L-carnitine salt and compositions containing same

L-carnitine glycolate, a novel stable and non-hygroscopic salt of L-carnitine and the use thereof for preparing orally administrable, particularly solid compositions in the form of pills, tablets, troches, capsules, powders and the like, are disclosed.

The present invention relates to a novel L-carnitine salt and the use 
thereof for producing orally administrable, particularly solid, 
compositions in the form of pills, tablets, troches, capsules, powders and 
the like. 
It is well known that L-carnitine lends itself to various therapeutical 
uses, 
For instance, L-carnitine has been used in the cardiovascular field in the 
treatment of acute and chronic myocardial ischaemia, angina pectrois, 
cardiac arrhythmias and insufficiency. In nephrology, L-carnitine has been 
administered to chronic uraemic patients who are subject to regular 
haemodialysis treatment with a view to counteracting muscular asthenia and 
the onset of muscular cramps. 
Further therapeutical uses are the restoration of HDL/LDL+VLDL ratio to 
normal and in total parenteral nutrition. 
It is also known that the salts of carnitine possess the same therapeutical 
activities as those of the so-called "inner salt" and can, therefore, be 
used in place thereof, provided that they are "pharmacologically 
acceptable" salts. So, practically, the choice between the "inner salt" 
and a true carnitine salt depends mostly on which compound is more easily 
or economically available and on pharmaceutical technology considerations 
rather than on therapeutical activity considerations. Thus, for instance, 
(see U.S. Pat. No. 4.968,719) suitable pharmaceutically acceptable salts 
include the acid addition salts and may contain as the anion: acetate, 
adipate, alginate, aspartate, benzoate. benzenesulfonate, bisulfate, 
butyrate, citrate, camphorate. camphorsulfonate, cyclopentanepropionate, 
digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, 
glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, 
iodide, 2-hydroxyethane-sulfonate, lactate, maleate, methanesulfonate, 
2-naphtalenesulfonate, nicotinate, oxalate, palmitate, pectinate, 
persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, 
tartrate, thiocyanate, tosylate, undecanoate and the like. 
Recently, an increasing number of non-ethical, over-the-counter 
L-carnitine-containing preparations have reached the market, following 
full scientifically-grounded recognition that in athletes L-carnitine 
markedly contributes to supplying the muscle with energy and improves 
endurance and stress tolerance. Moreover, L-carnitine is an indispensable 
nutritional supplement for vegetarians whose diets are low in carnitine 
and in the two aminoacids (lysine and methionine) which are the precursors 
for L-carnitine biosynthesis in human liver and kidneys. 
Consequently, among such consumers the need for suitable forms of 
administration, particularly of orally administrable preparations and 
preferably of solid formulations, has developed. 
As known, L-carnitine inner salt is a highly hygroscopic compound and, 
consequently, cannot be easily storaged, handled end compounded, 
particularly with regard to the manufacture of solid administration forms. 
Moreover, L-carnitine often presents an unpleasant fishy odour because of 
the presence of traces of trimethylsmine. 
The problem of converting L-carnitine into non hygroscopic, 
pharmaceutically acceptable salts has been already tackled. For instance, 
EP 0 150 688 discloses the preparation of some of such salts, e,g. 
L-carnitine acid fumarate. 
It is the object of this invention to provide a novel non-hygroscopic, 
stable and odourless pharmaceutically acceptable salt of L-carnitine, 
namely L-carnitine glycolate which has formula (I) 
##STR1## 
This novel salt can be easily, storaged and processed into stable solid 
orally administrable preparations particularly suitable for athletes and 
vegetarians nutritional supplements. This is quite surprising since 
glycolic acid is somewhat hygroscopic. 
L-carnitine glycolate can be prepared as follows:

EXAMPLE 
Preparation of L-carnitine glycolate (ST 1136). 
L-carnitine inner salt (16.1 g; 0.1 moles) was dissolved in 100 mL H.sub.2 
O, Glycolic acid (7.6 g; 0.1 moles) was added to the solution. 
The resulting solution was concentrated under vacuum at 40.degree. C. The 
residue was taken up with isopropanol and the solid residue filtered off. 
23 g were obtained. 
The compound was crystallized from hot isopropanol. 
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M.P. = 112.3.degree. C. (DSC) 
Elemental analysis C.sub.9 H.sub.17 NO.sub.6 
C % H % N % 
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Calculated 45.95 7.28 5.95 
Found 46.17 8.46 6.06 
Water content 0.3% 
pH = 3.9 
[.alpha.].sub.D.sup.25 = -19.9.degree. (c = 1%, H.sub.2 O) 
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HPLC 
Column: .mu. Bondapack-NH.sub.2 (10 .mu.m) 300 mm.times.3.9 mm 
Temperature: 30.degree. C. 
Mobile phase: CH.sub.3 CN/KH.sub.2 PO.sub.4 mM pH 5.2 65/35 
Flow rate: 1.0 ml/min 
Glycolic acid R.sub.t =4.91 min 31.6% 
L-carnitine R.sub.t =8.99 min 68.4% 
NMR D.sub.2 O .delta.4.5-4.4(1H.m,CHOH); 3.9(2H,s,CH.sub.2 OH); 
3.3(2H,m,CH.sub.2 N+); 3.1(9H,s,(CH.sub.3).sub.3 N+); 2.4(2H,dd,CH.sub.2 
COO) 
Hygroscopicity tests were carried out on L-carnitine glycolate and, for 
comparison sake, on the highly hygroscopic L-carnitine inner salt and two 
known, non-hygroscopic L-carnitine salts, namely L-carnitine L-tartrate 
(see Muller et al., Hoppe-Seyler's Z. Phisiol. Chem. 353, 618-622, 1972) 
and L-carnitine acid fumarate (see EP 150 688). Samples of the aforesaid 
salts were exposed to a 90% humidity environment, at 25.degree. C., and 
their Karl Fisher index (K.F.) was measured at various times. 
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Karl Fisher index after 
0 16 24 40 112 
hours hours hours hours hours 
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L-carnitine 
0.20 3.40 4.40 7.60 12.90 
inner salt 
L-carnitine 
0.30 0.30 0.30 0.30 0.50 
L-tartrate 
L-carnitine 
0.50 0.50 0.75 0.82 0.91 
acid fumarate 
L-carnitine 
0.30 0.50 0.50 0.50 0.50 
glycolate 
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According to the present invention, the tablets, pills, capsules, troches 
and the like may contain the following ingredients: a binder such as 
microcrystalline cellulose, gum tragacanth or gelatin; an excipient such 
as starch or lactose, a disintegrating agent such as alginic acid, 
Primogel, corn starch and the like; a lubricant such as magnesium stearate 
or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening 
agent such as sucrose or saccharin or flavorings agent such as peppermint, 
methyl salicylate, or orange flavouring. When the dosage unit form is a 
capsule it may contain, in addition to material of the above type, a 
liquid carrier such as a fatty oil. Other dosage unit forms may contain 
other various materials which modify the physical form of the dosage unit, 
for example, coatings. Thus tablets or pills may be Coated with sugar, 
shellac, or other enteric coating agents. A syrup may contain, in addition 
to the active compound, sucrose as a sweetening agent and certain 
preservatives, dyes and colorings and flavors. Materials used in preparing 
these various compositions should be pharmaceutically pure and non-toxic 
in the amounts used.