ENHANCED FORMULATIONS OF LAMOTRIGINE
A once-a-day, extended-release formulation of lamotrigine, exhibiting a significantly similar release rate throughout the GI tract irrespective of the pH of the environment, is provided. The formulation comprises lamotrigine, an organic acid, a release enhancing polymer and a release controlling polymer. The use of the formulation for the treatment of the neurological disorders is also disclosed.
1 . A pharmaceutical formulation of lamotrigine comprising lamotrigine or salts thereof admixed with a release-equalizing composition comprising a pharmaceutically acceptable organic acid and a release-enhancing polymer, said formulation exhibiting a significantly similar rate of release with a similarity factor of at least 50 throughout the GI tract.
2 . The formulation of claim 1 , wherein the release enhancing polymer is an enteric polymer.
3 . The formulation of claim 2 , wherein said enteric polymer is soluble at pH≧4.5.
4 . The formulation of claim 3 , wherein said enteric polymer is selected from the group consisting of cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic monoester copolymer, methyl acrylate-methacrylic acid copolymer, and methacrylate-methacrylic acid-octyl acrylate copolymer.
5 . The formulation of claim 2 , wherein said enteric polymer is Eudragit L100-55.
6 . The formulation of claim 1 , wherein said organic acid is selected from the group consisting of citric acid, fumaric acid, tartaric acid, adipic acid, succinic acid, and maleic acid.
7 . The formulation of claim 6 , wherein said organic acid is citric acid or fumaric acid.
8 . The formulation of claim 1 which is an extended-release formulation.
9 . The formulation of claim 8 , wherein said formulation provides for a maximum steady state plasma concentration (Cmax) in the range from C minIR to 110% of C maxIR , wherein C minIR and C maxIR are the minimum and the maximum plasma concentrations respectively produced by the same amount of lamotrigine administered as an immediate-release formulation BID.
10 . The formulation of claim 8 , wherein said formulation provides for a relative steady state AUC in the range of from 80% to 125% of an AUC IR , wherein AUC IR is an area under the curve produced by the same amount of lamotrigine administered as an immediate release formulation BID.
11 . The formulation of claim 8 further comprising a coating of a release-controlling polymer selected from a group consisting of ethylcellulose, Eudragit RL, Eudragit RS, cellulose acetate, hydroxypropylmethylcellulose HPMC, hydroxyethylcellulose (HEC), methylcellulose (MC), and PVA-PEG copolymer.
12 . The formulation of claim 8 wherein said release-equalizing composition further comprises a release-controlling polymer selected from a group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), methylcellulose (MC), powdered cellulose, cellulose acetate, sodium carboxymethylcellulose, calcium salt of carboxymethylcellulose and ethylcellulose; alginates, guar gum, xanthan gum; cross-linked polyacrylic acid derivatives; carageenan; polyvinyl pyrrolidone and its derivatives; polyethylene oxides; and polyvinyl alcohol.
13 . The formulation of claim 12 , wherein said release controlling-polymer is polyethylene oxide.
14 . The formulation of claim 1 comprising from 5 to 500 mg of lamotrigine or salts thereof.
15 . The formulation of claim 1 , comprising from 5 to 20 wt % organic acid.
16 . The formulation of claim 1 , comprising from 5-50 wt % release-enhancing polymer.
17 . The formulation of claim 12 , comprising up to 50 wt % release-controlling polymer.
18 . The formulation of claim 8 suitable for once-a-day administration.
19 . An extended-release formulation of lamotrigine exhibiting a significantly similar release rate with a similarity factor of at least 50 throughout the GI tract irrespective of the pH of the environment, said formulation comprising lamotrigine or salts thereof, a release-equalizing composition, and a release-controlling polymer.
20 . The formulation of claim 19 , wherein the release-equalizing composition comprises an organic acid and a release-enhancing polymer and is admixed with lamotrigine to form a matrix.
21 . The formulation of claim 20 , wherein said release controlling polymer is admixed into the matrix and has a dual function of controlling a rate of release, and equalizing the release profile synergistically with the organic acid and the release enhancing polymer.
22 . The formulation of claim 20 , wherein said release controlling polymer is coated onto the matrix.
23 . The formulation of claim 21 , wherein said release controlling polymer is selected from a group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), methylcellulose (MC), powdered cellulose, cellulose acetate, sodium carboxymethylcellulose, calcium salt of carboxymethylcellulose and ethylcellulose; alginates, guar gum, xanthan gum; cross-linked polyacrylic acid derivatives; carageenan; polyvinyl pyrrolidone and its derivatives; polyethylene oxides; and polyvinyl alcohol.
24 . The formulation of claim 23 , wherein said release controlling polymer is polyethylene oxide.
25 . The formulation of claim 22 , wherein said release controlling polymer is selected from a group consisting of ethylcellulose, Eudragit RL, Eudragit RS, cellulose acetate, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), methylcellulose (MC), and PVA-PEG copolymer.
26 . An oral dosage form comprising a formulation of lamotrigine exhibiting a significantly similar release rate with a similarity factor of at least 50 throughout the GI tract.
27 . The dosage of claim 26 , wherein said formulation comprises lamotrigine or salts thereof, a pharmaceutically acceptable organic acid and a release enhancing polymer admixed together and forming a matrix.
28 . The dosage form of claim 27 , wherein said formulation is an extended release formulation.
29 . The dosage form of claim 28 , wherein said formulation additionally comprises a release controlling polymer.
30 . The dosage form of claim 29 , wherein said release controlling polymer is admixed into the matrix and has a dual function of controlling a rate of release, and equalizing the release profile synergistically with the organic acid and the release enhancing polymer.
31 . The dosage form of claim 29 , wherein said release controlling polymer is coated onto the matrix.
32 . The oral dosage of claim 28 suitable for once a day administration.
33 . The dosage form of claim 26 selected from a group consisting of a tablet, a pill, a capsule, a caplet, a troche, a sachet, a cachet, a pouch, and sprinkles.
34 . A method of treatment of a neurological disorder in a mammalian subject comprising administering to said subject a formulation of lamotrigine exhibiting a significantly similar release rate with a similarity factor of at least 50 throughout the GI tract irrespective of the pH of the environment.
35 . The method of claim 34 , wherein said neurological disorder is selected from a group consisting of epilepsy, Lennox-Gastaut syndrome, and a bipolar disorder.
36 . The method of claim 34 , wherein said formulation comprises lamotrigine or salts thereof, a pharmaceutically acceptable organic acid and a release enhancing polymer admixed together and forming a matrix.
37 . The method of claim 34 , wherein said formulation is an extended release formulation.
38 . The method of claim 37 , wherein said formulation additionally comprises a release controlling polymer.
39 . The method of claim 38 , wherein said release controlling polymer is admixed into the matrix and has a dual function of controlling a rate of release, and equalizing the release profile synergistically with the organic acid and the release enhancing polymer.
40 . The method of claim 38 , wherein said release controlling polymer is coated onto the matrix.
41 . The method of claim 37 , wherein said formulation is administered once a day.
42 . An extended-release formulation of lamotrigine that exhibits a significantly similar release rate with a similarity factor of at least 50 throughout the GI tract irrespective of the pH of the environment, said formulation comprising a therapeutically effective amount of lamotrigine or salts thereof, fumaric acid, Eudragit L100-55, and polyethylene oxide, admixed together and forming a matrix.
43 . The formulation of claim 42 for once a day administration.