U.S. patent application number 09/381730 was filed with the patent office on 2001-10-04 for solid compositions suitable for oral administration comprising an alkanoyl-l-carnitine magnesium citrate.
Invention is credited to SCAFETTA, NAZARENO, TINTI, MARIA ORNELLA.
Application Number | 20010027214 09/381730 |
Document ID | / |
Family ID | 11404949 |
Filed Date | 2001-10-04 |
United States Patent
Application |
20010027214 |
Kind Code |
A1 |
SCAFETTA, NAZARENO ; et
al. |
October 4, 2001 |
SOLID COMPOSITIONS SUITABLE FOR ORAL ADMINISTRATION COMPRISING AN
ALKANOYL-L-CARNITINE MAGNESIUM CITRATE
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.
Inventors: |
SCAFETTA, NAZARENO; (PAVONA
DI ALBANO, IT) ; TINTI, MARIA ORNELLA; (ROME,
IT) |
Correspondence
Address: |
NIXON & VANDERHYE
1100 NORTH GLEBE ROAD
8TH FLOOR
ARLINGTON
VA
222014714
|
Family ID: |
11404949 |
Appl. No.: |
09/381730 |
Filed: |
September 24, 1999 |
PCT Filed: |
March 19, 1998 |
PCT NO: |
PCT/IT98/00058 |
Current U.S.
Class: |
514/547 ;
560/196; 562/551; 562/556; 562/561; 562/567 |
Current CPC
Class: |
A23K 20/105 20160501;
A61P 43/00 20180101; C07C 229/22 20130101; A61P 3/02 20180101; C07C
59/265 20130101 |
Class at
Publication: |
514/547 ;
562/551; 562/556; 562/561; 560/196; 562/567 |
International
Class: |
C07C 409/44; A61K
031/225 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 8, 1997 |
IT |
RM97A000198 |
Claims
1. A salt of alkanoyl-L-carnitine of formula (I) 3wherein R is a
straight or branched lower alkanoyl having 2-5 carbon atoms:
2. The salt of claim 1, wherein R is selected from the group
comprising acetyl, propionyl, butyryl, valeryl and isovaleryl.
3. Acetyl-L-carnitine magnesium citrate.
4. Propionyl-L-carnitine magnesium citrate.
5. A composition comprising as active ingredient a salt of claims
1-4.
6. The composition of claim 5, further comprising one or more
substances selected from pharmacologically acceptable excipients
and active ingredients.
7. The composition of claims 5 or 6 in the form of tablets,
chewable tablets, capsules, granulates or powders.
8. The composition of claims 5-7, in unit dosage form comprising as
active ingredient a salt of alkanoyl-L-carnitine of formula (I), in
an amount corresponding to 50-2,000, preferably 100-1,000, mg of
alkanoyl-L-carnitine inner salt.
9. The composition of claims 5-8 as dietary/nutritional supplement
for human use.
10. The composition of claims 5 or 6 as fodder supplement for
veterinary use.
Description
[0001] The present invention relates to stable, non-hygroscopic,
pharmacologically acceptable salts of lower alkanoyl-L-carnitines
which favourably lend themselves to the preparation of solid,
orally administrable compositions. The present invention also
relates to such compositions.
[0002] Various therapeutic uses of alkanoyl L-carnitines are
already known. For instance, acetyl-L-carnitine has been used for
the treatment of pathological disturbances of the CNS, particularly
Alzheimer's disease and diabetic neuropathy; propionyl-L-carnitine
has been used for treating peripheral vascular diseases and
congestive heart failure..
[0003] It is also known that the salts of L(-)-carnitine and its
alkanoyl derivatives present the same therapeutic or nutritional
activities as those of the so-called inner salts and can,
therefore, be used in their place, provided these salts are
"pharmacologically acceptable", i.e. they do not present unwanted
toxic or side effects.
[0004] In practice, then, the choice between an "inner salt" and a
true L(-)-carnitine or alkanoyl-L(-)-carnitine salt will depend
essentially on availability, economical and pharmacy considerations
rather than on therapeutic or nutritional considerations,
[0005] The object of the present invention is to provide stable and
non-hygroscopic salts of lower alkanoyl-L-carnitines which are
endowed with an enhanced therapeutical and/or nutritional efficacy
with respect to their inner salt counterparts.
[0006] It should, therefore, be clearly understood that the utility
of the salts of the present invention is not confined to their lack
of hygroscopicity and higher stability compared to the
corresponding inner salts, but also resides in their enhanced
therapeutic and/or nutritional value. This value is, therefore, no
longer to be attributed exclusively to the "alkanoyl-carnitine"
moiety of the salt.
[0007] Because of their lack of hygroscopicity these salts can be
easily compounded, particularly with a view of preparing solid,
orally administrable compositions.
[0008] As is well known to experts in pharmacy, the processing of
hygroscopic products entails the use of controlled-humidity
chambers both for storage and for the processing itself.
[0009] Moreover, the finished products must be packed in
hermetically sealed blisters in order to avoid unpleasant
consequences due to humidity.
[0010] All this involves extra costs both for the storage of raw
materials and for their processing and packaging.
[0011] Among the populations of the industrialised countries there
is an increasingly widespread use of food supplements or
"nutraceuticals" both by sportsmen (amateurs or professionals) and
by people in good health.
[0012] The former use L-carnitine or food supplements containing
L-carnitine because it facilitates the oxidation of fatty acids and
makes a larger amount of energy available to skeletal muscle, thus
allowing enhanced performance and giving rise to less accumulation
of lactic acid in the athletes' muscles.
[0013] People in good health use these food supplements as health
foods, i.e. for the purposes of favouring a reduction in serum fat
levels and normalisation of the ratio between the various
cholesterol fractions in order to prevent diseases related to lipid
metabolism disorders.
[0014] It has been estimated that the amount of L-carnitine and its
derivatives sold for non-ethical purposes is twice that sold for
ethical purposes.
[0015] The US market for food supplements or nutraceuticals amount
to approximately 250 billion dollars, whereas the estimated figure
for the European market is approximately 500 billion dollars (Food
Labeling News, 1994, "Nutraceuticals" Market said to be a vast one,
March, Vol. 2, n.degree. 25; King Communications Group Inc., 1993,
"Nutraceuticals" Foods, Drink in Global Market, Food and Drink
Daily, April, Vol. 3, n.degree. 503).
[0016] While some non-hygroscopic salts of L-carnitine are already
known, there is an increasingly widespread interest in developing
non-hygroscopic salts of lower alkanoyl-L-carnitines.
[0017] For instance, EP 0 150 688 (SIGMA-TAU) discloses the acid
fumarate of L-carnitine and EP 0 434 088 (LONZA) discloses the use
of the non-hygroscopic L(-)carnitine L(+)tartrare (2:1) (the
preparation and physico-chemical characterization of which were,
however, described by D. Muller 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.
[0018] This salt presents, however, some drawbacks, such as e.g.
the release, after prolonged storage, of traces of trimethylamine
which give the product an unpleasant fishy odour. U.S. Pat. No.
5,071,874 discloses L-carnitine magnesium citrate but does not
teach anything as regards the possibility of preparing magnesium
citrates of alkanoyl-L-carnitines, nor does it suggest that these
salts, if any, would be non-hygroscopic and stable to prolonged
storages. It should, furthermore, be noticed that when a
non-hygroscopic salt of L-carnitine is known, no conclusion can be
drawn about the possibility of obtaining similar salts of
alkanoyl-L-carnitines from the same salifying acid. Indeed, e.g.
L-(+)-tartaric acid which gives with L-carnitine a non-hygroscopic
salt, is unable to give non-hygroscopic salts with the
alkanoyl-L-carnitines, such as e.g. acetyl-L-carnitine.
[0019] The aforesaid object of the present invention, i.e. to
provide not only novel, pharmacologically acceptable salts of lower
alkanoyl-L-carnitines which are stable and non-hygroscopic but also
possess therapeutic and/or nutritional value higher than that of
the corresponding inner salts, is achieved by the salts of formula
(I): 1
[0020] wherein R is a straight or branched lower alkanoyl having
2-5 carbon atoms.
[0021] The preferred salts are those wherein R is selected from the
group comprising acetyl, propionyl, butyryl, valeryl and
isovaleryl.
[0022] In the light of the aforesaid reasons, the stability and
lack of hygroscopicity of the present salts was not at all
foreseeable on the ground of the prior art.
[0023] Since both magnesium and carnitine are eliminated in massive
amounts with the sweat and urine during prolonged, intense physical
activity, the compounds of the present invention can be used to
advantage as food supplements for sportsmen.
[0024] Magnesium is an important co-factor of the membrane enzymes
involved in muscle contraction.
[0025] Disorders of magnesium metabolism are usually associated
with a reduction in the total plasma concentration. Abnormally low
blood levels of magnesium are associated with cardiovascular,
neurological and skeletal muscle disorders deriving from cell
contractility and excitability abnormalities.
[0026] In physiological conditions, the equilibrium constants of
the reactions between Mg.sup.2++ and ATP favour the formation of an
MgATP.sup.2+ complex which is used as a substrate by many cellular
ATPases.
[0027] Magnesium also affects the properties of various ion
channels, many of which are situated in various excitable cells,
and thus performs a regulatory function with regard to the influx
of other ions such as sodium, calcium and potassium.
[0028] Magnesium exerts a protective action on cardiac function.
The involvement of magnesium in influencing cardiovascular function
has recently received considerable attention, both as a therapeutic
agent to minimise disorders of an electrophysiological nature and
as an aetiological factor in diseases such as myocardial
decompensation and hypertension. 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.
[0029] Hypomagnesaemia gives rise to muscle cramps and to increased
activity of the autonomic system.
[0030] 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 1304)
[0031] 2
[0032] Acetyl-L-carnitine inner salt (1 mole), citric acid (1 mole)
and Mg(OH).sub.2 (1 mole) were suspended in H.sub.2O and kept under
stirring for about 30 minutes.
[0033] The resulting solution was then concentrated under vacuum.
The residue was taken up with acetone and the resulting mixture
kept under stirring and then filtered.
[0034] A solid, non-hygroscopic product was obtained.
[0035] Yield: 95%.
1 Elementary analysis for C.sub.15H.sub.23NO.sub.11Mg C % H % N %
Mg Calculated (with 4.1% H.sub.2O): 41.37 5.78 3.22 5.58 Found:
40.69 5.47 2.50 5.6
[0036] [.alpha.].sub.D.sup.25=-12.7(c=1%, H.sub.2O)
[0037] DSC (dec.): 160.degree. C.-170.degree. C.
[0038] NMR D.sub.2O .delta. 5.6(1H,m,CHOH); 3.8(1H,dd,N.sup.+CHH);
3.4(1H,dd,N.sup.+--CHH); 3.2(9H,s,(CH.sub.3).sub.3N.sup.+);
3.4(1H,m,CHHCOOH); 2.8-2.75(2H,d,CH.sub.2COOH citrico);
2.65-2.60(2H,d,CH.sub.2COOH citrico) 2.7-2.5(1H,m,CHH--COOH);
2.2(3H,s,COCH.sub.3).
[0039] HPLC:
[0040] Colum: Inertsil-ODS-3 (5.mu.m) 250.times.4.6 mm
[0041] Eluant: NaClO.sub.4 0.15 M+NaH.sub.2PO.sub.4 0.05M/1
H.sub.2O
[0042] pH: 2 with H.sub.3PO.sub.4
[0043] Flow-rate: 0.75 mL/min
[0044] Citric acid: R.sub.t=9.53 min
[0045] Acetyl-L-carnitine: R.sub.t=19.47 min
[0046] The present invention also relates to compositions
comprising as active principle(s) at least one of the aforesaid
non-hygroscopic pharmacologically acceptable salts and, optionally,
one or more pharmacologically acceptable excipients and active
ingredients which are well-known to the experts in pharmacy and
food technology.
[0047] Particularly preferred are the solid, orally administrable
compositions such as tablets, chewable tablets and capsules, which
comprise a salt of alkanoyl-L-carnitine of formula (I) in an amount
corresponding to 50-2,000, preferably 100-1,000, mg
alkanoyl-L-carnitine inner salt.
[0048] For instance, a composition for preparing tablets is the
following:
2 Non-hygroscopic alkanoyl-L-carnitine salt of formula (I): 500 mg
Starch: 20 mg Talc: 10 mg Calcium stearate: 1 mg 531 mg
[0049] A composition suitable for preparing capsules is the
following:
3 Non-hygroscopic alkanoyl-L-carnitine salt of formula (I): 500 mg
Starch: 20 mg Lactose: 50 mg Talc: 5 mg Calcium stearate: 2 mg 577
mg
[0050] The compositions of the present invention may be used as
dietary/nutritional supplements for human use or as fodder
supplement for veterinary purposes.
[0051] Through the synergic action exerted by the component
moieties of the present salts, the following results are
achieved:
[0052] enhanced enzymatic activity bound to the energy
metabolism;
[0053] improved endurance and adaptation to programs of strenous
exercise with achievement of higher performances and shorter rest
periods;
[0054] strengthening of the functional capacity of the
cardiovascular system; and
[0055] less tendency to develop muscular cramps.
* * * * *