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

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.

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).

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 less than about 20% of the amylose present in said high amylose starch prior to (a) is chemically cross-linked to amylopectin.

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, less than about 20% of the amylose present prior to (a) is chemically cross-linked to and eluted with amylopectin.

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 is higher than that of the peak corresponding to amylopectin-containing entities.

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).

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 less than about 20% of the amylose present in said high amylose starch prior to (a) is chemically cross-linked to amylopectin.

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, less than about 20% of the amylose present prior to (a) is chemically cross-linked to and eluted with amylopectin.

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 is higher than that of the peak corresponding to amylopectin-containing entities.