Compositions Comprising S-Adenosylmethionine and a Gallic Acid Ester

• US 20150283161A1
• Filed: 10/16/2013
• Published: 10/08/2015
• Est. Priority Date: 10/17/2012
• Status: Active Grant

• Current Assignee: Msi-195 Holdings LLC
• Original Assignee: Methylation Sciences International SRL (MSI Methylation Sciences, Inc.)
• Inventors: Guan, Dechi, MacDonald, I. David
• Granted Patent: US 9,801,896 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/235 having an aromatic ring attached to a carboxyl group
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/18 Antioxidants, e.g. antiradicals preparations for protection against sunlight A61Q17/00
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/32 : Alcohol-abuse
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/06 : Free radical scavengers or antioxidants
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Provided herein are compositions and formulations comprising S-adenosyl-L-methionine (“SAM-e” or “SAMe”) and one or more gallic acid esters. Also provided herein are methods for improving the delivery of SAMe. Compositions and formulations provided herein increase SAMe plasma concentrations and area under the curve (AUC) values. Also provided herein are methods of treating a disease or disorder in a subject by administering compositions or formulations comprising exogenous SAMe and one or more gallic acid esters.

Claims

1. A composition comprising exogenous S-adenosylmethionine and at least one gallic acid ester, wherein said composition does not comprise epigallocatechin gallate.

2. The composition of claim 1, wherein said gallic acid ester is selected from the group consisting of ethyl gallate, isoamyl gallate, propyl gallate, octyl gallate, methyl gallate, butyl gallate, isobutyl gallate, dodecyl gallate, and hexadecyl gallate.

3. The composition of claim 1, wherein said gallic acid ester is ethyl gallate

4. The composition of claim 1, wherein said gallic acid ester is isoamyl gallate

5. The composition of claim 1, wherein said gallic acid ester is propyl gallate

6. The composition of claim 1, wherein said gallic acid ester is octyl gallate.

7. The composition of claim 1, wherein the ratio (weight:

weight) of gallic acid ester to exogenous S-adenosylmethionine is from 5;

1 to 1;

400.

8. The composition of claim 1, wherein the ratio (weight:

weight) of propyl gallate to exogenous S-adenosylmethionine is from 1;

1 to 1;

100.

9. The composition of claim 1, wherein the ratio (weight:

weight) of propyl gallate to exogenous S-adenosylmethionine is from 1;

2 to 1;

80.

10. The composition of claim 1, wherein said composition comprises from about 1 to 400 mg of said gallic acid ester.

11. The composition of claim 5, wherein said composition comprises from about 5 to 200 mg of propyl gallate.

12. The composition of claim 5, wherein said composition comprises from about 5 to 100 mg of propyl gallate.

13. The composition of claim 1, wherein said composition comprises 0.1 to 80%, 0.25 to 50%, 0.25 to 25%, 0.25 to 10%, or 0.5 to 10% by weight gallic acid ester.

14. The composition of claim 1, wherein the composition when administered to a selected subject group provides in said selected subject group an average maximum SAMe blood plasma concentration (average C_max) of at least about 1.2 ng/mL per each 1 mg dosage of SAMe ion.

15. The composition of claim 1, wherein the composition when administered to a selected subject group provides in said selected subject group an average SAMe C_max of at least about 1.3 ng/mL per each 1 mg dosage of SAMe ion.

16. The composition of claim 5, wherein said composition comprises SAMe and propyl gallate and wherein said composition when administered to a selected subject group provides in said selected subject group an average SAMe C_max of at least about 1.2 ng/mL per each 1 mg of SAMe ion.

17. The composition of claim 1, wherein the composition when administered to a selected subject group provides in said selected subject group an average SAMe plasma area under the curve (average AUC) of at least about 8 ng·

h/mL per each 1 mg dosage of SAMe ion.

18. The composition of claim 5, wherein said composition comprises SAMe and propyl gallate and wherein said composition when administered to a selected subject group provides in said selected subject group an average SAMe AUC of at least about 8.5 ng·

h/mL per each 1 mg of SAMe ion.

19. The composition of claim 1, wherein the dose of exogenous SAMe ion is at least 10 mg.

20. The composition of claim 1, wherein the dose of exogenous SAMe ion is from 10 mg to 3600 mg.

21. The composition of claim 1, wherein the composition when administered to a selected subject group provides in said selected subject group one of an average T_max or C_max with reduced variation or a reduced effective dose in comparison to a control group that has been administered SAMe alone.

22. The composition of claim 1, wherein the composition when administered to a selected subject group through once a day dosing provides in said selected subject group an improved SAMe pharmacokinetic profile in comparison to bi-daily or more frequent dosing of conventional SAMe formulations in a control group.

23. The composition of claim 21, wherein the composition when administered to a selected subject group provides in said selected subject group a reduced side effect profile in comparison to a control group that has been administered SAMe alone.

24. The composition of claim 1, wherein the composition when administered to a selected subject group provides in said selected subject group an improved rate of onset of exogenous SAMe supplementation in comparison to a control group that has been administered SAMe alone.

25. The composition of claim 1, wherein the composition is in a unit dosage form that comprises a functional coating, wherein the functional coating constitutes from 1 to 20% of the total weight of the unit dosage form.

26. The composition of claim 1, wherein the composition is an oral composition.

27. The composition of claim 26, wherein the composition is a capsule or non-capsule dosage form.

28. The composition of claim 27, wherein said capsule or non-capsule dosage form comprises an enteric, time-release non pH-dependent, or pH-dependent coating.

29. The composition of claim 27, wherein said capsule or non-capsule dosage form further comprises a seal coat.

30. The composition of claim 28, wherein said gallic acid ester is ethyl gallate, isoamyl gallate, propyl gallate or octyl gallate.

31. The composition of claim 28, wherein said gallic acid ester is propyl gallate.

32. A method of treating a disease or disorder selected from the group consisting of a mental or psychiatric disorder, nervous system disease or disorder, neurological disease or disorder, condition associated with injury to the central nervous system, liver disease or disorder, cancer, joint disease or disorder, inflammatory disease or disorder, autoimmune disease or disorder, degenerative disease or disorder, soft-tissue disease or disorder, pain disease or disorder, genetic disorder related to hyper- or hypo-methylation, gastrointestinal disease or disorder, cardiovascular disease or disorder, atherosclerosis, Lesch-Nyhan disease, and disorder induced in whole or in part by oxidative or free-radical damage, comprising administering a composition of claim 1 to a patient in need thereof.

34. The method of claim 32, wherein the mental or psychiatric disorder is selected from the group consisting of an anxiety disorder, schizophrenia, major depressive disorder, major depression, clinical depression, dysthymic disorder, anxiety depression, atypical depression, melancholic depression, catatonic depression, situational depression, reactive depression, late-life depression, Seasonal Affective Disorder (SAD), minor depression, postpartum depression, inflammatory depression, late-life depression, brief recurrent depression, mild depression, treatment-resistant depression (TRD), co-morbid depression, Parkinson'"'"'s depression, HIV-associated depression, multi-infarct dementia, and bipolar disorder;

the inflammatory disease or disorder is selected from the group consisting of systemic lupus, inflammatory bowel disease, allergic rhinitis, contact dermatitis, asthma, autoimmune hepatitis, and pelvic inflammatory disease;

the cardiovascular disease or disorder is selected from the group consisting of hyper- or hypo-homocysteinemia, coronary heart disease, stroke, peripheral vascular disease, and atherosclerotic disease;

the depressive disorder is a co-morbid depression arising in a subject who is or has been undergoing treatment for one or more diseases or disorders selected from the group consisting of cancer, Parkinson'"'"'s disease, and HIV;

the nervous system disease or disorder or injury is selected from the group consisting of Parkinson'"'"'s disease, Alzheimer'"'"'s disease, and cognitive impairment;

the liver disease or disorder is selected from the group consisting of alcoholic liver disease, non-alcoholic fatty liver disease, viral or non-viral hepatitis, liver cancer, oxidative liver disease, drug induced liver injury, cholestasis, and cirrhosis;

the cancer is selected from the group consisting of liver cancer, colon cancer, rectal cancer, stomach cancer, esophageal cancer, and adenocarcinoma;

the joint disease or disorder is arthritis or osteoarthritis;

the soft-tissue disease or disorder is fibromyalgia;

the pain disease or disorder is fibromyalgia or abdominal pain;

or

the genetic disorder related to hyper- or hypo-methylation is methylenetetrahydrofolate reductase deficiency.

35. The method of claim 32, wherein the patient that has fasted for at least 10 hours prior to administration of said composition.

33. (canceled)

36. (canceled)

37. A method for improving the uptake of SAMe, wherein said method comprises administering to said subject a composition comprising a physiologically effective amount of exogenous SAMe in combination with one or more gallic acid ester.

38. The method of claim 37, wherein said gallic acid ester is ethyl gallate, isoamyl gallate, propyl gallate or octyl gallate.

39. The method of claim 37, wherein said gallic acid ester is propyl gallate.