Method of use of monomeric insulin as a means for improving the reproducibility of inhaled insulin

Abstract

The need for the delivery of insulin by injection can be reduced or eliminated by delivering an aerosolized monomeric insulin formulation. Repeatability of dosing and more particularly the repeatability of the blood concentration versus time profile is improved relative to regular insulin. The blood concentration versus time profile is substantially unaffected by specific aspects of the patient's breathing maneuver at delivery. Further, the rate at which blood glucose is lowered is increased by the use of monomeric insulin. Particles of insulin and in particular monomeric insulin delivered to the surface of lung tissue will be absorbed into the circulatory system. The monomeric insulin may be a dry powder but is preferably in a liquid formulation delivered to the patient from a hand-held, self-contained device which automatically releases an aerosolized burst of formulation. The device includes a sensor which is preferably electronic which measures inspiratory flow and volume which measurement can be used to control the point of drug release.

1 . A method of improving reproducibility of insulin delivered by inhalation, comprising: 
 aerosolizing a formulation comprising monomeric insulin;    inhaling the aerosolized formulation into the lung of a patient in need of insulin in a manner which allows the particles of the insulin to deposit on the lung tissue.    
     
     
         2 . The method of  claim 1 , wherein the insulin is insulin lispro.  
     
     
         3 . The method of  claim 1 , further comprising: measuring the patient's glucose level.  
     
     
         4 . The method of  claim 3 , further comprising: 
 repeating the aerosolizing, inhaling and measuring in a manner so as to maintain the patients glucose level in a desired range.    
     
     
         5 . The method of  claim 4 , wherein each aerosolizing is carried out to create an aerosolized dose containing substantially the same amount of insulin.  
     
     
         6 . The method of  claim 5 , wherein the inhaling is carried out with different inhaled volumes of air while maintaining essentially the same blood concentration versus time profile in term of affect on glucose level.  
     
     
         7 . A method of maintaining a diabetic patient's blood glucose level within a desired range, comprising: 
 administering monomeric insulin to the patient by inhalation.    
     
     
         8 . The method of  claim 10 , wherein the monomeric insulin is insulin lispro.  
     
     
         9 . The method of  claim 7 , further comprising: 
 orally administering a sulfonylurea drug to the patient.    
     
     
         10 . The method of  claim 9 , wherein the sulfonylurea drug is selected from the group consisting of acetohexamide, chlorpropamide, tolazamide, tolbutamide, glipzide and glyburide.  
     
     
         11 . A method of enhancing the rate at which an inhaled drug migrates into a patient's circulatory system, comprising: 
 aerosolizing a formulation comprised of a monomeric insulin;    inhaling the aerosolized formulation into lungs of a patient and allowing particles of the monomeric insulin to deposit on lung tissue.    
     
     
         12 . The method of  claim 11 , wherein the monomeric insulin is insulin lispro.  
     
     
         13 . The method of  claim 11 , further comprising: 
 heating air surrounding the aerosolized formulation.    
     
     
         14 . The method of  claim 11 , wherein the aerosol comprises particles having a diameter in the range of about 1.0 to about 4.0 microns.  
     
     
         15 . The method of  claim 11 , further comprising: 
 repeating the aerosolizing and inhaling a plurality of times.    
     
     
         16 . The method of  claim 15 , wherein the formulation is aerosolized by being forced through a porous membrane from a disposable container.  
     
     
         17 . The method of  claim 1 , wherein the formulation is a liquid formulation comprised of a pharmaceutically acceptable carrier and insulin lispro and is present in the container; and 
 wherein the pores have a cross-sectional configuration with a small end opening of 0.25 to 6.0 microns in diameter and a large end opening of 2 to 20 times the diameter of the small end.    
     
     
         18 . A method of aerosolized insulin delivery comprising: 
 aerosolizing a formulation comprising insulin;    inhaling the aerosol with a volume of air;    measuring the inhaled volume of air; and    providing a signal when the inhaled volume reaches 80% or more of lung capacity of the lungs of an inhaling patient.    
     
     
         19 . The method of  claim 18 , further comprising: 
 repeating the aerosolizing, inhaling and measuring a plurality of times while obtaining substantially the same total inhaled volume for each delivery.    
     
     
         20 . The method of  claim 19 , wherein the aerosolizing and inhaling are repeatedly carried out at substantially the same inspiratory flow rate and inspiratory volume.