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Title:  Stable salts of S-adenosyl-l-methionine

United States Patent:  6,635,615

Issued:  October 21, 2003

Inventors:  Hebert; Rolland F. (427 Belleuve Ave. E. #301, Seattle, WA 98102)

Appl. No.:  713896

Filed:  November 16, 2000

Abstract

Stable salts of S-adenosyl-1-methionine with polycations such as chitosan are described. The salts according to the invention are very stable and are valuable for use as active constituents in pharmaceutical compositions.

SUMMARY OF THE INVENTION

Briefly stated, the present invention discloses new, stable salts of SAM-e, methods for the use thereof and synthetic methods for their preparation. These new salts of SAM-e of this present invention have utility in increasing blood and other tissue or fluid levels of SAM-e, as well as treating or preventing a wide variety of conditions associated with low blood or other tissue or fluid levels of SAM-e. Thus in one embodiment, a new SAM-e salt is administered to a warm-blooded animal in need thereof to increase SAM-e levels. In another embodiment, a new SAM-e salt is administered to a warm blooded animal in need thereof to prevent or treat a condition associated with low levels of SAM-e. In yet a further embodiment, a new SAM-e salt is administered to a warm blooded animal in need thereof to prevent and or treat the following conditions: aging, aging of the skin, Alzheimer's disease, arthritis, both as an anti-inflamrnatory as well as to promote new cartilage formation, nerve damage associated with HIV/AIDS, anxiety, obsessive compulsive disorder, attention deficit disorder and ADHD, sleep regulation, organ preservation for transplant industry, treatment of dyslipidemias, excess sebum production, migraines, prevention and treatment of bile dysfunction caused by pregnancy and use of contraceptive medications, cancer, depression, acute and chronic liver disease, cirrhosis of the liver, ischemic reperfusion injury of stroke as well as organ ischemic reperfusion in transplant technology, Parkinson's disease, memory disturbances, intrahepatic cholestasis, inflammation, pain and to counteract the decrease in SAM-e caused by various cancer drugs.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, this invention is generally directed to new salts of SAM-e. Such new SAM-e salts when administered to a warm blooded animal in need thereof have utility in the prevention or treatment of conditions associated with low levels of SAM-e in warm blooded animals, including humans.

As used herein, the term "conditions" includes diseases, injuries, disorders, indications and/or afflictions that are associated with decreased levels of SAM-e. The term "treat" or "treatment" means that the symptoms associated with one or more conditions associated with low levels of SAM-e are alleviated or reduced in severity or frequency and the term "prevent" means that subsequent occurrences of such symptoms are avoided or that the frequency between such occurrences is prolonged.

The following examples illustrate the synthetic process by which the new stabilized salts may be made. These examples are given to illustrate the present invention, but not by way of limitation. Accordingly, the scope of this invention should be determined not by the embodiments illustrated, but rather by the appended claims and their legal equivalents.

EXAMPLE 1

Chitosan (a polyglucosamine) (38.9 mg, degree of deacetylation 83.6%) was added to S-adenosylmethionine chloride (200 mg) in 5 ml deionized water. The solution was stirred for 4 hours, filtered and freeze dried.

EXAMPLE 2

Chitosan (a polyglucosamine) (30.5 mg, degree of deacetylation 83.6%) was added to S-adenosylmethionine sulfate p-toluenesulfonate (200 mg) in 5 ml deionized water. The solution was stirred for 4 hours, filtered and freeze dried.

EXAMPLE 3

Chitosan (a polyglucosamine) (38.9 mg, degree of deacetylation 83.6%) was added to S-adenosylmethionine chloride (200 mg) in 5 ml deionized water. The solution was stirred under nitrogen for 4 hours, filtered and freeze dried.

EXAMPLE 4

Chitosan (a polyglucosamine) (30.5 mg, degree of deacetylation 83.6%) was added to S-adenosylmethionine sulfate p-toluenesulfonate (200 mg) in 5 ml deionized water. The solution was stirred under nitrogen for 4 hours, filtered and freeze dried.

EXAMPLE 5

Chitosan (a polyglucosamine) (15.25 mg, degree of deacetylation 80.1%) was added to S-adenosylmethionine chloride (200 mg) in 5 ml deionized water. The solution was stirred for 4 hours, filtered and freeze dried.

EXAMPLE 6

Chitosan (a polyglucosamine) (39.5 mg, degree of deacetylation 80.1%) was added to S-adenosylmethionine chloride (200 mg) in 5 ml deionized water. The solution was stirred for 4 hours, filtered and freeze dried.

EXAMPLE 7

Chitosan (a polyglucosamine) (39.5 mg, degree of deacetylation 80.1%) was added to S-adenosylmethionine chloride (200 mg) in 5 ml deionized water. The solution was stirred under nitrogen for 4 hours, filtered and freeze dried.

EXAMPLE 8

Chitosan (a polyglucosamine) (39.5 mg, degree of deacetylation 80.1%) was added to S-adenosylmethionine chloride (200 mg) in 5 ml deionized water. The solution was stirred in an ice bath for 6 hours, filtered and freeze dried.

EXAMPLE 9

Chitosan (a polyglucosamine) (39.5 mg, degree of deacetylation 80.1%) was added to S-adenosylmethionine chloride (200 mg) in 5 ml deionized water. The solution was stirred under nitrogen for 4 hours, filtered and freeze dried.

S-adenosylmethionine chloride, S-adenosylmethionine sulfate-p-toluenesulfonate and chitosan are available commercially from Sigma Chemical Company, St. Louis, Mo.

EXAMPLE 10

                       Analysis:       Analysis:
                       May 11, 2000    Aug. 22, 2000
                       Concentration   Concentration
    compound           1:500 (nmol/L)  1:500 (nmol/L)  % Change
    SAM-e-1,4-butane-  1417.96         794.41          -43.9%
    disulphonate
    Chitosan salt of   617.31          536.22          -13.1%
    SAMe-1,4-butane-
    disulphonate

SAM-e-1, 4-butane-disulphonate and chitosan salt of SAM-e 1, 4-butane-disulphonate were stored at room temperature, in a closed, clear glass vial at constant humidity. HPLC analysis done according to Bottligleri, T. (1990) Isocratic high performance liquid chromatographic analysis of S-adenosylmethionine and S-adenosylhomocysteine in animal tissues: the effect of exposure to nitrous oxide. Biomed Chromatogr, 4(6):239-41. The SAM-e 1,4 butanedisulphonate deteriorated by 43% over the period of time. By contrast, however, chitosan salt of SAM-e 1, 4-butane-disulphonate deteriorated by only 13.1% over the same period.

EXAMPLE 11

Stability study-of polycation (chitosan) salt of SAM-e tosylate

                      Analysis:       Analysis:
                      Dec. 28, 1999   Apr. 4, 2000
                      Concentration   Concentration
                      0.5 mg/ml       0.5 mg/ml
    compound          1:125 (nmol/L)  1:125 (nmol/L)  % Change
    SAM-e tosylate    3492            247.9           -92.9.0%
    Chitosan salt of  3687            3280            -11.04%
    SAM-e tosylate

SAM-e tosylate and chitosan salt of SAM-e tosylate were stored at room temperature, in a closed, clear glass vial at constant humidity. HPLC analysis done according to Bottligleri, T. (1990) Isocratic high performance liquid chromatographic analysis of S-adenosylmethionine and S-adenosylhomocysteine in animal tissues: the effect of exposure to nitrous oxide. Biomed Chromatogr, 4(6):239-41. The SAM-e tosylate deteriorated by 92.9% over the period of time. By contrast, however, chitosan salt of SAM-e tosylate deteriorated by only 11.04% over the same period.

As can be seen from examples 10 and 11, the new chitosan salts of SAM-e are much more stable at room temperature than salts of SAM-e which are currently pharmaceutically available.

Claim 1 of 10 Claims

I claim:

1. A composition comprising S-adenosyl-1-methionine salts and a chitosan.



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