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 . A method of treating a diabetic patient, comprising: 
 orally administering to an early stage type II diabetic patient, at a time from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of a meal, a dose of a therapeutically effective amount of unmodified insulin with from about 20 to about 600 mg of a pharmaceutically acceptable delivery agent that facilitates absorption of said insulin from the gastrointestinal tract, said dose contained in one or more pharmaceutically acceptable tablets, to provide a time to maximum plasma concentration of insulin at a time point from about 15 to about 20 minutes after oral administration of said dose, said dose being sufficient to compensate for the lack of a first phase insulin response which occurs endogenously in a non-diabetic subject in response to an ingested meal.    
     
     
         2 . The method of  claim 1 , further comprising administering said dose such that said patient obtains a first peak plasma insulin concentration substantially from said administered dose and a second phase insulin response to said meal substantially from endogenous insulin release.  
     
     
         3 . A method of treating a patient with type I diabetes or late stage type II diabetes, comprising: 
 orally administering to said patient, at the time of or shortly prior to ingestion of a meal, a unit dose of from about 10 Units to about 600 Units (from about 0.4 mg to about 23 mg) of unmodified insulin with from about 20 to about 600 mg of a pharmaceutically acceptable delivery agent that facilitates absorption of said insulin from the gastrointestinal tract to provide a time to maximum plasma concentration of insulin at a time point from about 15 to about 20 minutes after oral administration of said dose, said dose being sufficient to compensate for the lack of a first phase insulin response which occurs endogenously in a non-diabetic subject in response to an ingested meal, and    administering to said patient a separate dose of insulin in an effective amount to replace a second phase insulin response to a meal which occurs a non-diabetic subject substantially from endogenous insulin release.    
     
     
         4 . The method of  claim 3 , further comprising orally administering said dose such that said patient obtains a first peak plasma insulin concentration substantially from said administered dose and administering said separate dose such that said patient obtains a second phase insulin response to said meal substantially from said administered separate dose.  
     
     
         5 . The method of  claim 3 , further comprising, instead of the step of administering to said patient a separate dose of insulin, the step of administering to said patient an effective amount of an agent that causes the patient to secrete sufficient insulin to provide a second phase insulin response similar to a second phase insulin response to a meal which occurs in a non-diabetic subject substantially from endogenous insulin release.  
     
     
         6 . The method of  claim 5 , further comprising orally administering said dose such that said patient obtains a first peak plasma insulin concentration substantially from said administered dose and administering said separate dose such that said patient obtains a second phase insulin response to said meal substantially from endogenous insulin release.  
     
     
         7 . The method of  claim 3 , wherein administration to said patient takes place from about 30 minutes prior to ingestion of one meal daily to concurrently with ingestion of one meal daily.  
     
     
         8 . The method of  claim 3 , wherein administration to said patient takes place at least once daily at a time point chosen from among the group consisting of at bedtime, in the morning and preprandial to one meal from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.  
     
     
         9 . The method of  claim 3  wherein chronic administration to said patient is for at least two consecutive weeks.  
     
     
         10 . A method of treating pre-diabetic patients, early stage type 2 patients and/or late stage type 2 diabetic patients comprising: 
 orally administering to the mammal on a chronic basis a pharmaceutical formulation comprising a therapeutically effective dose of insulin and a delivery agent that facilitates absorption of insulin from the gastrointestinal tract,    discontinuing said chronic administration, and    obtaining, as a result of said chronic administration, an improved effect as compared to baseline levels before said chronic administration, said improved effect selected from the group consisting of improved glucose tolerance, improved glycemic control, improved glucose homeostasis, spared β-cell function, prevention of β-cell death or dysfunction, reduction in systemic hyperinsulinemia, delay in the onset of overt or insulin dependent diabetes, reduction in the incidence of a disease state associated with chronic dosing of insulin, improved insulin utilization and insulin sensitivity, and improved insulin secretion capacity.    
     
     
         11 . The method of  claim 10  wherein said improved effect is improved glucose tolerance as demonstrated by better endogenous capacity of the mammal to handle sugar load as measured by blood glucose concentration, following a sugar load, that is reduced by a statistically significant amount as compared with baseline blood glucose concentration, following a glucose load, prior to said chronic administration.  
     
     
         12 . The method of  claim 11  wherein said statistically significant amount is a mean of about 15%.  
     
     
         13 . The method of  claim 10  wherein said improved effect is improved glycemic control as measured by fasting blood glucose concentration that is reduced by a statistically significant amount as compared with baseline fasting blood glucose concentration prior to treatment.  
     
     
         14 . The method of  claim 13  wherein said statistically significant amount is a mean of about 19%.  
     
     
         15 . The method of  claim 10  wherein said improved effect is improved glucose tolerance, further comprising the step of achieving said improved glucose tolerance without any statistically significant weight gain by said patient over said period of chronic administration.  
     
     
         16 . The method of  claim 15  wherein said improved effect is improved glucose tolerance, further comprising the step of achieving said improved glucose tolerance without any statistically significant risk of hypoglycemia in said mammal over said period of chronic administration.  
     
     
         17 . The method of  claim 10  wherein said improved effect is improved glucose tolerance, further comprising the step of achieving said improved glucose tolerance without any statistically significant risk of hyperinsulinemia in said mammal over said period of chronic administration.  
     
     
         18 . The method of  claim 10  wherein said improved effect is improved glucose tolerance, further comprising the step of achieving said improved glucose tolerance without the need for monitoring said patient's blood glucose concentrations or HbA1c levels over said period of chronic administration.  
     
     
         19 . The method of  claim 10  wherein said improved effect is improved glycemic control as measured by serum fructosamine level that is reduced by a statistically significant amount as compared with baseline serum fructosamine level prior to treatment.  
     
     
         20 . The method of  claim 19  wherein said statistically significant amount is a mean of about 9%.  
     
     
         21 . The method of  claim 10  wherein said improved effect is improved HbA 1 c levels as measured by an HbA 1 c concentration that is reduced by a statistically significant amount as compared with baseline HbA 1 c concentration prior to treatment.  
     
     
         22 . The method of  claim 10  wherein said improved effect is improved glycemic control, further comprising the step of achieving said improved glycemic control without any statistically significant weight gain by said patient over said period of chronic administration.  
     
     
         23 . The method of  claim 10  wherein said improved effect is improved glycemic control, further comprising the step of achieving said improved glycemic control without any statistically significant risk of hypoglycemia in said mammal over said period of chronic administration.  
     
     
         24 . The method of  claim 10  wherein said improved effect is improved glycemic control, further comprising the step of achieving said improved glycemic control without any statistically significant risk of hyperinsulinemia in said mammal over said period of chronic administration.  
     
     
         25 . The method of  claim 10  wherein said improved effect is improved glycemic control, further comprising the step of achieving said improved glycemic control without the need for monitoring said patient's blood glucose concentrations or HbA1c levels over said period of chronic administration.  
     
     
         26 . The method of  claim 10  wherein said improved effect is improved insulin utilization and insulin sensitivity as measured by HOMA (Homeostasis Model Assessment) that is reduced by a statistically significant amount as compared with baseline HOMA (Homeostasis Model Assessment) prior to treatment.  
     
     
         27 . The method of  claim 10  wherein said improved effect is improved insulin secretion capacity as measured by a Stumvoll first-phase insulin secretion capacity index as compared with a baseline Stumvoll first-phase insulin secretion capacity index prior to treatment.  
     
     
         28 . The method of  claim 10  wherein administration to said patient takes place from about 30 minutes prior to ingestion of one meal daily to concurrently with ingestion of one meal daily.  
     
     
         29 . The method of  claim 10  wherein administration to said patient takes place at least once daily at a time point chosen from among the group consisting of at bedtime, in the morning and preprandial to one meal from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.  
     
     
         30 . The method of  claim 10  wherein administration to said patient takes place at least twice daily at time points chosen from among the group consisting of at bedtime, in the morning and preprandial to at least one meal at from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.  
     
     
         31 . The method of  claim 10  wherein administration to said patient takes place at least three times daily at time points chosen from among the group consisting of at bedtime, in the morning and preprandial to at least one meal at from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.  
     
     
         32 . The method of  claim 10  wherein administration to said patient takes place at least four times daily at time points chosen from among the group consisting of at bedtime, in the morning and preprandial to at least one meal at from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.  
     
     
         33 . The method of  claim 10  wherein administration to said patient takes place at bedtime and preprandial to three meals at from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.  
     
     
         34 . The method of  claim 10  wherein chronic administration to said patient is for at least two consecutive weeks.  
     
     
         35 . The method of  claim 3  wherein the second pharmaceutical formulation is administered at least once orally.  
     
     
         36 . The method of  claim 3  wherein the second pharmaceutical formulation is administered at least once subcutaneously.  
     
     
         37 . The method of  claim 10 , wherein said method achieves a therapeutically effective reduction in blood glucose after treatment of said patient, and provides a ratio of portal vein to peripheral blood insulin concentration from about 2:1 to about 6:1.  
     
     
         38 . The method of  claim 10 , wherein administration of said oral dose provides a maximum blood glucose concentration reduction caused by said dose of insulin after about 30 minutes after oral administration.  
     
     
         39 . The method of  claim 10 , wherein the amount of insulin contained in said dose is from about 10 Units (0.4 mg) to about 600 Units (23 mg).  
     
     
         40 . The method of  claim 10 , wherein the amount of insulin contained in said dose is from about 100 Units (3.8 mg) to about 450 Units (15.3 mg).  
     
     
         41 . The method of  claim 10 , wherein the amount of insulin contained in said dose is from about 200 Units (5.75 mg) to about 350 Units (13.4 mg).  
     
     
         42 . The method of  claim 10 , 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).  
 
     
     
         43 . The method of  claim 42 , wherein X is a halogen, or wherein R=C3, or both.  
     
     
         44 . The method of  claim 43 , wherein said halogen is chlorine.  
     
     
         45 . The method of  claim 10 , wherein chronic administration to said patient is for at least two consecutive weeks.  
     
     
         46 . A method for treating a patient in accordance with the patient's stage of development of diabetes mellitus, comprising: 
 (a) identifying a patient's stage of diabetes along a continuum of development of diabetes as one of prediabetic stage, early stage type 2 diabetes, late stage type 2 diabetes and type 1 diabetes; and    (b) recommending a treatment to said patient that includes an oral insulin treatment appropriate to said patient's stage along the continuum of development of diabetes.    
     
     
         47 . The method of  claim 46  wherein said patient is at the prediabetic stage along said continuum of development of diabetes, and said treatment is administration to said patient on a chronic basis a pharmaceutical formulation comprising a therapeutically effective dose of insulin and a delivery agent that facilitates absorption of insulin from the gastrointestinal tract, at least once daily at a time point chosen from among the group consisting of at bedtime, in the morning and preprandial to one meal from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.  
     
     
         48 . The method of  claim 47  wherein administration to said patient is at bedtime.  
     
     
         49 . The method of  claim 46  wherein said patient is at the early diabetic stage along said continuum of development of diabetes, and said treatment is administration to said patient on a chronic basis a pharmaceutical formulation comprising a therapeutically effective dose of insulin and a delivery agent that facilitates absorption of insulin from the gastrointestinal tract, at least twice daily at time points chosen from among the group consisting of at bedtime and preprandial to at least one meal at from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.  
     
     
         50 . The method of  claim 49  wherein administration to said patient is at bedtime.  
     
     
         51 . The method of  claim 49  wherein administration to said patient is at bedtime and preprandial all meals.  
     
     
         52 . The method of  claim 46  wherein said patient is at the late diabetic stage along said continuum of development of diabetes, and said treatment is administration to said patient on a chronic basis a pharmaceutical formulation comprising a therapeutically effective dose of insulin and a delivery agent that facilitates absorption of insulin from the gastrointestinal tract, at least three times daily at time points chosen from among the group consisting of at bedtime and preprandial to at least one meal at from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.  
     
     
         53 . The method of  claim 52  wherein administration to said patient is at bedtime and preprandial all meals.  
     
     
         54 . The method of  claim 52  further comprising administering to the mammal on a chronic basis a therapeutically effective dose of a second pharmaceutical formulation comprising an intermediate-acting and/or a long-acting insulin.  
     
     
         55 . The method of  claim 54  wherein the second pharmaceutical formulation is administered at least once a day orally.  
     
     
         56 . The method of  claim 54  wherein the second pharmaceutical formulation is administered at least once a day subcutaneously.  
     
     
         57 . The method of  claim 54  wherein the pharmaceutical formulation and the second pharmaceutical formulation provide two different activity rates in order to simulate the endogenous biphasic release of insulin to an ingested meal in a non-diabetic subject.  
     
     
         58 . An oral solid dosage form comprising a dose of unmodified insulin and an effective amount of a delivery agent that facilitates the absorption of the insulin from the gastrointestinal tract and an excipient, one or more of said dosage forms upon 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 time to maximum plasma concentration of insulin at a time point from about 15 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, a delivery agent that facilitates absorption of insulin from the gastrointestinal tract and an excipient suitable for tableting, said tablet upon 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 (about 2 mg) to about 600 Units (about 23 mg), a delivery agent 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 after 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 (3.8 mg) to about 450 Units (15.3 mg).  
     
     
         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 after 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 (3.8 mg) to about 450 Units (15.3 mg).  
     
     
         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 . The method of  claim 1 , 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).  
 
     
     
         81 . The method of  claim 80 , wherein X is a halogen, or wherein R=C3, or both.  
     
     
         82 . The method of  claim 81 , wherein said halogen is chlorine.  
     
     
         83 . The method of  claim 1 , wherein said delivery agent is 4-[(4-chloro, 2-hydroxybenzoyl)amino]butanoic acid.  
     
     
         84 . The method of  claim 3 , 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).  
 
     
     
         85 . The method of  claim 84 , wherein X is a halogen, or wherein R=C3, or both.  
     
     
         86 . The method of  claim 85 , wherein said halogen is chlorine.  
     
     
         87 . The method of  claim 3 , wherein said delivery agent is 4-[(4-chloro, 2-hydroxybenzoyl)amino]butanoic acid.