Pulmonary delivery for bioconjugation

Abstract

Methods of and compositions for pulmonary delivery of therapeutic agents which are capable of forming covalent bonds with a site of interest or which have formed a covalent bond with a pulmonary solution protein are disclosed. Therapeutic agents useful in the invention include wound healing agents, antibiotics, anti-inflammatories, anti-oxidants, anti-proliferatives, immunosupressants, anti-infective and anti-cancer agents.

We claim:  
     
         1 . A modified therapeutic agent comprising: 
 a therapeutic agent and a reactive group which reacts in vivo with amino groups, hydroxyl groups or thiol groups on pulmonary components or blood components to form a stable covalent bond,    the therapeutic agent being selected from the group consisting of GP-41 peptides, BBB peptides, anti-cancer agents, antihistamines, bronchodilators, anti-hypertension agents, anti-angina agents, opioids, analgesics, anti-depressants, and hypothyroid agents.    
     
     
         2 . The modified therapeutic agent of  claim 1  wherein said reactive group is a succinimidyl or a maleimido group.  
     
     
         3 . The modified therapeutic agent of  claim 1  wherein said reactive group is a maleimido group which is reactive with a thiol group on a mobile pulmonary component.  
     
     
         4 . The modified therapeutic agent of  claim 1  wherein said reactive group is a maleimido group which is reactive with a thiol group on a fixed pulmonary component.  
     
     
         5 . The modified therapeutic agent of  claim 1  wherein said reactive group is a maleimido group which is reactive with a thiol group on a mobile blood component.  
     
     
         6 . The modified therapeutic agent of  claim 1  wherein said reactive group is a maleimido group which is reactive with a thiol group on albumin.  
     
     
         7 . The modified therapeutic agent of  claim 1  wherein said reactive group is a maleimido group which is reactive with a thiol group on a fixed blood component.  
     
     
         8 . The modified therapeutic agent of  claim 1  wherein said therapeutic agent is an anti-histamine.  
     
     
         9 . The modified therapeutic agent of  claim 1  wherein said therapeutic agent is a hypothyroid agent.  
     
     
         10 . The modified therapeutic agent of  claim 9  wherein said therapeutic agent is loratidine.  
     
     
         11 . The modified therapeutic agent of  claim 9  wherein said therapeutic agent is cetirizine.  
     
     
         12 . An aerosol composition for delivery of a therapeutic agent to the pulmonary system of a host comprising: 
 an aerosolized aqueous solution containing a modified therapeutic agent, the modified therapeutic agent comprising a therapeutic agent and a reactive group which reacts with amino groups, hydroxyl groups or thiol groups on pulmonary or blood components to form a stable covalent bond.    
     
     
         13 . The aerosol of  claim 12  further comprising a pharmaceutically acceptable carrier.  
     
     
         14 . The aerosol of  claim 12  wherein said modified therapeutic agent is 2.5-10% by weight.  
     
     
         15 . The aerosol of  claim 12  wherein said therapeutic agent an anti-histamine.  
     
     
         16 . The aerosol of  claim 15  wherein said therapeutic agent is loratidine.  
     
     
         17 . The aerosol of  claim 15  wherein said therapeutic agent is cetirizine.  
     
     
         18 . A particulate formulation for delivery of a therapeutic agent to the pulmonary system of a host comprising: 
 a dispersable dry powder containing a modified therapeutic agent, the modified therapeutic agent comprising a therapeutic agent and a reactive group which reacts with amino groups, hydroxyl groups or thiol groups on pulmonary components to form a stable covalent bond.    
     
     
         19 . The particulate formulation of  claim 18  wherein at least 50% of the dry powder is in the form of particles having a diameter of 10 um or less.  
     
     
         20 . The particulate formulation of  claim 18  wherein said therapeutic agent is an anti-histamine.  
     
     
         21 . The particulate formulation of  claim 20  wherein said therapeutic agent is loratidine.  
     
     
         22 . The particulate formulation of  claim 20  wherein said therapeutic agent is cetirizine.  
     
     
         23 . A method of delivering a therapeutic agent to a host comprising the steps of: 
 obtaining a modified therapeutic agent, the modified therapeutic agent comprising a therapeutic agent and a reactive group which reacts in vivo with amino groups, hydroxyl groups or thiol groups on pulmonary or blood components to form a stable covalent bond; and    administering the modified therapeutic agent to the pulmonary system of the host.    
     
     
         24 . The method of  claim 23  wherein said administering step further comprises the steps of aerosolizing the modified therapeutic agent for inhalation by the host.  
     
     
         25 . The method of  claim 23  wherein said administering step further comprises the steps of dispersing a dry formulation of the modified therapeutic agent for inhalation by the host.  
     
     
         26 . The method of  claim 23  wherein said administering step further comprises the steps of instilling the modified therapeutic agent into the pulmonary system of the host.  
     
     
         27 . The method of  claim 23  wherein said reactive group is a succinimidyl or a maleimido group.  
     
     
         28 . The method of  claim 23  wherein said reactive group is a maleimido group which is reactive with a thiol group on a mobile pulmonary component.  
     
     
         29 . The method of  claim 23  wherein said reactive group is a maleimido group which is reactive with a thiol group on a fixed pulmonary component.  
     
     
         30 . The method of  claim 23  wherein said reactive group is a maleimido group which is reactive with a thiol group on a mobile blood component.  
     
     
         31 . The method of  claim 23  wherein said reactive group is a maleimido group which is reactive with a thiol group on a fixed blood component.  
     
     
         32 . The method of  claim 23  wherein said reactive group is a maleimido group which is reactive with a thiol group on human serum albumin.  
     
     
         33 . The method of  claim 23  wherein said therapeutic agent is an anti-histamine.  
     
     
         34 . The method of  claim 33  wherein said therapeutic agent is loratidine.  
     
     
         35 . The method of  claim 33  wherein said therapeutic agent is cetirizine.  
     
     
         36 . Use of a composition for the manufacture of a medicament said composition comprising a derivative of an antihistamine and analogs thereof wherein the derivative includes a reactive functional group which reacts with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds, said reactive functional group being selected from N-hydroxysuccinimide, N-hydroxy-sulfosuccinimide and a maleimide group for use in the treatment of the human body to provide an anhistamine effect.  
     
     
         37 . Use of a composition according to  claim 36  wherein the antihistamine is selected from cetirizine, loratidine and analogs thereof.  
     
     
         38 . Use of a composition according to  claim 36  wherein the antihistamine is selected from cetirizine and analogs thereof.  
     
     
         39 . Use of a composition according to  claim 36  wherein the antihistamine is selected from loratidine and analogs thereof.  
     
     
         40 . Use of a composition for the manufacture of a medicament said composition comprising a derivative of an anti-angina agent and analogs thereof wherein the derivative includes a reactive functional group which reacts with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds, said reactive functional group being selected from N-hydroxysuccinimide, N-hydroxy-sulfosuccinimide and a maleimide group for use in the treatment of the human body to provide an anti-angina effect.  
     
     
         41 . Use of a composition according to  claim 40  wherein the anti-angina agent is tirofiban.  
     
     
         42 . Use of a composition for the manufacture of a medicament said composition comprising a derivative of an anti-hypertensive agent and analogs thereof wherein the derivative includes a reactive functional group which reacts with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds, said reactive functional group being selected from N-hydroxysuccinimide, N-hydroxy-sulfosuccinimide and a maleimide group for use in the treatment of the human body to provide an anti-hypertensive effect.  
     
     
         43 . Use of a composition according to  claim 42  wherein the anti-hypetensive agent is enalapril.  
     
     
         44 . Use of a composition for the manufacture of a medicament said composition comprising a derivative of an anti-arrhythmic agent and analogs thereof wherein the derivative includes a reactive functional group which reacts with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds, said reactive functional group being selected from N-hydroxysuccinimide, N-hydroxy-sulfosuccinimide and a maleimide group for use in the treatment of the human body to provide an anti-arrhythmic effect.  
     
     
         45 . Use of a composition according to  claim 44  wherein the anti-arrhythmic agent is capobenic acid.  
     
     
         46 . Use of a composition for the manufacture of a medicament said composition comprising a derivative of an anti-depressant agent and analogs thereof wherein the derivative includes a reactive functional group which reacts with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds, said reactive functional group being selected from N-hydroxysuccinimide, N-hydroxy-sulfosuccinimide and a maleimide group for use in the treatment of the human body to provide an anti-depressan effect.  
     
     
         47 . Use of a composition according to  claim 46  wherein the anti-depressant agent is fluoxetine.  
     
     
         48 . Use of a composition for the manufacture of a medicament said composition comprising a derivative of a bronchodilator and analogs thereof wherein the derivative includes a reactive functional group which reacts with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds, said reactive functional group being selected from N-hydroxysuccinimide, N-hydroxy-sulfosuccinimide and a maleimide group for use in the treatment of the human body to provide a bronchodilation effect.  
     
     
         49 . Use of a composition according to  claim 48  wherein the bronchodilator is theobromineacetamine and analogs thereof.  
     
     
         50 . Use of a composition for the manufacture of a medicament said composition comprising a derivative of an anti-inflammatory agent and analogs thereof, wherein the derivative includes a reactive functional group which reacts with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds, said reactive functional group being selected from N-hydroxysuccinimide, N-hydroxy-sulfosuccinimide and a maleimide group for use in the treatment of the human body to provide an anti-inflammatory effect.  
     
     
         51 . Use of a composition according to  claim 50  wherein the anti-inflammatory agent is loxoprofen and analogs thereof.  
     
     
         52 . Use of a composition for the manufacture of a medicament said composition comprising a derivative of an anti-thyroid deficiency agent and analogs thereof, wherein the derivative includes a reactive functional group which reacts with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds, said reactive functional group being selected from N-hydroxysuccinimide, N-hydroxy-sulfosuccinimide and a maleimide group for use in the treatment of the human body to provide an anti-thyroid deficiency effect.  
     
     
         53 . Use of a composition according to  claim 52  wherein the anti-thyroid deficiency agent is thyroxin and analogs thereof.  
     
     
         54 . A composition comprising a compound selected from the group consisting of: 
   2 -[2-[4-[(4-choloropheny)phenylmethyl[-1-piperazinyl]ethoxy]-maleimidopropionylacetamide; 11-(N-maleimidopropionyl-4-piperidylidene)-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridine;    N-(1(S)-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinylmaleimidopropionilamide;    Maleimidopropynamyl-ε-(3,4,5-trimethoxybenz-amido)-caproicamide; Maleimidopropionamyl-1-theobromineacetamide;    Maleimidopropamyl2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionamide N-maleimidopropionyl-N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine; 4-anilino-1-(2-phenethyl)piperdine and Maleimidopropionamyl-3,5-3′,5′ tetraiodothyroninamide.    
     
     
         55 . The composition of  claim 54 , wherein the compound is Maleimidopropionamyl-3,5-3′,5′ tetraiodothyroninamide.  
     
     
         56 . An aerosol composition for delivery of a therapeutic agent to the pulmonary system of a host comprising an aerosolized aqueous solution containing a modified therapeutic agent conjugated to a blood protein.  
     
     
         57 . The composition of  claim 56  wherein said protein is albumin.  
     
     
         58 . The aerosol of  claim 56  wherein said therapeutic agent an anti-histamine.  
     
     
         59 . The aerosol of  claim 56  wherein said therapeutic agent is loratidine.  
     
     
         60 . The aerosol of  claim 56  wherein said therapeutic agent is cetirizine.  
     
     
         61 . A particulate formulation for delivery of a therapeutic agent to the pulmonary system of a host comprising: 
 a dispersable dry powder containing a modified therapeutic agent, the modified therapeutic agent comprising a therapeutic agent and a reactive group which reacts with amino groups, hydroxyl groups or thiol groups on pulmonary components to form a stable covalent bond wherein said therapeutic agent is covalently bonded to a blood protein.    
     
     
         62 . The formulation of  claim 61  wherein said protein is albumin.  
     
     
         63 . The formulation of  claim 61  wherein said therapeutic agent is an anti-histamine.  
     
     
         64 . The formulation of  claim 61  wherein said therapeutic agent is loratidine.  
     
     
         65 . The particulate formulation of  claim 61  wherein said therapeutic agent is cetirizine.