the heating step, the temperature is less than 100 ° C; and the AAL dissolves predominantly in water.

45. A process according to claim 42, characterized in that the temperature varies from about 30 ° C to below 100 ° C.

46. A process according to claim 43, characterized in that the temperature varies from about 67 ° C to about 97 ° C.

47. A process according to any of claims 40 to 44, characterized in that the compound capable of forming hydrogen bonds is a polymer.

48. A process according to claim 45, characterized in that the polymer is polyvinyl alcohol.

49. A process according to claim 45, characterized in that the polymer is the polyvinyl thioalcohol.

50. A process according to any of the rei indications from 31 to 47, characterized in that the drinkable deoxygenator is a glycol.

51. A process according to claim 48, characterized in that the glycol is the glypylene glycol.

52. A "vitamin product" characterized in that it comprises an aqueous composition of AAL, stable, according to any of claims 12 to 39, inserted in an envelope or organic bag.

53 A vitamin product according to claim 50, characterized in that the organic bag has a predominantly globular shape.

54. A vitamin product according to the indication 50 or 51, characterized in that the bag has a statistical distribution of sizes of less than 800 ml.

55. A vitamin product according to claim 52, characterized in that the bag has a statistical distribution of sizes smaller than 100 micras

56. A vitamin product according to claim 3, characterized in that the bag has a statistical distribution of sizes ranging from 0.2 to 100 microns.

57. A vitamin product according to claim 54, characterized in that the bag has a statistical distribution of sizes ranging from 3 to 6 O mi eras

58. A vitamin product according to any one of claims 50 to 55, characterized in that the pouch comprises molecules selected from the group comprising protein molecules, amino glycosylated glycosid molecules, polysaccharide molecules and mixtures thereof .

59. A vitamin product according to claim 56, characterized in that the protein molecules and the amino acid molecules are of marine origin.

60. A vitamin product according to claim 56, characterized in that the protein molecules and the samino glycoside molecules come from terrestrial mammals.

61 A vitamin product according to claim 56, characterized in that the polysaccharide molecules are of vegetable origin.

62. A vitamin product according to any of claims 56 to 58, characterized in that the protein molecules are collagen molecules.

63. A vitamin product according to any of claims 56 to 58, characterized in that the aminoglycan glucose molecules are chondroitin sulfate molecules.

64. A vitamin product according to claim 59, characterized in that the polysaccharide molecules are "molecules of gal ac tomanano.

65. A method for cosmetic, pharmaceutical or nutritional treatment, by incorporating AAL to an individual in need of such treatment, characterized in that the incorporation is carried out by the administration, to the individual, of a composition as defined in any of claims 12 to 33.

66. A method according to the rei indication 63, characterized in that the composition is administered topically.

67. A method according to claim 64, characterized in that it is a cosmetic treatment for the purpose of removing signs from the skin.

68. A method according to claim 63, characterized in that the composition is administered orally.

69. A method according to claim 66, characterized in that it consists of a treatment for the purpose of raising the level of AAL in the individual.

70. A method according to claim 63, characterized in that the composition is administered intravas cul t

71. A method according to claim 68, characterized in that it consists of a pharmaceutical treatment for the purpose of raising the level of AAL in the bloodstream. SUMMARY OF THE INVENTION The present invention relates to a process for stabilizing Levogorous Ascorbic Acid (AAL) in an aqueous medium, which comprises the step of contacting the AAL with at least one compound capable of forming hydrogen bonds with the AAL. In another aspect the invention relates to an aqueous, stable AAL composition, which comprises, in addition to ascorbic acid, at least one compound that binds to AAL by hydrogen bonding, and to a process for preparing it. The present invention further relates to an emulsion that includes, in its aqueous phase, at least one compound bound to the levorotatory ascorbic acid (AAL) through hydrogen bonds. In addition, according to the present invention there is provided a vitamin product in which is contained an ALL composition, stable, as described above, inside bags or organic casings, which allows the gradual and prolonged release of the AAL towards the organism. The vitamin product may further comprise a compound capable of stimulating the metabolism of fibroblasts. The present invention also relates to a method for cosmetic, therapeutic or nutritional treatment, which comprises the administration of a composition such as that described above.