Pharmacokinetics of S-Adenosylmethionine Formulations

Abstract

Compositions and methods to improve the pharmacokinetic profile of S-Adenosylmethionine (SAMe) are provided, as are methods of treating various disorders using SAMe formulations with improved pharmacokinetic profiles. More specifically, the invention is directed to methods of treating a disease or disorder in a subject and/or improving the nutritional status of a subject by administering formulations exhibiting improved pharmacokinetic profiles of exogenous SAMe. The method also includes the step of orally administering compositions of the invention to the subject once per day after overnight fast; that is prior to food intake in the morning.

What is claimed is: 
     
         1 . A composition comprising a physiologically effective amount of S-adenosylmethionine (SAMe), wherein non-parenteral administration of said composition to a selected subject group produces in said selected subject group an effect comprising at least one of:
 a. an average maximum SAMe blood plasma concentration (average C max ) of at least about 1800 ng/mL for a 1600 mg dosage of SAMe ion;   b. an average SAMe plasma area under the curve (average AUC) of at least about 7500 ng·h/mL for a 1600 mg dosage of SAMe ion;   c. an average maximum SAMe blood plasma concentration (average C max ) of at least about 850 ng/mL and/or an average SAMe plasma area under the curve (average AUC) of at least about 4000 ng·h/mL for a 800 mg dosage of SAMe ion;   d. an average maximum SAMe blood plasma concentration (average Cmax) of at least about 400 ng/mL and/or an average SAMe plasma area under curve (average AUC) of at least about 1800 ng·h/mL for a 400 mg dosage of SAMe ion;   e. an average maximum. SAMe blood plasma concentration (average Cmax) of at least about 200 ng/mL and/or an average SAMe plasma area under curve (average AUC) of at least about 900 ng·h/mL for a 200 mg dosage of SAMe ion; or   f. an average maximum SAMe blood plasma concentration (average Cmax) of at least about 100 ng/mL and/or an average SAMe plasma area under curve (average AUC) of at least about 450 ng·h/mL for a 100 mg dosage of SAMe ion.   
     
     
         2 . The composition of  claim 1 , wherein the composition is formulated for oral administration, and wherein the composition comprises a suitable excipient. 
     
     
         3 . The composition of  claim 1  or  2 , wherein the composition comprises a dietary supplement. 
     
     
         4 . The composition of  claim 1  or  2 , wherein the composition comprises a medical food. 
     
     
         5 . The composition according to one of  claims 1 - 4  wherein said composition comprises physical or chemical dosage form characteristics which modulate one of said average SAMe C max  and said average SAMe AUC. 
     
     
         6 . The composition of  claim 5 , wherein the composition is in a dosage form manufactured at a relative humidity of less than 10%. 
     
     
         7 . The composition of  claim 5 , wherein the composition is in a dosage form that comprises a functional coating and the functional coating constitutes less than or equal to 5% of the total weight of the dosage form. 
     
     
         8 . The composition of  claim 7 , wherein the composition is in a unit dosage form that comprises a functional coating and the functional coating constitutes from 1 to 5% of the total weight of the unit dosage form. 
     
     
         9 . The composition according to  claim 5  wherein said dosage form characteristics comprise one of hardness, thickness, friability, speed of disintegration, speed of dissolution, shape, size, density, coating and combinations thereof. 
     
     
         10 . The composition according to  claim 5  wherein said dosage form characteristics are modulated by controllably manipulating during production or manufacturing of said composition one of physical mixing specifications, drying time, pressing conditions, environmental parameters and combinations thereof. 
     
     
         11 . The composition according to  claim 5  wherein said dosage form characteristics comprise a targeted dissolution profile at pH 6.0. 
     
     
         12 . The composition of one of  claims 1 - 4 , wherein the dosage is divided into two, three, four, five, six or more dosage units. 
     
     
         13 . The composition according to one of  claims 1 - 4  wherein said selected subject group is a group of selected human subjects. 
     
     
         14 . The composition according to one of  claims 1 - 4  wherein the composition when administered to a select subject group provides in said selected subject group an improved pharmacokinetic profile through: a reduced variation of T max  and equivalent AUC to bi-daily dosing and/or reduced side effects through once a day dosing. 
     
     
         15 . The composition according to one of  claims 1 - 4  wherein the composition when administered to a selected subject group provides in said selected subject group an average C max  within the range of about 100 ng/mL to about 500 ng/mL per 100 mg of SAMe ion. 
     
     
         16 . The composition according to one of  claims 1 - 4  wherein the composition when administered to a selected subject group provides in said selected subject group an average AUC within the range of about 400 ng·h/mL to about 800 ng·h/mL for a 100 mg dosage of SAMe ion. 
     
     
         17 . The composition according to one of  claims 1 - 4 , wherein the composition when administered to a subject provides in the subject one of an average T max  or C max  with reduced variation or a reduced effective dose in comparison to a SAMe reference data set. 
     
     
         18 . The composition according to one of  claims 1 - 4 , wherein the composition when administered to a subject provides in the subject a reduced side effect profile in comparison to a SAMe reference data set. 
     
     
         19 . The composition according to one of  claims 1 - 4  wherein the composition comprises an oral delivery system, or a transmucosal delivery system. 
     
     
         20 . The composition according to  claim 19 , wherein the composition comprises one of tablets, pastes, capsules, granules, caplets, lozenges, pastes, and suppositories. 
     
     
         21 . The composition according to  claim 19  wherein the composition comprises an oral delivery system. 
     
     
         22 . The composition according to  claim 19  wherein dissolution of the oral delivery system or dosage form provides about 25-80% release of SAMe after 60 minutes of being in an aqueous buffer having an initial pH of about 6. 
     
     
         23 . The composition according to  claim 22  wherein dissolution of the oral delivery system or dosage in a USP II dissolution apparatus in aqueous buffer having initial pH of about 6.0 provides about 30-70% release of SAMe after 60 minutes of being in the buffer phase. 
     
     
         24 . A method of treating a disease condition or disorder, comprising administering to a subject in need of such treatment an effective amount of the composition of one of  claim 1  or  2 . 
     
     
         25 . The method according to  claim 24  wherein said subject is a human. 
     
     
         26 . The composition according to one of  claims 1 - 4  wherein the composition comprises at least one excipient is one of matrix materials; binders; lubricants; glidants; coatings; disintegrants, super-disintegrants; polysaccharides, oligosaccharides; polypeptides, proteins synthetic oligomers, synthetic polymers, monomeric organic molecules, hydrophobic organic molecules, hydrophilic organic molecules, amphoteric organic molecules, inorganic salts inorganic metals, and combinations thereof. 
     
     
         27 . A method for improving the pharmacokinetic parameters of exogenous SAMe administered to a subject, said method comprising administering to the subject a non-parental composition comprising at least one physiologically effective dosage of SAMe in combination with at least one excipient selected to improve the pharmacokinetic parameters of said SAMe in a subject, said pharmacokinetic parameters measurable in the subject by one of a Cmax, an AUC, and combinations thereof in comparison to a selected SAMe reference data set. 
     
     
         28 . A method according to  claim 27 , wherein the at least one excipient is one of matrix materials; binders; lubricants; glidants; coatings; disintegrants, super-disintegrants; polysaccharides, oligosaccharides; polypeptides, proteins synthetic oligomers, synthetic polymers, monomeric organic molecules, hydrophobic organic molecules, hydrophilic organic molecules, amphoteric organic molecules, inorganic salts inorganic metals, and combinations thereof. 
     
     
         29 . A method according to  claim 27 , wherein the improvement of the pharmacokinetic parameters of said SAMe is a function of a physical or chemical dosage form characteristic of the composition. 
     
     
         30 . The method of  claim 27 , wherein the composition is manufactured at a relative humidity of less than 10%. 
     
     
         31 . The method of  claim 27 , wherein the composition is in a dosage form, which includes a functional coating, and the functional coating accounts for less than or equal to 5% of the total weight of the dosage form. 
     
     
         32 . A method according to  claim 31 , wherein the composition when administered to a selected subject group provides in the selected subject group an average C max  of at least about 1800 ng/mL for a 1600 mg dosage of SAMe ion. 
     
     
         33 . A method according to  claim 31 , wherein the composition when administered to a selected subject group provides in the selected subject group an average C max  of at least about 850 ng/mL and an average SAMe plasma area under the curve (average AUC) of at least about 4000 ng·h/mL for a 800 mg dosage of SAMe ion. 
     
     
         34 . A method according to  claim 31 , wherein the composition when administered to a selected subject group provides in the selected subject group an average C max  of at least about 100 ng/mL per 100 mg of SAMe ion in said physiologically effective dosage. 
     
     
         35 . A method according to  claim 31 , wherein the composition when administered to a selected subject group provides in the selected subject group an average C max  within the range of about 100 ng/mL to about 500 ng/mL per 100 mg of SAMe ion* in said physiologically effective dosage. 
     
     
         36 . A method according to  claim 31 , wherein the composition when administered to a selected subject group provides in the selected subject group one of an average T max  with reduced variation or a reduced effective dose in comparison to a SAMe reference data set. 
     
     
         37 . A method according to  claim 31 , wherein the composition when administered to a selected subject group provides in the selected subject group a reduced side effect profile in comparison to a SAMe reference data set. 
     
     
         38 . A method according to  claim 31 , wherein the composition when administered to a selected subject group provides in the selected subject group an average AUC of at least about 7500 ng·h/mL for a 1600 mg dosage of SAMe ion. 
     
     
         39 . A method according to  claim 31 , wherein the composition when administered to a selected subject group provides in the selected subject group an average AUC of at least about 4000 ng·h/mL for a 800 mg dosage of SAMe ion. 
     
     
         40 . A method according to  claim 31 , wherein the composition when administered to a selected subject group provides in the selected subject group an average AUC within the range of about 500 ng·h/mL to about 800 ng·h/mL for a 100 mg dosage of SAMe ion. 
     
     
         41 . A formulation comprising SAMe, wherein the formulation comprises a mixture of SAMe and at least one excipient and the mixture is produced by combining said SAMe and said excipient at a relative humidity less than about 10%. 
     
     
         42 . A formulation comprising SAMe, wherein the formulation comprises a mixture of SAMe and at least one excipient, wherein the mixture exhibits a dissolution profile at pH 6.0 suitable to target delivery to the proximal intestine. 
     
     
         43 . A process of improving the pharmacokinetic profile of a SAMe formulation, comprising manufacturing said SAMe formulation at a relative humidity of less than about 10%. 
     
     
         44 . A composition for oral administration, comprising SAMe and at least one excipient wherein the formulation exhibits an in vitro dissolution profile in pH 6.0 aqueous solution such that greater than 20% and less than 90% of total SAMe in the composition is dissolved from 30 to 90 minutes of incubation in said pH 6.0 aqueous solution. 
     
     
         45 . The composition of  claim 44 , wherein the formulation exhibits an in vitro dissolution profile in pH 6.0 aqueous solution such that greater than 25% and less than 80% of total SAMe in the composition is dissolved from 45 to 75 minutes of incubation in said pH 6.0 aqueous solution. 
     
     
         46 . The composition of  claim 44 , wherein the composition is in a dosage form manufactured at a relative humidity of less than 10%. 
     
     
         47 . The composition of  claim 46 , wherein the composition is in a dosage form that comprises a functional coating and the functional coating constitutes less than or equal to 5% of the total weight of the dosage form. 
     
     
         48 . A method for improving the uptake of SAMe, comprising administering to a patient SAMe in a formulation that exhibits an in vitro dissolution profile at pH 6.0, wherein greater than 20% and less than 90% of total SAMe is dissolved between 30 to 90 minutes of incubation in said pH 6.0 aqueous solution. 
     
     
         49 . The method of  claim 48 , wherein the formulation exhibits an in vitro dissolution profile in pH 6.0 aqueous solution such that greater than 25% and less than 80% of total SAMe in the composition is dissolved between 45 to 75 minutes of incubation in said pH 6.0 aqueous solution. 
     
     
         50 . The method of  claim 48 , wherein the composition is in a unit dosage form manufactured at a relative humidity of less than 10%. 
     
     
         51 . The method of  claim 48 , wherein the composition is in a unit dosage form that comprises a functional coating and the functional coating constitutes less than or equal to 5% of the total weight of the unit dosage form. 
     
     
         52 . The method of  claim 48 , wherein the composition is in a unit dosage form that comprises a functional coating and the functional coating constitutes from 1 to 5% of the total weight of the unit dosage form.