Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-12-21
2002-08-27
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S547000, C514S556000, C514S922000
Reexamination Certificate
active
06441039
ABSTRACT:
The present invention relates to a method for reducing and counteracting gastrointestinal disorders brought about by the intake of L-carnitine in an individual in need thereof. More specifically, the present invention relates to a method for reducing and counteracting increased volume and fluidity of stools and frequency of bowel movements relative to the individual's usual pattern following intake of exogenous L-carnitine for therapeutic, nutritional or dietetic purposes.
As is well known, therapeutical uses of L-carnitine inner salt (hereinbelow, simply “L-carnitine”) have long since been known. For instance, L-carnitine has been used in the cardiovascular field for the treatment of acute and chronic myocardial ischaemia, angina pectoris, heart failure and cardiac arrhythmias.
In the nephrological field, L-carnitine has been administered to chronic uraemic patients undergoing regular haemodialytic treatment to combat myasthenia and the onset of muscular cramps.
Other therapeutic uses relate to the normalisation of the HDL:(LDL+VLDL) ratio and total parenteral nutrition.
Besides the aforesaid uses in the therapeutical field, L-carnitine has increasingly established itself on the so-called health food, medical food or nutraceutical market. These terms, which have yet to be rigorously defined from the regulatory point of view, denote foods or food components such as food supplements, dietetic products, energy foods, and the like, i. e. formulations which are not addressed to mainly or exclusively therapeutic purposes but which are aimed rather at enhancing well-being and at producing a general improvement in fitness and performance on the part of the consumer or at preventing metabolic disorders caused by dietary deficiencies or by the inadequate biosynthesis of essential endogenous substances as a result of advancing age.
The growing interest in L-carnitine in this field, too, stems from the increasingly widespread recognition, coroborated by scientific evidence, that L-carnitine, in addition to its well-known therapeutic value in the treatment of various diseases, makes a marked contribution towards supplying energy to the skeletal musculature and increasing resistance to prolonged, intense stress in professional athletes or in any subject practising sport also at amateur level, enhancing the performance capability of such subjects.
In addition, L-carnitine constitutes an indispensable nutritional supplement for vegetarians, whose diets have a low carnitine content as well as a low content of the two amino acids, lysine and methionine, which are the precursors of the biosynthesis of L-carnitine in the kidneys and liver.
The same considerations apply not only to those subjects who have feel debilitated, experiencing a particular state of stress or physical and/or mental fatigue.
Particularly but not exclusively for the aforesaid applications in the nutritional/dietetic field, solid, orally administrable L-carnitine-containing compositions are the preferred presentation form, inasmuch as they make it particularly easy for the users to take the active ingredient and comply with optimal dosage regimens. Since L-carnitine is a highly hygroscopic compound, the preparation of solid compositions entails complex problems of processing, stability and storage both of the raw material and of the finished products.
For instance, 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.
L-carnitine hygroscopicity has prompted considerable efforts in synthesising non-hygroscopic salts which are solid and stable, particularly even in conditions of prolonged storage, which can therefore be easily processed and formulated with the usual excipients, using blending, tabletting devices, etc., of a traditional type, and which, in addition, pose no packaging problems when converted into finished products.
To date, two L-carnitine salts have been developed and marketed which overcome the hygroscopicity drawback entailed by L-carnitine: L-carnitine L-tartrate and L-carnitine acid fumarate.
Apart, however, from the hygroscopicity problem, L-carnitine presents a further bothersome drawback to L-carnitine users: episodes of diarrhoea have been frequently reported (see e.g. Martindale, The Extra Pharmacopoeia, 31
st
Edition, 1996, page 356, and Drug Information for the Health Care Professional, 18
th
Edition, 1998, page 1856) whose number is bound to increase having regard to the steadily growing population of L-carnitine users.
This adverse effect is dose-related and may only be reduced by decreasing (e.g. by halving) the dose of L-carnitine. This drastic reduction is, however, in disagreement with recent recommendations having regard to the role of L-carnitine as a energizing nutrient which provide for a daily intake of up to 4 grams for L-carnitine to be effective (Crayhon R., The carnitine miracle, M. Evans and Company, Inc., New York, 1998, page 61).
Replacement of L-carnitine with L-carnitine L-tartrate may even worsen the aforesaid adverse effect. This is far from being surprising since:
“Tartaric acid is used . . . as a saline purgative. Strong solutions of tartaric acid are mildly irritant and if ingested undiluted may cause violent vomiting, diarrhoea and abdominal pain”.
(Martindale, loc. cit., page 1757)
Apart from the aforesaid gastrointestinal adverse effect, large doses of tartaric acid should be avoided also because they may cause renal damage (Goodman, L. & Gilman, A.: The pharmacological basis of therapeutics. MacMillan, New York, 1965, 3
rd
ed., p. 818; The Merck Index, New Jersey, 1960, 7
th
ed., p. 1012; Sollman, T.: A manual of pharmacology, Saunders, 1957, 8
th
ed., p. 1055).
Also a fatal case of human tartrate nephropathy was reported (Robertson B. et al., Acta Path. Microbiol. Scandinav. 74, 305-310, 1968).
The intake of large doses of L-carnitine (up to 4 grams/day) in the form of L-carnitine L-tartrate would, therefore, seem unsafe having regard to the remarkable amount of tartaric acid which should be ingested, too.
There is, therefore, the need of providing an L-carnitine replacement, i.e. an L-carnitine derivative, which, while on one hand maintaining the useful and beneficial therapeutical, nutritional and dietary properties of L-carnitine, is free of the aforesaid troublesome adverse effect shown by both L-carnitine and L-carnitine-L-tartrate.
REFERENCES:
patent: 4602039 (1986-07-01), Cavazza
patent: 6013670 (2000-01-01), Cavazza
patent: 0 637 449 (1995-02-01), None
patent: 2 529 545 (1984-01-01), None
Henley III Raymond
Jagoe Donna
Nixon & Vanderhye P.C.
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
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