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.   
     
     
         2 . The sustained release tablet of  claim 1 , wherein said mixture further comprises one or more pharmaceutically acceptable excipients. 
     
     
         3 . The sustained release tablet of  claim 1 , wherein said mixture comprises 70-90% polyvinyl acetate and 15-20% polyvinyl pyrrolidone. 
     
     
         4 . The sustained release tablet of any of  claims 1 - 3 , wherein said mixture further comprises a surfactant. 
     
     
         5 . The sustained release tablet of  claim 4 , wherein said mixture further comprises silica. 
     
     
         6 . The sustained release tablet of any of  claims 1 - 5 , wherein said mixture consists of about 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% silica. 
     
     
         7 . The sustained release tablet of any of  claims 1 - 6 , wherein the compressed core further comprises a filler and a lubricant. 
     
     
         8 . The sustained release tablet of  claim 7 , wherein the filler is dibasic calcium phosphate dihydrate, and the lubricant is magnesium stearate. 
     
     
         9 . The sustained release tablet of any of  claims 1 - 8 , wherein the polyethylene oxide has a molecular weight between 4,000,000 and 8,000,000. 
     
     
         10 . The sustained release tablet of any of  claims 1 - 8 , wherein the polyethylene oxide has a molecular weight of 7,000,000. 
     
     
         11 . The sustained release tablet of any of  claims 1 - 10 , 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 sustained release tablet. 
     
     
         12 . The sustained release tablet of any of  claims 1 - 10 , 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. 
     
     
         13 . A sustained release tablet comprising:
 (a) a compressed core, wherein said compressed core comprises: (i) 4-aminopyridine, (ii) a polyethylene oxide with a molecular weight between about 1,000,000 and 10,000,000, (iii) a mixture consisting of about 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica, (iv) dibasic calcium phosphate dihydrate, and (v) magnesium stearate; 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 is in the range of about 4% w/w to about 6% w/w of the compressed core.   
     
     
         14 . The sustained release tablet of any of  claims 1 - 13 , wherein the amount of the ethylcellulose coat surrounding the compressed core is about 9% w/w of the compressed core. 
     
     
         15 . 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 7% w/w of the compressed core.   
     
     
         16 . The sustained release tablet of  claim 15 , wherein the amount of 4-aminopyridine is in the range of about 3% w/w to about 5% w/w of the compressed core and the amount of the ethylcellulose coat surrounding the compressed core is about 6% w/w of the compressed core. 
     
     
         17 . The sustained release tablet of any of  claims 1 - 16 , wherein the amount of 4-aminopyridine in the compressed core is in the range of about 12 mg to about 25 mg. 
     
     
         18 . The sustained release tablet of any of  claims 1 - 17 , wherein the amount of 4-aminopyridine in the compressed core is in the range of about 20 mg to about 25 mg. 
     
     
         19 . The sustained release tablet of any of  claims 1 - 18 , wherein the amount of 4-aminopyridine in the compressed core is about 22 mg. 
     
     
         20 . The sustained release tablet of any of  claims 1 - 19 , wherein the amount of 4-aminopyridine in the compressed core is about 16.5 mg. 
     
     
         21 . The sustained release tablet of any of  claims 1 - 16 , wherein the amount of 4-aminopyridine in the compressed core is in the range of about 5 mg to about 12 mg. 
     
     
         22 . A sustained release tablet comprising:
 (a) a compressed core, wherein said compressed core comprises: (i) 4-aminopyridine, wherein the amount of 4-aminopyridine is in the range of about 4% w/w to about 6% w/w of the compressed core; (ii) a polyethylene oxide with a molecular weight between about 1,000,000 and 10,000,000, wherein the amount of the polyethylene oxide is in the range of about 10% w/w to about 20% w/w of the compressed core; (iii) a mixture consisting of about 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica, wherein the amount of the mixture is in the range of about 20% w/w to about 30% w/w of the compressed core; (iv) dibasic calcium phosphate dihydrate, wherein 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 (v) magnesium stearate, wherein 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; 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.   
     
     
         23 . A sustained release tablet comprising:
 (a) a compressed core, wherein said compressed core comprises: (i) 4-aminopyridine, wherein the amount of 4-aminopyridine is in the range of about 4% w/w to about 6% w/w of the compressed core; (ii) a polyethylene oxide with a molecular weight of 7,000,000, wherein the amount of the polyethylene oxide is about 15% w/w of the compressed core; (iii) a mixture consisting of about 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica, wherein the amount of the mixture is about 25% w/w of the compressed core; (iv) dibasic calcium phosphate dihydrate, wherein the amount of dibasic calcium phosphate dihydrate is about 54% w/w of the compressed core; and (v) magnesium stearate, wherein the amount of magnesium stearate is about 1% w/w of the compressed core; and   (b) an amount of an ethylcellulose coat surrounding said compressed core, said amount of the ethylcellulose coat being about 9% w/w of the compressed core.   
     
     
         24 . The sustained release tablet of  claim 23 , wherein the amount of 4-aminopyridine is about 22 mg. 
     
     
         25 . A sustained release tablet comprising:
 (a) a compressed core, wherein said compressed core comprises: (i) 4-aminopyridine, wherein the amount of 4-aminopyridine is in the range of about 3% w/w to about 5% w/w of the compressed core; (ii) a polyethylene oxide with a molecular weight between about 1,000,000 and 10,000,000, wherein the amount of the polyethylene oxide is in the range of about 10% w/w to about 20% w/w of the compressed core; (iii) a mixture consisting of about 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica, wherein the amount of the mixture is in the range of about 20% w/w to about 30% w/w of the compressed core; (iv) dibasic calcium phosphate dihydrate, wherein 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 (v) magnesium stearate, wherein 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; 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 7% w/w of the compressed core.   
     
     
         26 . A sustained release tablet comprising:
 (a) a compressed core, wherein said compressed core comprises: (i) 4-aminopyridine, wherein the amount of 4-aminopyridine is in the range of about 3% w/w to about 5% w/w of the compressed core; (ii) a polyethylene oxide with a molecular weight of 7,000,000, wherein the amount of the polyethylene oxide is about 15% w/w of the compressed core; (iii) a mixture consisting of about 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica, wherein the amount of the mixture is about 25% w/w of the compressed core; (iv) dibasic calcium phosphate dihydrate, wherein the amount of dibasic calcium phosphate dihydrate is about 55% w/w of the compressed core; and (v) magnesium stearate, wherein the amount of magnesium stearate is about 1% w/w of the compressed core; and   (b) an amount of an ethylcellulose coat surrounding said compressed core, said amount of the ethylcellulose coat being about 6% w/w of the compressed core.   
     
     
         27 . The sustained release tablet of  claim 26 , wherein the amount of 4-aminopyridine is about 16.5 mg. 
     
     
         28 . 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, wherein the ratio of the amount of the ethylcellulose coat to the amount of 4-aminopyridine in the compressed core is in the range of about 0.5:1 to about 3:1;   wherein for calculating said ratio, the amount of the ethylcellulose coat is the weight percentage of the ethylcellulose coat by weight of the compressed core, and the amount of 4-aminopyridine is the weight percentage of 4-aminopyridine by weight of the compressed core.   
     
     
         29 . 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, wherein the ratio of the amount of the ethylcellulose coat to the amount of 4-aminopyridine in the compressed core is in the range of about 0.1:1 to about 0.7:1; wherein for calculating said ratio, the amount of the ethylcellulose coat is the weight percentage of the ethylcellulose coat by weight of the compressed core, and the amount of 4-aminopyridine is the weight in milligrams of 4-aminopyridine.   
     
     
         30 . The sustained release tablet of any of  claims 1 - 29 , wherein the sustained release tablet is the product of a process comprising a curing step after coating the compressed core with ethylcellulose, and wherein said curing step comprises heating the coated compressed core to a temperature above 23° C. for a period of time of at least 15 minutes. 
     
     
         31 . The sustained release tablet of  claim 30 , wherein said curing step comprises exposing the coated compressed core to a temperature in the range of 50-60° C. for a period of time of at least 1 hour. 
     
     
         32 . The sustained release tablet of any of  claims 1 - 31 , wherein the sustained release tablet does not further comprise an immediate release drug overcoat containing 4-aminopyridine. 
     
     
         33 . The sustained release tablet of any of  claims 1 - 32 , wherein the sustained release tablet provides a zero-order or near-zero-order release of the 4-aminopyridine. 
     
     
         34 . The sustained release tablet of  claim 33 , wherein the release is zero-order. 
     
     
         35 . The sustained release tablet of any of  claims 1 - 34 , wherein the sustained release tablet is suitable for once daily oral administration. 
     
     
         36 . The sustained release tablet of any of  claims 1 - 35 , wherein the sustained release tablet comprises an amount of 4-aminopyridine that is therapeutically effective over a period of 24 hours upon oral administration to a human patient. 
     
     
         37 . The sustained release tablet of any of  claims 1 - 36 , wherein the release of the 4-aminopyridine, upon subjecting the tablet to an in vitro dissolution test employing 50 mM Phosphate Buffer, pH 6.8 as dissolution medium, is as follows:
 within the first 2 hours after the start of the test at most 30% w/w of the total amount of the 4-aminopyridine contained in the sustained release tablet is released.   
     
     
         38 . The sustained release tablet of  claim 37 , wherein the release of the 4-aminopyridine is as follows:
 within the first 24 hours after the start of the test at least 80% w/w of the total amount of the 4-aminopyridine contained in the sustained release tablet is released.   
     
     
         39 . The sustained release tablet of any of  claims 1 - 31 , wherein the sustained release tablet further comprises an immediate release drug overcoat containing 4-aminopyridine. 
     
     
         40 . 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 (v) 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.   
     
     
         41 . The method of  claim 40 , wherein forming the compressed core comprises:
 (a) blending the 4-aminopyridine, polyethylene oxide, the mixture comprising polyvinyl acetate and polyvinyl pyrrolidone, and dibasic calcium phosphate dihydrate to form a blended mixture;   (b) adding magnesium stearate to the blended mixture to form a new blend; and   (c) compressing the new blend to form a compressed core.   
     
     
         42 . The method of  claim 40  or  41 , wherein said mixture consists of about 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% silica. 
     
     
         43 . The method of any of  claims 40 - 42 , wherein the polyethylene oxide has a molecular weight between 4,000,000 and 8,000,000. 
     
     
         44 . The method of any of  claims 40 - 43 , wherein the polyethylene oxide has a molecular weight of 7,000,000. 
     
     
         45 . The method of any of  claims 40 - 44 , wherein the coating comprises applying an aqueous ethylcellulose dispersion to the compressed core. 
     
     
         46 . The method of any of  claims 40 - 45 , wherein the total amount of the 4-aminopyridine in the sustained release tablet is in the range of about 1% w/w to about 10% w/w of the sustained release tablet. 
     
     
         47 . The method of any of  claims 40 - 45 , wherein the total amount of the 4-aminopyridine in the sustained release tablet is in the range of about 1% w/w to about 10% w/w of the compressed core. 
     
     
         48 . A method of making a sustained release tablet comprising 4-aminopyridine, which method comprises:
 (a) forming a compressed core comprising (i) 4-aminopyridine, wherein the amount of 4-aminopyridine is in the range of about 4% w/w to about 6% w/w of the compressed core, (ii) a polyethylene oxide with a molecular weight of 7,000,000, wherein the amount of the polyethylene oxide is about 15% w/w of the compressed core, (iii) a mixture consisting of about 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica, wherein the amount of the mixture is about 25% w/w of the compressed core; (iv) dibasic calcium phosphate dihydrate, wherein the amount of dibasic calcium phosphate dihydrate is about 54% w/w of the compressed core; and (v) magnesium stearate, wherein the amount of magnesium stearate is about 1% w/w of the compressed core;   (b) coating the compressed core with an amount of ethylcellulose to form a coated compressed core, said amount of the ethylcellulose coat being about 9% w/w of the compressed core; and   (c) curing the coated compressed core by exposing it to a temperature in the range of 50-60° C. for a period of time of at least 1 hour.   
     
     
         49 . The method of  claim 48 , wherein the amount of 4-aminopyridine in the compressed core is about 22 mg. 
     
     
         50 . A method of making a sustained release tablet comprising 4-aminopyridine, which method comprises:
 (a) forming a compressed core comprising (i) 4-aminopyridine, wherein the amount of 4-aminopyridine is in the range of about 3% w/w to about 5% w/w of the compressed core, (ii) a polyethylene oxide with a molecular weight of 7,000,000, wherein the amount of the polyethylene oxide is about 15% w/w of the compressed core, (iii) a mixture consisting of about 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica, wherein the amount of the mixture is about 25% w/w of the compressed core; (iv) dibasic calcium phosphate dihydrate, wherein the amount of dibasic calcium phosphate dihydrate is about 55% w/w of the compressed core; and (v) magnesium stearate, wherein the amount of magnesium stearate is about 1% w/w of the compressed core;   (b) coating the compressed core with an amount of ethylcellulose to form a coated compressed core, said amount of the ethylcellulose coat being about 6% w/w of the compressed core; and   (c) curing the coated compressed core by exposing it to a temperature in the range of 50-60° C. for a period of time of at least 1 hour.   
     
     
         51 . The method of  claim 50 , wherein the amount of 4-aminopyridine in the compressed core is about 16.5 mg. 
     
     
         52 . The method of any of  claims 40 - 51 , wherein the sustained release tablet is suitable for once daily oral administration. 
     
     
         53 . The method of any of  claims 40 - 52 , wherein the sustained release tablet comprises an amount of 4-aminopyridine that is therapeutically effective over a period of 24 hours. 
     
     
         54 . 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 any of  claims 1 - 53 . 
     
     
         55 . The method of  claim 54 , wherein the neurological disorder is multiple sclerosis or stroke. 
     
     
         56 . The method of  claim 55 , wherein the neurological disorder is multiple sclerosis. 
     
     
         57 . The method of  claim 56 , wherein the neurological disorder is a walking impairment associated with multiple sclerosis. 
     
     
         58 . The method of  claim 56 , wherein the neurological disorder is a neurocognitive or neuropsychiatric impairment associated with multiple sclerosis. 
     
     
         59 . The method of  claim 55 , wherein the neurological disorder is stroke. 
     
     
         60 . The method of  claim 59 , wherein the neurological disorder is a sensorimotor impairment associated with stroke. 
     
     
         61 . The method of  claim 59 , wherein the neurological disorder is a walking impairment associated with stroke. 
     
     
         62 . The method of any of  claims 54 - 61 , wherein the patient is a human patient. 
     
     
         63 . 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 8% w/w to about 10% w/w of the tablet,   wherein said tablet is the product of a process comprising a curing step after coating the compressed core with ethylcellulose, and wherein said curing step comprises heating the coated compressed core to a temperature above 23° C. for a period of time of at least 15 minutes.   
     
     
         64 . A sustained release tablet comprising:
 (a) a compressed core, wherein said compressed core comprises: (i) 4-aminopyridine, (ii) a polyethylene oxide with a molecular weight between about 1,000,000 and 10,000,000, (iii) a mixture consisting of about 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica, (iv) dibasic calcium phosphate dihydrate, and (v) magnesium stearate; and   (b) an amount of an ethylcellulose coat surrounding said compressed core, said amount of the ethylcellulose coat being in the range of about 8% w/w to about 10% w/w of the tablet,   wherein said sustained release tablet is the product of a process comprising a curing step after coating the compressed core with ethylcellulose, wherein said curing step comprises exposing the coated compressed core to a temperature in the range of 50-60° C. for a period of time of at least 1 hour, and wherein the amount of 4-aminopyridine is in the range of about 4% w/w to about 6% w/w of the sustained release tablet.   
     
     
         65 . 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 (v) 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 8% to about 10% w/w of the sustained release tablet; 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.   
     
     
         66 . The sustained release tablet of  claim 30 , wherein said curing step comprises exposing the coated compressed core to a temperature in the range of 40-70° C. for a period of time of at least 1 hour. 
     
     
         67 . The sustained release tablet of any of  claims 1 - 36 , wherein the release of the 4-aminopyridine, upon subjecting the tablet to an in vitro dissolution test employing 50 mM Phosphate Buffer, pH 6.8 as dissolution medium, is as follows:
 within the first 2 hours after the start of the test at most 20% w/w of the total amount of the 4-aminopyridine contained in the sustained release tablet is released.   
     
     
         68 . The sustained release tablet of  claim 67 , wherein the release of the 4-aminopyridine is as follows:
 within the first 24 hours after the start of the test at least 80% w/w of the total amount of the 4-aminopyridine contained in the sustained release tablet is released.