The present invention relates to novel alkaline-earth salts of carnitines with an organic polybasic acid useful as dietary/nutritional supplements or drugs, the processes for preparing same and the compositions containing such salts.

More particularly, the present invention relates to stable, non- hygroscopic magnesium and calcium salts of carnitines with mucic acid (also known as galactaric acid, name which will be used hereinbelow).

Therefore, these salts especially lend themselves to the production of solid compositions suitable for oral administration.

According to the present invention, the term"carnitines"means, collectively, both L-carnitine and alkanoyl L-carnitines wherein the alkanoyl group, straight or branched-chain, contains 2-5 carbon atoms.

Such alkanoyl shall be briefly referred to hereinbelow as" (C2-C5) alkanoyl".

With the term"non-hygroscopic"reference is herein made to the ability endowed by certain carnitine salts, when they occur as powders or granules, to withstand a relative humidity of at least 60%, at 25°C, for 24 hours, without giving rise to adverse phenomena of clotting, agglomeration or even deliquescence which result in loss of their flowability.

With the term"hygroscopic"reference is herein made to the property shown by most of carnitine salts (particularly by their"inner salts") to undergo, when they occur as powders or granules, significant alteration of their flowability due to their clotting, agglomeration or even deliquescence, following exposure to an environment of relative humidity lower than 50-60%, at 25°C, for 24 hours.

The problems of storage and processing brought about by the high hygroscopicity of L-carnitine and alkanoyl L-carnitine inner salts have long since been known. This high hygroscopicity renders the manufacture and storage of orally administrable solid presentation forms particularly troublesome.

However, administration forms such as tablets and capsules represent the preferred presentation forms inasmuch as they make it particularly easy for users to take the active ingredient and comply with optimal dosage regimens.

The problem of L-carnitine and alkanoyl L-carnitine inner salts hygroscopicity has been solved by converting these inner salts into salts of pharmacologically acceptable acids, based on the assumption that such salts maintain the same therapeutical/nutritional activities of the inner salts and do not exhibit unwanted toxic or side effects.

Although there is now an extensive body of literature, particularly patents, disclosing the production of allegedly stable, non-hygroscopic L-carnitine salts, actually only L-carnitine acid fumarate (US 4,602,039, Sigma-Tau) L-carnitine L- (+)-tartrate (US 5,703,376, Lonza) and, more recently, acetyl L-carnitine galactarate (US 5,952,379, Sigma-Tau) have been developed on an industrial scale and marketed to date.

It is interesting to note that both fumaric and L- (+)-tartaric acid which form non-hygroscopic salts with L-carnitine, are unsuitable to form stable, non-hygroscopic salts with the alkanoyl L-carnitines. On the other hand, as disclosed in US patent 5,952,379 (Sigma-Tau), galactaric acid is suitable to form stable, non hygroscopic salts with both L-carnitine and (C2-C6) alkanoyl L-carnitines, and is to-date the only known acid endowed with this property.

The important physiological role played by magnesium and calcium and the various pathological disturbances or states induced by serious deficiencies of these elements have also long since been known.

For instance, epidemiological studies have revealed that there is a distinct correlation between the incidence of cardiac ischaemia and the calcium/magnesium ratio in the diet and drinking water. Abnormally low haematic levels of magnesium (hypomagnesemia) manifest themselves with increasingly severe symptoms and signs, from weakness and tiredness to marked neuromuscular and central nervous system hyperirritability, convulsions and severe psychic alterations (delirium, hallucinations). For a detailed review of the physiological and pharmacological activities and therapeutical uses of magnesium and calcium, reference is made to Goodman and Gilman's"The pharmacological basis of therapeutics", Eight Edition, 1990, pages 704- 706 and 1496-1501, respectively. Moreover, disorders of calcium and magnesium concentration are dealt with in Current Medical Diagnosis & Treatment, 38th Edition, (1999) Appleton & Lauge Publishers, pages 848-852, whose disclosures are incorporated herein by reference.

Therefore, magnesium salts of carnitines with organic polybasic acids such as fumaric, L- (+)-tartaric acid and citric acid have been disclosed: L-carnitine magnesium fumarate and (C2-C5) alkanoyl L-carnitine magnesium fumatate in US 6,051,608 (Sigma-Tau); L-carnitine magnesium tartrate and (C2-C5) alkanoyl L-carnitine magnesium tartrate in the international patent application WO 98/45250 (Sigma- Tau); L-carnitine magnesium citrate in US 5,071,874 (Lonza) and (C2- C5) alkanoyl magnesium citrate in the international patent application WO 98/44918 (Sigma-Tau).

The present applicant is unaware of any known calcium salt of carnitines.

The aforesaid patents and patent applications (the disclosures of which are all incorporated herein by reference) report on the valuable properties of the foregoing magnesium salts of carnitines both as dietary/nutritional supplements (e. g., for sportsmen diet) and as pharmacologically active ingredients.

Since both magnesium and carnitine are eliminated in massive amounts with the sweat and urine during prolonged, intense physical activity, it is apparent that magnesium salts of carnitine can be used to advantage as dietary supplement for sportsmen.

Moreover, in the light of the firmly established therapeutical properties of L-carnitine, acetyl L-carnitine and propionyl L-carnitine (such as, e. g., L-carnitine protective action on the cardiovascular system), magnesium and carnitine salts can also be used as drugs.

It is therefore felt the need to have available stable and non- hygroscopic alkaline-earth salts of carnitine with pharmacologically acceptable acids in order to allow the preparation of orally administrable solid compositions to be used as dietary/nutritional supplements in all those situations wherein magnesium and/or calcium supplementation reverses or prevents the onset of the prejudicial effects brought about by their deficiency.

It is furthermore advantageous, from an industrial viewpoint, that the aforesaid solid compositions lend themselves to be prepared with conventional apparatuses, and avoiding to resort to dehumidified facilities. This object can only be achieved if the aforesaid salts are stable and non-hygroscopic.

The aforesaid known magnesium salts do not fulfil such requirements due to their hygroscopicity.

It has now been found that the novel alkaline-earth carnitine salts with galactaric acid having formula (I): wherein: M++ is Mg++ or Ca++ ; R = H or a straight or branched-chain alkanoyl group having 2-5 carbon atoms; n is 1 or 1/2; m is 1 or 2 ; and (a) if m = 1 COOY is COO-if n = 1 ; or COOY is COOH if n = 1/2; or (b) if m=2 the COOYs are both COO-if n = 1 ; or one COOY = COOH, the other is COO-if n = 1/2 are stable and non hygroscopic, thus fully complying with the aforesaid prerequisites.

It is surprising that the salts of formula (I) are non-hygroscopic insofar as it could have been foreseen that, although L-carnitine and (C2-C5) alkanoyl L-carnitine galactarates are non-hygroscopic, the corresponding alkaline-earth salts, particularly the magnesium salts were hygroscopic. Indeed, although L-carnitine acid fumarate and L- (+)-tartrate are non-hygroscopic, the corresponding magnesium salts, i. e. L-carnitine magnesium fumarate and L-carnitine magnesium tartrate are hygroscopic.

It is therefore, surprising that in the formation of magnesium and carnitines salts with polybasic organic salts, galactaric acid's behaviour is different from that of fumaric and L- (+)-tartaric acid.

Preferably, the alkanoyl group of the galactarates of the invention is selected from the group consisting of acetyl, propionyl, butyryl, valeryl and isovaleryl.

With one of the codes"1: 1: 1","1: 1/2: 1,"2: 1: 1" and"2 : 1/2: 1" placed after the name of a particular galactarate, it is concisely represented the carnitine: magnesium (or calcium): galactaric acid molar ratio characterizing that specific galactarate.

Particularly preferred galactarates of formula (I) are the following: L-carnitine and magnesium galactarate 1: 1: 1; - L-carnitine and magnesium galactarate 1: 1/2: 1; - acetyl L-carnitine and magnesium galactarate 1: 1: 1; - acetyl L-carnitine and magnesium galactarate 1: 1/2: 1; - propionyl L-carnitine and magnesium galactarate 1: 1: 1; - propionyl L-carnitine and magnesium galactarate 1: 1/2: 1; - isovaleryl L-carnitine and magnesium galactarate 1 : 1 : 1 ; - isovaleryl L-carnitine and magnesium galactarate 1: 1/2: 1; - L-carnitine and calcium galactarate 1: 1: 1; - L-carnitine and calcium galactarate 1: 1/2: 1; - acetyl L-carnitine and calcium galactarate 1: 1: 1; - acetyl L-carnitine and calcium galactarate 1: 1/2: 1; - propionyl L-carnitine and calcium galactarate 1: 1: 1; - propionyl L-carnitine and calcium galactarate 1: 1/2: 1; - isovaleryl L-carnitine and calcium galactarate 1: 1: 1; - isovaleryl L-carnitine and calcium galactarate 1 : 1/2 : 1; - L-carnitine and magnesium galactarate 2: 1: 1; - L-carnitine and magnesium galactarate 2: 1/2: 1; - L-carnitine and calcium galactarate 2: 1: 1; - L-carnitine and calcium galactarate 2: 1/2: 1; - acetyl L-carnitine and magnesium galactarate 2: 1: 1; - propionyl L-carnitine and magnesium galactarate 2: 1: 1; - isovaleryl L-carnitine and magnesium galactarate 2: 1: 1.

- acetyl L-carnitine and calcium galactarate 2: 1: 1; - propionyl L-carnitine and calcium galactarate 2: 1: 1; and - isovaleryl L-carnitine and calcium galactarate 2: 1: 1.

The galactarates of formula (I) can be prepared via one of the alternative procedures which are illustrated hereinbelow. The average- skilled expert shall be able to easily select the most suitable procedure in the light of the available apparatuses.

According to a first process, suitable molar amounts of galactaric acid, the selected carnitine and Mg or Ca hydroxide, finely powdered, are thoroughly mixed and 15 to 25% of water (20 to 35% for calcium salts) is added to the mixture. The resulting mixture is rapidly heated to about 70-100°C and upon reaching the consistency of a pasty semi- liquid slurry, it is vigorously stirred for a few minutes and then discharged into collection tanks. On cooling the mass takes on the consistency of a dough which, mechanically stirred, under heating and by blowing thereon a current of dry, warm air, rapidly solidifies. The solid product thus obtained is then brought to the wanted water content by means of conventional drying apparatuses and then ground to the wanted particle size.

Alternatively, the aforesaid semi-liquid slurry is poured into a heated ball-mill, wherein a current of dry, warm air is circulated; the solid product which thus forms is brought to the wanted water content and then ground to the selected particle size.

According to a further process, suitable molar amounts of galactaric acid, the selected carnitine and Mg or Ca hydroxide finely powdered are thoroughly mixed and 25 to 40% of water is added to the mixture.

The resulting mixture is then rapidly heated to about 70-100°C and vigorously stirred for a few minutes. A ten-fold amount (in mL) of acetone with respect to the weight of the salt to be prepared is then added. Two phases form, the more viscous and heavier of which comprises the salt which is being prepared. This phase, due to the extracting action of acetone, becomes progressively lower in water, increasing in viscosity and hardening, until, after 5 to 15 minutes, it is completely transformed into a crystalline solid mass.

In order to avoid a hard crust formation on the reactor bottom, the reactor should be equipped with a potent stirrer. If such a stirrer is not available, the previously described procedure should be preferably adopted.

The following non-limiting examples show the preparation and the physico-chemical characteristics of some compounds of the present invention. The elementary analyses relate to the anhydrous compounds. Depending on the relative humidity the compounds are exposed to, they absorb small amounts of water resulting in the formation of stable hydrates.

Example 1 L-carnitine and magnesium galactarate 1: 1: 1 To 21 g (0.1 moles) of galactaric acid, 16.1 g (0.1 moles) of L-carnitine inner salt and 5.83 g (0.1 moles) of magnesium hydroxide, finely powdered and thoroughly mixed, 14 mL of water were added and the resulting mixture was rapidly brought under stirring to a temperature from 70°C to 80°C with an outer heating bath at 100-110°C. As soon as the mixture was sufficiently fluid, it was vigorously stirred for about two minutes and then discharged into collection tanks. The solidification process was aided by moving the reaction mixture, blowing a current of warm, dry air onto the mixture and also by heating the collection tanks.

The yield was quantitative.

IR (KBr), cm-1 3500-2900 (OH) ; 1598 (COO-) ; 1395 (COO-); 1120,1060 (C-O) Analysis for Ci3HzsMgNOll Calc. C 39.67; H 5.89; Mg 6.17; N 3.56 Found C 39.50; H 6.08; Mg 6.14; N 3.45 Example 2 L-carnitine and magnesium galactarate 1: 1 : 1 : To 21 g (0.1 moles) of galactaric acid, 16.1 g (0.1 moles) of L-carnitine inner salt and 5.83 g (0.1 moles) of magnesium hydroxide, finely powdered and thoroughly mixed, 14 mL of water were added and the resulting mixture was rapidly brought under stirring to a temperature from 70°C to 80°C with an outer heating bath at 100-110°C. As soon as the mixture was sufficiently fluid, it was vigorously stirred for about two minutes and then 450 mL of acetone were added thereto. Two phases thus formed: the heavier and more viscous one was kept dispersed into the other by means of a vigorous stirring.

In about ten minutes the whole mass turned, via a progressive increase in viscosity and consistency, into a crystalline solid which was filtered and dried under vacuum.

The characteristics of the resulting product were the same as those of the compound of Example 1.

Example 3 L-carnitine and calcium galactarate 1: 1: 1 The title compound was prepared as described in Example 1, substituting 0.1 moles of calcium hydroxide for 0.1 moles of magnesium hydroxide, and using in the starting reaction mixture about 30% of water.

The yield was quantitative.

IR (KBr), cm-1 3500-2900 (OH); 1598 (COO-) ; 1385 (COO-); 1100,1065 (C-O) Analysis for Cl3H23CaNOll Calc. C 38.14; H 5.66; Ca 9.79; N 3.42 Found C 37.90; H 5.76; Ca 9.65; N 3.34 Example 4 L-carnitine and magnesium galactarate 1: 1/2: 1 The title compound was prepared as described in Example 1, using 2.92 g (0.05 moles) of magnesium hydroxide instead of the double amount.

The yield was quantitative.

IR (KBr), cm-1 3500-2900 (OH); 1730 (COOH); 1598 (COO-) ; 1395 (COO-) ; 1100,1065 (C-O) Analysis for C13H24MgO. 5NOll Calc. C 40.82; H 6.32; Mg 3.18; N 3.66 Found C 40.53; H 6.45; Mg 3.14; N 3.52 Example 5 L-carnitine and calcium galactarate 1: 1/2: 1 The title compound was prepared as described in Example 4, substituting 0.05 moles of calcium hydroxide for 0.05 moles of magnesium hydroxide and using in the starting reaction mixture about 30% of water.

The yield was quantitative.

IR (KBr), cm-1 3500-2900 (OH); 1730 (COOH); 1598 (COO-); 1385 (COO-) ; 1100,1065 (C-O) Analysis for Ci3H24Cao. 5NOn Calc. C 40.00; H 6.20; Ca 5.10; N 3.59 Found C 39.90; H 6.35; Ca 5.13; N 3.52 Examples 6 and 7 Acetvl L-carnitine and magnesium galactarate 1: 1: 1 Starting from 21 g (0.1 moles) of galactaric acid, 20.3 g (0.1 moles) of acetyl L-carnitine inner salt and 5.83 g (0.1 moles) of magnesium hydroxide, finely powdered and thoroughly mixed, and 13 mL of water, the same procedures as those described in Example 1 (Example 6) and, respectively in Example 2 (Example 7) were repeated.

The yields were quantitative.

IR (KBr), cm-1 3500-3000 (OH); 1740 (COCH3) ; 1598 (COO-) ; 1385 (COO-) ; 1240,1100,1065 (C-O) Analysis for ClsH2sMgNOi2 Calc. C 41.35; H 5.78; Mg 5.58; N 3.21 Found C 41.04; H 5.90; Mg 5.59; N 3.20 Examples 8 and 9 Propionyl L-carnitine and magnesium galactarate 1: 1: 1 Starting from 21 g (0.1 moles) of galactaric acid, 21.7 g (0.1 moles) of propionyl L-carnitine inner salt and 5.83 g (0.1 moles) of magnesium hydroxide, finely powdered and thoroughly mixed, and 14 mL of water, the same procedures as those described in Example 1 (Example 8) and, respectively in Example 2 (Example 9) were repeated.

The yields were quantitative.

IR (KBr), cm-1 3500-3000 (OH); 1738 (COCH2CH3) ; 1598 (COO-) ; 1385 (COO-) ; 1240,1100,1065 (C-O) Analysis for Cl6H27MgNO12 Calc. C 42.73; H 6.05; Mg 5.40; N 3.11 Found C 42.53; H 6.15; Mg 5.49; N 3.20 Example 10 L-carnitine and magnesium galactarate 2: 1: 1 The procedure of Example 1 was repeated, using the double amount of L-carnitine inner salt (32.2 g; 0.2 moles).

The yield was quantitative.

IR (KBr), cm-1 3500-2900 (OH); 1598 (COO-) ; 1395 (COO-) ; 1120,1060 (C-O) Analysis for CzoH3sMgN2NOl4 Calc. C 43.30; H 6.90; Mg 4.38; N 5.05 Found C 42.82; H 7.07; Mg 4.20; N 4.98 Example 11 L-carnitine and magnesium galactarate 2: 1: 1: To 21 g (0.1 moles) of galactaric acid, 32.2 g (0.2 moles) of L-carnitine inner salt and 5.83 g (0.1 moles) of magnesium hydroxide, finely powdered and thoroughly mixed, 14 mL of water were added and the resulting mixture was rapidly brought under stirring to a temperature from 70°C to 80°C with an outer heating bath at 100-110°C. As soon as the mixture was sufficiently fluid, it was vigorously stirred for about two minutes and then 600 mL of acetone were added thereto. Two phases thus formed: the heavier and more viscous one was kept dispersed into the other by means of a vigorous stirring.

In about fifteen minutes the whole mass turned, via a progressive increase in viscosity and consistency, into a crystalline solid which was filtered and dried under vacuum.

The characteristics of the resulting product were the same as those of the compound of Example 10.

Example 12 L-carnitine and calcium galactarate 2: 1: 1 The title compound was prepared as described in Example 10, substituting 0.1 moles of calcium hydroxide for 0.1 moles of magnesium hydroxide, using in the starting reaction mixture about 30% of water.

The yield was quantitative.

IR (KBr), cm-1 3500-2900 (OH); 1730 (COOH); 1598 (COO-) ; 1395 (COO-) ; 1100,1065 (C-O) Analysis for C2oH38CaN2014 Calc. C 42.10; H 6.71; Ca 7.02; N 4. 91 Found C 42.00; H 6.91; Ca 6.90; N 4.98 Example 13 L-carnitine and magnesium galactarate 2: 1/2: 1 The title compound was prepared as described in Example 10, using 2.92 g (0.05 moles) of magnesium hydroxide instead of the double amount.

The yield was quantitative.

IR (KBr), cm-1 3500-2900 (OH); 1730 (COOH); 1598 (COO-) ; 1395 (COO-) ; 1100,1065 (C-O) Analysis for C20H39Mgo. 5N2O14 Calc. C 44.18; H 7.23; Mg 2.24; N 5.15 Found C 43.99; H 7.37; Mg 2.20; N 5. 04 Examples 14 and 15 Acetyl L-carnitine and magnesium galactarate 2: 1: 1 Starting from 21 g (0.1 moles) of galactaric acid, 40.6 g (0.2 moles) of acetyl L-carnitine inner salt and 5.83 g (0.1 moles) of magnesium hydroxide, finely powdered and thoroughly mixed, and 18 mL of water, the same procedures as those of Example 1 (Example 14) and, respectively Example 2 (Example 15) were repeated.

The yields were quantitative.

IR (KBr), cm-1 3500-3000 (OH); 1740 (COCHs) ; 1598 (COO-) ; 1385 (COO-) ; 1240,1100,1065 (C-O) Analysis for C24H42MgN2016 Calc. C 45.12; H 6.63; Mg 3.80; N 4.38 Found C 44.94; H 6.80; Mg 3.72; N 4.32 Examples 16 and 17 Acetyl L-carnitine and calcium galactarate 2: 1: 1 The title compound was prepared as described in Examples 14 and 15, using 0.1 moles of calcium hydroxide and about 30% of water in the starting reaction mixture.

The yields were quantitative.

IR (KBr), cm-1 3500-3000 (OH); 1740 (COCH3) ; 1598 (COO-) ; 1385 (COO-) ; 1240,1100,1065 (C-O) Analysis for C24H42CaN20i6 Calc. C 44.03; H 6.47; Ca 6.12; N 4. 28 Found C 44.04; H 6.50; Ca 6.30; N 4.22 Following the alternative procedures shown in Examples 1 and 2, the following compounds were also prepared: - acetyl L-carnitine and magnesium galactarate 1: 1/2: 1; - acetyl L-carnitine and calcium galactarate 1: 1: 1; - acetyl L-carnitine and calcium galactarate 1: 1/2: 1; - propionyl L-carnitine and magnesium galactarate 1: 1/2: 1; - propionyl L-carnitine and calcium galactarate 1: 1: 1; - propionyl L-carnitine and calcium galactarate 1: 1/2: 1; - propionyl L-carnitine and magnesium galactarate 2: 1: 1; - propionyl L-carnitine and calcium galactarate 2: 1: 1; - isovaleryl L-carnitine and magnesium galactarate 2: 1: 1; and - isovaleryl L-carnitine and calcium galactarate 2: 1: 1; The present invention also relates to compositions which comprise as active ingredient at least one of the aforesaid carnitine and alkaline- earth galactarates, and a pharmacologically acceptable excipient.

The compositions can present themselves as pharmaceuticals, OTC compositions, nutritional supplements, dietary supplements, veterinary products or fodders.

The compositions according to the present invention can also comprise further nutritional and/or pharmacological active ingredients. In particular, the compositions can comprise other pharmacologically acceptable salts of L-carnitine and/or (C2-C5) alkanoyl L-carnitines.

The compositions can also comprise fillers, binders, lubricants, mold- release agents, flow-regulating agents, dispersing agents, colorants, flavoring agents and the like as it will be apparent to any expert in pharmaceutical technology or pharmacy.

The orally administrable, solid forms comprise tablets, chewable tablets, pills, troches, lozenges, capsules, powders or granulates. In case of powders or granulates the presentation form can occur as sachets.

Since magnesium's Recommended Dietary Allowance (RDA) is from 280-350 mg/day and calcium's RDA is about 1,000 mg/day (Goodman and Gilman's, loc. cit., page 1525) the compositions of the present invention, in unit dosage form, suitably contain the whole magnesium and/or calcium's RDA, i. e. 280-350 mg of magnesium and about 1,000 mg of calcium, or a lower amount, e. g. from 80 to about 160, preferably 100-120, mg of magnesium and from about 200 to 400, preferably 250- 300, mg of calcium.