Chemically modified small molecules

Abstract

Methods of modifying the rate of systemic absorption of a drug administered to a subject by a pulmonary route, the method comprising covalently conjugating a hydrophilic polymer to a drug, wherein the drug has a half-life of elimination from the lung of less than about 180 minutes, to form a drug-polymer conjugate, wherein the drug-polymer conjugate has a net hydrophilic character and a weight average molecular weight of from about 50 to about 20,000 Daltons, and wherein the half-life of elimination from the lung of the drug-polymer conjugate is at least about 1.5-fold greater than the half-life of elimination from the lung of the drug, wherein the half-life of elimination from the lung is measured by bronchoalveolar lavage followed by assaying residual lung material.

1 . A method of modifying the rate of systemic absorption of a drug administered to a subject by a pulmonary route, the method comprising covalently conjugating a hydrophilic polymer to a drug, wherein the drug has a half-life of elimination from the lung of less than about 180 minutes, to form a drug-polymer conjugate, wherein the drug-polymer conjugate has a net hydrophilic character and a weight average molecular weight of from about 50 to about 20,000 Daltons, and wherein the half-life of elimination from the lung of the drug-polymer conjugate is at least about 1.5-fold greater than the half-life of elimination from the lung of the drug, wherein the half-life of elimination from the lung is measured by bronchoalveolar lavage followed by assaying residual lung material.  
     
     
         2 . The method according to  claim 1 , wherein the hydrophilic polymer comprises a polymer chosen from polyethylene glycols and polyethylene oxides.  
     
     
         3 . The method according to  claim 1 , wherein the weight average molecular weight of the polymer is from about 1000 to about 5000 Daltons.  
     
     
         4 . The method according to  claim 1 , wherein the drug has a molecular weight of less than about 1500.  
     
     
         5 . The method according to  claim 1 , wherein the hydrophilic polymer comprises a polyethylene glycol.  
     
     
         6 . The method according to  claim 5 , wherein the polyethylene glycol is chosen from linear polyethylene glycols, branched polyethylene glycols, forked polyethylene glycols, and dumbbell polyethylene glycols.  
     
     
         7 . The method according to  claim 1 , wherein the hydrophilic polymer comprises a polymer from a polydisperse population.  
     
     
         8 . The method according to  claim 1 , wherein the hydrophilic polymer is a polymer chosen from monodisperse, bimodal, trimodal, or tetramodal polymer populations.  
     
     
         9 . A method of controlling the lung residence time of a drug pulmonarily administered, comprising covalently attaching to the drug a hydrophilic polymer molecule having a weight average molecular weight of from about 50 to about 4000 Daltons, to form a drug-polymer conjugate.  
     
     
         10 . The method according to  claim 9 , wherein the hydrophilic polymer is polyethylene glycol.  
     
     
         11 . The method according to  claim 9 , wherein the weight average molecular weight of the hydrophilic polymer is from about 1000 to about 3500 Daltons.  
     
     
         12 . The method according to  claim 9 , wherein the drug has a molecular weight of less than about 1500.  
     
     
         13 . The method according to  claim 9 , wherein the drug-polymer conjugate exhibits a net hydrophilic character.  
     
     
         14 . A method of controlling the rate of systemic absorption of a drug pulmonarily administered comprising covalently attaching to the drug a hydrophilic polymer having a weight average molecular weight of from about 50 to about 4000 Daltons, to form a drug-polymer conjugate.  
     
     
         15 . A pharmaceutical compound for pulmonary administration comprising a drug covalently attached to a hydrophilic polymer, wherein the pharmaceutical compound has a net hydrophilic character, and wherein the weight average molecular weight of the hydrophilic polymer is from about 50 to about 5000 Daltons.  
     
     
         16 . A composition comprising the pharmaceutical compound according to  claim 15 , and at least one pharmaceutically acceptable excipient.  
     
     
         17 . The pharmaceutical composition according to  claim 16 , in liquid form.  
     
     
         18 . The pharmaceutical composition according to  claim 16 , in dry form.  
     
     
         19 . An aerosol comprising the composition according to  claim 16 .  
     
     
         20 . The composition according to  claim 17 , in an inhaler device.  
     
     
         21 . The composition according to  claim 16 , wherein the composition comprises particles having a mass median aerodynamic diameter (MMAD) of less than about 10 microns.  
     
     
         22 . The composition according to  claim 16 , wherein the composition comprises particles having a MMAD of less than about 5 microns.  
     
     
         23 . The composition according to  claim 18 , wherein said composition comprises a dry powder.  
     
     
         24 . The composition according to  claim 16 , characterized by an emitted dose of at least about 30 percent.  
     
     
         25 . A spray-dried composition of  claim 16 .  
     
     
         26 . The composition according to  claim 16 , wherein hydrophilic polymer is covalently attached to the active ingredient molecule by a hydrolytically unstable linkage.  
     
     
         27 . The composition according to  claim 26 , wherein the hydrolytically unstable linkage is a linkage chosen from ester, thioester, and amide.  
     
     
         28 . The compound according to  claim 15 , wherein the hydrophilic polymer is covalently attached to the active ingredient by a hydrolytically stable linkage.  
     
     
         29 . The compound according to  claim 15 , wherein the hydrophilic polymer is polyethylene glycol.  
     
     
         30 . The composition according to  claim 29 , wherein the polyethylene glycol is chosen from linear polyethylene glycols, branched polyethylene glycols, forked polyethylene glycols, and dumbbell polyethylene glycols.  
     
     
         31 . A unit dosage form comprising the composition according to  claim 16 .  
     
     
         32 . The compound according to  claim 15 , wherein the weight average molecular weight of the hydrophilic polymer is from about 50 to about 5000 Daltons and wherein pulmonary administration of the compound results in a half-life of elimination from the lung that can be described by the equation, t 1/2 −el=12.84*(1−e −kmW ), where k=0.000357, MW=molecular weight in Daltons, and t 1/2 =elimination half-life in hours.  
     
     
         33 . A method of treating a systemic disease in a patient comprising pulmonarily administering the compound according to  claim 15 .  
     
     
         34 . The method according to  claim 1 , wherein the half-life of elimination from the lung of the drug-polymer conjugate is at least about 2-fold greater than the half-life of elimination from the lung of the drug.  
     
     
         35 . The method according to  claim 34 , wherein the half-life of elimination from the lung of the drug-polymer conjugate is at least about 4-fold greater than the half-life of elimination from the lung of the drug.  
     
     
         36 . The method according to  claim 35 , wherein the half-life of elimination from the lung of the drug-polymer conjugate is at least about 10-fold greater than the half-life of elimination from the lung of the drug.  
     
     
         37 . The method according to  claim 36 , wherein the half-life of elimination from the lung of the drug-polymer conjugate is at least about 100-fold greater than the half-life of elimination from the lung of the drug.  
     
     
         38 . The composition according to  claim 18 , in an inhaler device.