Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-11-16
2003-10-21
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S012200, C514S021800, C514S046000, C514S055000, C536S020000, C536S026130, C536S027300, C536S027310, C435S088000, C435S176000, C435S113000, C424S063000
Reexamination Certificate
active
06635615
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new salts of S-adenosyl-1-methionine.
TECHNICAL FIELD
This patent relates to new salts of S-adenosyl-1-methionine (known as SAM-e) with polycations, the processes for obtaining them and to therapeutic uses of these new salts. More particularly, the invention relates to salts deriving from the reaction between SAM-e, SAM-e salts and polycations such as chitosan, their production process, and pharmaceutical compositions that contain them as active principles.
BACKGROUND OF THE INVENTION:
SAM-e is a naturally occurring substance that is present in all living organisms and has a number of very important biological functions. SAM-e exists in two enantiomeric forms as (S,S) S-adenosyl-1-methionine and (R,S) S-adenosyl-1-methionine. Among these functions are the following:
methyl group donor in transmethylation reactions (it is the sole methyl group donor in such reactions-including methylation of DNA, proteins, hormones, catechol and indoleamines and phosphatidylethanolamine to phosphatidylcholine); it is a substrate of an enzyme lyase that converts S-adenosyl-1-methionine to the molecule methylthioadenosine and homoserine; it is an aminobutyric chain donor to tRNA; it is an aminoacidic chain donor in the biosynthesis of biotin; SAM, after decarboxylation, is the donor of aminopropyl groups for the biosynthesis of neuroregulatory polyamines spermidine and spermine. (Zappia et al (1979) Biomedical and Pharmacological roles of Adenosylmethionine and the Central Nervous System, page 1, Pergamon Press. NY.)
SAM has been used clinically for more than twenty years in the treatment of liver disease (Friedel H, Goa, K. L., and Benfield P., (1989) S-Adenosyl-1-methionine: a review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. Drugs. 38, 389-416), arthritis (Di Padova C, (1987) S-adenosyl-1-methionine in the treatment of osteoarthritis: review of the clinical studies. Am J. Med. 83, (Suppl. 5), 6-65), and depression (Kagan, B, Sultzer D. L., Rosenlicht N and Gerner R. (1990) Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am. J. Psychiatry 147, 591-595.) Alzheimer's patients have reduced cerebral spinal fluid levels of S-adenosyl-1-methionine (Bottiglieri et al, (1990) Cerebrospinal fluid S-adenosyl-1-methionine in depression and dementia: effects of treatment with parenteral and oral S-adenosyl-1-methionine. J. Neurol. Neurosurg. Psychiatry 53, 1096-1098.) In a preliminary study, SAM was able to produce cognitive improvement in patients with Alzheimer's disease. (Bottiglieri et al (1994) The clinical potential of admetionine (S-adenosyl-1-methionine) in neurological disorders. Drugs 48, 137-152.) SAM-e brain levels in patients with Alzheimer's disease are also severely decreased. (Morrison et al, (1996) Brain S-adenosylnethionine levels are severely decreased in Alzheimer's disease, Journal of Neurochemistry, 67, 1328-1331. Patients with Parkinson's disease have also been shown to have significantly decreased blood levels of SAM. (Cheng et al, (1997) Levels of L-methionine S-adenosyltransferase activity in erythrocytes and concentrations of S-adenosylmethionine and S-adenosylhomocysteine in whole blood of patients with Parkinson's disease. Experimental Neurology 145, 580-585.) Oral SAM-e administration to patients with and without liver disease has resulted in increases in liver glutathione levels. (Vendemiale G et al, Effect of oral S-adenosyl-1-methionine on hepatic glutathione in patients with liver disease. Scand J Gastroenterol 1989;24:407-15. Oral administration of SAM-e to patients with suffering from intaahepatic cholestasis had improvements in both the pruritus as well as the biochemical markers of cholestasis. (Giudici et al, The use of admetionine (SAM-e) in the treatment of cholestatic liver disorders. Meta-analysis of clinical trials. In: Mato et al editors. Methionine Metabolism: Molecular Mechanism and Clinical Implications. Madrid: CSIC Press; 1992 pp 67-79.) Oral SAM-e administration to patients suffering from primary fibromyalgia resulted in significant improvement after a short term trial. (Tavoni et al, Evaluation of S-adenosylmethionine in Primary Fibromyalgia. The American Journal of Medicine, Vol 83 (suppl 5A), pp 107-110, 1987.)
SAM-e is clinically useful in many apparently unrelated areas because of its important function in basic metabolic processes. One of its most string clinical uses is in the treatment of alcoholic liver cirrhosis that, until now, remained medically untreatable. Mato et al, in 1999, demonstrated the ability of oral SAM in alcoholic liver cirrhosis to decrease the overall mortality and/or progression to liver transplant by 29% vs 12% as compared with a placebo treated group. (Mato et al, (1999) S-adenosylmethionine in alcohol liver cirrhosis: a randomized, placebo-controlled, double blind, multi-center clinical trial, Journal of Hepatology, 30, 1081-1089.) The extensive clinical use of SAM-e has proven its efficacy as well as its absence of toxicity in a number of different clinical conditions. Indeed, further basic science as well as clinical studies on this very important molecule may elucidate new uses for SAM-e in medicine.
SAM-e, however, presents certain difficult problems in terms of its stability at ambient temperature that result in degradation of the molecule to undesirable degradation products. SAM-e has therefore been the subject of numerous patents directed both towards the obtaining of new stable salts, and towards the provision of preparation processes which can be implemented on an industrial scale. There exist numerous patents disclosing many new salts of SAM-e but none discloses polycation salts such as chitosan salts of SAM-e. The following are representative patents of SAM-e salts currently on the pharmaceutical marketplace: Gennari, U.S. Pat. No. 5,102,791 Apr. 7, 1992, discloses, among others, a 1,4 butanedisulfonate salt of SAM-e but not polycation salts such as chitosan salts of SAM-e or of other SAM-e salts. Fiecchi, U.S. Pat. No. 4,028,183, Jun. 7, 1977, discloses, among others, p-toluene sulfonate as a means to stabilize the SAM-e molecule but does not disclose polycation salts such as chitosan salts of SAM-e or a salt of SAM-e. Kozaki et al, U.S. Pat. No. 4369177, Jan. 18, 1983, discloses stable compositions of SAM-e and SAM-e salts using a salt of a bivalent or trivalent metal but does not disclose the use of polycation salts such as chitosan salts of SAM-e or a salt of SAM-e. Zappia, U.S. Pat. No. 4764603, Aug. 16, 1988, discloses the use of polyanions such as polyphosphates, polyvinylsulfonates-sulfates or phosphates, polyacrylates, and polystyrene sulfonates. However, this patent does not disclose the use of a polycation salts such as chitosan salts of SAM-e or of SAM-e salts.
Administration of new SAM-e salts of the present invention would have significant utility over a wide range of disorders or conditions associated with low levels of SAM-e. These new salts would not cause gastrointestinal upset often associated with the current SAM-e salts. In this regard, and in view of the molecular instability of SAM-e at room temperature over time, it has been suggested that a more ideal salt of SAM-e would be able to withstand the conditions of room temperature over long periods of time which would duplicate the shelf life conditions under which these new SAM-e salts would be stored.
Accordingly, there is need in the art for new, stable salts of SAM-e as well as methods related to the use of such salts to increase blood and other tissue and fluid levels of SAM-e and to treat conditions which result from low blood and tissue levels of SAM-e. There is also a need in the art for synthetic routes to make such new salts. The author of this present invention fulfills these needs and provides further related advantages.
SUMMARY OF THE INVENTION
Briefly stated, the present invention
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