Process to reduce endotoxin in gelatin

Abstract

The present disclosure is directed to processes for reducing the endotoxin level in gelatin and the resulting gelatin with low endotoxin content. The process includes dissolving a salt in a gelatin solution and filtering the gelatin-salt solution using anion exchange to reduce the endotoxin level. After reducing the endotoxin level of the gelatin-salt solution, the low endotoxin gelatin-salt solution is desalted to remove the salt, thereby producing a low endotoxin gelatin solution.

1 . A low endotoxin gelatin solution prepared by a process comprising:
 dissolving salt in a gelatin solution comprising gelatin and a solvent to form a gelatin-salt solution, wherein the endotoxin content of the gelatin is at least 6,000 EU/g of gelatin;   filtering the gelatin-salt solution through an anion exchange adsorber such that a filtrate gelatin-salt solution has an endotoxin content of less than 2,500 EU/g; and   desalting the filtrate gelatin-salt solution to form a low endotoxin gelatin solution that has an endotoxin content of less than 2,500 EU/g.   
     
     
         2 . The low endotoxin gelatin solution of  claim 1 , wherein the salt concentration in the gelatin-salt solution is 75-300 mM. 
     
     
         3 . The low endotoxin gelatin solution of  claim 2 , wherein the salt concentration of the gelatin-salt solution is about 145-155 mM. 
     
     
         4 . The low endotoxin gelatin solution of  claim 1 , wherein the gelatin solution is a 1-20% w/w gelatin solution. 
     
     
         5 . The low endotoxin gelatin solution of  claim 1 , wherein the salt is sodium chloride. 
     
     
         6 . The low endotoxin gelatin solution of  claim 1 , wherein the gelatin is fish gelatin. 
     
     
         7 . The low endotoxin gelatin solution of  claim 1 , wherein dissolving the salt in the gelatin solution comprises heating the gelatin solution to 50-70° C. 
     
     
         8 . The low endotoxin gelatin solution of  claim 1 , wherein the solvent is water. 
     
     
         9 . The method of  claim 1 , wherein the endotoxin content of the gelatin-salt solution and the low endotoxin gelatin solution is less than 1,000 EU/g. 
     
     
         10 . The low endotoxin gelatin solution of  claim 1 , wherein filtering the gelatin-salt solution through an anion exchange adsorber reduces the endotoxin content of the solution by at least 95%. 
     
     
         11 . The low endotoxin gelatin solution of  claim 1 , wherein at least about 85% of the gelatin content is recovered in the filtrate gelatin-salt solution after filtering the gelatin-salt solution through an anion exchange adsorber. 
     
     
         12 . The low endotoxin gelatin solution of  claim 1 , wherein desalting the filtrate gelatin-salt solution is accomplished by a diafiltration process. 
     
     
         13 . The low endotoxin gelatin solution of  claim 12 , wherein the diafiltration process comprises diluting the filtrate gelatin-salt solution with a second solvent and filtering the diluted filtrate gelatin-salt solution to form a diluted filtrate gelatin solution. 
     
     
         14 . The low endotoxin gelatin solution of  claim 13 , wherein the diluted filtrate gelatin-salt solution is filtered until a conductivity of the diluted filtrate gelatin solution is within less than 25% of a conductivity of the gelatin solution. 
     
     
         15 . The low endotoxin gelatin solution of  claim 14 , wherein the ratio of filtrate gelatin-salt solution to second solvent is 1:1-1:4. 
     
     
         16 . The low endotoxin gelatin solution of  claim 15 , wherein the second solvent is removed from the diluted filtrate gelatin solution to form the low endotoxin gelatin solution. 
     
     
         17 . The low endotoxin gelatin solution of  claim 16 , wherein the second solvent is removed from the diluted filtrate gelatin solution until a weight of the diluted filtrate gelatin solution is within less than 5% of a weight of the filtrate gelatin-salt solution. 
     
     
         18 . The low endotoxin gelatin solution of  claim 17 , wherein the second solvent comprises water. 
     
     
         19 . The low endotoxin gelatin solution of  claim 1 , wherein the process further comprises removing the solvent from the low endotoxin gelatin solution to form a low endotoxin gelatin that has an endotoxin content of less than 2,500 EU/g. 
     
     
         20 . A method of producing a dosage form for the delivery of a pharmaceutically active ingredient comprising:
 dosing a formulation comprising the low endotoxin gelatin solution of  claim 1  into a preformed mold; and   freeze drying the formulation to form the dosage form.   
     
     
         21 . A dosage form for the delivery of a pharmaceutically active ingredient prepared by the method of  claim 20 . 
     
     
         22 . A low endotoxin gelatin solution comprising a solvent and a gelatin, wherein the gelatin solution has an endotoxin content of less than 2,500 EU/g.