Methods and formulations for the delivery of pharmacologically active agents

Abstract

In accordance with the present invention, novel formulations have been developed which are much more effective for the delivery of hydrophobic drugs to patients in need thereof than are prior art formulations. Invention formulations are capable of delivering more drug in shorter periods of time, with reduced side effects caused by the pharmaceutical carrier employed for delivery.

1 . A formulation comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is free of micelle-forming components, wherein said formulation is characterized by one or more of the following:
 wherein said formulation provides a higher concentration of said agent in the cellular compartment than a formulation of the same agent with a micelle-forming component;   wherein said formulation provides increased infra-cellular availability of said agent relative to a formulation of the same agent with a micelle-forming component;   wherein said formulation provides prolonged activity of said agent relative to a formulation of the same agent with a micelle-forming component;   wherein said formulation facilitates delivery of said agent to red blood cells, relative to delivery of said agent to red blood cells by a formulation comprising the same agent and a carrier containing micelle-forming components;   wherein said formulation releases a portion of said agent contained therein to the lipid membrane of a cell;   wherein said formulation provides reduced levels of said agent in the bloodstream relative to a formulation of the same agent with a micelle-forming component;   wherein said formulation delivers said agent to the bloodstream over an extended period of time relative to a formulation of the same agent with a micelle-forming component;   wherein the rate of metabolism of said agent in said formulation is reduced relative to the rate of metabolism of said agent in a formulation with a micelle-forming component;   wherein said agent has a longer half life in said formulation relative to the half life of said agent in a formulation with a micelle-forming component;   wherein said formulation provides a higher red blood cell/plasma ratio of said agent than does a formulation of the same agent with a micelle-forming component;   wherein said formulation provides a higher tumor/plasma ratio of said agent than does a formulation of the same agent with a micelle-forming component;   wherein the area under the curve for delivery of said agent to a tumor via said formulation is higher than the area under the curve for delivery of said agent to a tumor via a formulation of the same agent with a micelle-forming component;   wherein said formulation provides a higher concentration maximum (C max ) for said agent in tumor cells than does a formulation of the same agent with a micelle-forming component;   wherein said formulation provides a lower concentration maximum (C max ) for said agent in plasma than does a formulation of the same agent with a micelle-forming component;   wherein said formulation provides more rapid uptake of said agent by tumor cells than does a formulation of the same agent with a micelle-forming component; and   wherein said formulation enhances delivery of said agent to tissue, relative to a formulation of the same agent with a micelle-forming component.   
     
     
         2 . A method for the delivery of a substantially water insoluble pharmacologically active agent to a subject in need thereof, said method comprising administering an effective amount of a formulation according to  claim 1  to said subject. 
     
     
         3 . A method according to  claim 2  wherein said agent is paclitaxel. 
     
     
         4 . A method according to  claim 2  wherein said pharmaceutically acceptable carrier is albumin. 
     
     
         5 . A method according to  claim 2  wherein said formulation is administered by oral, intravenous, subcutaneous, intraperitoneal, intrathecal, intramuscular, intracranial, inhalational, topical, transdermal, rectal, or pessary route of administration. 
     
     
         6 . A method to reduce entrapment of a substantially water insoluble pharmacologically active agent in vehicle employed for delivery thereof, said method comprising employing a formulation according to  claim 1  for delivery of said agent, thereby reducing entrapment of said substantially water insoluble pharmacologically active agent relative to a formulation comprising the same agent and a carrier containing micelle-forming components. 
     
     
         7 . A method to prolong exposure of a subject to a substantially water insoluble pharmacologically active agent upon administration thereof to a subject in need thereof, said method comprising combining said agent with a pharmaceutically acceptable carrier which is free of micelle-forming components to produce a formulation according to  claim 1  prior to delivery thereof, thereby prolonging exposure of said subject to said substantially water insoluble pharmacologically active agent relative to a formulation comprising the same agent and a carrier containing micelle-forming components. 
     
     
         8 . A method to facilitate transport of a substantially water insoluble pharmacologically active agent across cell membranes and/or into the cellular compartment upon administration thereof to a subject in need thereof, said method comprising combining said agent with a pharmaceutically acceptable carrier which is free of micelle-forming components to produce a formulation according to  claim 1  prior to delivery thereof, thereby facilitating transport of said substantially water insoluble pharmacologically active agent across cell membranes relative to transport of a formulation comprising the same agent and a carrier containing micelle-forming components. 
     
     
         9 . A formulation according to  claim 1 , wherein said formulation provides a higher concentration of said agent in the cellular compartment than a formulation of the same agent with a micelle-forming component and/or said formulation provides increased intra-cellular availability of said agent relative to a formulation of the same agent with a micelle-forming component. 
     
     
         10 . A formulation according to  claim 1 , wherein said formulation provides prolonged activity of said agent relative to a formulation of the same agent with a micelle-forming component and/or said formulation delivers said agent to the bloodstream over an extended period of time relative to a formulation of the same agent with a micelle-forming component. 
     
     
         11 . A formulation according to  claim 1 , wherein said formulation facilitates delivery of said agent to red blood cells, relative to delivery of said agent to red blood cells by a formulation comprising the same agent and a carrier containing micelle-forming components and/or said formulation provides reduced levels of said agent in the bloodstream relative to a formulation of the same agent with a micelle-forming component. 
     
     
         12 . A formulation according to  claim 1 , wherein said formulation releases a portion of said agent contained therein to the lipid membrane of a cell. 
     
     
         13 . A formulation according to  claim 1 , wherein the rate of metabolism of said agent in said formulation is reduced relative to the rate of metabolism of said agent in a formulation with a micelle-forming component and/or said agent has a longer half life in said formulation relative to the half life of said agent in a formulation with a micelle-forming component. 
     
     
         14 . A formulation according to  claim 1 , wherein said formulation provides a higher red blood cell/plasma ratio of said agent than does a formulation of the same agent with a micelle-forming component and/or said formulation provides a higher tumor/plasma ratio of said agent than does a formulation of the same agent with a micelle-forming component. 
     
     
         15 . A formulation according to  claim 1 , wherein the area under the curve for delivery of said agent to a tumor via said formulation is higher than the area under the curve for delivery of said agent to a tumor via a formulation of the same agent with a micelle-forming component. 
     
     
         16 . A formulation according to  claim 1 , wherein said formulation provides a higher concentration maximum (C max ) for said agent in tumor cells than does a formulation of the same agent with a micelle-forming component and/or said formulation provides a lower concentration maximum (C max ) for said agent in plasma than does a formulation of the same agent with a micelle-forming component. 
     
     
         17 . A formulation according to  claim 1 , wherein said formulation provides more rapid uptake of said agent by tumor cells than does a formulation of the same agent with a micelle-forming component. 
     
     
         18 . A formulation according to  claim 1 , wherein said formulation enhances delivery of said agent to tissue, relative to a formulation of the same agent with a micelle-forming component. 
     
     
         19 . A formulation according to  claim 1  wherein said tissue is a tumor. 
     
     
         20 . A formulation according to  claim 1  wherein said tissue is peritoneal tissue, bladder tissue or lung tissue.