WO2008015535A2

WO2008015535A2 - Composition with improved antioxidant and antiglycating activity

Info

Publication number: WO2008015535A2
Application number: PCT/IB2007/002186
Authority: WO
Inventors: Pierluigi Guasti
Original assignee: Difass S.A.
Priority date: 2006-08-01
Filing date: 2007-07-27
Publication date: 2008-02-07
Also published as: WO2008015535A3; ITMI20061522A1

Abstract

In a first aspect, the present invention refers to a composition for human use comprising at least an effective amount of α-lipoic acid and at least an effective amount of carnosine per daily dosage amount. In a second aspect, the present invention refers to a composition for human use comprising at least an effective amount of zinc and at least an effective amount of carnosine per daily dosage amount. In other aspects, the present invention also refers to a composition for oral use comprising one of said compositions and to a kit comprising a) a liquid phase which is acceptable from the nutritional standpoint, and b) a powder phase, wherein said liquid phase or said powder phase comprise said compositions. Advantageously, such compositions allow to attain an unexpected increase of the antioxidant and antiglycating activity, without inducing undesired side effects, in particular to prevent and/or to reduce the risk of onset, as well as to reduce the impact and/or to assist the treatment of the chronic complications of diabetes.

Description

Composition with improved antioxidant and antiglycating activity

DESCRIPTION

In a general aspect thereof, the present invention refers to an innovative composition, in particular to a composition for human use having an improved antioxidant and antiglycating activity.

The invention also makes reference to a dietary supplement and to a kit of parts including the aforesaid composition, in particular to a composition for oral use and to a kit useful for the prevention and/reduction of the risk of onset, as well as reduction of the impact and/or adjuvant in the treatment of the chronic complications of diabetes.

Diabetes is a carbohydrate metabolism alteration due to an insulin deficiency or to an abnormal resistance to insulin, a glucose increase in the tissues deriving therefrom. Lipid and protein metabolism alteration is often linked to diabetes .

There are two main types of diabetes: type I, or insulin- dependent diabetes mellitus wherein the insulin production ceases completely, and type II diabetes, wherein the organism does not produce a sufficient amount of insulin or is not capable of using it.

Recent statistics reported in literature art have calculated that the prevalence of both types of diabetes is increasing by 4-5% each year in the world population; in particular, 40-45% of individuals over age 65 are affected by type II diabetes or by IGT (Impaired Glucose Tolerance)

(Wagman, A. S. and Nuss, J. M. (2001) Curr. Pharm. Des., 7 (6) ,417-450) . In Italy, about 3% of the population is affected by type II diabetes or by IGT.

Nowadays it is known that the most dangerous aspect of diabetes is the induction of complications, such as for example the anatomic-functional alterations in numerous organs and apparatuses with micro- and macro-vascular effects, and the nerve structure compromising. These manifestations are mainly due to hyperglycaemia and to metabolic disorders correlated therewith. Hyperglycaemia tends, through various mechanisms, to damage the sheath, called myelin, which covers the nerve and which allows a rapid and complete transmission of nerve stimulus. During the course of the disease, the destruction of the myelin sheath causes the blocking or slowing of the impulses going from the central nervous system towards the different parts of the body, and vice versa. One of the most common chronic complications of diabetes is diabetic neuropathy, which can hit any nerve termination and any nerve. Diabetic neuropathy constitutes a frequent cause of disability.

Recent literature data has underlined the fact that the principal biochemical mechanisms responsible for the origin and spread of diabetes complications are mainly ascribable to the increase of oxidative stress and to non-enzymatic glycosylation of proteins, with the formation of non- degradable advanced glycosylation end-products (AGE) .

Moreover, it is also known that oxygen free radicals, deriving from hyperglycaemia, are mediators of micro- and macro-vascular complications for diabetic. In fact, in the persons plagued with diabetes, the production of oxygen reactive species and the reduction of the antioxidant defence mechanisms has been proved.

Currently, the diabetes treatment and its chronic complications is based on the variable and combined use of diet, anti-diabetic oral agents or insulin or its analogues, based on the type of diabetes or patient needs.

In the scope of the aforesaid treatments and with the aim to reduce such oxidative stress, it is also known to use substances with anti-oxidant activity as useful adjuvants in the diet of the diabetic.

On this subject, it has been reported in literature (Kramer, K. and Packer, L. (2001) In Nutraceuticals in Health and Disease Prevention. New York, Marcel Dekker, Inc.; pp. 129-164; Biewenga, G. P. et al . (1997) Gen. Pharmacol., 29(3), 315-331) that α-lipoic acid is able of carrying out a powerful antioxidant action, being able to trap a large number of reactive oxygen species. Due to the small dimensions and particular molecule structure, the α- lipoic acid exerts antioxidant activity both in aqueous and lipophilic environments, thus both at the intracellular and extracellular level, in hydrophilic and lipophilic matrices. In patients affected by diabetes or insulin resistance, an α-lipoic acid supplement, in addition to antioxidant protection, is able to reduce the glucose level in blood because it increases the insulin action (Jacob, S. et all. (1995) Arzneimittelforschung, 45, 872-874) . Different clinical studies on humans have shown an improvement of the endothelial function in diabetics treated with α-lipoic acid (Haak, E. et al. (2000) Exp. Clin. Endocrinol. Diabet . , 108, 168-174; Heitzer, T. et al. (2001) Free Radic. Biol. Med., 31(1), 53-61; Morcos, M. et all. (2001) Diabet. Res. Clin. Pract . , 52(3), 175-183).

Even if the drug therapy based on α-lipoic acid allows the reduction of the oxidative stress, a further increase of the antioxidant action is nevertheless desirable, in order to reduce and mainly to prevent the impact of the chronic complications of diabetes.

On the other hand, the non-enzymatic glycosylation of proteins leads to the formation of AGE and represents a biochemical phenomenon, which is slow in conditions of quick cell metabolism, but relatively fast and gradual in slowed cell metabolism conditions, typical of senescence. The AGE are involved in a considerable way in protein degradation processes, with the alteration of their normal three-dimensional molecular structure. In these cases, irregularities can arise in all tissues; in fact, even if most of the proteins have short lifetimes, some of them, such as those of crystalline and collagen, have a low turnover. Therefore, all structures and tissues containing collagen, such as the basal membrane, are more vulnerable to these alterations.

Moreover, the AGEs make the proteins no longer recognisable by catabolic enzymes, such as for example collagenase, thus starting a residence process in the tissues of such modified proteins, which is the cause of inflammatory processes activation and immunologic reactions. On this subject, it has been reported in literature that carnosine (CAS number 305-84-0 or 7683-28-5), a dipeptide composed of L-histidine and β-alanine, carries out an inhibiting activity of AGE formation (Hipkiss AR, et al. (1998), "Pluripotent protective effects of carnosine, a naturally occurring dipeptide", Ann N Y Acad Sci 20; 854:37-53; Hipkiss AR, Chana H (1998), "Carnosine protects proteins against methylglyoxal-mediated modifications", Biochem Biophys Res Commun. 248 (1) : 28-32) .

Although, as previously mentioned, antioxidant compounds and, separately, antiglycating compounds are known in literature, the problem of the present invention is thus that of devising and providing a composition having an improved antioxidant and antiglycating activity able to reduce the impact of diabetes chronic complications and the increasingly widespread diabetic neuropathy.

According to a first aspect of the invention, this problem is solved by a composition as defined in the attached claim 1.

According to the invention, it has been found that a composition for human use comprising, for each daily dosage amount, at least an effective amount of α-lipoic acid and at least an effective amount of carnosine is surprisingly able to attain an unexpected increase of the antioxidant and antiglycating activity, without inducing any undesired side effect.

The composition of the invention therefore has a particularly advantageous and preferred use in the prevention and/or reduction of the risk of onset, as well as reduction of the impact and/or adjuvant in the treatment of the chronic complications of diabetes.

More in particular, it has been found that the aforesaid association of ingredients shows an unexpected synergistic effect and is capable of attaining the desired antioxidant and antiglycating effect.

In the scope of the present invention and in the subsequent claims, with the term "composition for human use" is intended any composition intended for use on man comprising, for example, all the foods which are edible by man, such as for example enriched foods, dietary supplements or dietetic foods; all drugs in all drug forms intended for administration to humans, such as for examples specialties with oral, rectal, buccal, or parenteral use; all cosmetics and medical devices applied on man.

In the scope of the present description and in the following claims, with the term α-lipoic acid is intended to indicate properly called α-lipoic acid (IUPAC name: 5- (1, 2-thiolan-3-yl) pentanoic acid; CAS number 62-46-4, 1077- 28-7 or 1200-22-2), and its reduced form, known also with the name of dihydrolipoic acid (IUPAC name, 6,8-bis- sulphanyloctanoic acid; CAS number 462-20-4), wherein the sulphur atoms are present as free thiols (-SH) , and both enantiomer forms of the α-lipoic acid and dihydrolipoic acid (form R and form L) , as well as the racemic form and their mixtures in any proportion, and any derivative thereof. By derivative of α-lipoic acid it is intended any substance or mixture of substances capable of liberating α- lipoic acid, such as for example salts, esters, amides, adopted with amino acids or peptides of α-lipoic acid, as well as all the mixtures thereof. As merely exemplifying and non-limiting, such substances may be: α-lipoic acid salts with alkaline metals (such as sodium lipoate and potassium lipoate) , with alkaline earth metals (such as magnesium lipoate) , with transition metals (such as zinc lipoate) , salts with amines (such as the compound of lipoic acid with 2-amino-2-hydroxymethylpropan-l, 3-diol in 1:1 ratio) , esters with aliphatic carboxylic acids (such as methyl-lipoate and ethyl-lipoate) , amides with amines (such as lipoamide) .

In the scope of the present description and in the subsequent claims, with the term carnosine is intended to indicate the compound N-β-alanyl-histidine (IUPAC name: 2- (3-aminopropanoylamine) -3- (3H-imidazol-4-yl) propanoic acid; CAS number 305-84-0 or 7683-28-5), both enantiomer forms D- Carnosine (N-β-alanyl-D-histidine) and L-Carnosine (N-β- alanyl-L-histidine) , as well as the racemic form and their mixtures in any proportion, and any derivative thereof. By derivative of carnosine it is intended any substance or mixture of substances capable of liberating carnosine, such as for example a carnosine salt, for example with zinc, copper or manganese, or derivatives, such as anserine (methylated form of carnosine) , homocarnosine, N-α- acetylcarnosine, carcinine and numerous other variants of imidazole dipeptides, as described, for example in "Carnosine And Other Elixirs of Youth-The Miraculous Anti- Ageing Supplement, Kyriazis, 2003, Watkins Publishing, London.", or a salt of derivative compounds.

Carnosine is preferably used in the non-complexed form.

In the scope of the present invention and in the subsequent claims, with the term daily dosage amount of an active ingredient is intended the total amount of the single active ingredient taken in one day (one or more times per day), by means of the various dosage forms. The daily dosage amounts and the related proportions are based on the active ingredient content, such that an appropriate conversion is required when the ingredient is in salt or derivative form.

For the objects of the invention, the composition preferably comprises, for each daily dosage amount, α- lipoic in an amount from about 100 to about 2,000 mg, and carnosine, in an amount from about 50 to about 2,000 mg.

More preferably, the composition comprises, for each daily dosage amount, α-lipoic acid, in an amount from about 250 to about 1,300 mg, and carnosine, in an amount from about 150 to about 1,300 mg.

Still more preferably, the composition comprises, for each daily dosage amount, α-lipoic acid, in an amount from about 350 to about 900 mg, and carnosine, in an amount from about 250 to about 700 mg.

In such a manner, it was possible to utilize the necessary amounts of active ingredients from the standpoint of an increase of the antioxidant and antiglycating activities, obtaining the aforesaid unexpected and advantageous synergistic effect.

In the scope of the present invention, it was moreover found that it is possible to attain an antioxidant and antiglycating effect with particular effectiveness when the various ingredients of the composition are present in specific weight ratios with respect to each other.

Preferably, the composition comprises, for each daily dosage amount, α-lipoic acid and carnosine, in a 0.4:1 to 5:1 ratio in parts by weight, preferably in a 1:1 to 2:1 ratio in parts by weight.

In a preferred embodiment, the composition further comprises, for each daily dosage amount, an effective amount of zinc-based compounds.

As merely exemplifying and non-limiting, such zinc-based compounds may be chosen among those commonly used in the sector, such as for example those authorised by the Italian Health Ministry for the formulation of foods and attached to Ministerial Decree 17/02/2005 No. 46 or to the Legislative Decree 21/05/2004 No. 169. Zinc-based compounds useful for the present invention are, for example, zinc acetate, zinc chloride, zinc citrate, zinc gluconate, zinc pidolate, zinc lactate, zinc oxide, zinc carbonate, zinc sulphate, zinc aspartate, zinc ascorbate, zinc phosphate, zinc stearate, zinc-methionine, and the like. Among these, the zinc gluconate and the zinc pidolate have a particularly preferred and advantageous use.

In such preferred embodiment, the composition comprises, for each daily dosage amount, α-lipoic acid, in a amount from about 100 to about 2,000 mg, carnosine, in an amount from about 50 to about 2,000 mg, and a zinc-based compound wherein the amount of elementary zinc is from about 1 to about 100 mg; more preferably, α-lipoic acid, in an amount from about 250 to about 1,300 mg, carnosine, in an amount from about 150 to about 1,300 mg, and a zinc-based compound wherein the amount of elementary zinc is from about 5 to about 75 mg; still more preferably, α-lipoic acid, in an amount from about 350 to about 900 mg, carnosine, in an amount from about 250 to about 700 mg, and a zinc-based compound wherein the amount of elementary zinc is from about 10 to about 45 mg.

In such a manner, it was possible to utilize the necessary amounts of active ingredients from the standpoint of a further increase of the antioxidant and antiglycating activities .

In the scope of the present invention, it has been moreover found that it is possible to attain an antioxidant and antiglycating effect with further particular effectiveness when the various ingredients of the composition are present in specific weight ratios with respect to each other.

In such a preferred embodiment, the composition of the invention comprises, for each daily dosage amount, carnosine and a zinc-based compound wherein the carnosine to elementary zinc ratio is from 5:1 to 50:1 in parts per weight; more preferably, from 15:1 to 30:1.

The composition of the invention may be formulated in solid or liquid form as a function of the nature of the various ingredients used, employing preparation techniques and modes which are known to the man skilled in the art.

The composition of the invention may therefore be advantageously formulated in powder form, micro-granular form, granular form, as micro-spheres, micro-capsules, both ready-release and modified-release (where the technology for the modified release refers to the release of the active principle from the matrix with a slower kinetics than the ready-release formulations, due to the chemical- physical properties of the excipients composing it so as to be able to influence the absorption kinetics of the molecule of interest in a controlled and rational manner) .

Preferably, the composition of the invention in powder, micro-granular, granular, micro-capsule form is packaged for oral use in rigid capsules, soft capsules, tablets or pills, bags, aqueous solutions, oily solutions, oral drops or suspensions, appropriately choosing the various ingredients in the suitable physical form according to the knowledge of the man skilled in the art.

Preferably, the composition of the invention is in the form of tablets, hard gelatine capsules, soft gelatine capsules wherein the active ingredients are dispersed in an oily vehicle, or in bags.

Preferably, the composition of the invention furthermore comprises, for each dosage unit, at least one excipient, in particular an excipient chosen among those commonly employed in the sector of the formulation of the invention compounds .

As merely exemplifying and non-limiting, such excipients may be chosen among those commonly used in the sector, such as for example those authorised by the Italian Health Ministry for the formulation of foods and attached to Ministerial Decree 27/02/96 No. 209 and subsequents.

Advantageously, according to the form type of the composition of the invention, such excipients allow good workability and powder flowing, good tablet hardness, good dispersability of the ingredients in the liquids, or good organoleptic characteristics of the finished product, such as taste, odour, and colour.

In particular, among them, micro-crystalline cellulose or dibasic calcium phosphate, as bulking agent, magnesium stearate, as lubricant for powder flowing, and colloidal silica or talc to improve the workability of the powder at the time of compression, have a preferred and advantageous use for making tablets of the composition of the present invention.

According to a second aspect of the invention, the problem of having a composition with an improved antioxidant and antiglycating activity capable of preventing and/or reducing the risk of onset, as well as reducing the impact and/or assisting the treatment of the chronic complications of diabetes is solved by a composition as defined by the attached claim 14. In fact, according to the invention, it has been found that a composition for human use comprising, for each daily dosage amount, at least an effective amount of zinc-based compounds and at least an effective amount of carnosine is surprisingly able to attain an unexpected increase of the antioxidant and antiglycating activity, without inducing any undesired collateral effect.

Zinc-based compounds useful for said second aspect of the invention are, for example, those above indicated with reference to the first aspect of the invention.

For the objects of the invention, the composition preferably comprises, for each daily dosage amount, a zinc- based compound whose elementary zinc amount is from about 1 to about 100 mg, and carnosine in an amount from about 50 to about 2,000 mg.

More preferably, the composition comprises, for each daily measure amount, a zinc-based compound whose elementary zinc amount is from about 5 to about 75 mg, and carnosine, in an amount from about 150 to about 1,300 mg.

Still more preferably, the composition comprises, for each daily dosage amount, a zinc-based compound whose elementary zinc amount is from about 10 to about 45 mg, and carnosine in an amount from about 250 to about 700 mg.

In such a way, it is possible to utilize the necessary amounts of active ingredients from the standpoint of an increase of the antioxidant and antiglycating activities, attaining the aforesaid unexpected and advantageous synergistic effect.

According to a third aspect of the invention, a dietary supplement is also provided comprising the above described composition.

According to a fourth aspect of the invention, a composition formulated for oral use is also provided, comprising the above-described compositions for an effective use in the prevention and/or reduction of the risk of onset, as well as reduction of the impact and/or adjuvant in the treatment of the chronic complications of diabetes .

According to another further aspect of the invention, a multipart kit is also provided comprising:

a liquid phase acceptable from the nutritional standpoint, and

a powder phase,

characterised in that said liquid phase or said powder phase comprises an above-described composition for human use .

Preferably, said composition is included in said powder phase .

Preferably, the parts kit of the invention has an advantageous and effective use in the prevention and/or reduction of the risk of onset, as well as reduction of the impact and/or adjuvant in the treatment of the chronic complications of diabetes.

In preferred embodiment, the kit of the invention comprises a bag including a metered amount of microcapsules including a predetermined amount of the aforesaid hydro-dispersible composition for human use, intended to be added to a suitable amount of water or other drink, before being consumed.

In another preferred embodiment, the kit of the invention comprises a small bottle including a metered amount of a liquid phase acceptable from the nutritional standpoint and a dosage cap, at least one of said small bottle or said cap including a predetermined amount of the aforesaid composition.

Further characteristics and advantages will be clearer from the following description of several non-limiting examples of compositions according to the invention.

EXAMPLE 1

Starting from commercially available powder ingredients and with per se known modes, compositions 1-6 for human use were prepared containing the ingredients indicated in the following Table 1 (expressed in mg) .

Every single component of Compositions 1-6 (active principles and excipients) was weighed on a suitable balance; when necessary, the powder was sieved. The weighed powder was introduced in the mixer where it remained for the time necessary to obtain a perfect homogenisation. Then, it was discharged in a suitable food-use container. The powder was inserted into the hopper of the compressor to be subjected to compression and transformed into a tablet. Once all of the parameters of the compressor have been adjusted, so to have a tablet with the required hardness and weight, the manufacturing process started to obtain 600 mg tablets, which were then stored in suitable food-use containers until packaging.

Table 1

EXAMPLE 2

The bags containing the ingredients indicated in the following Table 2 (expressed in mg) were prepared in an analogous way to that above described with reference to the preparation of tablets. The products remained stored in suitable food-use containers until bag-packaging time, when such containers were opened and the metering hoppers of the packeting machine were loaded, setting the operating parameters so to obtain bags of weight as indicated in

Table 2.

From in vitro tests, wherein the compositions of Tables 1 and 2 were used in appropriately adequate dosages (maintaining unaltered, however, the weight ratios of the elements of the composition thereof) and corresponding to the daily dose of 4 tablets as those described in Table 1 (or to the daily dose of 2 bags as those described in Table 2) to be administered to patients plagued with diabetes, the compositions of the present invention were found to have surprising synergistic antioxidant and antiglycating effects, with a substantial lack of side effects.

Table 2

EXAMPLE 3_

Antioxidant Property Evaluation

In order t _CTlo evaluate their related antioxidant properties, samples 1-6 obtained by dissolving in culture media the ingredients and the mixtures of ingredients, in the amounts reported in the following table 3, were examined. For every sample, two working concentrations were chosen based on bibliographical material related to the evaluation of the effectiveness of the single ingredients on human and murine cells and based on cytotoxicity tests.

Table 3 - Antioxidant properties

% with

Zinc respect to citrate L-Carnosine negative dihydrate control

Sample 1 (comparison) 5 μg/ml 0 140

Sample 2 (comparison) 0.5 μg/ml 0 162

Sample 3 (comparison) 0 10 mg/ml 167

Sample 4 (comparison) 0 1 mg/ml 169

Sample 5 (invention) 5 μg/ml 10 mg/ml 291

Sample (invention) 5 μg/ml 10 mg/ml 297

The adopted cell model consisted of normal human fibroblasts from human skin (HFF: "Human Foreskin

Fibroblasts"; Source: ATCC SRC-1041) cultivated on plates.

The cells were set on 96-well plates with 800 cells/well and left growing for 24 hours, until semiconfluence occurred. Then, fresh culture medium containing the samples to be tested was added. The exposure was prolonged for additional 72 hours.

At the end of treating process, the medium containing the sample was eliminated, the cells were washed in PBS and lysed for the determination of the antioxidant activity.

The evaluation of the total antioxidant property was executed through the colorimetric method. The method provided for the formation of the ferryl myoglobin radical (starting from methemoglobin and oxygenated water) which oxidises the ABTS compound (2, 2' -azino-bis/3- ethylbenzothiazoline-β-sulphonic acid) to form a green, soluble cation which absorbs at 405 nm. The presence of direct antioxidant agents reduces the formation of this cation in a dose-dependent manner and reduces the intensity of the colour in an inversely proportional manner. As negative reference control, untreated cells were used. In Table 3, the percentages with respect to the negative control are reported, wherein a certain antioxidant effect of the comparison samples 1-4 containing only one ingredient (L-carnosine or a zinc-based compound) with respect to the negative control may be noted, and a surprising synergistic effect of samples 5-6 of the invention containing mixtures of the two above-mentioned ingredients.

Of course, the compositions reported in the above examples must be intended as a merely non-limiting example of several possible formulations of the composition of the invention, it being intended that the dosage and the specific characteristics of the various ingredients may be varied by the man skilled in the art in order to satisfy specific and contingent needs still remaining within the scope of what is described and claimed.

Claims

- -CLAIMS

1. Composition for human use comprising at least one effective amount of α-lipoic acid and at least one effective amount of carnosine for each daily dosage amount.

2. Composition according to claim 1 comprising for each daily dosage amount:

from about 100 to about 2,000 mg of α-lipoic acid, and

from about 50 to about 2,000 mg of carnosine.

3. Composition according to claim 1 comprising for each daily dosage amount:

from about 250 to about 1,300 mg of α-lipoic acid, and

from about 150 to about 1,300 mg of carnosine.

4. Composition according to claim 1 comprising for each daily dosage amount:

- from about 350 to about 900 mg of α-lipoic acid, and

from about 250 to about 700 mg of carnosine.

5. Composition according to claim 1 comprising, for each daily dosage amount, α-lipoic acid and carnosine in a ratio ranging from 0.4:1 to 5:1 in parts by weight.

6. Composition according to claim 1 comprising, for each daily dosage amount, α-lipoic acid and carnosine in a ratio ranging from 1:1 to 2:1 in parts by weight.

7. Composition according to any one of the preceding claims further comprising, for each daily dosage amount, an effective amount of zinc-based compounds.

8. Composition according to claim 7 comprising, for each daily dosage amount, an effective amount of zinc gluconate, zinc pidolate or zinc citrate.

9. Composition according to claim 7 wherein the amount of elementary zinc is from about 1 to about 100 mg for each daily dosage amount.

10. Composition according to claim 7 wherein the amount of elementary zinc is from about 5 to about 75 mg for each daily dosage amount.

11. Composition according to claim 7 wherein the amount of elementary zinc is from about 10 to about 45 mg for each daily dosage amount.

12. Composition according to claim 7 comprising, for each daily dosage amount, carnosine and a zinc-based compound wherein the carnosine to elementary zinc ratio is from 5:1 to 50:1 in parts by weight.

13. Composition according to claim 7 comprising, for each daily dosage amount, carnosine and a zinc-based compound wherein the carnosine to elementary zinc ratio is from 15:1 to 30:1 in parts by weight.

14. Composition for human use comprising at least an effective amount of zinc and at least an effective amount of carnosine for each daily dosage amount.

15. Composition according to claim 14 wherein the amount of elementary zinc is from about 1 to about 100 mg and the amount of carnosine is from about 50 to about 2,000 mg for each daily dosage amount.

16. Composition according to claim 14 wherein the amount of elementary zinc is from about 5 to about 75 mg and the amount of carnosine is from about 150 to about 1,300 mg for each daily dosage amount.

17. Composition according to claim 14 wherein the amount of elementary zinc is from about 10 to about 45 mg and the - -

amount of carnosine is from about 250 to about 7300 mg for each daily dosage amount.

18. Composition according to any one of the preceding claims, further comprising, for each dosage unit, at least one excipient which is acceptable from the nutritional standpoint .

19. Composition according to any one of the preceding claims, in solid or liquid form.

20. Composition according to claim 19, in powder, micro- granular, granular and micro-capsule form.

21. Composition according to claim 20 packaged in a rigid capsule, soft capsule, tablet or pill, bag, solution, aqueous suspension, oily solution, or oral drops.

22. Composition according to any one of the preceding claims, for use in the prevention and/or reduction of the risk of onset, as well as reduction of the impact and/or adjuvant in the treatment of the chronic complications of diabetes .

23. Composition according to any one of the claims 1-22 formulated for oral use.

24. Kit comprising:

a) a liquid phase which is acceptable from the nutritional standpoint, and

b) a powder phase,

characterised in that said liquid phase or said powder phase comprises a composition for human use according to any one of the claims 1-23.

25. Kit according to claim 24, comprising a small bottle including a metered amount of a liquid phase which is - -

acceptable from the nutritional standpoint and a dosage cap, at least one of said small bottle or said cap including a predetermined amount of said composition.

26. Kit according to claim 24, for use in the prevention and/or reduction of the risk of onset, as well as reduction of the impact and/or adjuvant in the treatment of the chronic complications of diabetes.

27. Use of a composition according to any one of claims 1- 22 for the prevention and/or reduction of the risk of onset, as well as reduction of the impact and/or adjuvant in the treatment of the chronic complications of diabetes.