WO2000000183A2

WO2000000183A2 - Antioxidant, cytostatic and sustained energy composition which ameliorates the metabolic utilization of glucose comprising acetyl-l-carnitine and a catechin

Info

Publication number: WO2000000183A2
Application number: PCT/IT1999/000176
Authority: WO
Inventors: Claudio Cavazza
Original assignee: Sigma-Tau Healthscience S.P.A.
Priority date: 1998-06-30
Filing date: 1999-06-17
Publication date: 2000-01-06
Also published as: TNSN99138A1; WO2000000183A3; ITRM980433A0; ITRM980433A1; AR019737A4; IT1299197B1; AU4391199A

Abstract

A composition for the prevention and/or therapeutic treatment of various alterations and pathological states induced by free radicals, that may take the form of a dietary supplement, dietetic support or of an actual medicine, is disclosed which comprises as characterizing active ingredients acetyl L-carnitine and at least one of the catechins (e.g. epigallocatechin gallate) that can be extracted from the green tea.

Description

Antioxidant, cytostatic and sustained energy composition which ameliorates the metabolic utilization of glucose.

The present invention relates to a composition for:

(a) preventing and/or treating diseases brought about by the presence of free radicals due to environmental pollution; brain or myocardial damages induced by free radicals following cerebral or myo- cardial ischaemia and attendant reperfusion; atherosclerotic damages and tissue proliferative processes; cataract and diabetic neuropathy;

(b) increasing glucose utilization in diabetics or subjects with an insufficient response to insulin acivity; and

(c) promoting muscle adaptation to programs of strenuous exercise.

Accordingly, the composition may take the form and exert the action of a dietary supplement or of an actual medicine, depending upon the support or preventive action, or the strictly therapeutic action, which the composition is intended to exert in relation to the particular individuals it is to be used in.

More particularly, the present invention relates to an orally, parenterally, rectally or transdermally administrable composition which comprises in combination:

(a) acetyl L-carnitine or a pharmacologically acceptable salt thereof, optionally in combination with at least a further "carnitine" where for "carnitine" is intended L-carnitine or an alkanoyl L-carnitine selected from the group comprising propionyl-L-carnitine, valeryl L-carnitine, isovaleryl L-carnitine or their pharmacologically acceptable salts; and

(b) a catechin selected from the group comprising epicatechin, epicatechin gallate, epigallocatechin, epigallocatechin gallate or mixture thereof.

It is well known that L-carnitine and its derivatives have proved useful in the treatment of ischaemic heart disease, angina pectoris, peripheral vascular disease, situations of increased muscular energy requirement and the various forms of atherosclerosis. These therapeutic activities of carnitine and its derivatives are related to the complex biochemical activity which this substance is capable of exerting at cell and tissue level.

In addition to being essential for the β-oxidation of fatty acids and activating ATP synthesis, carnitine plays an important role as an antioxidant, as demonstrated by its protective effect against hyperoxidation of the cell phospholipid membranes and against the oxidative stress induced at myocardial and endothelial cell level. In particular, carnitine has also proved capable of intervening in carbohydrate metabolism and insulin secretion. In performing these various activities, all the various carnitines studied prove effective, though with a different intensity of action, with the result that, in many cases, it would appear to be more useful to administer the various carnitines in combination rather than any single carnitine alone. This is probably due to their different kinetics and different types of intervention in the stages of mitochondrial functional activation, which results in an amplification of the metabolic effect desired. The carnitines indicated as being interactive with one another are mostly L-carnitine, acetyl L-carntitine, propionyl L-carnitine and isovaleryl L-carnitine.

It has also been demonstrated that the polyphenols, too, and, in particular, the catechins present in green tea perform an important regulatory function on carbohydrate metabolism and insulin activity, as well as on tissue proliferative reactions and oxidising activity.

Though the beneficial effects of tea on human health have long been known, it has only recently proved possible to isolate the most important soluble tea components so as to be able to study their pharmacological properties.

Using chromatographic fractionation methods, it has proved possible to isolate at least five different catechins from green tea as active components, namely: (-)gallo-catechin (GC), (-)epigallocatechin (EGC), (-)epicatechin (EC), (-)epigallocatechin gallate (EGCg) and (-)epi- catechin gallate (ECg).

In the case of black tea, whether of tropical origin or obtained by various extraction processes, the catechins are oxidised and preferably form theaflavins and thearubigins, which are also endowed, albeit to a lesser extent, with pharmacological activity. Epidemiological studies in populations submitted to the same degree of oxidative stress, such as that due to environmental pollutants or to cigarette smoking, in equally industrially developed countries of the Far East, have demonstrated a lower incidence of cardiovascular accidents in populations such as the Japanese and Chinese, where, unlike others, there is extensive consumption of tea as a beverage, so much so, indeed, as to suggest a "Far East Paradox" along the lines of the "French Paradox".

The antioxidant capacity of the total catechins present in green tea or of the crude catechins, as well as of the various catechins considered singly, has been evaluated in numerous experimental and clinical tests. An intense antioxidant capacity has been demonstrated for all the various different catechins, for example on linoleic acid and on saturated fatty acids such as lard; this capacity is very marked even as compared with other antioxidants such as, for instance, α-tocopherol.

Significant results have also been obtained in experiments conducted on the low-density lipoprotein (LDL) oxidation induced by copper salts, which was inhibited both by total crude catechins and by epigallocatechin gallate.

The ability of tea catechins to inhibit LDL oxidation mediated by the presence of macrophages has also been demonstrated in an in-υiυo study. In addition to the level of lipid antioxidant capacity, one of the biological effects of the tea catechins most extensively studied is the regulation of carbohydrate metabolism.

The administration of tea catechins is, in fact, capable of reducing the serum glucose and insulin levels induced by the administration of starch or sucrose in the rat. In animals with streptozotocin-induced diabetes, it has also been shown that the administration of tea catechins reduces serum glucose and may exert a preventive and curative effect on the occurrence of diabetes.

In addition to their antioxidant activities, then, it has also been demonstrated that tea catechins are capable of intervening in carbohydrate metabolism and insulin secretion, as well as in regulating tissue proliferative processes.

The risk of pancreatic tumours and oncogene expression can be reduced by administration of tea.

Research studies conducted by subcutaneously injecting a carcinogen such as methylcholantrene in the mouse have demonstrated that tea catechins can delay the onset of subcutaneous solid tumours in these animals as well as the onset of spontaneous mammary tumours in female mice (C3H/HeN stock).

These beneficial effects of the catechins present in green tea may be due to stimulation of glutathione peroxidase and catalase, and to inhibition of ornithine decarboxylase and urokinase.

Among the various catechins studied, epigallocatechin gallate is the one which has proved mos active in inhibiting tumour necrosis factor (TNF) and ornithine decarboxylase mRNA gene expression.

Surprisingly, it has been found that a composition comprising, as its characterising components, a combination of: (a) acetyl L-carnitine or a pharmacologically acceptable salt thereof; and

(b) a catechin selected from the group consisting of (-)epicatechin, (-)epicatechin gallate, (-)epigallocatechin and (-)epigallocatechin gallate, or mixtures thereof, is extremely effective in the prevention and therapeutic treatment of damage induced by the presence of free radicals due to environmental pollution, cerebral or myocardial lesions induced by free radical after cerebral or myocardial ischaemia and as a result of rerperfusion; in the prevention and treatment of atherosclerotic lesions and tissue proliferative processes and cataract; to increase the glucose utilisation capacity in diabetic subjects or in subjects with an inadequate insulin activity response; in the prevention and treatment of diabetic neuropathies and in situations of increased muscular energy requirement, owing to the potent synergistic effect of its components.

It has also been found that, advantageously, component (a) can further comprise a "carnitine" selected from the group consisting of L- carnitine, propionyl L-carnitine, valeryl L-carnitine, isovaleryl L- carnitine or their pharmacologically acceptable salts, or mixtures thereof, and that component (b) may consist of a green tea extract (Camellia sinensis, Camellia thea Link, Theaceae family).

The (a):(b) weight-to-weight ratio ranges from 1:0.1 to 1:1.

Toxicology

The low toxicity and good tolerability of both tea catechins and carnitines are well known. These favourable toxicological characteristics of catechins and carnitines have been confirmed by combining these components and administering them at high doses to both rats and mice. In these animals, it proved possible, in fact, to administer parenterally more than 75 mg kg of catechin complex and 200 mg/kg of carnitines (50 mg L-carnitine + 50 mg/kg acetyl L-carnitine + 50 mg propionyl L-carnitine + 50 mg isovaleryl L-carnitine) or 250 mg/kg of acetyl L-carnitine, and more than 500 mg/kg catechin complex and 400 mg/kg of carnitines (combined in identical weight amount to one another), or 400 mg/kg of acetyl L-carnitine orally, without any of the animals thus treated dying. Prolonged administration with the diet for thirty days consecutively, in both a group of rats and a group of mice, of a combination of 200 mg/kg of catechin complex or 50 mg/kg of epigallocatechin plus 200 mg/kg of carnitine mixture or 250 mg/kg of acetyl L-carnitine was also well tolerated and led to the detection of no signs of toxicity. Both the weight increase and the various blood chemistry examinations performed in these animals showed normal values, as did the histopathological examinations performed on the main organs after sacrificing the animals at the end of treatment.

Tests of neuroprotective activity in experimental cerebral ischaemia

In view of the fact that the lesions caused by cerebral ischaemia are related to the production of free radicals and nitrous oxide (Lipton, S.A., Nature 364, 625, 1993) and in view of the favourable protective effect of both carnitines and green-tea catechins against the damage caused by free radicals, it was decided to evaluate their activity on experimental cerebral ischaemia. To this end, cerebral ischaemia was induced by occluding the middle cerebral artery (MCA) according to the method described by Scharkey (Scharkey, Y., Nature. 371-336, 1994) by 3-minute injections of endothelin-1 (120 pmol in 3 nl) in anaesthetised rats via a microcannula positioned stereotactically in the piriform cortex at the level of the middle cerebral artery. Occlusion of the artery is induced, and the resulting ischaemic area can be checked three days after this procedure by transcardiac perfusion of a solution of parafomaldehyde (4% in PBS).

After removing the brain, the latter was placed for 24 hours in a fixative containing 10% sucrose, and the cryostatic sections (20 nm) were fixed with cresyl violet and examined under the optical microscope. Carnitine mixture (50 mg/kg of a combination consisting of L-carnitine + acetyl L-carnitine + propionyl L-carnitine + isovaleryl L- carnitine in identical weight amount to one another, acetyl L-carnitine (50 mg/kg), green-tea catechin complex (50 mg/kg), epigallocatechin gallate (50 mg/kg), or various combinations of these products, were administered intravenously 5 minutes after injection of endothelin.

The volume of the infarcted area was calculated according to the method described by Park (Park, C.K., Anns. NeuroL. 20, 150, 1989). The results of these tests (Table 1) demonstrate that the carnitine mixture, acetyl L-carnitine, the catechin complex and epigallocatechin gallate are equally capable of reducing the ischaemic area, but a surprisingly greater and more significant result is achieved only with the combination of the carnitine mixture plus the catechin complex or with epigallocatechin gallate plus acetyl L-carnitine.

An unforeseeable synergistic action produced by the combination of these products was thus demonstrated.

Table 1

Magnitude of ischaemia (volume in mm³) induced by occlusion of the MCA (percentage reduction in volume compared to controls).

Volume (mm³)

Carnitine mixture 25.6 ± 1.9

Acetyl L-carnitine 27.2 ± 2.2

Catechin complex 33.5 ± 2.5

Epigallocatechin gallate 30.7 ± 3.3

Carnitine mixture + catechin complex 86.7 ± 4.7

Carnitine mixture + epigallocatechin gallate 80.2 ± 5.1

Acetyl L-carnitine + catechin complex 80.5 ± 4.9

Acetyl L-carnitine + epigallocatechin gallate 89.7 ± 5.3

Test of reduction of lens opacification in galactosaemic rats induced by the administration of carnitine mixture, acetyl L-carnitine. catechin complex, epigallocatechin gallate. or combinations of these products

The administration of galactose with the diet causes the onset of ocular cataracts in rats. The opacification of the lens which occurs after approximately eight days of treatment is classified in increasing order of severity as stages I, II or III, according to the method described by Sippel (Sippel T.O., Invest. Ophthalmol.. 5, 568, 1966). Treatment for eight days, together with the galactose -containing diet, with carnitine mixture (300 mg/kg of a combination of L-carnitine + acetyl L-carnitine + propionyl L-carnitine + isovaleryl L-carnitine in an identical weight amount to one another), acetyl L-carnitine (300 mg/kg), catechin complex (100 mg/kg), or epigallocatechin gallate (50 mg/kg), or with various combinations of these products, induces a reduction in the severity of lens opacification. The combination of carnitine mixture plus catechin complex, or, better still, the combination of acetyl L- carnitine plus epigallocatechin gallate almost completely inhibits the onset of opacification (Table 2). These tests, then, also demonstrate an intense, unexpected synergistic effect produced by the combination of the various components.

Table 2

Tests of inhibition of lens opacification in galactosaemic rats treated with carnitine mixture, acetyl L-carnitine, catechin complex or epigallocatechin gallate or with various combinations of these products (groups of 10 rats).

Treatment Degree of lens opacification (mg/kg) (number of lenses examined)

I II III

Controls 0 10 10

Carnitine mixture 5 16 4

Acetyl L-carnitine 5 15 5

Catechin complex 8 8 4

Epigallocatechin gallate 9 7 4

Carnitine mixture + catechin complex 16 4 0

Carnitine mixture + epigallocatechin gallate 15 5 0

Acetyl L-carnitine + epigallocatechin gallate 16 4 0 Tests of reduction of sorbitol content in the lens and sciatic nerve in rats with streptozotocin-induced diabetes

In view of their ability to intervene in carbohydrate metabolism, it was decided to test whether the administration of the carnitine mixture, or acetyl L-carnitine, or the catechin complex or epigallocatechin gallate, or of various combinations of these substances could improve insulin control of high glucose concentrations and prevent the occurrence of the most frequent diabetic complications such as neuropathies, retinopathies, or cataracts.

High glucose concentrations not controlled by insulin can lead, as is well known, to intracellular accumulation of sorbitol, with a reduction in cell integrity and osmotic capacity. In these tests, groups of rats with streptozotocin-induced diabetes received oral administrations of carnitine mixture (300 mg/kg of a combination of L-carnitine + acetyl L-carnitine + propionyl L-carnitine + isovaleryl L-carnitine in an identical weight amount to one another), or catechin complex (100 mg/kg), or epigallocatechin gallate (50 mg/kg), or various combinations of these products at the same doses. After eight days of treatment and suitable chemical isolation, the sorbitol concentration present in the lens and sciatic nerve of the animals thus treated was measured.

A reduction in sorbitol concentration was observed in the animals treated with carnitine mixture, acetyl L-carnitine, catechin complex, or epigallocatechin gallate, but was distinctly greater in the animals treated with the combinations, thus confirming the potent synergistic effect of their components (Table 3). Table 3

Reduction of sorbitol concentrations in the lens and sciatic nerve induced by the administration of carnitine mixture, acetyl L-carnitine, catechin complex, or epigallocatechin gallate, or various combinations of these, in rats with streptozotocin-induced diabetes.

Treatment Sorbitol (nmol/mg)

Lens Sciatic nerve

Controls 0.55 ± 0.04 0.085 ± 0.01

Diabetic rats 38.25 ± 3.1 1.405 ± 0.11

Carnitine mixture 34.70 ± 2.9 1.260 ± 0.14

Acetyl L-carnitine 32.75 ± 2.6 1.125 ± 0.10

Catechin complex 25.25 ± 3.7 0.830 ± 0.22

Epigallocatechin gallate 27.55 ± 3.3 0.705 ± 0.15

Carnitine mixture + catechin complex 19.40 ± 2.75 0.405 ± 0.10

Carnitine mixture + epigallocatechin gallate 16.80 ± 2.55 0.395 ± 0.00

Acetyl L-carnitine + epigallocatechin gallate 14.75 ± 3.1 0.290 ± 0.01

Antiproliferation tests and evaluation of ornithine decarboxylase

The method used to assess antiproliferative activity consisted in the sub-cutaneous injection in mice of teleocidin, which, like the phorbol- myristates, causes proliferative abnormalites at the level of the animal's skin which can lead to the formation of cancer-type keratotic processes (Fujiki, H., Biochem. Biophys. Res. Comm.. 90, 976, 1979).

The cutaneous abnormalities are accompanied by an increase in the enzyme ornithine decarboxylase and this increase is proportional to the severity of the lesion induced, and can therefore be used as a marker of the tumour proliferation reaction.

Teleocidin was injected subcutaneously in the depilated backs of the mice at a dose of 5 meg/mouse dissolved in 0.2 cc of aqueous solution. Carnitine mixture (300 mg/kg of a combination of L-carnitine + acetyl L-carnitine + propionyl L-carnitine + isovaleryl L-carnitine in an identical weight amount to one another), or acetyl L-carnitine alone (300 mg/kg), or catechin complex extracted from green tea (100 mg/kg), or epigallocatechin gallate (50 mg/kg), or various combinations of these were administered orally to the animals for the seven-day period preceding the test, or were applied to the skin area half an hour before injection of teleocidin after suitable dispersion in lanolin so as to reach a 200 mg/cc concentration of carnitine mixture or acetyl L-carnitine, or a 100 mg/cc concentration of catechin complex, or a 50 mg/cc concentration of epigallocatechin gallate.

0.33 cc of these preparations were applied to the skin area where the teleocidin was injected and the treated area was protected with occlusive bandages.

The ornithine decarboxylase assay was performed on the homogenised epidermis of both the orally and locally treated animals five hours after injection of teleocidin according to the method described by O'Brien and Nakadata (O'Brien, T.G., Cancer Res.. 42, 2841, 1982).

The protein concentration of the epidermal extract was measured according to the method described by Lowry (Lowry, O.H., J. Biol. Chem.. 193, 265, 1951).

The results obtained in these tests (Table 4) demonstrate that the modest protection against cutaneous proliferative phenomena and increased ornithine decarboxylase activity afforded by the carnitine mixture, or by the catechin complex, or by epigallocatachin gallate is surprisingly much greater and more easily detectable when the carnitine mixture is combined with the catechin complex or with epigallocatechin gallate.

The results of these tests, too, then, demonstrate the surprising, unexpected synergistic effect of the various components of the compositions according to the invention. Table 4

Ornithine decarboxylase activity

Treatment Ornithine decarboxylase activity (nMol of CO2/6O min/mg protein)

Controls 0.06 ± 0.007 0.04 ± 0.004

Teleocidin 2.3 ± 0.3 2.7 ± 0.2

Carnitine mixture 1.96 ± 0.4 1.85 ± 0.03

Acetyl L-carnitine 1.85 ± 0.5 1.70 ± 0.04

Catechin complex 1.88 ± 0.2 1.80 ± 0.03

Epigallocatechin gallate 1.75 ± 0.4 1.68 ± 0.05

Carnitine mixture + catechin complex 0.45 ± 0.07 0.65 + 0.08

Carnitine mixture + epigallocatechin gallate 0.40 ± 0.05 0.45 ± 0.06

Acetyl L-carnitine + epigallocatechin gallate 0.37 + 0.06 0.30 ± 0.07

Some illustrative, non-limiting examples of formulations according to the invention are reported hereinbelow.

1) Carnitine mixture mg 500

(L-carnitine mg 125, acetyl L-carnitine mg 125, propionyl L-carnitine mg 125, isovaleryl L-carnitine mg 125)

Catechin complex mg 200

(green tea extract with around 60% of polyphenols concentration - of which 40% is epigallocatechin gallate)

2) Carnitine mixture mg 500

Catechin complex mg 200

(green tea extract with around 90% of polyphenols concentration - of which 50% is epigallocatechin gallate)

3) Carnitine mixture mg 300

(L-carnitine mg 75, acetyl L-carnitine mg 75, propionyl L-carnitine mg 75, 'isovaleryl L-carnitine m 75)

Catechin complex mg 100

(green tea extract with around 60% of polyphenols concentration - of which 40% is epigallocatechin gallate) 4) Carnitine mixture mg 300

(L-carnitine mg 75, acetyl L-carnitine mg 75, propionyl L-carnitine mg 75, isovaleryl L-carnitine mg 75)

Catechin complex mg 100

5) Carnitine mixture mg 500

Epigallocatechin gallate mg 200

6) Carnitine mixture mg 300

Epigallocatechin gallate mg 100

7) Acetyl L-carnitine mg 500

Catechin complex mg 200

8) Acetyl L-carnitine mg 500

Catechin complex mg 200

9) Acetyl L-carnitine mg 300

Catechin complex mg 100

10) Acetyl L-carnitine mg 300

Catechin complex mg 100

11) Acetyl L-carnitine mg 500

Epigallocatechin gallate mg 200 12) Acetyl L-carnitine mg 300

Epigallocatechin gallate mg 100

13) Carnitine mixture mg 300

Catechin complex mg 100

(green tea extract with around 90% of polyphenols concentration - of which 50% is epigallocatechin gallate) β-carotene mg 10

CoQIO mg 10

Vit. E mg 10

Magnesium stereate mg 10

Zinc glycinate mg 10

Selenium methionine mg 0.2

14) Acetyl L-carnitine mg 300

Epigallocatechin gallate mg 100

CoQIO mg 10

Vit. E mg 10 β-carotene mg 10

Vit. C mg 50

Vit. Bl mg 2

Vit. B2 mg 2

Vit. B6 mg 1

Vit. B12 meg 50

Folic acid meg 100

Vit. PP mg 20

Vit. D U.I. 500

Calcium pantothenate mg 15

Magnesium stereate mg 5

Zinc glycinate mg 10

Selenium methionine mg 0.2 What is meant by pharmacologically acceptable salt of L-carnitine or alkanoyl L-carnitine is any salt of these active ingredients with an acid that does not give rise to unwanted toxic or side effects. These acids are well known to pharmacy experts.

Non-limiting examples of suitable salts are the following: chloride; bromide; iodide; aspartate, acid aspartate; citrate, acid citrate; tartrate; phosphate, acid phosphate; fumarate; acid fumarate; glycerophosphate; glucose phosphate; lactate; maleate, acid maleate; orotate; oxalate, acid oxalate; sulphate, acid sulphate, trichloroacetate, trifiuoroacetate and methane sulphonate.

A list of FDA-approved pharmacologically acceptable salts is given in Int. J. of Pharm. 33, (1986), 201-217; this latter publication is incorporated herein by reference.

The compositon according to the invention may also comprise vitamins, coenzymes, minerals substances and antioxidants.

Appropriate excipients to be used to prepare the compositions having regards to the specific route of administration, will be apparent to the pharmacy and food industry experts.

Claims

1. A composition which comprises:

(a) acetyl L-carnitine or a pharmacologically acceptable salt thereof; and

2. The composition of claim 1, wherein the ingredient (a) further comprises a "carnitine" selected from the group comprising L-carnitine, propionyl L-carnitine, valeryl L-carnitine, isovaleryl L-carnitine or their pharmacologically acceptable salts or mixtures thereof.

3. The composition of claim 1 or 2 wherein the weight ratio (a):(b) is from 1:0.01 to 1:1.

4. The composition of any of the preceding claims,wherein the ingredient (b) is in the form of vegetal exctracts which contain the ingredient itself.

5. The composition of claim 4, wherein said vegetal extract is a green tea extract.

6. The composition of any of the preceding claims wherein the pharmacologically acceptable salt of L-carnitine or alkanoyl L-carnitine is selected from the group comprising: chloride; bromide; iodide; aspartate, acid aspartate; citrate, acid citrate; tartrate; phosphate, acid phosphate; fumarate, acid fumarate; glycerophosphate; glucose phosphate; lactate; maleate, acid maleate; orotate; acid oxalate; sulphate, acid sulphate; trichloroacetate; trifluoroacetate and methane sulphonate.

7. The composition of any of the preceding claims, which further comprises vitamins, coenzymes, mineral substances and antioxidants.

8. The composition of any of the preceding claims, orally administrable, in the form of a dietary supplement.

9. The composition of any of the preceding claims, orally, parenterally, rectally or transdermally administrable in the form of a medicament.

10. The dietary supplement of claim 8, for:

(a) preventing diseases brought about by the presence of free radicals due to environmental pollution; brain or myocardial damages induced by free radicals following cerebral or myocardial ischaemia and attendant riperfusion; atherosclerotic damages and tissue proliferative processes; cataract and diabetic neuropathy;

(c) promoting muscle adaptation to programs of strenuous exercise.

11. The medicament of claim 9, for treating diseases brought about by the presence of free radicals due to environmental pollution; brain or myocardial damages induced by free radicals following cerebral or myocardial ischaemia and attendant reperfusion; atherosclerotic damages and tissue proliferative processes; cataract and diabetic neuropathy.

12. The dietary supplement of claim 8 or 10, in solid, semi-solid or liquid form.

13. The medicament of claim 9 or 11, in solid, semi-solid or liquid form.

14. The dietary supplement of claim 12, in the form of pills, tablets, capsules, granulates or syrup.

15. The medicament of claim 13, in the form of pills, tablets, capsules, granulates, syrups, vials, drops and collyria.