Tranexamic acid formulations with reduced adverse effects

Abstract

Tranexamic acid formulated in an oral dosage form with at least one agent that decreases tranexamic acid release in the stomach. Such formulations minimize nausea, vomiting, and other adverse gastric effects that may accompany tranexamic acid therapy, for example, to treat heavy menstrual bleeding. One embodiment is an extended release formulation with waxes, polymers, etc. that prevent a bolus release of tranexamic acid in the stomach. An alternative embodiment is a delayed release formulation with polymers that prevent release of tranexamic acid in the acid environment of the stomach and delay its release until the formulation reaches the less acid environment of the intestines. Such formulations enhance patient compliance with therapy because adverse effects of tranexamic acid therapy are reduced.

1 . A composition comprising a pharmaceutically acceptable ingestable solid formulation comprising tranexamic acid and at least one agent that modifies the release of tranexamic acid from the formulation in the gastrointestinal tract.  
     
     
         2 . The composition of  claim 1  wherein the agent retards the rate of tranexamic acid release from the composition in the stomach and intestine.  
     
     
         3 . The composition of  claim 1  wherein the agent substantially prevents tranexamic acid release in the stomach.  
     
     
         4 . The composition of  claim 1  wherein the agent substantially prevents release of tranexamic acid at a pH<5.5.  
     
     
         5 . The composition of  claim 1  wherein the agent comprises at least one of a wax, a polymer, or a time-released matrix.  
     
     
         6 . The composition of  claim 1  wherein an amount of tranexamic acid is in the range between about 375 mg to about 1 gram.  
     
     
         7 . A composition comprising tranexamic acid in a pharmaceutically acceptable modified release ingestable formulation.  
     
     
         8 . The composition of  claim 7  in a delayed release tablet.  
     
     
         9 . The composition of  claim 7  in an extended release tablet.  
     
     
         10 . The composition of  claim 7  wherein the formulation is chosen from at least one of a tablet, a capsule, a granule, a powder, a pellet, a dragee, a troche, a non-pareil, a sachet, and a pill.  
     
     
         11 . A composition comprising tranexamic acid in an ingestable solid pharmaceutically acceptable formulation with at least one agent in an amount sufficient to provide extended release of tranexamic acid from the composition.  
     
     
         12 . The composition of  claim 11  wherein the at least one agent reduces the rate of tranexamic release from the composition.  
     
     
         13 . The composition of  claim 11  wherein the rate is substantially uniformly reduced.  
     
     
         14 . The composition of  claim 11  wherein the agent is selected from at least one of gel-forming polymers, hydratable polymers, water soluble polymers or water swellable polymers.  
     
     
         15 . The composition of  claim 11  wherein the polymers are selected from at least one of hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, vinyl acetate/crotonic acid copolymers, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers, derivatives thereof, and mixtures thereof.  
     
     
         16 . The composition of  claim 11  wherein a total concentration of the polymer is in the range of about 5% by weight to about 50% by weight of the composition.  
     
     
         17 . The composition of  claim 11  wherein a total concentration of the polymer is in the range of about 10% by weight to about 35% by weight of the composition.  
     
     
         18 . The composition of  claim 11  wherein a total concentration of the polymer is in the range of about 10% by weight to about 30% by weight of the composition.  
     
     
         19 . The composition of  claim 11  wherein the polymer is hydroxypropylmethylcellulose.  
     
     
         20 . A composition comprising tranexamic acid in an ingestable solid pharmaceutically acceptable formulation with at least one agent sufficient to delay the release of tranexamic acid from the composition until encountering a pH>about 5.5.  
     
     
         21 . The composition of  claim 20  wherein the agent is at least one of phthalic acid derivatives of vinyl polymers, phthalic acid derivatives of vinyl copolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates, hydroxyalkylcellulose acetates, cellulose ethers, alkylcellulose acetates, and partial esters thereof, and polymers and copolymers of lower alkyl acrylic acids and lower alkyl acrylates, and partial esters thereof.  
     
     
         22 . The composition of  claim 20  wherein a total concentration of the at least one agent is in the range of about 1% by weight to about 20% by weight of the composition.  
     
     
         23  The composition of  claim 20  wherein a total concentration of the at least one agent is in the range of about 5% by weight to about 12% by weight of the composition.  
     
     
         24 . The composition of  claim 20  wherein a total concentration of the at least one agent is about 10% by weight of the composition.  
     
     
         25 . A therapeutic method comprising providing to a patient in need of tranexamic acid therapy an ingestable solid pharmaceutically acceptable formulation comprising a therapeutic dose of tranexamic acid and at least one excipient wherein the excipient retards tranexamic release in the stomach and substantially releases tranexamic acid in the small intestine thereby reducing the concentration of tranexamic acid in the stomach during therapy.  
     
     
         26 . The method of  claim 25  further reducing adverse gastrointestinal side effects of therapy.  
     
     
         27 . The method of  claim 25  wherein the at least one excipient controls release of tranexamic acid in the stomach.  
     
     
         28 . The method of  claim 25  wherein the at least one excipient retards release of tranexamic acid in the stomach.  
     
     
         29 . The method of  claim 25  wherein the therapeutic dose is in the range of about 375 mg tranexamic acid to about 1 gram tranexamic acid per dose.  
     
     
         30 . The method of  claim 25  wherein the dose is administered either three times a day or four times a day.  
     
     
         31 . The method of  claim 30  wherein the dose is at least two solid tablets or one sachet containing granules.  
     
     
         32 . A therapeutic method comprising providing tranexamic acid therapy to a patient in need thereof in a pharmaceutically acceptable oral formulation comprising at least one excipient sufficient to result in a decreased stomach concentration of tranexamic acid after oral ingestion thereby decreasing at least one gastrointestinal adverse effect of said therapy.  
     
     
         33 . The method of  claim 32  decreasing a gastrointestinal adverse effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, cramping, bloating, and combinations thereof.  
     
     
         34 . The method of  claim 32  provided to a patient having menorrhagia.  
     
     
         35 . A method of reducing gastrointestinal adverse side effects comprising administering an effective amount of an extended release pharmaceutical composition comprising tranexamic acid and at least one agent that controls release of tranexamic acid from the composition in the gastrointestinal tract.  
     
     
         36 . A method of reducing gastrointestinal adverse side effects comprising administering an effective amount of a composition comprising tranexamic acid in an oral administrable formulation selected from the group consisting of extended release, delayed release, and combinations thereof, wherein upon oral administration tranexamic acid is substantially released in the small intestine.  
     
     
         37 . A method of reducing gastrointestinal adverse side effects comprising directing oral administration of an effective amount of a delayed release pharmaceutical composition comprising tranexamic acid and at least one agent that delays release of tranexamic acid from the composition until the small intestine.