Oral insulin therapy

An oral dosage form comprising a dose of unmodified insulin that achieves a therapeutically effective reduction in blood glucose after oral administration to a human diabetic patient, and which provides a ratio of portal vein to peripheral blood insulin concentration from about 2.5:1 to about 6:1.

An oral dosage form comprising a dose of unmodified insulin that achieves a therapeutically effective reduction in blood glucose after oral administration to human diabetic patients, the oral solid dosage form providing an insulin Tmax at a time point from about 0.25 to about 1.5 hours after oral administration to said patients, at least about 80% of the blood glucose concentration reduction caused by said dose of insulin occurring within about 2 hours after oral administration of said dosage form.

An oral dosage form comprising a therapeutically effective amount of unmodified insulin, said dosage form upon pre-prandial oral administration to human diabetic patients causing the mean plasma glucose concentration in said patients to be reduced for the first hour after oral administration relative to a mean baseline (fasted) plasma glucose concentration in said patients.

An oral dosage form comprising a therapeutically effective amount of unmodified insulin, said oral dosage form upon pre-prandial oral administration provides a mean plasma glucose concentration which does not vary by more than about 40% for the first hour after oral administration, relative to a mean baseline (fasted) plasma glucose concentration in said patients, where a meal is eaten by said patients within about one half hour of oral administration of said dosage form.

A method of providing a therapeutically effective orally administrable unit dose of unmodified insulin, comprising combining from about 2 to about 23 mg of unmodified insulin with from about 100 to about 600 mg of a pharmaceutically acceptable delivery agent which facilitates absorption of said insulin from the gastrointestinal tract of human diabetic patients, and orally administering said unit dose to a human diabetic patient to provide a therapeutic effect.

A method of treating human diabetic patients comprising orally administering to human diabetic patients on a chronic basis an oral insulin treatment comprising a dose of unmodified insulin together with a delivery agent that facilitates the absorption of the dose of insulin from the gastrointestinal tract to provide a therapeutically effective reduction in blood glucose and a blood plasma insulin concentration that is reduced relative to the systemic blood insulin concentration of an equivalent therapeutically effective reduction in blood glucose concentration achieved by subcutaneous injection of insulin.

A method of reducing the incidence and/or severity of one or more disease states associated with chronic administration of insulin, comprising treating human diabetic patients via oral administration on a chronic basis with a therapeutically effective dose of a (preferably solid) pharmaceutical composition comprising a dose of unmodified insulin and a delivery agent that facilitates the absorption of said unmodified insulin from the gastrointestinal tract in an effective amount such that the pharmaceutical composition provides therapeutically effective control of mean blood glucose concentration and a mean systemic blood insulin concentration in diabetic patients that is reduced on a chronic basis relative to the mean systemic blood insulin concentration provided by chronic subcutaneous administration of insulin in an amount effective to achieve equivalent control of mean blood glucose concentration in a population of human diabetic patients.

A method of treating diabetes and reducing the incidence and or severity of hyperinsulinemia associated with chronic dosing of insulin, comprising orally administering on a chronic basis to a diabetic patient a dose of insulin and a delivery agent that facilitates the absorption of the dose of insulin from the gastrointestinal tract to provide therapeutically effective control and/or reduction in blood glucose concentrations, and a mean systemic blood insulin concentration of the diabetic patient that is reduced relative to the mean systemic blood insulin concentration provided by subcutaneous injection of insulin in an amount effective to achieve equivalent control and/or reduction in blood glucose concentration in a population of human diabetic patients.

A method of treating diabetics, comprising:

• orally administering to diabetic patients on a chronic basis an oral insulin treatment comprising a dose of unmodified insulin together with a delivery agent which facilitates the absorption of the dose of insulin from the gastrointestinal tract to provide a therapeutically effective reduction in blood glucose and a peak serum insulin concentration that is reduced relative to the peak serum insulin concentration of an equivalent therapeutically effective reduction in blood glucose concentration achieved by subcutaneous injection of insulin.

A method of reducing the incidence and/or severity of one or more disease states associated with chronic administration of insulin, comprising treating diabetic patients via oral administration on a chronic basis of a therapeutically effective dose of a pharmaceutical composition which comprises insulin and a delivery agent that facilitates the absorption of insulin from the gastrointestinal tract, such that the pharmaceutical composition provides a therapeutically effective reduction in blood glucose and a peak serum insulin concentration of the diabetic patient that is reduced relative to the peak serum insulin concentration of an equivalent therapeutically effective reduction in blood glucose concentration achieved by subcutaneous injection of insulin.

A method of treating diabetes and reducing the incidence and or severity of hyperinsulinemia associated with chronic dosing of insulin, comprising orally administering on a chronic basis to a diabetic patient a dose of insulin and a delivery agent that facilitates the absorption of the dose of insulin from the gastrointestinal tract to provide a therapeutically effective reduction in blood glucose and a peak serum insulin concentration of the diabetic patient that is reduced relative to the peak serum insulin concentration of an equivalent therapeutically effective reduction in blood glucose concentration achieved by subcutaneous injection of insulin.

A method of screening a drug for vascular injury associated with route of administering the drug, comprising

• administering a drug to a first test animal parenterally;
• administering the drug to a second test animal orally, and
• comparing the expression of early response genes selected from the group consisting of c-myc, c-fos, Jun B, Erg-1 and combinations thereof for the first and second test animal, wherein an increase in the expression of one or more early response genes is indicative of vascular injury.

A method of reducing the incidence of, the severity of, or the incidence and severity of disease states associated with chronic insulin administration to diabetics, comprising orally administering an oral insulin treatment comprising a dose of insulin together with a delivery agent which facilitates the absorption of said insulin from the gastrointestinal tract on a chronic basis to diabetic patients to reduce blood glucose levels in said diabetic patients by a desired amount, such that the concentration of insulin circulating in the blood of said diabetic patients as a result of insulin treatment is reduced relative to the peak serum insulin concentration of an equivalent therapeutically effective reduction in blood glucose concentration achieved by subcutaneous injection of insulin.

A method for reducing the incidence of, the severity of, or the incidence and severity of vascular diseases associated with chronic insulin therapy in diabetics, comprising orally administering an oral insulin treatment comprising a dose of insulin together with a delivery agent which facilitates the absorption of said insulin from the gastrointestinal tract on a chronic basis to diabetic patients to reduce blood glucose levels in said diabetic patients by a desired amount, such that the concentration of insulin circulating in the blood of said diabetic patients as a result of insulin treatment is reduced relative to the peak serum insulin concentration of an equivalent therapeutically effective reduction in blood glucose concentration achieved by subcutaneous injection of insulin.

A method of reducing the exposure of the vasculature of diabetic patients to hyperinsulinemic conditions, comprising orally administering an oral insulin treatment comprising a dose of insulin together with a delivery agent which facilitates the absorption of said insulin from the gastrointestinal tract on a chronic basis to diabetic patients to reduce blood glucose levels in said diabetic patients by a desired amount, such that the concentration of insulin circulating in the blood of said diabetic patients as a result of insulin treatment is reduced relative to the peak serum insulin concentration of an equivalent therapeutically effective reduction in blood glucose concentration achieved by subcutaneous injection of insulin.

A method of attenuating processes resulting from the reaction to a mild injurious stimulus in multiple areas of the response to increases in mRNA during insulin treatment, comprising

• orally administering an oral insulin treatment comprising a dose of insulin together with a delivery agent which facilitates the absorption of said insulin from the gastrointestinal tract on a chronic basis to diabetic patients to reduce blood glucose levels in said diabetic patients by a desired amount, such that the concentration of insulin circulating in the blood of said diabetic patients as a result of insulin treatment is reduced relative to the peak serum insulin concentration of an equivalent therapeutically effective reduction in blood glucose concentration achieved by subcutaneous injection of insulin.

A method of treating diabetic patients, comprising orally administering an oral insulin treatment comprising a dose of insulin together with a delivery agent which facilitates the absorption of said insulin from the gastrointestinal tract on a chronic basis to diabetic patients to reduce blood glucose levels in said diabetic patients by a desired amount, such that the concentration of insulin circulating in the blood of said diabetic patients as a result of said oral insulin treatment is not substantially greater than normal physiological levels.