Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-05-20
2004-08-24
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S909000, C536S020000, C536S124000
Reexamination Certificate
active
06780851
ABSTRACT:
The present invention relates to a composition suitable for the prevention and/or treatment of disorders due to abnormal lipid metabolism, such as hypercholesterolaemia, atherosclerosis, hyperlipidaemia and obesity, comprising as characterising active ingredients propionyl L-carnitine or a pharmacologically acceptable salt thereof, and chitosan.
Corresponding, the composition may take the form and exert the activity of a dietary supplement or of an actual medicine, depending upon the support or preventive action or the strictly therapeutic action which the composition is intended to exert according to the particular individuals for whom it is to be used.
The action of the carnitines in general, and of propionyl L-carnitine in particular, on lipid metabolism is well known, as is their antiatherosclerotic action and their action on lipid metabolism disorders.
The carnitines activate the processes of &bgr;-oxidation of intramitochondrial fatty acids and the oxidation of branched-chain amino acids, as well as regulating insulin activity. In particular, propionyl L-carnitine is capable of stabilising the phospholipid membranes and the deformability of erythrocytes, as well as of acting on lipid peroxidation phenomena.
All these properties of the carnitines, and particularly of propionyl L-carnitine, therefore emphasis their importance in the regulation of the metabolism of lipids and related phenomena such as atherosclerosis, hypercholesterolaemia, hypertriglyceridaemia, lipid accumulation and weight gain.
In the same sense, though with a different mechanism, a class of substances known as chitosans may take effect on lipid metabolism. The chitosans consist mainly of naturally occurring chitins of a polysaccharide type present above all in the exodermal part of shellfish in the form of poly-&bgr;-1,4-acetylglucosamine, the de-acetylation of which can lead to simpler structures such as poly-&bgr;-1,4-D-glucosamine, which also determine a greater solubility of the product related to the lower molecular weight which may range from 100,000 to 1,000 according to the procedure used for preparing the various oligomers.
The main characteristic of these products is related to their lipophilicity and consists, via their basic charges, in binding to fatty acids, preventing their absorption, for instance, at the intestinal level.
Experiments conducted in animals treated with chitosan have, in fact, demonstrated its efficacy in reducing hypercholesterolaemia, as well as serum and hepatic lipids, while experiments in human subjects have demonstrated its efficacy particularly in diets suitable for reducing body weight and in obese patients.
The lipid-lowering and weight-reducing effect of chitosan occurs fairly rapidly, and no signs of intolerance or toxicity have been reported in the course of its use.
It has now surprisingly been found that a composition containing as its characterising active ingredients:
(a) propionyl L-carnitine or a pharmacologically acceptable salt thereof, and
(b) chitosan is particularly useful, thanks to an unexpected, potent synergistic action between the components, in the prevention and/or treatment of disorders due to abnormal lipid metabolism, such as hypercholesterolaemia, atherosclerosis, hyperlipidaemia and obesity.
It has also been found that, advantageously, component (a) may additionally contain a “carnitine” selected from the group consisting of acetyl L-carnitine, valeryl L-carnitine, isovaleryl L-carnitine and butyryl L-carnitine or a pharmacologically acceptable salt thereof or mixtures thereof.
In the composition of the present invention, the weight ratio of (a) to (b) may range from 1:1 to 1:5, and preferably from 1:1 to 1:3.
The composition of the present invention may further comprise vitamins, coenzymes, mineral substances, amino acids and antioxidants.
The new composition, which is the object of the present invention, exploits the favourable activities exerted on lipid metabolism and on absorption of fats by alkanoyl L-carnitines, and particularly propionyl L-carnitine, or by propionyl L-carnitine together with acetyl L-carnitine, valeryl L-carnitine, isovaleryl L-carnitine and/or butyryl L-carnitine, or a pharmacological acceptable salt thereof, when these are combined with chitosan, achieving an unexpected and surprising synergistic effect between its components which is extremely advantageous for exploitation in the field of the prevention and treatment of disorders due to abnormal lipid metabolism, such as hypercholesterolaemia, atherosclerosis, hyperlipidaemia and obesity.
Experimental Atherosclerosis Tests
According to the regimen suggested by Malinow (Malinow M. R.,
Atherosclerosis
, 48:105, 1983) an atherogenic diet consisting of 24% casein, 10% cotton oil, 5% sodium chloride, 60% sugar, 1% cholesterol, and Vit. D
2
200 mUST/g diet was administered for six weeks consecutively to different groups of male Wistar rats.
While one group of rate served as a control group, the other groups were administered chitosan (100 mg/kg) or propionyl L-carnitine (100 mg/kg) or chitosan (100 mg/kg) plus propionyl L-carnitine (100 mg/kg).
Another group of animals was administered acetyl L-carnitine (100 mg/kg) and butyryl L-carnitine (100 mg/kg) in addition to chitosan and propionyl L-carnitine.
The results of these tests demonstrated a substantial protective effect against the atherosclerotic lesions induced by the atherogenic diet by both propionyl L-carnitine and by chitosan, but surprisingly the maximum protective effect was detectable when chitosan was combined with propionyl L-carnitine.
In this group of rats, in fact, morphometric measurement of the thickness of the abdominal aorta and the intensity of the staining induced by Sudan IV reveal a substantial synergistic action of the protective effect afforded by the combination of the two components. The protection appears even more marked with the combination of the various alkanoyl L-carnitines (propionyl L-carnitine, acetyl L-carnitine, butyryl L-carnitine) plus chitosan.
Tests in Experimentally Obese Rats
In these tests, male Wistar rats aged approximately two months were administered a lipogenic diet containing 50% glucose, 20% casein, 4% cellulose, 1% hazel nut oil, 18% starch, 2% vitamin mixture, and 5% salt mixture. The diet was administered for fifteen days consecutively to different groups of rats, one of which served as a control group, whereas the remaining groups were administered daily, per 100 g of diet, 2 g of propionyl L-carnitine or 1 g of chitosan, or the two compounds in combination at the same doses.
Another group was also administered acetyl L-carnitine (2 g/100 g diet) and butyryl L-carnitine (0.5 g/100 g diet) in addition to propionyl L-carnitine and chitosan.
At the end of the fifteenth day since the beginning of the diet, feed consumption and increase in body weight were calculated for each group of rats. The results are presented in Tables 1 and 2 here below.
TABLE 1
Mean daily feed consumption (g)/animal
Before
At the end of
treatment
treatment
Propionyl L-carnitine
19.8 ± 0.71
18.9 ± 0.50
Chitosan
18.5 ± 0.45
16.6 ± 0.95
Propionyl L-carnitine + chitosan
19.3 ± 0.60
13.1 ± 0.71
Propionyl L-carnitine + acetyl L-carnitine +
18.9 ± 0.55
12.5 ± 0.75
butyryl L-carnitine + chitosan
TABLE 2
Mean body growth
Final weight increase
Controls
65.6 ± 4.1
Propionyl L-carnitine
60.8 ± 5.2
Chitosan
49.5 ± 3.9
Propionyl L-carnitine + chitosan
29.7 ± 2.9
Propionyl L-carnitine + acetyl L-carnitine +
26.3 ± 3.4
butyryl L-carnitine + chitosan
On the basis of the data presented, there is a marked reduction in body weight together with a reduction in feed consumption, particularly in the group of animals treated with propionyl L-carnitine plus chitosan, thus demonstrating in this case a true synergistic effect between these two compounds.
Tests in Experimentally Hypercholesterolaemic Rabbits
Another type of experiment was conducted in New Zealand rabbits kept on a hype
Nixon & Vanderhye P.C.
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
White Everett
Wilson James O.
LandOfFree
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