Modified release pharmaceutical compositions of huperzine and methods of using the same

Abstract

The present application discloses pharmaceutical compositions for modified release of huperzine. The pharmaceutical compositions and methods described herein, allow for dosing of huperzine at higher therapeutic thresholds, while avoiding rapid serum peak plasma levels, thereby avoiding the adverse nausea and vomiting associated with the immediate release pharmaceutical compositions. Methods of treating neurological disorders and/or seizure disorders with the modified release compositions is also described.

1 . A pharmaceutical composition for oral delivery comprising:
 a. about 74 weight % to about 86 weight % of a sugar sphere core wherein the sugar sphere core has a particle size of about 500-710 μm;   b. a huperzine layer coating the sugar sphere, wherein the huperzine layer comprises about 0.95% to about 1 weight % huperzine or a pharmaceutically acceptable salt of huperzine that is equivalent to about 0.95% to about 1 weight % huperzine, and one or more excipients, wherein the total amount of excipients is about 5 weight % to about 9 weight %; and   c. about 7 weight % to about 16 weight % of a plasticized ethyl cellulose polymer layer coating the huperzine layer, wherein the huperzine layer contains a therapeutically-effective amount of huperzine.   
     
     
         2 . The pharmaceutical composition of  claim 1  wherein the huperzine is huperzine A or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The pharmaceutical composition of  claim 1 , further comprising a seal coat layer coating the huperzine layer between the huperzine layer and the plasticized ethyl cellulose polymer layer. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the one or more excipients is selected from hydroxypropyl methylcellulose, and polyvinylpryrrolidone or combinations thereof. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the one or more excipients is selected from low viscosity hydroxypropyl methylcellulose, and polyvinylpryrrolidone K30 or combinations thereof. 
     
     
         6 . The pharmaceutical composition of  claim 1  wherein one or more excipients is a combination of about 5 weight % to about 7 weight % hydroxypropyl methylcellulose and about 0.5 weight % to about 1.5 weight % polyvinylpryrrolidone. 
     
     
         7 . The pharmaceutical composition of  claim 1  wherein the plasticized ethyl cellulose is SurRelease® Type B NF E. 
     
     
         8 . The pharmaceutical composition of  claim 1  wherein the huperzine is huperzine A; one or more excipients is a combination of low viscosity hydroxypropyl methylcellulose and polyvinylpyrrolidone K30; and the plasticized ethyl cellulose is SurRelease® Type B NF E. 
     
     
         9 . The pharmaceutical composition of  claim 1 , comprising about 80 weight % to about 86 weight % of the sugar sphere. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the plasticized ethyl cellulose polymer layer is about 7 weight % to about 12 weight %. 
     
     
         11 . The pharmaceutical composition of  claim 1  comprising:
 a. about 79 weight % to about 84 weight % of the sugar sphere core; 
 b. a huperzine layer coating the sugar sphere, wherein the huperzine layer comprises about 0.95 weight % to about 1 weight % huperzine A, or a pharmaceutically acceptable salt of huperzine A that is equivalent to about 0.95 weight % to about 1 weight % of huperzine A; about 6 weight % hydroxypropyl methylcellulose, and about 0.95 weight % to about 1 weight % polyvinylpryrrolidone; and 
 c. about 8 weight % to about 13 weight % of a plasticized ethyl cellulose polymer layer coating the huperzine layer, wherein the huperzine layer contains a therapeutically-effective amount of huperzine A. 
 
     
     
         12 . The pharmaceutical composition of  claim 1  comprising:
 a. about 80 weight % to about 83 weight % of a sugar sphere core wherein the sugar sphere core has a particle size of about 500-710 μm; 
 b. a huperzine layer coating the sugar sphere, wherein the huperzine layer comprises about 0.95 weight % to about 1 weight % huperzine A, about 5 weight % to about 6 weight % hydroxypropyl methylcellulose, and about 0.95 weight % to about 1 weight % polyvinylpryrrolidone; and 
 c. about 8 weight % to about 12 weight % of a plasticized ethyl cellulose polymer layer coating the huperzine layer, wherein the huperzine layer contains a therapeutically-effective amount of huperzine A. 
 
     
     
         13 . The pharmaceutical composition of  claim 1  comprising:
 a. about 81 weight % to about 82 weight % of a sugar sphere core wherein the sugar sphere core has a particle size of about 500-710 μm; 
 b. a huperzine layer coating the sugar sphere, wherein the huperzine layer comprises about 0.95 weight % to about 1 weight % huperzine A, about 5 weight % to about 6 weight % hydroxypropyl methylcellulose, and about 0.95 weight % to about 1 weight % polyvinylpryrrolidone; and 
 c. about 10 weight % to about 11 weight % of a plasticized ethyl cellulose polymer layer coating the huperzine layer, wherein the huperzine layer contains a therapeutically-effective amount of huperzine A. 
 
     
     
         14 . The pharmaceutical composition of  claim 1  comprising:
 a. about 82 weight % to about 83 weight % of a sugar sphere core wherein the sugar sphere core has a particle size of about 500-710 μm; 
 b. a huperzine layer coating the sugar sphere, wherein the huperzine layer comprises about 0.95 weight % to about 1 weight % huperzine A, about 6 weight % hydroxypropyl methylcellulose, and about 0.95 weight % to about 1 weight % polyvinylpryrrolidone; and 
 c. about 9 weight % to about 10 weight % of a plasticized ethyl cellulose polymer layer coating the huperzine layer, wherein the huperzine layer contains a therapeutically-effective amount of huperzine A. 
 
     
     
         15 . The pharmaceutical composition of  claim 2  comprising:
 a. about 76 weight % to about 76 weight % of a sugar sphere core wherein the sugar sphere core has a particle size of about 500-710 μm; 
 b. a huperzine layer coating the sugar sphere, wherein the huperzine layer comprises about 0.9 weight % to about 1 weight % huperzine A, about 5 weight % to about 6 weight % hydroxypropyl methylcellulose, and 0.9 weight % to about 1 weight % polyvinylpryrrolidone; 
 c. a seal coat layer coating the huperzine layer, comprising about 1 weight % to about 2 weight % hydroxypropylmethyl cellulose; and 
 d. about 15 weight % to about 16 weight % of a plasticized ethyl cellulose polymer layer coating the seal coat layer, wherein the huperzine layer contains a therapeutically-effective amount of huperzine A. 
 
     
     
         16 . The pharmaceutical composition of  claim 1  wherein the pharmaceutical composition is in a capsule. 
     
     
         17 . A pharmaceutical composition comprising huperzine A, characterized by a C max  of huperzine in plasma of about 4 ng/mL to about 8 ng/mL, a T max  of about 4 hours to about 8 hours and a t 1/2  of about 8 hours to about 12 hours upon oral administration of a therapeutically effective dose of the pharmaceutical composition to a human subject. 
     
     
         18 . The pharmaceutical composition of  claim 17  wherein the C max  is about 4 ng/mL to about 6 ng/mL, T max  is about 4 hours to about 8 hours and the t 1/2  is about 10 hours to about 12 hours. 
     
     
         19 . The pharmaceutical composition of  claim 17  wherein the C max  is about 6 ng/mL, the T max  is about 4 hours and the t 1/2  is about 8.3 hours. 
     
     
         20 . A pharmaceutical composition comprising a therapeutically-effective amount of huperzine, characterized by a T max  of about 4 to about 8 hours and a C max  that is reduced by about 25% to about 50% when compared with a C max  of an immediate release huperzine pharmaceutical composition administered at an equivalent dose. 
     
     
         21 . The pharmaceutical composition of  claim 20  wherein the C max  is reduced by about 50%. 
     
     
         22 . The pharmaceutical composition of  claim 1  that exhibits the following dissolution profile when tested according to USP 1 type apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8) at 37° C.: about 36% to about 46% of the huperzine is released after 2 hours, about 61% to about 77% of the huperzine is released after 4 hours, about 84% to about 97% of the huperzine is released after 8 hours and not less than about 89% of the huperzine is released after 12 hours. 
     
     
         23 . The pharmaceutical composition of  claim 1  that exhibits the following dissolution profile when tested according to USP 1 type apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8) at 37° C.: about 36% of the huperzine is released after 2 hours, about 63% of the huperzine is released after 4 hours, about 84% of the huperzine is released after 8 hours and not less than about 89% of the huperzine is released after 12 hours. 
     
     
         24 . The pharmaceutical composition of  claim 1  that exhibits the following dissolution profile when tested according to USP 1 type apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8) at 37° C.: about 46% of the huperzine is released after 2 hours, about 77% of the huperzine is released after 4 hours, about 97% of the huperzine is released after 8 hours and not less than about 99% of the huperzine is released after 12 hours. 
     
     
         25 . The pharmaceutical composition of  claim 1  that exhibits the following dissolution profile when tested according to USP 1 type apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8) at 37° C.: about 43% of the huperzine is released after 2 hours, about 68% of the huperzine is released after 4 hours, about 88% of the huperzine is released after 8 hours and not less than about 96% of the huperzine is released after 12 hours. 
     
     
         26 . The pharmaceutical composition of  claim 1  that exhibits the following dissolution profile when tested according to USP 1 type apparatus at 50 revolutions per minute in 50 mM phosphate (pH 6.8) at 37° C.: about 38% of the huperzine is released after 2 hours, about 61% of the huperzine is released after 4 hours, about 84% of the huperzine is released after 8 hours and not less than about 94% of the huperzine is released after 12 hours. 
     
     
         27 . A method of treating a disorder selected from a neurological disorder or a seizure disorder, comprising administering to a patient in need thereof, a pharmaceutical composition according to  claim 1 . 
     
     
         28 . The method of  claim 27  wherein the seizure disorder is selected from epilepsy and complex partial seizure. 
     
     
         29 . The method of  claim 27  wherein the pharmaceutical composition is administered twice a day. 
     
     
         30 . The method of  claim 27  wherein said administering comprises
 a. administering one or more titration doses of the pharmaceutical composition followed by 
 b. administering a maintenance dose of the pharmaceutical composition wherein the maintenance dose is a therapeutically effective dose. 
 
     
     
         31 . The method of  claim 27 , wherein the patient experiences a better side effect profile, comprising administering a first dosing regimen of at least one dosing regimen selected from a. to h. and administering a second dosing regimen of at least one dosing regimen selected from a. to i., provided the second dosing regimen ascends from the first dosing regimen and further provided the last dosing regimen is the maintenance dose and therefore will be administered for as long as the patient is in need of treatment thereof:
 a. optionally administering a dose of about 0.25 mg of huperzine A, once every about 12 hours for at least two days and up to two weeks;   b. optionally administering a dose of about 0.5 mg of huperzine A, once every about 12 hours for at least two days and up to two weeks;   c. optionally administering a dose of about 0.75 mg of huperzine A, once every about 12 hours for at least two days and up to two weeks;   d. optionally administering a dose of about 1 mg of huperzine A, once every about 12 hours for at least two days and up to two weeks;   e. optionally administering a dose of about 1.25 mg of huperzine A, once every about 12 hours for at least two days and up to two weeks;   f. optionally administering a dose of about 1.5 mg of huperzine A, once every about 12 hours for at least two days and up to two weeks;   g. optionally administering a dose of about 1.75 mg of huperzine A, once every about 12 hours for at least two days and up to two weeks;   h. optionally administering a dose of about 2 mg of huperzine A, once every about 12 hours for at least two days and up to two weeks;   i. optionally administering a dose of about 2.5 mg of huperzine A, once every about 12 hours for at least two days;   
       wherein the huperzine A of a.-i. is administered in the pharmaceutical composition of  claim 1 . 
     
     
         32 . The method of  claim 31 , comprising:
 a. administering a dose of about 0.25 mg of huperzine A, once every about 12 hours for two days to two weeks;   b. administering a dose of about 0.5 mg of huperzine A, once every about 12 hours for two days to two weeks;   c. administering a dose of about 0.75 mg of huperzine A, once every about 12 hours for two days to two weeks;   d. administering a dose of about 1 mg of huperzine A, once every about 12 hours for at least two days.   
     
     
         33 . The method of  claim 32 , wherein step d is administered for as long as the patient is in need of treatment. 
     
     
         34 . The method of  claim 32 , further comprising after step d:
 e. administering a dose of about 1.25 mg of huperzine A once every about 12 hours for as long as the patient is in need thereof.   
     
     
         35 . The method of  claim 32 , further comprising after step d.:
 e. administering a dose of about 1.25 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   f. administering a dose of about 1.5 mg of huperzine A once every about 12 hours for as long as the patient is in need thereof.   
     
     
         36 . The method of  claim 32 , further comprising after step d.:
 e. administering a dose of about 1.25 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   f. administering a dose of about 1.5 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   g. administering a dose of about 1.75 mg of huperzine A once every about 12 hours for as long as the patient is in need thereof.   
     
     
         37 . The method of  claim 32 , further comprising after step d.:
 e. administering a dose of about 1.25 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   f. administering a dose of about 1.5 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   g. administering a dose of about 1.75 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   h. administering a dose of about 2.0 mg of huperzine A once every about 12 hours for as long as the patient is in need thereof.   
     
     
         38 . The method of  claim 32 , further comprising after step d.:
 e. administering a dose of about 1.25 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   f. administering a dose of about 1.5 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   g. administering a dose of about 1.75 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   h. administering a dose of about 2.0 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   i. administering a dose of about 2.5 mg of huperzine A once every about 12 hours for as long as the patient is in need thereof.   
     
     
         39 . A method of treating a disorder selected from the group consisting of a neurological disorder and a seizure disorder, in a patient in need thereof, wherein the patient experiences a better side effect profile, comprising administering one or more titration doses of huperzine A, followed by administering a therapeutically effective dose of huperzine A; wherein the huperzine A is administered in a modified release pharmaceutical composition. 
     
     
         40 . The method of  claim 39  wherein the modified release pharmaceutical composition comprises a dissolvable core; an active huperzine A layer coating the dissolvable core; and a polymer coating, coating the huperzine A layer; wherein the huperzine A layer comprises a therapeutically-effective amount of huperzine. 
     
     
         41 . A method of treating a disorder selected from the group consisting of a neurological disorder and a seizure disorder, in a patient in need thereof, wherein the patient experiences a better side effect profile, comprising administering a first dosing regimen of at least one dosing regimen selected from a. to h. (as described below) and administering a second dosing regimen of at least one dosing regimen selected from a. to i. (as described below), provided the second dosing regimen ascends from the first dosing regimen and further provided the last dosing regimen is the maintenance dose and therefore will be administered for as long as the patient is in need of treatment thereof
 a. administering a dose of about 0.25 mg of huperzine A, once every about 12 hours at least two days and up to two weeks;   b. administering a dose of about 0.5 mg of huperzine A, once every about 12 hours for at least two days and up to two weeks;   c. administering a dose of about 0.75 mg of huperzine A, once every about 12 hours for at least two days and up to two weeks;   d. administering a dose of about 1 mg of huperzine A, once every about 12 hours for at least two days and up to two weeks;   e. administering a dose of about 1.25 mg of huperzine A, once every about 12 hours for at least two days and up to two weeks;   f. administering a dose of about 1.5 mg of huperzine A, once every about 12 hours for at least two days and up to two weeks;   g. administering a dose of about 1.75 mg of huperzine A, once every about 12 hours for at least two days and up to two weeks;   h. administering a dose of about 2 mg of huperzine A, once every about 12 hours for at least two days and up to two weeks;   i. administering a dose of about 2.5 mg of huperzine A, once every about 12 hours for at least two days;   
       wherein the huperzine A of a.-i. is administered in a modified release pharmaceutical composition. 
     
     
         42 . The method of  claim 41  comprising:
 a. administering a dose of about 0.25 mg of huperzine A, once every about 12 hours for two days to two weeks; 
 b. administering a dose of about 0.5 mg of huperzine A, once every about 12 hours for two days to two weeks; 
 c. administering a dose of about 0.75 mg of huperzine A, once every about 12 hours for two days to two weeks; 
 d. administering a dose of about 1 mg of huperzine A, once every about 12 hours for at least two days 
 
     
     
         43 . The method of  claim 42 , wherein step d. is administered for as long as the patient is in need of treatment. 
     
     
         44 . The method of  claim 42 , further comprising after step d:
 e. administering a dose of about 1.25 mg of huperzine A once every about 12 hours for as long as the patient is in need thereof.   
     
     
         45 . The method of  claim 42 , further comprising after step d.:
 e. administering a dose of about 1.25 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   f. administering a dose of about 1.5 mg of huperzine A once every about 12 hours for as long as the patient is in need thereof.   
     
     
         46 . The method of  claim 42 , further comprising after step d.:
 e. administering a dose of about 1.25 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   f. administering a dose of about 1.5 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   g. administering a dose of about 1.75 mg of huperzine A once every about 12 hours for as long as the patient is in need thereof.   
     
     
         47 . The method of  claim 42 , further comprising after step d.:
 e. administering a dose of about 1.25 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   f. administering a dose of about 1.5 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   g. administering a dose of about 1.75 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   h. administering a dose of about 2 mg of huperzine A once every about 12 hours for as long as the patient is in need thereof.   
     
     
         48 . The method of  claim 42 , further comprising after step d.:
 e. administering a dose of about 1.25 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   f. administering a dose of about 1.5 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   g. administering a dose of about 1.75 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   h. administering a dose of about 2 mg of huperzine A once every about 12 hours for 2 days to 2 weeks;   i. administering a dose of about 2.5 mg of huperzine A once every about 12 hours for as long as the patient is in need thereof.   
     
     
         49 . A method of treating a disorder selected from the group consisting of a neurological disorder and a seizure disorder, to a patient in need thereof, wherein the patient experiences a better side effect profile, comprising administering a modified release pharmaceutical composition of huperzine A, wherein the modified release pharmaceutical composition of huperzine A is characterized by a C ss  of huperzine A in plasma selected from the group consisting of: about 0.52 to about 0.82 ng/mL at a 0.25 mg dose; about 1.91 to about 2.99 ng/mL at a 0.50 mg dose; about 3.56 to about 5.55 ng/mL at a 0.75 mg dose; about 5.58 to about 8.72 ng/mL at a 1 mg dose; about 8.22 to about 12.84 ng/mL at a 1.25 mg dose; about 9.02 to about 14.09 ng/mL at a 1.5 mg dose; about 10.04 to about 15.69 ng/mL at a 1.75 mg dose; about 16 to about 25 ng/mL at a 2.0 mg dose; and about 18.48 to about 28.88 ng/mL at a 2.5 mg dose. 
     
     
         50 . A method of treating a disorder selected from the group consisting of a neurological disorder and a seizure disorder, to a patient in need thereof, wherein the patient experiences a better side effect profile, comprising administering a modified release pharmaceutical composition of huperzine A, wherein the modified release pharmaceutical composition of huperzine A is characterized by a C ss  of huperzine A in plasma of at least 8 ng/mL when administered at a therapeutically effective dose. 
     
     
         51 . A method of treating a disorder selected from the group consisting of a neurological disorder and a seizure disorder, to a patient in need thereof, wherein the patient experiences a better side effect profile, comprising administering a modified release pharmaceutical composition of huperzine A, wherein the modified release pharmaceutical composition of huperzine A is characterized by a C max  of huperzine in plasma of about 0.76 ng/mL to about 1.19 ng/mL, a T max  of about 4 hour to about 6.25 hours and an AUC 0-8  of about 4.18 to about 6.53 upon oral administration of a therapeutically effective dose of the pharmaceutical composition to a human patient. 
     
     
         52 . A method of treating a disorder selected from the group consisting of a neurological disorder and a seizure disorder, to a patient in need thereof, wherein the patient experiences a better side effect profile, comprising administering a modified release pharmaceutical composition of huperzine A, wherein the modified release pharmaceutical composition of huperzine A is characterized by a C max  of huperzine in plasma of about 2.51 ng/mL to about 3.93 ng/mL, a T max  of about 4 hour to about 6.25 hours and an AUC 0-8  of about 13.76 to about 21.5 upon oral administration of a therapeutically effective dose of the pharmaceutical composition to a human patient.