Methods and systems for improved bioavailability of active pharmaceutical ingredients including esomeprazole

Abstract

The present disclosure relates to delivery systems and methods for increasing the bioavailability and increasing the absorption rate by monolithic enteric capsule administration to humans of active ingredients compared to the bioavailability of active ingredients enterically coated for modified release or gastric protection, particularly acid sensitive active ingredients such as esomeprazole, omeprazole, and other proton pump inhibitors, systems for delivering active pharmaceutical ingredients to humans or animals via monolithic enteric capsules, and improved methods of treating gastrointestinal disorders with such methods and delivery systems.

1 . An enteric drug delivery system comprising: a monolithic enteric hard capsule filled with the active pharmaceutical ingredient, wherein the active pharmaceutical ingredient has not been enterically coated for modified release or gastric protection, wherein less than about 10% of the active pharmaceutical ingredient is released from the monolithic enteric capsule after about 2 hours in a pH of about 1.2, wherein at least about 80% of the active pharmaceutical ingredient is released from the monolithic enteric capsule after about 30 min at pH of about 6.8, and wherein more than about 95% of the active ingredient is released in the intestine; wherein the active pharmaceutical ingredient is a proton pump inhibitor selected from the group consisting of dexlanzoprazole, esomeprazole, ilaprazole, leminoprazole, lanzoprazole, omeprazole, pantoprazole, paripiprazole, rabeprazole, tenatoprazole and combinations, pharmaceutically acceptable salts, derivatives, and enantiomers thereof. 
     
     
         2 . The system according to  claim 1 , wherein the monolithic enteric capsule yields a peak plasma concentration (C max ) that is equal to or higher than the peak plasma concentration achieved by the active pharmaceutical ingredient from administration of an oral dosage form comprising at least one enteric coating for modified release or gastric protection, particularly where C max  is increased by up to about 279%. 
     
     
         3 . The system according to  claim 1 , wherein the monolithic enteric capsule yields an Area Under Curve (AUC 0-t ) plasma concentration of the active pharmaceutical ingredient equal to or higher than the AUC 0-t  achieved by the active pharmaceutical ingredient from administration of an oral dosage form comprising at least one enteric coating for modified release or gastric protection, particularly where AUC 0-t  is increased up to about 220%. 
     
     
         4 . The system according to  claim 1 , wherein the monolithic enteric capsule yields an Area Under Curve (AUC 0-∞ ) plasma concentration of the active pharmaceutical ingredient equal to or higher than the AUC 0-∞  achieved by the active pharmaceutical ingredient from administration of an oral dosage form comprising at least one enteric coating for modified release or gastric protection, particularly where AUC 0- ∞ is increased up to about 162%. 
     
     
         5 . The system according to  claim 1 , wherein the monolithic enteric capsule has an increase in oral bioavailability from about 10% to about 50% on average compared to bioavailability of the active pharmaceutical ingredient in an oral dosage form comprising at least one enteric coating for modified release or gastric protection. 
     
     
         6 . The system according to  claim 1 , wherein the active pharmaceutical ingredient is esomeprazole or its pharmaceutically acceptable salts. 
     
     
         7 . A method of increasing bioavailability of an active pharmaceutical ingredient (API), comprising administering to a human in need thereof a therapeutically effective amount of at least one API in a monolithic enteric hard capsule, wherein said API has not been coated for modified release or gastric protection, wherein the bioavailability of said API is increased compared to API having an enteric coating for modified release or gastric protection. 
     
     
         8 . The method according to  claim 7 , wherein the API is acid labile or has gastric side effects. 
     
     
         9 - 10 . (canceled) 
     
     
         11 . A monolithic enteric capsule, comprising:
 a non-salified functional polymer, said polymer being present in an amount ranging from about 50% to about 75% by weight of the total weight of the empty capsule;   at least one processing aid present in an amount ranging from about 10.5% to about 20% by weight of the total weight of the empty capsule; and   water present in an amount ranging from about 1% to about 20% by weight over the total weight of the empty capsule.   
     
     
         12 . The monolithic enteric capsule according to  claim 11 , wherein the monolithic enteric capsule provides an increased rate of absorption C max /(T max −T lag ) for the active pharmaceutical ingredient after administration to a patient as compared to the rate of absorption of the active pharmaceutical ingredient having an enteric coating for modified release or gastric protection from about 30 ng/mL/hr to about 3400 ng/mL/hr. 
     
     
         13 . The monolithic enteric capsule according to  claim 11 , wherein the monolithic enteric capsule decreases the time to achieve peak plasma concentration (T max −T lag ) for the active pharmaceutical ingredient compared to the active pharmaceutical ingredient coated for modified release or gastric protection in pellets or tablets, preferably decreasing by from about 0.1 hour to about 2.0 hours. 
     
     
         14 . The monolithic enteric capsule according to  claim 11 , wherein the monolithic enteric capsule decreases the time to achieve peak plasma concentration for the active pharmaceutical ingredient compared to the active pharmaceutical ingredient coated for modified release or gastric protection in solid dosage forms selected from the group consisting of beads, caplets, capsules, granules, microparticles, multiparticulates, microspheres; powders, pellets, solid lipid pellets, tablets, and combinations thereof, preferably decreasing by from about 10 minutes to about 90 minutes. 
     
     
         15 . The monolithic enteric capsule according to  claim 11 , wherein the monolithic enteric capsule provides an increased lag time after administration to a patient for release of the active pharmaceutical ingredient compared to the active pharmaceutical ingredient coated for modified release or gastric protection in solid dosage forms selected from the group consisting of beads, caplets, capsules, granules, microparticles, multiparticulates, microspheres; powders, pellets, solid lipid pellets, tablets, and combinations thereof, preferably where the increase in lag time is from about 0.1 hour to about 4.3 hours. 
     
     
         16 . The monolithic enteric capsule according to  claim 11 , wherein the monolithic enteric capsule lacks internal excipients. 
     
     
         17 . An oral pharmaceutical dosage form, comprising the monolithic enteric hard capsule of  claim 11 , wherein the monolithic enteric hard capsule is filled with at least one proton pump inhibitor free of enteric coating, wherein the monolithic enteric hard capsule yields a peak plasma concentration higher than the peak plasma concentration achieved by the proton pump inhibitor having an enteric coating for modified release or gastric protection.