Sustained release compositions of 4-aminopyridine

Abstract

The present invention generally relates to sustained release 4-aminopyridine tablets, which include a core and a coating. The sustained release tablets of the invention are generally suitable for once daily oral administration for the treatment of neurological disorders.

1 . A sustained release tablet comprising:
 (a) a compressed core, said compressed core comprising 4-aminopyridine, a polyethylene oxide with a molecular weight between about 1,000,000 and 10,000,000, and a mixture comprising polyvinyl acetate and polyvinyl pyrrolidone, and   (b) an amount of an ethylcellulose coat surrounding said compressed core, said amount of the ethylcellulose coat being in the range of about 5% w/w to about 10% w/w of the compressed core;   wherein the amount of 4-aminopyridine in the sustained release tablet is about 22 mg, and upon once daily oral administration to a human subject in a fasted state, the sustained release tablet provides one or more of the following pharmacokinetic parameters: (a) a mean steady state plasma 4-aminopyridine C max  in the range of about 18.61 ng/mL to about 37.19 ng/mL, (b) a mean steady state plasma 4-aminopyridine C min  in the range of about 7.73 ng/mL to about 19.47 ng/mL, (c) a mean steady state plasma 4-aminopyridine AUCo-24 in the range of about 324 ng·h/mL to about 638 ng·h/mL, and (d) a median steady state plasma 4-aminopyridine T max  in the range of about 3 h to about 12 h.   
     
     
         2 - 10 . (canceled) 
     
     
         11 . The sustained release tablet of  claim 1 , wherein said mixture further comprises one or more pharmaceutically acceptable excipients. 
     
     
         12 - 14 . (canceled) 
     
     
         15 . The sustained release tablet of  claim 1 , wherein said mixture consists of about 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% silica. 
     
     
         16 . The sustained release tablet of  claim 1 , wherein the compressed core further comprises a filler and a lubricant. 
     
     
         17 . The sustained release tablet of  claim 16 , wherein the filler is dibasic calcium phosphate dihydrate, and the lubricant is magnesium stearate. 
     
     
         18 . The sustained release tablet of  claim 1 , wherein the polyethylene oxide has a molecular weight between 4,000,000 and 8,000,000. 
     
     
         19 . The sustained release tablet of  claim 1 , wherein the polyethylene oxide has a molecular weight of 7,000,000. 
     
     
         20 . (canceled) 
     
     
         21 . The sustained release tablet of  claim 1 , wherein the total amount of the 4-aminopyridine in the tablet is in the range of about 1% w/w to about 10% w/w of the compressed core. 
     
     
         22 . The sustained release tablet of  claim 1 , wherein
 said mixture consists of about 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica; wherein the compressed core further comprises dibasic calcium phosphate dihydrate and magnesium stearate; and   wherein the amount of 4-aminopyridine is in the range of about 4% w/w to about 6% w/w of the compressed core, said amount of the 4-aminopyridine being equal to 22 mg.   
     
     
         23 - 26 . (canceled) 
     
     
         27 . The sustained release tablet of  claim 1 , wherein the amount of the ethylcellulose coat surrounding the compressed core is about 9% w/w of the compressed core. 
     
     
         28 - 33 . (canceled) 
     
     
         34 . The sustained release tablet of  claim 1 , wherein
 (a) the amount of the polyethylene oxide is in the range of about 10% w/w to about 20% w/w of the compressed core; (b) the amount of the mixture is in the range of about 20% w/w to about 30% w/w of the compressed core; (c) the amount of dibasic calcium phosphate dihydrate is in the range of about 50% w/w to about 60% w/w of the compressed core; and (d) the amount of magnesium stearate is in the range of about 0.7% w/w to about 1.3% w/w of the compressed core.   
     
     
         35 - 38 . (canceled) 
     
     
         39 . The sustained release tablet of  claim 34 , wherein (a) the polyethylene oxide is a polyethylene oxide with a molecular weight of 7,000,000 and the amount of the polyethylene oxide is about 15% w/w of the compressed core; (b) the amount of the mixture is about 25% w/w of the compressed core; (c) the amount of dibasic calcium phosphate dihydrate is about 54% w/w of the compressed core; (d) the amount of magnesium stearate is about 1% w/w of the compressed core; and
 (e) the amount of the ethylcellulose coat is about 9% w/w of the compressed core.   
     
     
         40 - 75 . (canceled) 
     
     
         76 . The sustained release tablet of  claim 1 , wherein the sustained release tablet does not further comprise an immediate release drug overcoat containing 4-aminopyridine. 
     
     
         77 . The sustained release tablet of  claim 1 , wherein the sustained release tablet provides a zero-order or near-zero-order release of the 4-aminopyridine. 
     
     
         78 . The sustained release tablet of  claim 77 , wherein the release is zero-order. 
     
     
         79 - 80 . (canceled) 
     
     
         81 . A method of making a sustained release tablet comprising 4-aminopyridine, which method comprises:
 (a) forming a compressed core comprising (i) 4-aminopyridine, (ii) a polyethylene oxide with a molecular weight between about 1,000,000 and 10,000,000, (iii) a mixture comprising polyvinyl acetate and polyvinyl pyrrolidone; (iv) dibasic calcium phosphate dihydrate, and (ν) magnesium stearate;   (b) coating the compressed core with an amount of ethylcellulose to form a coated compressed core, said amount of the ethylcellulose coat being in the range of about 5% w/w to about 10% w/w of the compressed core; and   (c) curing the coated compressed core by exposing it to a temperature in the range of 40-70° C. for a period of time of at least 1 hour;   wherein the amount of 4-aminopyridine in the sustained release tablet is about 22 mg, and upon once daily oral administration to a human subject in a fasted state, the sustained release tablet provides one or more of the following pharmacokinetic parameters: (a) a mean steady state plasma 4-aminopyridine C max  in the range of about 18.61 ng/mL to about 37.19 ng/mL, (b) a mean steady state plasma 4-aminopyridine C min  in the range of about 7.73 ng/mL to about 19.47 ng/mL, (c) a mean steady state plasma 4-aminopyridine AUCo-24 in the range of about 324 ng·h/mL to about 638 ng·h/mL, and (d) a median steady state plasma 4-aminopyridine T max  in the range of about 3 h to about 12 h.   
     
     
         82 - 91 . (canceled) 
     
     
         92 . A method of treating a neurological disorder in a patient in need thereof comprising orally administering to the patient once daily the sustained release tablet of  claim 1 . 
     
     
         93 . The method of  claim 92 , wherein the neurological disorder is multiple sclerosis or stroke. 
     
     
         94 - 100 . (canceled)