Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Reexamination Certificate
1999-11-30
2001-07-03
Carr, Deborah D. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
C554S121000, C562S553000, C562S562000, C562S561000
Reexamination Certificate
active
06255503
ABSTRACT:
This application is a 371 of PCT/IT98/00144 filed May 29, 1998.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to water-soluble salts of dodecandioic acid and compositions with therapeutic or nutritional activity containing such salts.
Dodecandioic acid, HOOC(CH
3
)
10
COOH, and its derivatives such as amides with amino acids, triglycerides and their pharmacologically acceptable salts have recently aroused substantial interest in the nutritional field.
2. Description of the Related Art
EP 0569393 B1 discloses the use of linear C6-C12 dicarboxylic acids, including dodecandioic acid, and their esters, amides and triglycerides in enteral and parenteral nutrition in which the use of such dicarboxylic acids with an even number of carbon atoms as an alternative energy substrate proves particularly useful in those conditions wherein the utilisation of glucose and/or free fatty acids is prevented.
Since these linear acids with an even number of carbon atoms are symmetrical, they can be &bgr;-oxidised starting from the &agr; or &ohgr;-carboxyl group supplying acetyl CoA and succinic acid as the end product The increased availability of succinic acid stimulates the metabolism of other substrates via the Krebs cycle. In addition, succinic acid is a gluconeogenic precursor, with the result that the administration of such acids is believed to increase the accumulation of glycogen in those clinical conditions that give rise to a decrease in glycogen owing to inadequate glycogen-synthase activity (as occurs in diabetes mellitus) and to reduce the catabolic breakdown of amino acids in conditions of increased glycogenolysis (as occurs in conditions of sepsis, trauma or major abdominal surgery).
Dodecandioic acid has also recently been proposed for cosmetic use, particularly for the production of creams for the treatment of wrinkles, for the regeneration of the skin and to combat the damage of ageing and exposure to the sun's rays.
BRIEF SUMMARY OF THE INVENTION
All the above-mentioned applications are facilitated when derivatives of dodecandioic acid are available which are water-soluble, since dodecandioic acid is known to be practically insoluble in water (0.05 g in 1 liter of H
2
O at 23° C.; Ber. 23, 2347 [18901]). Water-soluble derivatives of dodecandioic acid could, on the other hand, be easily administered and promptly used as an energy substrate.
Water-soluble salts of dodecandioic acid are already known.
Such salts are, however, dodecandioates of alkaline metals, particularly sodium. The administration of substantial amounts of these salts, particularly by parenteral nutrition, may alter the electrolyte balance in subjects who are already severely debilitated by the disease or surgical intervention that makes parenteral nutrition necessary and may prove damaging in general in anyone obliged to go on a low-sodium diet.
One object of the present invention is to provide water-soluble salts of dodecandioic acid which do not present the aforesaid drawbacks.
A further object of the present invention is to provide water-soluble salts of dodecandioic acid, whose cationic moiety, unlike the above-mentioned known salts, presents an intrinsic therapeutic or nutritional value.
It should, therefore, be clearly understood that the usefulness of the salts of the present invention does not consist merely in their water-solubility but also in the fact that such salts present as a whole an increased therapeutic and/or nutritional value as compared to the known dodecandioates, this latter value therefore not being exclusively brought about by the anionic moiety of the salt.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, the aforesaid objects are achieved by the dodecandioic acid salts of general formula (I):
[
−
OOC(CH
2
)
10
COO
−
]X
+
Y
+
(I)
wherein:
if X
+
is the same as Y
+
, it is selected from the group comprising the cations of basic amino acids and choline; or
if X
+
is other than Y
+
, they are selected from:
(a) the cations of basic aminoacids and choline; and
(b) the cations of alkaline metals and ammonium, provided that if either of X
+
or Y
+
is a (b) cation, the other is an (a) cation.
The cations of the basic aminoacids are the cations of lysine, arginine, hystidine and ornithine, while the cations of the alkaline metals are selected from the groups comprising Na
+
and K
+
.
The compositions of the present invention comprise a salt of formula (I) as active ingredient, optionally in combination with one or more further active ingredients and, optionally, a pharmacologically acceptable excipient.
The aforesaid compositions comprise the enterally or parenterally administrable compositions. These generally occur as aqueous solutions generally containing 0.1-1.0 moles/liter of salt of formula (I) or a molar equivalent amount of a pharmacologically acceptable salts thereof.
In the compositions which comprise a further active ingredient, preferably this is L-carnitine or an alkanoyl L-carnitine wherein the alkanoyl group has 2-6 carbon atoms or a pharmacologically acceptable salt thereof. The composition comprises 0.1-0.5 moles/liter of L-carnitine or alkanoyl L-carnitine or a molar equivalent amount of a pharmacologically acceptable salt thereof.
What is meant by pharmacologically acceptable salt of L-carnitine or alkanoyl L-carnitine is any salt of these with an acid that does not give rise to unwanted toxic or side effect. These acids are well known to pharmacologists and to experts in pharmacy.
Non-limiting examples of such salts are: chloride; bromide; iodide; aspartate; acid aspartate; citrate; acid citrate; tartrate; phosphate; acid phosphate; fumarate; acid fumarate; glycerophosphate; glucose phosphate; lactate; maleate; acid maleate; orotate; oxalate; acid oxalate; sulphate; acid sulphate; trichloroacetate; trifluoroacetate and methanesulphonate.
A list of FDA-approved pharmacologically acceptable salts is disclosed in Int. J. Pharm. 33, (1986), 201-217; this latter publication is incorporated herein by reference.
The following non-limiting examples show the preparation of some dodecandioic salts according to the invention.
REFERENCES:
patent: 733119 (1966-04-01), None
patent: 0 000 158 (1979-01-01), None
patent: 2 235 938 (1975-01-01), None
patent: 2 048 262 (1980-12-01), None
patent: 48 043 487 (1973-06-01), None
patent: WO 92 12960 (1992-08-01), None
Santaniello Mose
Scafetta Nazareno
Tinti Maria Ornella
Carr Deborah D.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Sigma-Tau HealthScience S.p.A.
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