Levodopoa and Carbidopa Intestinal Gel and Methods of Use

Abstract

The present disclosure relates to (a) an improved pharmaceutical composition comprising a levodopa active agent and a carbidopa active agent (b) methods of producing the pharmaceutical composition and (c) methods of treating Parkinson's disease and associated conditions comprising administering the pharmaceutical composition to a subject with Parkinson's disease.

1 . A pharmaceutical composition for intraduodenal administration comprising:
 (a) a levodopa active agent in an amount of about 4.0 weight/weight percent of the total composition;   (b) a carbidopa monohydrate active agent in an amount of about 1.0 weight/weight percent of the total composition;   (c) one or more acrylic acid-based polymer suspending agents; and   (d) water,   
       wherein the pharmaceutical composition has:
 (i) a high shear viscosity of no more than about 4500 cps at 22° C. and 24.1 s −1 ; 
 (ii) a low shear viscosity of no less than about 45000 cps at 5° C. and 1 s −1 ; and 
 (iii) a ratio of low shear viscosity to high shear viscosity of not less than 10. 
 
     
     
         2 - 5 . (canceled) 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the one or more acrylic acid-based polymer suspending agents is Carbopol®. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein the concentration of water is in an amount of from about zero percent to about 95 weight/weight percent of the total composition. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition does not experience degradation into DHPA at a rate faster than 0.06 w/w % per week. 
     
     
         11 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition does not experience degradation into DHPPA at a rate faster than 0.06 w/w % per week. 
     
     
         12 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition does not experience degradation producing hydrazine at a rate faster than 0.75 μg/g per week. 
     
     
         13 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition is present in a lower O 2  permeable primary or secondary container. 
     
     
         14 . A pharmaceutical dosage form comprising the pharmaceutical composition of  claim 1  in a disposable drug reservoir having an oxygen impermeable enclosure disposed therein, wherein the oxygen impermeable enclosure is purged with an inert gas and an oxygen scavenger is added. 
     
     
         15 . The pharmaceutical dosage form according to  claim 14 , wherein the pharmaceutical dosage form is suitable for use in a continuous infusion pump capable of delivering the composition in a therapeutically effective manner. 
     
     
         16 . A method of preparing a pharmaceutical composition for intraduodenal administration comprising:
 (a) a levodopa active agent in an amount of about 4.0 weight/weight percent of the total composition;   (b) a carbidopa monohydrate active agent in an amount of about 1.0 weight/weight percent of the total composition;   (c) one or more polymer-based suspending agents; and   (d) water,   
       wherein the pharmaceutical composition has:
 (i) a high shear viscosity of no more than about 4500 cps at 22° C. and 24.1 s −1 ; 
 (ii) a low shear viscosity of no less than about 45000 cps at 5° C. and 1 s −1 ; and 
 (iii) a ratio of low shear viscosity to high shear viscosity of not less than 10, 
 wherein the method comprises: 
 adding a levodopa active agent and a carbidopa monohydrate active agent to water to form a slurry; 
 adding the slurry to one or more polymer-based suspending agents to form a suspension; and 
 subjecting the suspension to N 2  sparging. 
 
     
     
         17 . The method according to  claim 16 , further comprising loading the suspension into a lower oxygen permeability container. 
     
     
         18 . The method according to  claim 16 , wherein, prior to forming the suspension, the levodopa active agent has a particle size distribution of:
 (i) D50 less than or equal to about 5 μm;   (ii) D90 less than or equal to about 11 μm; and   (iii) D100 less than or equal to about 22 μm; and   
       the carbidopa active agent has a particle size distribution of:
 (i) D50 less than or equal to about 3 μm; 
 (ii) D90 less than or equal to about 7 μm; and 
 (iii) D100 less than or equal to about 21 μm. 
 
     
     
         19 . The method according to  claim 16 , wherein the one or more polymer-based suspending agents is selected from the group consisting of hydroxypropylcellulose, hydroxymethylcellulose, and sodium carboxymethyl cellulose. 
     
     
         20 . The method according to  claim 16 , wherein the one or more polymer-based suspending agent is an acrylic acid-based polymer. 
     
     
         21 - 25 . (canceled) 
     
     
         26 . A method of treating Parkinson's disease in a patient in need thereof, wherein the method comprises intraduodenal administration to the patient a pharmaceutical composition comprising:
 (a) a levodopa active agent in an amount of about 4.0 weight/weight percent of the total composition; and   (b) a carbidopa monohydrate active agent in an amount of about 1.0 weight/weight percent of the total composition;   (c) one or more polymer-based suspending agents; and   (d) water,   
       wherein the pharmaceutical composition has:
 (i) a high shear viscosity of no more than about 4500 cps at 22° C. and 24.1 s −1 ; 
 (ii) a low shear viscosity of no less than about 45000 cps at 5° C. and 1 s −1 ; and 
 (iii) a ratio of low shear viscosity to high shear viscosity of not less than 10. 
 
     
     
         27 . The method according to  claim 26 , wherein the method comprises substantially continuous administration of the pharmaceutical composition for a period of at least about 16 hours. 
     
     
         28 - 31 . (canceled) 
     
     
         32 . The method according to  claim 26 , wherein the one or more polymer-based suspending agent is selected from the group consisting of hydroxypropylcellulose, hydroxymethylcellulose, and sodium carboxymethyl cellulose. 
     
     
         33 . (canceled) 
     
     
         34 . The method according to  claim 26 , wherein the one or more polymer-based suspending agent is an acrylic acid-based polymer 
     
     
         35 . A kit comprising the pharmaceutical composition of  claim 1 . 
     
     
         36 . A kit comprising the pharmaceutical dosage form of  claim 14 .