Cross-linked high amylose starch for use in controlled-release pharmaceutical formulations and processes for its manufacture

Abstract

The present invention relates to a novel form of cross-linked high amylose starch and processes for its manufacture. Such cross-linked high amylose starch is useful as an excipient in a controlled-release pharmaceutical formulation when compressed with pharmaceutical agent(s) in a tablet. Such cross-linked high amylose starch is prepared by (a) cross-linking and chemical modification of high amylose starch, (b) gelatinization, and (c) drying to obtain a powder of said controlled release excipient. In a preferred embodiment, such cross-linked high amylose starch is prepared in the following steps: (1) granular cross-linking and additional chemical modification (e.g., hydroxypropylation) of high-amylose starch; (2) thermal gelatinization of the starch from step (1); and (3) drying the starch from step (2) to yield a powder capable of being used as a controlled release excipient.

We claim:  
     
         1 . A process for manufacturing, in an aqueous medium, a controlled release excipient consisting primarily of cross-linked high amylose starch, for use in preparation of tablets, said process comprising 
 (a) cross-linking high amylose starch thereby forming a reaction medium containing a reaction product consisting of a cross-linked high amylose starch slurry;    (b) subjecting said cross-linked high amylose starch slurry from step (a) to chemical modification at a temperature of about 10 to about 90° C. for about 1 to about 72 hours;    (c) neutralizing said reaction medium obtained in step (b) with an acid, washing the slurry formed and optionally dewatering or to form a starch cake or a dry powder;    (d) diluting said slurry or re-slurrifying said starch cake or said dry powder from step (c) with water to form a slurry at a concentration of about 2% to about 40% w/w, adjusting pH to a desired value between about 3 and about 12, and gelatinizing said slurry at a temperature of about 80 to 180° C. for about 1 second to about 120 minutes; and    (e) drying the thermally treated product obtained in step (d) to obtain said controlled release excipient consisting mainly of chemically modified and cross-linked high amylose starch in form of a powder.    
     
     
         2 . The process according to  claim 1 , wherein steps (a) and (b) are performed at the same time.  
     
     
         3 . The process according to  claim 1  comprising, 
 (a) cross-linking high amylose starch containing at least 70% w/w of amylose with about 0.005 g to about 0.3 g cross-linking reagent per 100 g of dry-based high amylose starch in an aqueous medium at a temperature of about 10 to about 90° C. thereby forming a reaction medium containing a reaction product consisting of a cross-linked high amylose starch slurry;  
 (b) subjecting said cross-linked high amylose starch slurry from step (a) to hydroxypropylation with propylene oxide at a temperature of about 10 to about 90° C. for about 1 to about 72 hours to yield a reaction medium containing a hydroxypropylated cross-linked high amylose starch slurry;  
 (c) neutralizing said reaction medium obtained in step (b) with a dilute aqueous acid, washing slurry formed and optionally dewatering to obtain a starch cake or a dry powder;  
 (d) diluting said slurry, or re-slurrifying starch cake or dry powder from step (c) with water to form a slurry at a concentration of about 2% to about 40% w/w, adjusting pH to about 4.0 to about 9.0, and gelatinizing said slurry formed in current step at a temperature of about 80 to about 180° C. for about 1 second to about 120 minutes; and  
 (e) drying said thermally treated product obtained in step (d) to obtain said controlled release excipient consisting mainly of hydroxypropylated and cross-linked high amylose starch in form of a powder.  
 
     
     
         4 . The process of  claim 3 , wherein, in step (a), said cross-linking reagent is phosphorous oxychloride in an amount of between about 0.01 and about 0.2 g per 100 g starch dry basis or sodium trimetaphosphate in an amount of between about 0.05 and about 0.3 g per 100 g starch dry basis.  
     
     
         5 . The process of  claim 3  wherein step (a) is performed in an aqueous alkaline medium.  
     
     
         6 . The process of  claim 4 , wherein, in step (a), said cross-linking is carried out at a pH of about 10 to about 14 and at a temperature of about 15 to about 90° C. for about 0.2 to about 40 hours.  
     
     
         7 . The process of  claim 3 , wherein, in step (b), said hydroxypropylation is carried out with up to 10% propylene oxide at a temperature of about 40 to about 80° C. for about 10 to about 72 hours.  
     
     
         8 . The process of  claim 3 , wherein, in step (c), said neutralization of said reaction medium is carried out with dilute sulfuric acid or hydrochloric acid.  
     
     
         9 . The process of  claim 3 , where, in step (d), said gelatinization is carried out by direct steam injection into an aqueous suspension of said cross-linked high amylose starch.  
     
     
         10 . The process of  claim 3 , wherein, in step (d), said pH is adjusted to about 6.0 and said temperature is kept at about 80 to about 180° C. for about 2 to about 10 minutes.  
     
     
         11 . The process of  claim 3 , wherein, in step (e), said drying is carried out by spray-drying.  
     
     
         12 . The process of  claim 11 , wherein, in step (e), inlet temperature is from about 60 to about 350° C., and outlet temperature is set from about 40 to about 210° C.  
     
     
         13 . A process for manufacturing, in an aqueous medium, a controlled release excipient consisting primarily of cross-linked high amylose starch, for use in preparation of tablets, said process comprising 
 (a) subjecting high amylose starch to chemical modification at a temperature of about 10 to about 90° C. for about 1 to about 72 hours thereby forming a reaction medium containing a chemically modified high amylose slurry;    (b) cross-linking said chemically modified high amylose starch in said slurry obtained in step (a);    (c) neutralizing said slurry obtained in step (b) with an acid, washing the slurry formed and optionally dewatering to form a starch cake or drying to form dry powder;    (d) diluting said slurry, or re-slurrifying said starch cake or said dry powder from step (c) with water to form a slurry at a concentration of about 2% to about 40% w/w, adjusting pH to a desired value between about 3 and about 12, and gelatinizing said slurry at a temperature of about 80 to 180° C. for about 1 second to about 120 minutes; and    (e) drying the thermally treated product obtained in step (d) to obtain said controlled release excipient consisting mainly of chemically modified and cross-linked high amylose starch in form of a powder.    
     
     
         14 . The process according to  claim 13 , wherein steps (a) and (b) are performed at the same time.  
     
     
         15 . The process according to  claim 13  comprising 
 (a) subjecting high amylose starch containing at least 70% w/w of amylose to hydroxypropylation with propylene oxide at a temperature of about 10 to about 90° C. for about 1 to about 72 hours to yield a reaction medium containing a reaction product of consisting primarily of a hydroxypropylated high amylose starch slurry;  
 (b) cross-linking said hydroxypropylated high amylose starch slurry with about 0.005 g to about 0.3 g cross-linking reagent per 100 g of dry-based high amylose starch in an aqueous medium at a temperature of about 10 to about 90° C. to yield a reaction medium containing a cross-linked hydroxypropylated high amylose starch slurry;  
 (c) neutralizing said reaction medium obtained in step (b) with a dilute aqueous acid, washing slurry formed and optionally dewatering to obtain a starch cake or a dry powder;  
 (d) diluting said slurry, or re-slurrifying said starch cake or said dry powder from step (c) with water to form a slurry at a concentration of about 2% to about 40% w/w, adjusting pH to about 4.0 to about 9.0, and gelatinizing said slurry formed in current step at a temperature of about 80 to about 180° C. for about 1 second to about 120 minutes; and  
 (e) drying said thermally treated product obtained in step (d) to obtain said controlled release excipient consisting mainly of hydroxypropylated and cross-linked high amylose starch in form of a powder.  
 
     
     
         16 . The process of  claim 15 , wherein, in step (a), said cross-linking reagent is phosphorous oxychloride in an amount of between about 0.01 and about 0.2 g per 100 g starch dry basis or sodium trimetaphosphate in an amount of between about 0.05 and about 0.3 g per 100 g starch dry basis.  
     
     
         17 . The process of  claim 15  wherein step (b) is performed in an aqueous alkaline medium.  
     
     
         18 . The process of  claim 16 , wherein, in step (b), said cross-linking is carried out at a pH of about 10 to about 14 and at a temperature of about 15 to about 90° C. for about 0.2 to about 40 hours.  
     
     
         19 . The process of  claim 15 , wherein, in step (a), said hydroxypropylation is carried out with up to 10% propylene oxide at a temperature of about 40 to about 80° C. for about 10 to about 72 hours.  
     
     
         20 . A controlled release tablet comprising a compressed blend of at least two dry powders, including a powder of at least one pharmaceutical agent and a powder of a controlled release excipient; 
 wherein said controlled release excipient comprises a chemically-modified, cross-linked high amylose starch prepared by a method comprising: 
 (a) cross-linking high amylose starch, followed by  
 (b) chemically modifying the cross-linked high amylose starch, followed by  
 (c) gelatinization, and  
 (d) drying to obtain a powder of said controlled release excipient;  
   wherein said cross-linked high amylose starch is characterized in that upon solubilization in 90% DMSO at 80° C. for about three days and gel permeation chromatography, the height of the peak corresponding to amylose in said cross-linked high amylose starch is at least 90% of that of the peak corresponding to amylose in said high amylose starch prior to (a).