Salts of L-carnitine and lower alkanoyl L-carnitine

Details Salts of L-carnitine and lower alkanoyl L-carnitine Salts of L-carnitine and lower alkanoyl L-carnitine

2001-11-27

2004-03-09

Venkat, Jyothsna (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

C424S451000, C424S463000, C424S489000, C562S561000, C562S562000, C562S563000

Reexamination Certificate

active

06703042

ABSTRACT:

The present invention relates to stable, non-hygroscopic salts of L-carnitine and lower alkanoyl L-carnitine endowed with enhanced nutritional and/or therapeutical efficacy with respect to their inner salts congeners and to solid compositions containing such salts, particularly suited to oral administration.
It has long since known that carnitine and its alkanoyl derivatives lend themselves to various therapeutical utilizations such as e.g. in the cardiovascular field for the treatment of acute and chronic myocardial ischaemia, angina pectoris, heart failure and cardiac arrhythmias. Acetyl L-carnitine is used in the neurologic field for the treatment of both central nervous system disturbances and peripheral neuropathies, particularly diabetic peripheral neuropathy. Propionyl L-carnitine is used for the treatment of chronic arteriosclerosis obliterans, particularly in patients showing the symptom of severely disabling intermittent claudication.
On the other hand, a widespread promotion of carnitine and derivatives thereof has rapidly been taking place towards utilizations other than those purely therapeutical, ever though allied to them.
It has, in fact, been widely recognized that in professional athletes as well as in any subject practising sport at amateur level, L-carnitine supplies energy to the skeletal musculature and increases the resistance to prolonged, intense stress, enhancing the performance capability of such individuals.
In addition, L(−)-carnitine or its lower alkanoyl derivatives constitute indispensable nutritional supplements for both vegetarians, whose diets have a low carnitine content as well as a low content of the two amino acids, lysine and methionine (the precursors of the biosynthesis of L(−)-carnitine in the kidneys and liver) and those subjects who have to live on a diet poor in protein for prolonged periods of time.
Consequently, various compositions containing carnitine or derivatives thereof, either as single components or in combinations with further active ingredients, have recently reached the market of the dietary supplements, health foods, energy foods and similar products.
It has long since been known that L(−)-carnitine and its alkanoyl derivatives are extremely hygroscopic and not very stable when they occur as inner salts (or “betaines”) as represented by the formula
wherein R═H or C
1
-C
5
lower alkanoyl.
This leads to complex problems of processing, stability and storage both of the raw materials and of the finished products. For example, L(−)-carnitine tablets have to be packaged in blisters to keep them out of contact with the air, since, otherwise, even in the presence of normal humidity conditions, they would undergo alterations, swelling up and becoming pasty and sticky.
Since the salts of L(−)-carnitine and its alkanoyl derivatives known to-date present the same therapeutic, nutritional or dietetic activities, respectively, as the so-called inner salts (or “betaines”), the problem of the hygroscopicity of the inner salts has tentatively been solved by salifying them with “pharmacologically acceptable” acids, which do not present unwanted toxic or side effects.
There is now an extensive body of literature, particularly patents, disclosing the production of such stable, non-hygroscopic salts.
Among L-carnitine salts, particularly L-carnitine tartrate and L-carnitine acid fumarate have to-date found practical utilization.
Although the aforesaid “pharmacologically acceptable” salts solve the problem of the hygroscopicity of L-carnitine inner salt more or less satisfactorily, in none of the known salts the anion moiety co-operates to enhance the nutritional, energetic and/or therapeutical efficacy which can be attributed to the “carnitine” moiety of the salts themselves.
Furthermore, none of the acids used for producing non-hygroscopic L-carnitine salts is capable of forming non-hygroscopic salts of alkanoyl L-carnitine. Thus, for example, whereas L(−)-carnitine acid fumarate and L(−)-carnitine tartrate are non-hygroscopic compounds, acetyl L(−)-carnitine acid fumarate and tartrate, respectively, are strongly hygroscopic compounds, which present the same drawbacks as the corresponding inner salt.
L-carnitine and acyl L-carnitine derivatives with aminoacids are already known.
EP-A1-0 150 688 discloses acetyl L-carnitine acid L-aspartate which is reported as a non-hygroscopic salt.
EP-A2-0 167 115 discloses condensation products of L-carnitine or acyl L-carnitine with an optically active acid aminoacid monosalified with potassium ion. Potassium-salified glutamic and aspartic acids are mentioned and preparation of L-carnitine potassium aspartate is exemplified.
Finally, EP-A1-0 354 848 discloses pharmaceutical compositions comprising L-carnitine lysinate as active ingredient, whose preparation and physico-chemical characterization are not reported.
Neither EP-A2-0 167 115 nor EP-A1-0 354 848 disclose whether the aforesaid L-carnitine derivatives are hygroscopic or non-hygroscopic
The object of the present invention is to provide stable, non-hygroscopic salts of L-carnitine and lower alkanoyl L-carnitine which possess an enhanced therapeutical and/or nutritional efficacy with respect to the corresponding inner salts.
It is, therefore, apparent that the utility of the salts of the present invention is to be found not only in their lack of hygroscopicity and higher stability with respect to their corresponding inner salts, but also insofar as their anion moiety contributes to the nutritional, energetic and/or therapeutic efficacy of the salt as whole. The aforesaid efficacy of these novel salts is, therefore, not to be attributed exclusively to the “carnitine” moiety of the salt.
The aforesaid object, is achieved by the salts of L-carnitine and alkanoyl L-carnitine with amino acids having the formula (I):
wherein:
R is hydrogen or a straight or branched-chain alkanoyl group having 2-5 carbon atoms; and
Y is the anion of an amino acid occurring in proteins selected from the group consisting of: leucine, isoleucine, vahine, cysteine, arginine, glutamic acid, glutamine, asparagine, glycine, alanine, threonine, serine, proline, hystidine, methionine, phenylalanine and tryptophane.
By “amino acid occurring in proteins” is meant any one of the twenty amino acids which are obtained via controlled hydrolysis of naturally occurring proteins (see, e.g., J. David Rawn,
Biochemistry
, Chapter 3 “Amino acids and the primary structure of proteins”; McGraw-Hill, 1990).
The anion Y
−
can optionally be salified at the amino group, preferably with a hydrohalogen acid such as hydrochloric acid or phosphoric acid.
When R is an alkanoyl group, it is preferably selected from the group consisting of acetyl, propionyl, butyryl, valeryl and isovaleryl.
Whilst in order to illustrate the nutritional and therapeutic efficacy of the amino acids in general reference is made to the conspicuously vast literature published to-date on this matter (see, e.g., F. Fidanza and G. Liguori,
Nutrizione umana
, Chapter 3: “Le proteine”, Casa Editrice Libraria Idelson, 1995; and I. Goldberg (Ed.),
Functional Foods
, Chapter 12, “Amino acids, peptides and proteins” Chapman & Hall, Inc. 1994), it is deemed useful to briefly address the topic of the essential amino acids, in view of their peculiar role, and, among these, of the branched-chain amino acids.
It has long since been known that out of the nine essential amino acids (i.e. those normally occurring in proteins which can not be synthesized by the organism and must therefore be supplemented through the diet), the branched-chain amino acids (BAA) valine, leucine and isoleucine stimulate protein synthesis in skeletal muscle and liver. It is also well known that skeletal muscle is the main site for the initial step in BAAs catabolism resulting in energy production.
With reference to the attached figure which illustrates in a simplified form the relationships between proteins and amino acids within muscle cells, the first metabolic reaction in BAAs oxidative cataboli

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