Controlled release formulation of lamotrigine

Abstract

Rapidly disintegrating multiparticulate controlled release formulations of lamotrigine having an improved pharmacokinetic profile and improved patient compliance, and process of preparing the formulations. It provides better control of blood plasma levels than conventional tablet formulations that is administered once or more times a day.

1 - 25 . (canceled) 
     
     
         26 : A method for reducing fluctuation in the troughs and peaks of drug concentration in patient's blood plasma, which comprise administering orally to a patient in need thereof a controlled release formulation containing Lamotrigine as an active ingredient. 
     
     
         27 : A method as claimed in  claim 26 , wherein the ratio of peak and trough is in the range of 1.0 to 1.6. 
     
     
         28 : A method for improving the patient's compliance by reducing the frequency of dosing to once daily, which comprises administering orally to a patient in need thereof a controlled release formulation containing Lamotrigine as an active ingredient. 
     
     
         29 : A method for the safer administration of Lamotrigine while in combination with drugs selected from the group consisting of phenyloin, carbanazepine, sodium valproate, which comprises administering orally to a patient in need thereof a controlled release formulation containing Lamotrigine as an active ingredient. 
     
     
         30 : A method for providing therapeutic blood plasma concentration of Lamotrigine over a 24 hours period with diminished incidence of ataxia, diplopia, somnolence, headache and rash, which comprises administering orally to a patient in need thereof a controlled release formulation containing Lamotrigine as an active ingredient. 
     
     
         31 . A method for reducing fluctuation in the troughs and peaks of drug concentration in a patient's blood plasma, which comprises administering orally to a patient in need thereof a multiparticulate controlled release dosage formulation of lamotrigine or a pharmaceutically acceptable salt thereof, which comprises:
 (a) core particles, comprising lamotrigine and,   said core particles being covered with a release rate controlling polymer selected from the group consisting of poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1; poly(ethyl acrylate, methyl methacrylate, trimethylamonioethyl methacrylate chloride) 1:2:0.2; polymethacrylic acid, ethyl acrylate 1:1; poly(ethyl acrylate, methyl methacrylate) 1:1 or mixtures thereof wherein said release rate controlling polymer includes a plasticizer in the release rate controlling polymer; and   (b) a rapidly disintegrating binder on said core particles which allows said core particles to rapidly disperse in an aqueous environment and is further characterized in that when orally administered to a human subject, said core particles will achieve a peak to trough plasma concentration ratio of between 1 to 1.6.   
     
     
         32 . A method as defined in  claim 31  where the core particles are in the form of a discrete pellet. 
     
     
         33 . A method as defined in  claim 31  wherein the core particles are homogenous. 
     
     
         34 : A method as defined in  claim 31 , wherein the core particles are heterogenous. 
     
     
         35 . A method as defined in  claim 31  wherein the formulation is in the form of tablet. 
     
     
         36 . A method as defined in  claim 31  which comprises a once a day dosage formulation. 
     
     
         37 . A method as defined in  claim 31  wherein the core comprises an organic acid. 
     
     
         38 . A method as defined in  claim 31  wherein the rate controlling polymer is coated with an enteric coating. 
     
     
         39 . A method as defined in  claim 31 , wherein the core comprises a blend of different types of controlled release particles of lamotrigine having different release profiles. 
     
     
         40 . A method as defined in  claim 31 , wherein the particles have the following release profile when measured in a U.S.P.XXII Type II (paddle) apparatus at a temperature of 37° C. at 50 rpm using a 0.1M HCl medium for 1 hour and thereafter a trisodium phosphate buffer at pH 6.8 for the remaining hours:
 a) not more than 60% of the total lamotrigine is released in 1 hour; 
 b) not less than 35% of the total lamotrigine is released after 6 hours of measurement; 
 c) not less than 60% of the total lamotrigine is released after 25 hours of measurement. 
 
     
     
         41 : A method as defined in  claim 31  wherein the particles have the following release profile when measured in a U.S.P.XXII Type II (paddle) apparatus at a temperature of 37° C. at 50 rpm using a pH 4.5 buffer:
 a) not more than 60% of the total lamotrigine is released in 1 hour; 
 b) not less than 35% of the total lamotrigine is released after 6 hours of measurement; 
 c) not less than 60% of the total lamotrigine is released after 24 hours of measurement. 
 
     
     
         42 . A method as defined in  claim 31  wherein the particles have the following release profile when measured in a U.S.P.XXII Type II (paddle) apparatus at a temperature of 37° C. at 50 rpm in 0.1 M HCl:
 a) not more than 60% of the total lamotrigine is released in 1 hour; 
 b) not less than 35% of the total lamotrigine is released after 6 hours of measurement; 
 c) not less than 60% of the total lamotrigine is released after 24 hours of measurement. 
 
     
     
         43 . A method as defined in  claim 31  wherein the particles have the release profile, when measured in a U.S.P.XXII Type II (paddle) apparatus at a temperature of 37° C. at 50 rpm at pH 7.5, not more than 60% of the total lamotrigine is released in 1 hour. 
     
     
         44 . TA method as defined in  claim 31  wherein the particles have the release profile, when measured in a U.S.P.XXII Type II (paddle) apparatus at a temperature of 37° C. at 50 rpm at a pH of 6.8, not more than 60% of the total lamotrigine is released in 1 hour. 
     
     
         45 . A method as defined in  claim 31  wherein the controlled release formulation is in admixture with free lamotrigine or a pharmaceutically acceptable salt thereof. 
     
     
         46 . A method as defined in  claim 39 , wherein the particles have the following release profile when measured in a U.S.P.XXII Type II (paddle) apparatus at a temperature of 37° C. at 50 rpm using a 0.1M HCl medium for 1 hour and thereafter a trisodium phosphate buffer at pH 6.8 for the remaining hours:
 a) not more than 60% of the total lamotrigine is released in 1 hour; 
 b) not less than 35% of the total lamotrigine is released after 6 hours of measurement; 
 c) not less than 60% of the total lamotrigine is released after 25 hours of measurement. 
 
     
     
         47 : A method as defined in  claim 39  wherein the particles have the following release profile when measured in a U.S.P.XXII Type II (paddle) apparatus at a temperature of 37° C. at 50 rpm using a pH 4.5 buffer:
 a) not more than 60% of the total lamotrigine is released in 1 hour; 
 b) not less than 35% of the total lamotrigine is released after 6 hours of measurement; 
 c) not less than 60% of the total lamotrigine is released after 24 hours of measurement. 
 
     
     
         48 . A method as defined in  claim 39  wherein the particles have the following release profile when measured in a U.S.P.XXII Type II (paddle) apparatus at a temperature of 37° C. at 50 rpm in 0.1 M HCl:
 a) not more than 60% of the total lamotrigine is released in 1 hour; 
 b) not less than 35% of the total lamotrigine is released after 6 hours of measurement; 
 c) not less than 60% of the total lamotrigine is released after 24 hours of measurement. 
 
     
     
         49 . A method as defined in  claim 39  wherein the particles have the release profile, when measured in a U.S.P.XXII Type II (paddle) apparatus at a temperature of 37° C. at 50 rpm at pH 7.5, not more than 60% of the total lamotrigine is released in 1 hour. 
     
     
         50 . TA method as defined in claim  1  wherein the particles have the release profile, when measured in a U.S.P.XXII Type II (paddle) apparatus at a temperature of 37° C. at 50 rpm at a pH of 6.8, not more than 60% of the total lamotrigine is released in 1 hour.