Stable flowable protien and nucleic acd formulations using non-aqueous, anhydrous, aprotic, hydrophobic, non-polar vehicles with low reactivity

Abstract

This invention relates to stable non-aqueous formulations which are suspensions of proteinaceous substances or nucleic acids in non-aqueous, anhydrous, aprotic, hydrophobic, non-polar vehicles with low reactivity. More specifically, the present invention relates to stable protein or nucleic acid formulations wherein the compound remains in stable, dry powder form, yet the formulation is flowable and, therefore amenable to delivery to an animal via injection transdermal administration, oral delivery or using an implantable device for sustained delivery. These stable formulations may be stored at elevated temperatures (e.g., 37° C.) for long periods of time and are especially useful as flowable formulations which can be shipped and/or stored at high temperatures or in implantable delivery devices for long term delivery (e.g., 1-12 months or longer) of drug.

What is claimed is:  
     
         1 . A stable non-aqueous composition of an active agent comprising: 
 a) an active agent containing powder wherein the active agent hydration in said powder is less than about 10%; and    b) at least one anhydrous, aprotic, hydrophobic, non-polar, low-reactivity vehicle, wherein said active agent is selected from the group consisting of proteins, proteinaceous compounds, and nucleic acids.    
     
     
         2 . The composition of  claim 1  wherein at least about 80% of the active agent remains stable for at least one month at 37° C.  
     
     
         3 . The composition of  claim 1  wherein said active agent hydration is less than about 5%.  
     
     
         4 . The composition of  claim 1  wherein said vehicle is selected from the group consisting of perhalohydrocarbons, unsubstituted saturated hydrocarbons, halogenated hydrocarbons, esters of unsubstituted saturated or halogenated hydrocarbons and ethers of unsubstituted saturated or halogenated hydrocarbons.  
     
     
         5 . The composition of  claim 1  wherein said vehicle is selected from the group consisting of MO, PFD, MF, PTA and TD.  
     
     
         6 . The composition of  claim 1  wherein said powder comprises up to about 30% (w/w) of said composition.  
     
     
         7 . The composition of  claim 1  wherein said active agent is a protein selected from the group consisting of Factor IX, Factor VIII, alpha-interferon, consensus interferon, beta-galactosidase, lactate dehydrogenase, chymotrypsin, trypsinogen, an antibody, and analogs thereof.  
     
     
         8 . The composition of  claim 1  wherein said active agent is a nucleic acid selected from the group consisting of DNA, RNA and oligonucleotides.  
     
     
         9 . The composition of  claim 8  wherein said nucleic acid is in the form of at least one selected from the group consisting of a nucleic acid/lipid complex, a nucleic acid-containing liposome, a ribozyme, a viral vector, a virosome, nucleic acid-containing dendrimers, nucleic acid-containing cationic polymers and nucleic-acid-containing PLGA particles.  
     
     
         10 . The composition of  claim 1  wherein said active agent is pharmaceutically useful.  
     
     
         11 . A method for preparing the composition of  claim 1  comprising suspending an active agent-containing powder with active agent hydration less than about 10% in at least one anhydrous, aprotic, hydrophobic, non-polar, low-reactivity vehicle.  
     
     
         12 . A method for treating a subject suffering from or susceptible to a condition which may be alleviated or prevented by administration of an active agent according to  claim 1 , said method comprising administering to said subject an effective amount of the composition of  claim 1 .  
     
     
         13 . The method of  claim 12  wherein said condition is hemophilia and the active agent in said composition is selected from the group consisting of Factor VIII, Factor IX, and analogs thereof.  
     
     
         14 . The invention of any of claims  1  and  11  wherein said powder comprises about 10 to about 30% (w/w) of said composition.  
     
     
         15 . The invention of any of claims  1  and  12  wherein administration of the composition is via a route selected from the group consisting of parenteral, transdermal, mucosal, oral and enteral.  
     
     
         16 . The invention of any of claims  1  and  12  wherein administration of the composition is via an implantable delivery device.  
     
     
         17 . The invention of any of claims  1  and  12  wherein administration of the composition is long-term continuous administration.