Processes for the Manufacture and Use of Pancreatin

Abstract

A process for the manufacture and use of pancreatin in which the concentration of one or more biological contaminants is reduced, such as viruses and/or bacteria, through heating the pancreatin at a temperature of at least 85° C. for a period of less than about 48 hours.

We claim: 
     
         1 . A process for the manufacture of pancreatin, comprising the steps of:
 heating a dispersed form of pancreatin containing one or more solvents at a temperature of at least 85° C.;   wherein the total amount of the one or more solvents is less than about 9% by weight at any point during the heating step; and   wherein the titer level of a viral contaminant present in the dispersed pancreatin after heating is at least about 1000 times less than the titer level of said viral contaminant present in the dispersed pancreatin prior to heating.   
     
     
         2 . The process of  claim 1  wherein the pancreatin lipase activity after heating is at least about 50% of the lipase activity prior to heating. 
     
     
         3 . The process of  claim 1  wherein the pancreatin lipase activity after heating is at least about 70% of the lipase activity prior to heating. 
     
     
         4 . The process of  claim 1  wherein the pancreatin lipase activity after heating is at least about 90% of the lipase activity prior to heating. 
     
     
         5 . The process of  claim 1  wherein the heating of the pancreatin is for a duration equal to or less than about 48 hours. 
     
     
         6 . The process of  claim 1  wherein the heating of the pancreatin is for a duration of from about 1 hour to about 36 hours. 
     
     
         1 . cess of  claim 1  wherein the heating of the pancreatin is for a duration of from about 8 hours to about 30 hours. 
     
     
         8 . The process of  claim 1  wherein the titer level of a viral contaminant present in the pancreatin after heating is at least about 5000 times less than the titer level of the viral contaminant present in the pancreatin prior to heating. 
     
     
         9 . The process of  claim 1  wherein the titer level of a viral contaminant present in the pancreatin after heating is at least about 10,000 times less than the titer level of the viral contaminant present in the pancreatin prior to heating. 
     
     
         10 . The process of  claim 1  wherein the total amount of solvents is below about 3.5% by weight. 
     
     
         11 . The process of  claim 1  wherein the total amount of solvents is between about 0.1% and about 3.5% by weight. 
     
     
         12 . The process of  claim 1  wherein the total amount of solvents is between about 0.1% and about 3% by weight. 
     
     
         13 . The process according to  claim 1  wherein the temperature is between at least 85° C. and about 100° C. 
     
     
         14 . The process according to  claim 1  wherein the temperature is between about 90° C. and about 95° C. 
     
     
         15 . A method for treating pancreatic exocrine insufficiency in a mammalian subject, comprising the steps of:
 (1) heating a dispersed form of pancreatin containing one or more solvents at a temperature of at least 85° C.;
 wherein the total amount of the one or more solvents is less than about 9% by weight at any point during said heating step; and 
 wherein the titer level of a viral contaminant present in the dispersed pancreatin after heating is at least about 1000 times less than the titer level of the viral contaminant present in the dispersed pancreatin prior to heating; 
   (2) combining the pancreatin with one or more pharmaceutically acceptable excipients to create a dosage form suitable for oral administration; and   (3) orally administering said dosage form to the subject in an amount sufficient to treat the pancreatic exocrine insufficiency.   
     
     
         16 . The method of  claim 15  wherein the pancreatin lipase activity after heating is at least about 50% of the lipase activity prior to heating. 
     
     
         17 . The method of  claim 15  wherein the pancreatin lipase activity after heating is at least about 70% of the lipase activity prior to heating. 
     
     
         18 . The method of  claim 15  wherein the pancreatin lipase activity after heating is at least about 90% of the lipase activity prior to heating. 
     
     
         19 . The method of  claim 15  wherein the heating of the pancreatin is for a duration equal to or less than about 48 hours. 
     
     
         20 . The method of  claim 15  wherein the heating of the pancreatin is for a duration of from about 1 hour to about 36 hours. 
     
     
         21 . The method of  claim 15  wherein the heating of the pancreatin is for a duration of from about 8 hours to about 30 hours. 
     
     
         22 . The method of  claim 15  wherein the titer level of a viral contaminant present in the pancreatin after heating is at least about 5000 times less than the viral contaminant present in the pancreatin prior to heating. 
     
     
         23 . The method of  claim 15  wherein the titer level of a viral contaminant present in the pancreatin after heating is at least about 10,000 times less than the level of the viral contaminant present in the pancreatin prior to heating. 
     
     
         24 . The method of  claim 15  wherein the total amount of solvents is below about 3.5% by weight. 
     
     
         25 . The method of  claim 15  wherein the total amount of solvents is between about 0.1% and about 3.5% by weight. 
     
     
         26 . The method of  claim 15  wherein the total amount of solvents is between about 0.1% and about 3% by weight. 
     
     
         27 . The method of  claim 15  wherein the temperature is between at least 85° C. and about 100° C. 
     
     
         28 . The method of  claim 15  wherein the temperature is between about 90° C. and about 95° C. 
     
     
         29 . A pharmaceutical composition, comprising:
 (1) a pharmacologically effective quantity of pancreatin
 wherein said pancreatin has been heated, in the form of a dispersed pancreatin containing one or more solvents, to a temperature of at least 85° C.; 
 wherein the total amount of the one or more solvents is less than about 9% by weight at any point during said heating step; and 
 wherein the titer level of a viral contaminant present in the dispersed pancreatin after heating is at least about 1000 times less than the titer level of the viral contaminant present in the dispersed pancreatin prior to heating; and 
   (2) one or more pharmaceutically acceptable excipients.   
     
     
         30 . The pharmaceutical composition according to  claim 29  wherein the pancreatin is present in a dosage form which is suitable for oral administration and for immediate or modified release wherein said dosage form is selected from the group consisting of tablets, microtablets, pellets, micropellets, microspheres, granules, granulates, powders, suspensions, emulsions, dispersions, capsules and sachets. 
     
     
         31 . The pharmaceutical composition according to  claim 29  wherein the pancreatin is present in a dosage form coated with a gastric acid resistant coating. 
     
     
         32 . The pharmaceutical composition of  claim 29  in the form of a capsule or sachet. 
     
     
         33 . The pharmaceutical composition according to  claim 32  wherein the composition is in a dosage form which is suitable for oral administration and for immediate or modified release wherein said dosage form is selected from the group consisting of tablets, microtablets, pellets, micropellets, microspheres, granules, granulates, powders, suspensions, emulsions, dispersions, capsules and sachets. 
     
     
         34 . The pharmaceutical composition according to  claim 33  wherein the dosage form is coated with a gastric acid resistant coating. 
     
     
         35 . The pharmaceutical composition according to  claim 29  wherein the pancreatin lipase activity after heating is at least about 50% of the lipase activity prior to heating. 
     
     
         36 . The pharmaceutical composition according to  claim 29  wherein the pancreatin lipase activity after heating is at least about 70% of the lipase activity prior to heating. 
     
     
         37 . The pharmaceutical composition according to  claim 29  wherein the pancreatin lipase activity after heating is at least about 90% of the lipase activity prior to heating. 
     
     
         38 . The pharmaceutical composition according to  claim 29  wherein the heating of the pancreatin is for a duration equal to or less than about 48 hours. 
     
     
         39 . The pharmaceutical composition according to  claim 29  wherein the heating of the pancreatin is for a duration of from about 1 hour to about 36 hours. 
     
     
         40 . The pharmaceutical composition according to  claim 29  wherein the heating of the pancreatin is for a duration of from about 8 hours to about 30 hours. 
     
     
         41 . The pharmaceutical composition according to  claim 29  wherein the titer level of a viral contaminant present in the pancreatin after heating is at least about 5000 times less than the titer level of the viral contaminant present in the pancreatin prior to heating. 
     
     
         42 . The pharmaceutical composition according to  claim 29  wherein the titer level of a viral contaminant present in the pancreatin after heating is at least about 10,000 times less than the titer level of the viral contaminant present in the pancreatin prior to heating. 
     
     
         43 . The pharmaceutical composition according to  claim 29  wherein the total amount of solvents is below about 3.5% by weight. 
     
     
         44 . The pharmaceutical composition according to  claim 29  wherein the total amount of solvents is between about 0.1% and about 3.5% by weight. 
     
     
         45 . The pharmaceutical composition according to  claim 29  wherein the total amount of solvents is between about 0.1% and about 3% by weight. 
     
     
         46 . The pharmaceutical composition according to  claim 29  wherein the temperature is between at least 85° C. and about 100° C. 
     
     
         47 . The pharmaceutical composition according to  claim 29  wherein the temperature is between about 90° C. and about 95° C. 
     
     
         48 . A pharmaceutical composition, comprising:
 (1) about 50% to about 90% by weight of pancreatin
 wherein said pancreatin has been heated in a dispersed form of pancreatin containing one or more solvents at a temperature of at least 85° C.; 
 wherein the total amount of the one or more solvents is less than about 9% by weight at any point during said heating step; and 
 wherein the titer level of a viral contaminant present in the dispersed pancreatin after heating is at least about 1000 times less than the titer level of the viral contaminant present in the dispersed pancreatin prior to heating; and 
   (2) about 10% to about 50% by weight of pharmaceutically acceptable excipients.   
     
     
         49 . A process for the manufacture of pancreatin, comprising
 (1) heating a dispersed form of pancreatin containing one or more solvents at a temperature of at least 85° C. for a period of less than about 48 hours, and   (2) obtaining a total solvents content in the dispersed form of pancreatin of less than about 9% by weight at any point during said heating step.   
     
     
         50 . The process of  claim 49  wherein the solvents content is less than about 3.5% by weight. 
     
     
         51 . The process of  claim 49  wherein the solvents content is between about 0.1% and about 3.5% by weight. 
     
     
         52 . The process of  claim 49  wherein the heating of the pancreatin is for a duration from about 1 hour to about 36 hours. 
     
     
         53 . The process of  claim 49  wherein the heating of the pancreatin is for a duration from about 8 hour to about 30 hours. 
     
     
         54 . The process according to  claim 49  wherein the temperature is between at least 85° C. and about 100° C. 
     
     
         55 . The process according to  claim 1  wherein the temperature is between at least 85° C. and about 95° C. 
     
     
         56 . The process of  claim 49  wherein the heating step is performed continuously. 
     
     
         57 . The process of  claim 49  wherein the heating step is performed discontinuously. 
     
     
         58 . The process of  claim 49  wherein the titer level of a viral contaminant present in the dispersed pancreatin after heating is at least about 1000 times less than the titer level of said viral contaminant present in the dispersed pancreatin prior to heating. 
     
     
         59 . The process of  claim 49  wherein the solvents content in the pancreatin is determined by a Karl Fischer water titration method or by an infrared spectroscopy method. 
     
     
         60 . A method for treating pancreatic exocrine insufficiency in a mammalian subject, comprising the steps of:
 (1) heating a dispersed form of pancreatin containing one or more solvents at a temperature of at least 85° C. for a period of less than about 48 hours;   (2) obtaining a total solvents content in the pancreatin of less than about 9% by weight at any point during said heating step;   (3) combining the pancreatin with one or more pharmaceutically acceptable excipients to create a dosage form suitable for oral administration; and   (4) orally administering said dosage form to the subject in an amount sufficient to treat the pancreatic exocrine insufficiency.   
     
     
         61 . A pharmaceutical composition, comprising:
 (1) a pharmacologically effective quantity of pancreatin
 (a) wherein said pancreatin has been heated, in the form of a dispersed pancreatin containing one or more solvents, to a temperature of at least 85° C. for a period of less than about 48 hours; 
 (b) wherein the total solvents content in the pancreatin is less than about 9% by weight at any point during said heating step; and 
   (2) one or more pharmaceutically acceptable excipients.   
     
     
         62 . A pharmaceutical composition prepared by a process comprising the steps of:
 heating a dispersed form of pancreatin containing one or more solvents at a temperature of at least 85° C.;   wherein the total amount of the one or more solvents is less than about 9% by weight at any point during the heating step; and   wherein the titer level of a viral contaminant present in the dispersed pancreatin after heating is at least about 1000 times less than the titer level of said viral contaminant present in the dispersed pancreatin prior to heating.   
     
     
         63 . The pharmaceutical composition of  claim 62  wherein the composition is in a dosage form selected from the group consisting of tablets, microtablets, pellets, micropellets, microspheres, granules, granulates, powders, suspensions, emulsions, dispersions, capsules and sachets. 
     
     
         64 . A pharmaceutical composition prepared by a process comprising the steps of:
 (1) heating a dispersed form of pancreatin containing one or more solvents at a temperature of at least 85° C. for a period of less than about 48 hours;   (2) obtaining a total solvents content in the pancreatin of less than about 9% by weight at any point during said heating step; and   (3) combining the pancreatin with one or more pharmaceutically acceptable excipients to create a dosage form suitable for oral administration.   
     
     
         65 . The pharmaceutical composition of  claim 64  wherein the composition is in a dosage form selected from the group consisting of tablets, microtablets, pellets, micropellets, microspheres, granules, granulates, powders, suspensions, emulsions, dispersions, capsules and sachets.