MXPA99009184A - Solid compositions suitable for oral administration comprising an alkanoyl-l-carnitine magnesium citrate - Google Patents

Abstract

Stable and non hygroscopic salts consisting of lower alkanoyl-L-carnitine magnesium citrates are disclosed which are suitable for preparing solid compositions useful as dietary/nutritional supplements for human use and as fodder supplement for veterinary purposes.

Description

SOLID COMPOSITIONS SUITABLE FOR ORAL ADMINISTRATION COMPRISING A MAGNESIUM CITRATE OF ALCANOIL-L-CARNITINE DESCRIPTION OF THE INVENTION The present invention relates to stable, non-hygroscopic pharmacologically acceptable salts of lower alkanoyl-L-carnitines which favorably lend themselves to the preparation of solid, orally administrable compositions. The present invention also relates to such compositions. Various therapeutic uses of the alkanoyl-L-carnitines are already known. For example, acetyl-L-carnitine has been used for the treatment of pathological changes of the CNS, particularly Alzheimer's disease and diabetic neuropathy; propionyl-L-carni-tine has been used to treat peripheral vascular diseases and congestive heart failure. It is also known that the salts of L (-) - carnitine and its alkanoyl derivatives have the same therapeutic or nutritional activities as those of the so-called internal salts and REF: 31213 can, therefore, be used instead, as long as these salts are "pharmacologically acceptable", that is, they do not have undesired toxic or secondary effects. In practice, then, the selection between an "internal salt" and a true salt of L (-) - carnitine or alkanoyl-L. { -) -carnitine will depend essentially on considerations of availability, economic and pharmacy rather than therapeutic or nutritional considerations. The object of the present invention is to provide stable and non-hygroscopic salts of lower alkanoyl-L-carnitines which are endowed with an increased therapeutic and / or nutritional efficacy with respect to their internal salt counterparts. Therefore, it should be clearly understood that the utility of the salts of the present invention is not confined to their lack of hygroscopicity and their greater stability compared to the corresponding internal salts, but also resides in their improved therapeutic and / or nutritional value. Therefore, this value will no longer be attributed exclusively to the "alkanoyl-carnitine" portion of the salt. Due to their lack of hygroscopicity, these salts can be easily combined, particularly with protopes IO-IG p2 Gp3 .-? 3.i COlüjpOSlClOuS S SO ± l S ^ orally administrable. As is well known to the experts in iñ Cl, e _? _ ¿J ±. O coaitLldn w j. J-? JLJ. V- O XA J_ VJ J_ O V- J K ^ -L.

C a j- J_ e a. J_U. or J j. \ ~ C ± J? L c J_ a. or vj.tr: íi? uu t? v. to. VJ. um? _ VJ _ o. VJ. CL o. ± J. L. VJ SrS trl Qj.Iua ???? aüiJ.c ???,? Lu u ca. J_ ci ciiLu themselves. For l .ooss they should be packed in tightly sealed bubble packs to avoid unpleasant consequences due to moisture. All this involves extra costs both for the storage of raw materials and for their processing and packaging. Among the populations of the industrialized countries there is a use that extends from ilidix t_: x. CL ui c -cnuc -? bu ifc? c? i Ub a ± lillcll I L V ^ J- O J "nutraceutical agents" both by athletes (amateurs or professionals) and by people who are in good health. The previous use of L-carnitine or food supplements containing L-carnitine is because it facilitates the oxidation of fatty acids and provides a greater amount of energy available to the skeletal muscle, thus allowing for improved efficiency and causing less accumulation of lactic acid in the muscles of athletes. People who are in good health use these food supplements as healthy foods, ie for the purposes of promoting a reduction in serum fat levels and the normalization of the relationship between the various fractions of cholesterol, to prevent diseases related to disorders of lipid metabolism. It has been estimated that the amount of L-carnitine and its derivatives sold for unethical purposes is double that sold for ethical purposes. The market in the United States for food supplements or nutraceutical agents reaches approximately 250 billion dollars, while the figure estimated for the European market is approximately 500 billion dollars (Food Labeling News, 1994, "Nutraceuticals" Market said to be a vast one, March, Vol. 2, No. 25; King Communications Group Inc., 1993, "Nutraceuticals" Foods, Drink in Global Market, Food and Drink Daily, April, Vol. 3, no. 503).

While some non-hygroscopic salts of L-carnitine are already known, there is an increasing interest to develop non-hygroscopic salts of lower alkanoyl-L-carnitines. For example, EP 0 150 688 (SIGMA-TAU) describes the acid fumarate of L-carnitine and EP 0 434 088 (LONZA) describes the use of L (+) non-hygroscopic L (-) carnitine tartrate (2: 1) (the preparation and physical-chemical characterization of which were, however, described by D. Müller and E. Strack in Hoppe Seyler's Z. Physiol. Chem 353, 618-622, April 1972) for the preparation of solid forms suitable for oral administration. This salt has, however, some disadvantages, such as for example the release, after prolonged storage of traces of trimethylamine, which give the product an unpleasant fish odor. U.S. Patent No. 5,071,874 discloses magnesium citrate of L-carnitine, but teaches nothing with respect to the possibility of preparing magnesium citrates of alkanoyl-L-carni tines, nor does it suggest that these salts, if any, they would be non-hygroscopic and stable for prolonged storage. Additionally, it should be noted that when a non-hygroscopic salt of L-carnitine is known, no conclusion can be made about the possibility of obtaining similar salts of alkanoyl-L-carnitines from the same salifying acid. Actually, for example, the L- (+) - tartaric acid which gives a non-hygroscopic salt with L-carnitine is incapable of providing non-hygroscopic salts with the alkanoyl-L-carnitines, such as for example acetyl-L-carnitine. The aforementioned object of the present invention, namely to provide not only novel pharmacologically acceptable salts of lower alkanoyl-L-carnitines which are stable and non-hygroscopic, but also have a therapeutic and / or nutritional value greater than that of the internal salts corresponding, is achieved by the salts of the formula (I): ro wherein R is a straight or branched chain lower alkanoyl having 2-5 carbon atoms.

Preferred salts are those in which R is selected from the group comprising acetyl, propionyl, butyryl, valeryl and isovaleryl. In view of the reasons mentioned above, the stability and lack of hygroscopicity of the present salts was not at all predictable on the basis of the prior art. Since both magnesium and carnitine are removed in massive amounts with sweat and urine during intense, prolonged physical activity, the compounds of the present invention can be used for advantages as food supplements for athletes. Magnesium is an important co-factor of the membrane enzymes involved in muscle contraction. Disorders of magnesium metabolism are usually associated with a reduction in total plasma concentration. Abnormally low blood levels of magnesium are associated with cardiovascular, neurological, and skeletal muscle disorders that result from abnormalities in cell contractility and excitability.

Under physiological conditions, the equilibrium constants of the reactions between Mg "and ATP favor the formation of a MgATP2 * complex, which is used as a substrate by many cellular ATPases.Magnesium also affects the properties of various ion channels, many of which are located in various excitable cells, and thus performs a regulatory function with respect to the influx of other ions such as sodium, calcium and potassium.Magnesium exerts a protective action on cardiac function.The complication of magnesium to influence the Cardiovascular function has recenreceived considerable attention, both as a therapeutic agent to minimize disorders of an electrophysiological nature and as an etiologic factor in diseases such as myocardial decompensation and hypertension.Epidemiological studies have revealed that there is a distinct correlation between the incidence of cardiac ischemia and the ratio of calcium: agnesium in the diet and in drinking water. Hypomagnesemia causes muscle cramps and an increased activity of the autonomic system.

The following non-limiting example shows the preparation of a non-hygroscopic salt according to the present invention.

EXAMPLE Preparation of acetyl-L-carnitine magnesium citrate (ST 1304J The internal salt of acetyl-L-carnitine (1 mole), citric acid (1 mole) and Mg (OH) 2 (1 mole) were suspended in H 0 (water) and kept under stirring for approximately 30 minutes. The resulting solution was then concentrated under vacuum. The residue was dissolved with acetone and the resulting mixture was kept under stirring and then filtered. A solid, non-hygroscopic product was obtained.

Yield: 95%. Elemental analysis for C ^ HasNO-Mg "6 íl? N% Mg Calculated (with 4.1% of H20): 41.37 5.7 3.22 5.58 Found: 40.69 5.47 2.50 5.6 [a] 2 D = -12.7 (c = 1%, H20) DSC (decomposition): 160 ° C-170 ° C NMR D20 d 5.6 (lH, m, CHOH); 3.8 (ÍH, dd, N + CHH) 3.4 (lH, dd, N ~ CHH); 3.2 (9H, s, (CH3) 3N +); 3.4 (lH, m, CHHCOOH); 2.8-2.75 (2H, d, CH2C00H citric); 2.65-2.60 (2H,, CH2COOH Citrus) 2.7-2.5 (lH, m, CHH-COOH); 2.2 (3H, s, COCH3). CLAP: Column: Inertsil-ODS-3 (5 um) 250 X 4.6 mm Eluent: NaC104 0.15 M + NaH2P04 0.05 M / l H20 pH: 2 with H3P04 Flow rate: 0.75 ml / minute Citric acid: Rt = 9.53 minutes Acetyl-L-carnitine: Rt = 19.47 minutes The present invention also relates to compositions comprising as a principle or active principles at least one of the non-hygroscopic pharmacologically acceptable salts mentioned above and, optionally, one or more pharmacologically acceptable excipients and active ingredients. They are well known to experts in pharmacy and food technology.

Particularly preferred are solid, orally administrable compositions such as tablets, chewable tablets and capsules, which comprise an alkanoyl-L-carnitine salt of formula (I) in an amount corresponding to 50-2,000, preferably 100-1,000 mg of internal salt of alkanoyl-L-carnitine. For example, a composition for preparing tablets is as follows: Non-hygroscopic salt of alkanoyl-L-carnitine of formula (I): 500 mg Starch: 20 mg Talc: 10 mg Calcium stearate: 1 mg 531 mg A suitable composition for preparing capsules is as follows: Non-hygroscopic salt of alkanoyl-L-carnitine of formula (I) 500 mg Starch 20 mg Lactose 50 mg Talc 5 mg Calcium stearate 2 mg 577 mg The compositions of the present invention can be used as dietary / nutritional supplements for human use or forage supplement for veterinary purposes. Through the synergistic action exerted by the component portions of the salts present, the following results were achieved: - improved enzymatic activity bound to the energy metabolism; - improved endurance and adaptation to vigorous exercise programs with greater efficiencies and shorter rest periods; - strengthening of the functional capacity of the cardiovascular system; and - less tendency to develop muscle cramps. 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.

Claims (10)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. An alkanoyl-L-carnitine salt of the formula (1) ro characterized in that R is a straight or branched chain lower alkanoyl having 2-5 carbon atoms.

2. The salt according to claim 1, characterized in that R is selected from the group comprising acetyl, propionyl, butyryl, valeryl and isovaleryl.

Magnesium citrate of acetyl 1-L-carnitine

4. Magnesium citrate of propionyl-L-carnitine.

5. A composition characterized in that it comprises as an active ingredient a salt according to claims 1-4.

6. The composition according to claim 5, further characterized in that it comprises one or more substances selected from excipients and pharmacologically acceptable active ingredients.

7. The composition according to claims 5 or 6, characterized in that it is in the form of tablets, chewable tablets, capsules, granules or powders.

8. The composition according to claims 5-7, characterized in that it is in unit dosage form comprising as active ingredient an alkanoyl-L-carnitine salt of formula (I), in an amount corresponding to 50-2,000, preferably 100-1,000 mg of alkanoyl-L-carnitine internal salt.

9. The composition according to claims 5-8, characterized in that it is used as a dietary / nutritional supplement for human use.

10. The composition according to claims 5 or 6, characterized in that it is used as a forage supplement for veterinary use.