Levodopa 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.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising a levodopa active agent and a carbidopa active agent for intraduodenal administration wherein the levodopa active agent and the carbidopa active agent are suspended in an aqueous carrier, characterized in that the levodopa active agent and the carbidopa active agent in the carrier has a high shear viscosity of no more than about 4500 cps at room temperature and a low shear viscosity of no less than about 45000 cps under refrigerated conditions and a ratio of low shear viscosity to high shear viscosity of not less than 10. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition comprises:
 a levodopa active agent in an amount of about 4.0 weight/weight percent of the total composition;   a carbidopa monohydrate active agent in an amount of about 1.0 weight/weight percent of the total composition;   a liquid vehicle, and   
       wherein the aqueous carrier comprises a suspending agent. 
     
     
         3 . The pharmaceutical composition according to  claim 1  wherein the aqueous carrier comprises one or more polymer-based suspending agent. 
     
     
         4 . The pharmaceutical composition according to  claim 3 , wherein the one or more polymer-based suspending agent is selected from the group consisting of hydroxypropylcellulose, hydroxymethylcellulose, and sodium carboxymethyl cellulose. 
     
     
         5 . The pharmaceutical composition according to  claim 4 , wherein the one or more polymer-based suspending agent is sodium carboxymethyl cellulose. 
     
     
         6 . The pharmaceutical composition according to  claim 3 , wherein the one or more polymer-based suspending agent is an acrylic acid-based polymer. 
     
     
         7 . The pharmaceutical composition according to  claim 2 , wherein the concentration of the liquid vehicle is in an amount of from about zero percent to about 95 weight/weight percent of the total composition. 
     
     
         8 . The pharmaceutical composition according to  claim 2 , wherein the liquid vehicle is selected from the group consisting of water or polyethylene glycol. 
     
     
         9 . The pharmaceutical composition according to  claim 7 , wherein the liquid vehicle is water only. 
     
     
         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 the pharmaceutical composition according to  claim 1 , wherein the method comprises:
 adding a levodopa active agent and a carbidopa active agent to water to form a slurry;   adding the slurry to one or more 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;   (i) 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; 
 (i) 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 suspending agent 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 suspending agent is an acrylic acid-based polymer. 
     
     
         21 . A pharmaceutical composition prepared according to the method of  claim 16 . 
     
     
         22 . A pharmaceutical composition prepared according to the method of  claim 17 . 
     
     
         23 . A pharmaceutical composition prepared according to the method of  claim 18 . 
     
     
         24 . A pharmaceutical composition prepared according to the method of  claim 19 . 
     
     
         25 . A pharmaceutical composition prepared according to the method of  claim 20 . 
     
     
         26 . A method of treating Parkinson's disease in a patient in need thereof, wherein the method comprises administering to the patient a pharmaceutical composition comprising a levodopa active agent and a carbidopa active agent for intraduodenal administration, wherein the levodopa active agent and carbidopa active agent are provided in a therapeutically effective manner for the patient and, suspended in an aqueous carrier, characterized in that the levodopa active agent and the carbidopa active agent in the carrier has a high shear viscosity of no more than about 4500 cps at room temperature and a low shear viscosity of no less than about 45000 cps under refrigerated conditions and 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 . The method according to  claim 27 , wherein the method comprises substantially continuous administration of the pharmaceutical composition for a period of at least about 24 hours. 
     
     
         29 . The method according to  claim 26 , wherein the pharmaceutical composition comprises:
 a levodopa active agent in an amount of about 4.0 weight/weight percent of the total composition; and   a carbidopa monohydrate active agent in an amount of about 1.0 weight/weight percent of the total composition.   
     
     
         30 . The method according to  claim 26 , wherein the pharmaceutical composition is administered in a pharmaceutical dosage form wherein
 the pharmaceutical composition is disposed inside 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.   
     
     
         31 . The method according to  claim 26 , wherein the aqueous carrier comprises one or more polymer-based suspending agent. 
     
     
         32 . The method according to  claim 31 , wherein the one or more polymer-based suspending agent is selected from the group consisting of hydroxypropylcellulose, hydroxymethylcellulose, and sodium carboxymethyl cellulose. 
     
     
         33 . The method according to  claim 32 , wherein the one or more polymer-based suspending agent is sodium carboxymethyl cellulose. 
     
     
         34 . The method according to  claim 31 , 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 .