Oral insulin therapies and protocol

Abstract

Methods for treating impaired glucose tolerance and early and late stage diabetes in mammals, for prophylactically sparing β-cell function, aiding in preventing β-cell death, preventing the onset of overt diabetes in a mammal with type 2 diabetes, treating the current level of glycemic control dysfunction of a mammal with impaired glucose tolerance or diabetes, comprising orally administering insulin and a delivery agent that facilitates insulin absorption from the gastrointestinal tract at the time of or shortly before mealtime, e.g., within about 10 minutes prior to ingestion of a meal, on a chronic basis. The methods also comprise, in addition to administering a rapid-acting insulin to provide a first insulin peak, administering a slow acting insulin to provide a second insulin peak occurring at a later time but of a longer duration. These methods achieve improved glycemic control without the risks of hypoglycemia, hyperinsulinemia and weight gain and the need for frequent blood glucose monitoring that are normally associated with insulin therapy.

1 - 57 . (canceled) 
     
     
         58 . An oral solid dosage form comprising a dose of insulin and an effective amount of the delivery agent 4-CNAB in an amount that facilitates the absorption of the insulin from the gastrointestinal tract, one or more of said dosage forms upon oral administration to a diabetic patient at a time from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of a meal providing a therapeutically effective reduction in blood glucose after oral administration and a maximum plasma concentration of insulin at a time point from about 10 to about 20 minutes after oral administration, said total dose being sufficient to replace an endogenous first phase insulin response to an ingested meal in a non-diabetic subject. 
     
     
         59 . The oral dosage form of  claim 58 , wherein said dosage form is a tablet. 
     
     
         60 . A substantially homogeneous oral tablet comprising a therapeutically effective dose of insulin, the delivery agent 4-CNAB in an amount that facilitates absorption of insulin from the gastrointestinal tract and an excipient suitable for tableting, said tablet upon oral administration to a diabetic patient at a time from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of a meal providing a therapeutically effective reduction in blood glucose after oral administration. 
     
     
         61 . The substantially homogeneous oral tablet of  claim 60 , further comprising per dosage unit a dose of insulin within the range of from about 10 Units to about 600 Units, the delivery agent 4-CNAB in an amount that facilitates absorption of insulin from the gastrointestinal tract within the range of from about 20 mg to about 600 mg, and at least one pharmaceutically acceptable excipient, such that an effective dose comprising one or more of said tablets upon administration to a diabetic mammal providing a therapeutically effective reduction in blood glucose of said mammal. 
     
     
         62 . The tablet of  claim 60 , wherein said delivery agent is of the formula or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 X is hydrogen or halogen; 
 R is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C3 alkenylene, substituted or unsubstituted C1-C3 alkyl (arylene), substituted or unsubstituted C1-C3 aryl (alkylene). 
 
     
     
         63 . The tablet of  claim 62 , wherein X is a halogen, or wherein R=C3, or both. 
     
     
         64 . The tablet of  claim 63 , wherein said halogen is chlorine. 
     
     
         65 . The tablet of  claim 60 , wherein said delivery agent is 4-[(4-chloro, 2-hydroxybenzoyl)amino]butanoic acid. 
     
     
         66 . The tablet of  claim 60 , which provides a maximum plasma insulin concentration at from about 5 minutes to about 25 minutes after oral administration. 
     
     
         67 . The tablet of  claim 60 , which provides a maximum blood glucose concentration reduction caused by said dose of insulin at from about 10 to about 30 minutes after oral administration. 
     
     
         68 . The tablet of  claim 60 , wherein the amount of insulin contained in said tablet is from about 100 Units to about 450 Units. 
     
     
         69 . The tablet of  claim 60 , wherein the amount of delivery agent contained in said tablet is from about 20 mg to about 600 mg. 
     
     
         70 . The tablet of  claim 60 , wherein the ratio of Insulin Units to delivery agent (mg) ranges from 10:1 (Units:mg) to 1:10 (Units:mg) 
     
     
         71 . The tablet of  claim 58 , wherein said delivery agent is of the formula or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 X is hydrogen or halogen; 
 R is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C3 alkenylene, substituted or unsubstituted C1-C3 alkyl (arylene), substituted or unsubstituted C1-C3 aryl (alkylene). 
 
     
     
         72 . The tablet of  claim 58 , wherein X is a halogen, or wherein R=C3, or both. 
     
     
         73 . The tablet of  claim 58 , wherein said halogen is chlorine. 
     
     
         74 . The tablet of  claim 58 , wherein said delivery agent is 4-[(4-chloro, 2-hydroxybenzoyl)amino]butanoic acid. 
     
     
         75 . The tablet of  claim 58 , which provides a maximum plasma insulin concentration at from about 5 minutes to about 25 minutes after oral administration. 
     
     
         76 . The tablet of  claim 58 , which provides a maximum blood glucose concentration reduction caused by said dose of insulin at from about 10 to about 30 minutes after oral administration. 
     
     
         77 . The tablet of  claim 58 , wherein the amount of insulin contained in said tablet is from about 100 Units to about 450 Units. 
     
     
         78 . The tablet of  claim 58 , wherein the amount of delivery agent contained in said tablet is from about 20 mg to about 600 mg. 
     
     
         79 . The tablet of  claim 58 , wherein the ratio of Insulin (Units) to delivery agent (mg) ranges from 10:1 (Units:mg) to 1:10 (Units:mg). 
     
     
         80 - 87 . (canceled) 
     
     
         88 . The oral dosage form of  claim 58 , wherein said insulin is unmodified. 
     
     
         89 . The oral dosage form of  claim 60 , wherein said insulin is unmodified.