Tranexamic acid formulations

Abstract

Disclosed are modified release oral tranexamic acid formulations and methods of treatment therewith.

1 . A modified release oral dosage form comprising tranexamic acid or pharmaceutically acceptable salt thereof and a modified release material which provides for the modified release of the tranexamic acid or pharmaceutically acceptable salt thereof from the dosage form such that the dosage form is suitable for administration on a two or three times a day basis; said dosage form providing an in-vitro dissolution release rate of the tranexamic acid or pharmaceutically acceptable salt thereof, when measured by a USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37±0.5° C., of less than about 70% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 45 minutes and about 100% by weight of said tranexamic acid or pharmaceutically acceptable salt thereof released by about 120 minutes.  
     
     
         2 . The modified release oral dosage form of  claim 1 , wherein said dosage form provides an in-vitro dissolution release rate of the tranexamic acid or pharmaceutically acceptable salt thereof, when measured by the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37±0.5° C., of about 0% to about 40% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 15 minutes, from about 20% to about 60% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 30 minutes, from about 40% to about 65% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 45 minutes, from about 50% to about 95% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 60 minutes, and not less than about 60% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 90 minutes.  
     
     
         3 . The modified release oral dosage form of  claim 1 , wherein the dosage form releases about 10% to about 25% by weight tranexamic acid or pharmaceutically acceptable salt thereof every 15 minutes when measured in vitro utilizing the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37±0.5° C.  
     
     
         4 . The modified release oral dosage form of  claim 1 , wherein the dosage form releases about 1% tranexamic acid or pharmaceutically acceptable salt thereof every minute when measured in-vitro utilizing the USP 27 Apparatus Type II paddle method at 50 RPM in 900 ml water at 37±0.5° C.  
     
     
         5 . The modified release oral dosage form of  claim 1  which provides a mean maximum plasma concentration (C max ) of tranexamic acid of from about 9 to about 14.5 mcg/ml after single dose oral administration of about 1300 mg of tranexamic acid or pharmaceutically acceptable salt thereof included in one or more of said modified release oral dosage form to humans.  
     
     
         6 . The modified release oral dosage form of  claim 1  which provides a mean maximum plasma concentration (C max ) of tranexamic acid of from about 5 to about 25 mcg/ml after steady state oral administration of about 1300 mg of tranexamic acid or pharmaceutically acceptable salt thereof included in one or more of said modified release oral dosage form to humans.  
     
     
         7 . The modified release oral dosage form of  claim 1  which provides a mean maximum plasma concentration (C max ) of tranexamic acid of from about 10 to about 20 mcg/ml after steady state oral administration of about 1300 mg of tranexamic acid or pharmaceutically acceptable salt thereof included in one or more of said modified release oral dosage form to humans.  
     
     
         8 . The modified release oral dosage form of  claim 1  which provides mean time to maximum plasma concentration (T max ) at from about 1.0 to about 5.5 hours after oral administration of one or more of said modified release oral dosage form to humans.  
     
     
         9 . The modified release oral dosage form of  claim 1 , wherein the dosage form provides a mean transit time of said tranexamic acid of 7.70±0.72 hours when orally administered across a patient population.  
     
     
         10 . The modified release oral dosage form of  claim 1 , wherein the dosage form provides a mean absorption time of said tranexamic acid of 4.18±0.70 hours when orally administered across a patient population.  
     
     
         11 . The modified release oral dosage form of  claim 1 , which provides for the reduction of at least one side effect selected from the group consisting of headache, nausea, vomiting, diarrhea, constipation, cramping, bloating, and combinations thereof, as compared to an immediate release oral dosage form containing an equivalent amount of tranexamic acid or pharmaceutically acceptable salt thereof, when administered across a same or different population of patients as said modified release dosage form, and wherein said immediate release dosage form releases all of said tranexamic acid or pharmaceutically acceptable salt thereof within about 45 minutes when measured in vitro utilizing the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37±0.5° C.  
     
     
         12 . The modified release oral dosage form of  claim 1 , which provides a mean transit time of said tranexamic acid which is at least about 20 minutes longer than the immediate release formulation when administered across a patient population.  
     
     
         13 . The modified release oral dosage form of  claim 1 , which provides a mean absorption time of said tranexamic acid which is at least about 20 minutes longer than the immediate release formulation when administered across a patient population.  
     
     
         14 . The modified release oral dosage form of  claim 1 , wherein said dosage form provides less headache, nausea, or combination thereof in comparision to a therapeutically equivalent amount of tranexamic acid or pharmaceutically acceptable salt thereof administered intravenously in five minutes or less when administered across a patient population.  
     
     
         15 . The modified release oral dosage form of  claim 1 , wherein said tranexamic acid or pharmaceutically acceptable salt thereof is included in said dosage form in an amount of from about 375 mg to about 1 gram.  
     
     
         16 . The modified release oral dosage form of  claim 1 , wherein said tranexamic acid or pharmaceutically acceptable salt thereof is included in said dosage form in an amount of about 650 mg.  
     
     
         17 . The modified release oral dosage form of  claim 1 , wherein said dosage form is selected from the group consisting of one or more tablets, capsules, granules, powders, pellets, dragees, troches, non-pareils, and pills.  
     
     
         18 . The modified release oral dosage form of  claim 1 , wherein said dosage form provides a bioavailability of said tranexamic acid of greater than 40% when administered to humans.  
     
     
         19 . A method of treating a human patient in need of tranexamic acid therapy comprising administering at least one oral dosage form of  claim 1  to a human patient suffering from menorrhagia, conization of the cervix, epistaxis, hyphema, hereditary angioneurotic edema, a patient with a blood coagulation disorder undergoing dental surgery, or combination thereof.  
     
     
         20 . A method of treating a patient in need of tranexamic acid therapy comprising: orally administering to said patient about 1300 mg of tranexamic acid or pharmaceutically acceptable salt thereof in at least one oral dosage form comprising said tranexamic acid or pharmaceutically acceptable salt thereof and a modified release material which provides a mean maximum plasma concentration (C max ) of tranexamic acid of from about 5 to about 17.5 mcg/ml after single dose oral administration to humans.  
     
     
         21 . The method of  claim 20 , wherein said at least one oral dosage form provides a mean maximum plasma concentration (C max ) of tranexamic acid of from about 9 to about 14.5 mcg/ml after single dose oral administration to humans.  
     
     
         22 . The method of  claim 20 , wherein said at least one oral dosage form provides a mean maximum plasma concentration (C max ) of tranexamic acid of from about 5 to about 25 mcg/ml after steady state oral administration to humans.  
     
     
         23 . The method of  claim 20 , wherein said at least one oral dosage form provides a mean maximum plasma concentration (C max ) of tranexamic acid of from about 10 to about 20 mcg/ml after steady state oral administration to humans.  
     
     
         24 . The method of  claim 20 , wherein said at least one oral dosage form provides a mean time to maximum plasma concentration (T max ) at from about 1.0 to about 5.5 hours after oral administration to humans.  
     
     
         25 . The method of  claim 20 , wherein said at least one oral dosage form is two oral dosage forms.  
     
     
         26 . A dose of tranexamic acid comprising two or three unit dosage forms of a modified release formulation, each unit dosage form of said modified release formulation comprising about 585 to about 715 mg of tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release material which provides for the release of the tranexamic acid or pharmaceutically acceptable salt thereof from the dosage form such that said dosage form is suitable for administration two or three times a day.  
     
     
         27 . The dose of  claim 26 , wherein each unit dosage form comprises about 650 mg of tranexamic acid or pharmaceutically acceptable salt thereof.  
     
     
         28 . The dose of  claim 26 , wherein the modified release material is selected from the group consisting 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, and mixtures thereof.  
     
     
         29 . The dose of  claim 26 , wherein the modified release material is selected from the group consisting of gel-forming polymers, hydratable polymers, water soluble polymers, water swellable polymers, and mixtures thereof.  
     
     
         30 . The dose of  claim 26 , wherein the modified release material is selected from the group consisting of hydroxypropylcellulose, hydryoxpropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, vinyl acetate/crotonic acid copolymers, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers, derivatives thereof, and mixtures thereof.  
     
     
         31 . The dose of  claim 26 , which provides a mean maximum plasma concentration (C max ) of tranexamic acid of from about 5 to about 17.5 mcg/ml after single dose oral administration to humans.  
     
     
         32 . The dose of  claim 26 , which provides a mean maximum plasma concentration (C max ) of tranexamic acid of from about 9.0 to about 14.5 mcg/ml after single dose oral administration to humans.  
     
     
         33 . The dose of claims  26 , which provides a mean maximum plasma concentration (C max ) of tranexamic acid of from about 5 to about 25 mcg/ml after steady state oral administration to humans.  
     
     
         34 . The dose of  claim 26 , which provides a mean maximum plasma concentration (C max ) of tranexamic acid of from about 10 mcg/ml to about 20 mcg/ml after steady state oral administration to humans.  
     
     
         35 . The dose of  claim 26 , which provides a mean time to maximum plasma concentration (T max ) of tranexamic acid at from about 1 to about 5.5 hours oral administration to humans.  
     
     
         36 . The dose of  claim 26 , which provides for a reduction in menstrual blood loss per menstrual cycle by about 20% to 100% after oral administration to a human patient suffering from heavy menstrual bleeding.  
     
     
         37 . The dose of  claim 26 , wherein the unit dosage forms provide a dissolution release rate in-vitro of the tranexamic acid or pharmaceutically acceptable salt thereof, when measured by the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37±0.5° C., of less than about 70% by weight tranexamic acid released at about 45 minutes.  
     
     
         38 . A modified release oral dosage form comprising tranexamic acid and a modified release material which provides for the modified release of the tranexamic acid from the dosage form such that the dosage form is suitable for administration on a two or three times a day basis, the dosage form providing a reduction of at least one side effect selected from the group consisting of headache, nausea, vomiting, diarrhea, constipation, cramping, bloating, and combinations thereof, as compared to an equivalent amount of tranexamic acid in an immediate release oral dosage form when administered across a patient population.  
     
     
         39 . The modified release oral dosage form of  claim 38 , wherein said side effect is headache or nausea.  
     
     
         40 . The modified release oral dosage form of  claim 38 , which provides a mean transit time of said tranexamic acid which is at least about 20 minutes longer than the immediate release formulation.  
     
     
         41 . The modified release oral dosage form of  claim 38 , which provides a mean absorption time of said tranexamic acid which is at least about 20 minutes longer than the immediate release formulation.  
     
     
         42 . A modified release oral dosage form comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release excipient, said dosage form providing for the release of the tranexamic acid or pharmaceutically acceptable salt thereof which is slower than an immediate release oral dosage form and faster than a controlled release oral dosage form, such that the modified release oral dosage form is suitable for administration two or three times a day.  
     
     
         43 . The modified release oral dosage form of  claim 42 , wherein said tranexamic acid is included in the dosage form in an amount of from about 375 mg to about 1 gram.  
     
     
         44 . The modified release oral dosage form of  claim 42 , wherein said modified release material is selected from the group consisting 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, and mixtures thereof.  
     
     
         45 . The modified release oral dosage form of  claim 42 , wherein the modified release material is selected from the group consisting of hydroxypropylcellulose, hydryoxpropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, vinyl acetate/crotonic acid copolymers, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers, derivatives thereof, and mixtures thereof.