Pulmonary administration of chemically modified insulin

Abstract

The present invention provides active, hydrophilic polymer-modified derivatives of insulin. The insulin derivatives of the invention are, in one aspect, suitable for delivery to the lung and exhibit pharmakokinetic and/or pharmacodynamic properties that are significantly improved over native insulin.

1 - 38 . (canceled)  
     
     
         39 . A method for providing a substantially non-immunogenic insulin composition for administration to the lung of a subject in need thereof, said method comprising: 
 covalently coupling insulin to one or more molecules of a non-naturally occurring hydrophilic polymer to provide a composition comprising an insulin-hydrophilic polymer conjugate, and    administering said composition to the lung of a subject in need thereof by inhalation, whereby as a result of said administering, said insulin passes through the lung and enters into the blood circulation.    
     
     
         40 . The method of  claim 39 , wherein said non-naturally occurring hydrophilic polymer is a polyalkylene glycol.  
     
     
         41 . A method for providing a prolonged-effect insulin composition for administration to the lung of a subject in need thereof, said method comprising: 
 covalently coupling insulin to one or more molecules of a non-naturally occurring hydrophilic polymer to provide a composition comprising an insulin-hydrophilic polymer conjugate,    administering said composition to the lung of a subject in need thereof by inhalation, whereby as a result of said administering, (i) said insulin passes through the lung and enters the blood circulation, and (ii) elevated blood levels of insulin are sustained for at least 8 hours post administration.    
     
     
         42 . The method of  claim 41 , wherein said non-naturally occurring hydrophilic polymer is a polyalkylene glycol.  
     
     
         43 . The method of  claim 42 , wherein said non-naturally occurring hydrophilic polymer is polyethylene glycol.  
     
     
         44 . The method of  claim 43 , whereby elevated levels of insulin are sustained for at least 10 hours post-administration.  
     
     
         45 . The method of  claim 43 , whereby elevated levels of insulin are sustained for at least 12 hours post-administration.  
     
     
         46 . The method of  claim 43 , whereby further as a result of said administering, glucose levels in said subject are suppressed for at least 10 hours post administration.  
     
     
         47 . The method of  claim 46 , whereby further as a result of said administering, glucose levels in said subject are suppressed for at least 12 hours post administration.  
     
     
         48 . The method of  claim 43 , wherein said administering step comprises administering said composition in aerosolized form.  
     
     
         49 . The method of  claim 43 , further comprising the step of aerosolizing said composition prior to administering.  
     
     
         50 . The method of  claim 43 , wherein said coupling step comprises covalently coupling insulin to polyethylene glycol in a site-specific fashion.  
     
     
         51 . The method of  claim 43 , wherein said coupling step comprises covalently coupling insulin to polyethylene glycol in a random fashion.  
     
     
         52 . The method of  claim 43 , wherein said conjugate when administered to the lung is further characterized by an absolute pulmonary bioavailability that is greater than that of native insulin.  
     
     
         53 . The method of  claim 43 , wherein said coupling step comprises covalently coupling insulin to one or more molecules of end-capped polyethylene glycol.  
     
     
         54 . The method of  claim 43 , wherein said coupling step comprises covalently coupling insulin to one or more molecules of polyethylene glycol selected from the group consisting of linear, branched, forked, and dumbbell polyethylene glycol.  
     
     
         55 . The method of  claim 43 , wherein said conjugate is absent a lipophilic moiety.  
     
     
         56 . The method of  claim 43 , wherein said composition is absent a lipophilic component.  
     
     
         57 . The method of  claim 43 , wherein said coupling step comprises covalently coupling insulin to one or more molecules of polyethylene glycol comprising a biodegradable linkage.  
     
     
         58 . The method of  claim 43 , wherein said polyethylene glycol comprises a number of (OCH 2 CH 2 ) subunits selected from the group consisting of from about 2 to 300 subunits, from about 4 to 200 subunits, and from about 10 to 100 subunits.  
     
     
         59 . The method of  claim 43 , wherein said polyethylene glycol has a nominal average molecular weight from about 200 to about 10,000 daltons.  
     
     
         60 . The method of  claim 43 , wherein said polyethylene glycol has a nominal average molecular weight from about 200 to about 5,000 daltons.  
     
     
         61 . The method of  claim 43 , wherein said polyethylene glycol has a nominal average molecular weight from about 200 to about 2,000 daltons.  
     
     
         62 . The method of  claim 43 , wherein said polyethylene glycol has a nominal average molecular weight from about 200 to about 1,000 daltons.  
     
     
         63 . The method of  claim 43 , wherein said coupling comprises coupling polyethylene glycol to insulin at one or more of its reactive amino sites.  
     
     
         64 . The method of  claim 63 , wherein said polyethylene glycol is coupled to insulin at more or more of its reactive amino sites via a bond selected from the group consisting of amide, urethane, and methylene amino.  
     
     
         65 . The method of  claim 63 , wherein said coupling comprises reacting a polyethylene glycol having a terminal reactive group selected from the group consisting of N-hydroxysuccinimide active esters, active carbonates, aldehydes, and acetals with one or more reactive amino sites on insulin.  
     
     
         66 . The method of  claim 43 , wherein said coupling results in a composition wherein at least about 75% of the B-1Phe sites on insulin are covalently coupled to polyethylene glycol.  
     
     
         67 . The method of  claim 43 , wherein said coupling results in a composition wherein at least about 90% of the B-1Phe sites on insulin are covalently coupled to polyethylene glycol.  
     
     
         68 . The method of  claim 43 , wherein said coupling results in a composition comprising a mixture of monomer and dimer conjugates of insulin.  
     
     
         69 . The method of  claim 68 , wherein said coupling results in a composition further comprising a trimer conjugate of insulin.  
     
     
         70 . The method of  claim 43 , wherein said polyethylene glycol comprises an activated linking moiety at one terminus suitable for covalent coupling with insulin.  
     
     
         71 . The method of  claim 43 , wherein said activated linking moiety comprises a reactive functional group selected from the group consisting of N-hydroxysuccinimide active esters, active carbonates, aldehydes, and acetals.  
     
     
         72 . The method of  claim 70 , wherein said linking moiety has a length of from about 2 to about 20 atoms.  
     
     
         73 . The method of  claim 43 , wherein said administering step comprises administering said composition by dry powder inhaler.  
     
     
         74 . The method of  claim 43 , wherein said administering step comprises administering said composition by a metered dose inhaler.  
     
     
         75 . The method of  claim 43 , wherein said administering step comprises administering said composition by a nebulizer.  
     
     
         76 . The method of  claim 43 , wherein said composition further comprises a pharmaceutically acceptable excipient.  
     
     
         77 . The method of  claim 43 , whereby as a result of administering said conjugate composition, serum levels of insulin that are at least 2 times greater than basal levels are achieved within 1 hour post administration.