Oral Delivery of Peptides

Abstract

Bioavailability of peptide active agents to be administered orally is enhanced by a pharmaceutical composition providing an active peptide that is amidated at a site that is not naturally amidated.

1 - 65 . (canceled) 
     
     
         66 . An oral pharmaceutical composition comprising an active peptide agent that has an amide group at its C-terminus, and is not found in nature with an amide group at its C-terminus, wherein the active peptide agent is a human parathyroid hormone analog having the first 31 amino acids of human parathyroid hormone wherein the 31 st  amino acid is amidated at its C-terminus, the composition further comprising an absorption enhancer effective to promote bioavailability of the active peptide agent, or a pharmaceutically acceptable pH-lowering agent that is present in the pharmaceutical composition in a quantity which, if the composition were added to ten milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of the solution to no higher than 5.5. 
     
     
         67 . The pharmaceutical composition of  claim 66  comprising at least one pharmaceutically acceptable pH-lowering agent. 
     
     
         68 . The pharmaceutical composition of  claim 66  further comprising an acid resistant protective vehicle effective to transport said pharmaceutical composition through the stomach of a patient while preventing contact between said active peptide agent and stomach proteases. 
     
     
         69 . The pharmaceutical composition of  claim 66  comprising an absorption enhancer, wherein the absorption enhancer is a surface active agent. 
     
     
         70 . The pharmaceutical composition of  claim 69  wherein said surface active agent is selected from the group consisting of acylcarnitines, phospholipids and bile acids. 
     
     
         71 . The pharmaceutical composition of  claim 66  further including a sucrose ester. 
     
     
         72 . The pharmaceutical composition of  claim 66  comprising an absorption enhancer, wherein the absorption enhancer is a surface active agent selected from the group consisting of (i) an anionic agent that is a cholesterol derivative, (ii) a mixture of a negative charge neutralizer and an anionic surface active agent, (iii) non-ionic surface active agents, and (iv) cationic surface active agents. 
     
     
         73 . The pharmaceutical composition of  claim 66  further comprising an amount of a second peptide that is not physiologically active effective to enhance bioavailability of said peptide active agent. 
     
     
         74 . The pharmaceutical composition of  claim 68  further comprising a water soluble barrier that separates said pH-lowering agent from said protective vehicle. 
     
     
         75 . The pharmaceutical composition of  claim 67  wherein said composition includes at least one pH-lowering agent that has a pKa no higher than 4.2. 
     
     
         76 . The pharmaceutical composition of  claim 67  wherein at least one pH-lowering agent has a solubility in water of at least 30 grams per 100 milliliters of water at room temperature. 
     
     
         77 . The pharmaceutical composition of  claim 68  wherein all ingredients other than said protective vehicle are uniformly dispersed. 
     
     
         78 . The pharmaceutical composition of  claim 69  wherein said pharmaceutical composition comprises granules containing a pharmaceutical binder and, uniformly dispersed in said binder, said pH-lowering agent, said absorption enhancer and said peptide active agent. 
     
     
         79 . The pharmaceutical composition of  claim 66  comprising a pharmaceutically acceptable pH-lowering agent and an absorption enhancer wherein said composition is a solid dosage form wherein a weight ratio of said pH-lowering agent to said absorption enhancer is between 3:1 and 20:1. 
     
     
         80 . The pharmaceutical composition of  claim 66  comprising a pharmaceutically acceptable pH-lowering agent and an absorption enhancer wherein said composition is a solid dosage form wherein the weight ratio of said pH-lowering agent to said absorption enhancer is between 5:1 and 10:1. 
     
     
         81 . The pharmaceutical composition of  claim 67  wherein said pH-lowering agent is selected from the group consisting of citric acid, tartaric acid and an acid salt of an amino acid. 
     
     
         82 . The pharmaceutical composition of  claim 67  wherein said pH-lowering agent is present in an amount not less than 300 milligrams. 
     
     
         83 . The pharmaceutical composition of  claim 67  wherein said pH-lowering agent is present in an amount which is not less than 400 milligrams. 
     
     
         84 . The pharmaceutical composition of  claim 68  wherein said protective vehicle is a viscous protective syrup. 
     
     
         85 . The pharmaceutical composition of  claim 68  wherein a water soluble barrier separates said pH-lowering agent from said protective vehicle.