Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1998-03-17
2001-04-17
Kishore, Gollamudi S. (Department: 1205)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S451000, C424S464000, C424S489000, C514S557000, C514S824000
Reexamination Certificate
active
06217898
ABSTRACT:
The present invention relates to a novel therapeutic use of L-carnitine, some alkanoyl L-carnitines and the pharmacologically acceptable salts thereof in combination with hydroxycitric or pantothenic acid or derivatives thereof (wherein “derivatives thereof” also encompasses natural products and their extracts containing same) for the prevention and therapeutic treatment of diseases brought about by lipid metabolism disorders, such as cardiovascular disorders, atherosclerosys, hyperlipidaemias and obesity, and for controlling and decreasing the appetite.
According to its broadest aspect the invention relates to the co-ordinated use of L-carnitine or an alkanoyl L-carnitine or the pharmacologically acceptable salts thereof with hydroxycitric or pantothenic acid or derivatives thereof. By “co-ordinated use” of the aforesaid compounds it is meant indifferently either the co-administration, i.e. the substantially concomitant supplementation of L-carnitine or alkanoyl L-carnitine or a pharmacologically acceptable salt thereof and hydroxycitric or pantothenic acid or a derivative thereof, as active ingredients, or the administration of a combination preparation comprising a mixture of the aforesaid active ingredients, in addition to suitable excipients, if any.
The present invention also relates to orally, parenterally, rectally or transdermally administrable pharmaceutical compositions suitable for treating the aforesaid disorders and for controlling and decreasing the appetite, which comprise, as active ingredients, L-carnitine or an alkanoyl L-carnitine or a pharmacologically acceptable salt thereof and hydroxycitric acid or pantothenic acid or derivative thereof. Preferred hydroxycitric acid derivatives are the salts and esters thereof and the natural products and their extracts containing same, as specified in more detail hereinbelow. It should be understood that whenever in the present specification reference is made for the sake of simplicity to “hydroxycitric acid”, the naturally occurring compound, i.e (−)-treo hydroxycitric acid, is meant.
Preferred pantothenic acid derivatives comprise 4′-phospho-pantothenate, 4′-phosphopantothenylcisteine, 4′-phosphopantotheine, pantotheine and pantethine. Pantethine is particularly preferred.
Hydroxycitric acid and derivatives thereof may occur as extracts of natural products containing hydroxycitric acid at high concentrations, such as the extract of the fruits of Garcinia (Garcinia cambodia, Garcinia atroviridis, Garcinia indica, Garcinia citrin), of the fruits of Malabar Tamarind or Gorikapuli (Lewis Y. L., Neelakantan S., Phyto-chemistry 4, 619, 1965), (Streenivasan A., Vankataraman R., Current Science 4, 151, 1959) or other extract of natural products containing same.
A preferred salt of hydroxycitric acid is calcium hydroxycitrate.
The alkanoyl L-carnitines useful for the novel therapeutic use of the present invention are those wherein the alkanoyl group is a straight or branched group, having from 2 to 8 carbon atoms, preferably from 2 to 6 carbon atoms
Particularly preferred are acetyl, propionyl, butyryl, valeryl and isovaleryl L-carnitine.
Pharmaceutically acceptable salts of L-carnitine or alkanoyl L-carnitine include, in addition to the inner salts, any salt of these with acids which do not give rise to undesired or side effects. The formation of pharmaceutically acceptable acid addition salt is well known to the experts in pharmacy and pharmaceutical technology.
Non-limiting examples of suitable salts include the chloride, bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarate, acid fumarate, lactate, maleate, acid maleate, acid oxalate, acid sulfate, glucose phosphate, tartrate and acid tartrate salts.
Previous therapeutic uses of L-carnitine are already known.
For instance L-carnitine has been used in the cardiovascular field in the treatment of acute and chronic myocardial ischaemia, angina pectoris, cardiac arrhythmias and insufficiency, and peripheral vascular diseases.
In nephrology, L-carnitine has been administered to chronic uraemic patients who are subjected to regular haemodialysis treatment with a view to counteracting muscular asthenia and the onset of muscular cramps.
Moreover, U.S. Pat. No. 3,810,994 (Ethyl Corporation) discloses the therapeutic utility of pharmaceutical compositions of L-carnitine or salts or esters thereof, for the treatment of obesity.
U.S. Pat. No. 4,255,449 (Cavazza) and U.S. Pat. No. 4,268,524 (Cavazza) disclose the use of L-carnitine and alkanoyl L-carnitine to normalize the abnormal ratio between low density lipoprotein (LDL)+very low density lipoproteins (VLDL) and high density lipoprotein (HDL) which is an aetiological factor for various cardiovascular diseases.
As known, through the beta-oxidation of fatty acids L-carnitine is capable of preventing their accumulation and of supplying the energy requirement of cells (Bremer Y., TIBS 2, 207, 1977) via modulation of extra- and intramitochondrial CoA.
The carnitine pool not only regulates the bio-oxidation of intramitochondrial fatty acids, but also inhibits the formation of triglycerides (Bieber L. L., J. Biol. Chem. 254, 8163, 1979; Pande D. V., Proc. Nat. Acad. Sci. USA 72, 883, 1975).
Hydroxycitric acid, too, has for some time now been known as a metabolic factor. It is present, in fact, in large amounts in a number of plants used as foodstuffs and, in particular, in Malabar Tamarind and in the fruits of various species of Garcinia and its extraction and isolation have permitted extensive biochemical and pharmacological study of the substance. Recent data have revealed its importance as a regulator of the synthesis of cholesterol and fatty acids (Hamilton Y. G., Lipids 12, 1, 1976).
Hydroxycitric acid is capable of inhibiting the activity of ATP-citratolyase, an enzyme which catalyses the extramitochondrial conversion of citrates to oxoacetates and acetyl Coenzyme A.
The importance of this enzyme consists in its ability to maintain the Coenzyme A pool necessary for lipid and cholesterol synthesis. The enzymatic reaction catalysed by citratolyase which leads to the synthesis of cholesterol and fatty acids from carbohydrates is inhibited by hydroxycitric acid which together with the reduction in lipid synthesis also leads to a greater storage of carbohydrates in the form of glycogen in the liver (Berkbout T. A., Biochem. J. 48, 6, 1990; Triscari Y., Sullivan A. C., Lipids 12, 357, 1976; Watson Y. A., Fang M., Arch. Biochem. Biophys. 135, 209, 1969).
Both L-carnitine and hydroxycitric acid are, therefore, capable of exerting an action upon lipid metabolism via different mechanisms: on the one hand, L-carnitine facilitates the oxidation and intramitochondrial utilization of fatty acids and prevents the accumulation of triglycerides, and, on the other, hydroxycitric acid prevents their actual synthesis (Lowenstein Y. M., J. Biol. Chem. 246, 629, 1971; Hood R. L., Comp. Biochemical Physiol. 81B, 667, 1985).
What have proved very surprising and unexpected, however, are the synergistic effects which can be obtained on energy metabolism and on lipid metabolism by combining these two compounds or by co-ordinately administering them.
This unexpected synergistic effect obtained by the co-ordinated use of L-carnitine or its derivatives and hydroxycitric or pantothenic acid or derivatives thereof has been demonstrated in numerous studies, so much so, indeed, as to suggest that this combination can be used to advantage in facilitating the elimination of lipids and cholesterol from tissues, in the treatment of cardiovascular diseases, and in preventing abnormal formation and accumulation of fats.
The research conducted to date has shown that the co-ordinated use of the two compounds proves surprisingly effective in inhibiting the formation of atherosclerosis and the infiltration of tissues, as well as the formation of cholesterol and triglycerides.
In addition to the anticholesterolaemic and antidyslipidaemic effects induced by this combination, the research has also revealed a reduction of appetite
Kishore Gollamudi S.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Sigma-Tau HealthScience S.p.A.
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