Drug delivery system for hydrophobic drugs

Abstract

Compositions comprising microaggregates containing hydrophobic drugs, as well as methods for their production, are described. Such microaggregates may include micelle structures or combinations thereof with liposomes, and constitute an effective delivery vehicle for a hydrophobic agent. Methods for microaggregate production include the use of preferred lipid compounds and processing conditions favo the production of small aggregates for improved filter sterilization.

1 . A composition comprising aggregates, said aggregates comprising saturated and unsaturated phospholipids and one or more photosensitizer, and 
 wherein the aggregates have an average diameter of below about 100 nm.    
   
   
       2 . The composition of  claim 1  wherein said aggregates comprise micelles.  
   
   
       3 . The composition of  claim 2  wherein the composition further comprises liposomes.  
   
   
       4 . The composition of  claim 1  wherein the one or more photosensitizers is a green porphyrin.  
   
   
       5 . The composition of  claim 4  wherein the green porphyrin is a hydro-monobenzo-porphyrin photosensitiser.  
   
   
       6 . The composition of  claim 1  wherein said one or more photosensitizer is BPD-MA, A-EA6, B-EA6 or a combination thereof.  
   
   
       7 . The composition of  claim 1  wherein one or more of said saturated and unsaturated phospholipids comprise a negatively charged headgroup.  
   
   
       8 . The composition of  claim 7  wherein said phospholipids comprise DOPG and DMPC.  
   
   
       9 . The composition of  claim 8  wherein the ratio of DOPG:DMPC is 40:60.  
   
   
       10 . The composition of  claim 9  wherein said aggregates further comprise at least one antioxidant.  
   
   
       11 . The composition of  claim 10  wherein said at least one antioxidant is BHT and/or AP.  
   
   
       12 . The composition of  claim 1  wherein the ratio of phospholipids:photosensitizer is 8:1.  
   
   
       13 . The composition of  claim 1  wherein said one or more photosensitizer is one or more hydro-monobenzo-porphyrin photosensitizer.  
   
   
       14 . The composition of  claim 13  wherein said photosensitizer is BPD-MA, A-EA6 or B-EA6 or combinations thereof.  
   
   
       15 . The composition of  claim 13  wherein the one or more photosensitizers is A-EA6 or B-EA6 or a combination thereof.  
   
   
       16 . The composition of  claim 1  wherein the average diameter is below about 50 nm.  
   
   
       17 . The composition of  claim 1  wherein the average diameter is below about 30 nm.  
   
   
       18 . The composition of  claim 1  wherein the average diameter is below about 20 nm.  
   
   
       19 . The composition of  claim 1  wherein the unsaturated phospholipid is from a non-animal source.  
   
   
       20 . The composition of  claim 1  wherein the phospholipid is an egg phospholipid.  
   
   
       21 . The composition of  claim 1  wherein the phospholipid is not egg phosphatidylglycerol.  
   
   
       22 . A composition comprising 
 aggregates, said aggregates comprising saturated and unsaturated phospholipids, at least one of which comprises a negatively charged head group; and    one or more photosensitizer;    wherein the aggregates have an average diameter of less than 100 nm.    
   
   
       23 . A composition of aggregates comprising micelles, said micelles comprising saturated and unsaturated phospholipids and one or more photosensitizers, wherein either 
 a) said phospholipids are capable of forming a lipid bilayer and do not comprise egg phospholipid or egg phosphatidylglycerol; or    b) said phospholipids are capable of forming a lipid bilayer and said one or more photosensitizer is not a combination of approximately equal amounts of BPD-MA C  and BPD-MA D .    
   
   
       24 . A method for making a composition comprising micelles, said micelles comprising one or more hydrophobic agent and a mixture of saturated and unsaturated phospholipids, wherein said method comprises the steps of: 
 producing a mixture of an organic solvent, a hydrophobic-agent and phospholipids capable of forming a lipid bilayer to form an “intermediate complex”;    removing said solvent to produce a “presome” material;    hydrating said “presome” material with an aqueous solvent; and    processing said hydrated material to produce micelle comprising aggregates.    
   
   
       25 . The method of  claim 24  wherein either 
 a) said phospholipids are capable of forming a lipid bilayer and do not comprise egg phospholipid or egg phosphatidylglycerol; or    b) said phospholipids are capable of forming a lipid bilayer and said one or more hydrophobic agent is not a combination of approximately equal amounts of BPD-MA C  and BPD-MA D .    
   
   
       26 . The method of  claim 25  wherein said one or more hydrophobic agent is a photosensitizer but is not a combination of approximately equal parts of BPD-MA C  and BPD MA D .  
   
   
       27 . The method of  claim 26  wherein said one or more photosensitizers is BPD-MA, A-EA6, B-EA6, or a combination thereof.  
   
   
       28 . The method of  claim 27  wherein said one or more photosensitizers is BPD-MA.  
   
   
       29 . The method of  claim 27  wherein said one or more photosensitizers is A-EA6, B-EA6, or a combination thereof.  
   
   
       30 . The method of  claim 24  wherein said “intermediate complex” and said aqueous solvent are low salt.  
   
   
       31 . The method of  claim 30  wherein said hydrating and processing steps occur at a temperature of less than about 30° C.  
   
   
       32 . The method of  claim 24  wherein said steps comprise 
 a) supplying at a constant speed an organic solvent solution of a mixture of phospholipids capable of forming a lipid bilayer to a tubular heater heated externally,    b) evaporating the organic solvent in the heater to prepare a mixture substantially of solids and over heated organic solvent vapor,    c) introducing this mixture at a high speed of over 0.1 times the sound of speed into the vacuum chamber of not more than 300 mm Hg to volatize the organic solvent instantaneously and dry the solids, whereby lipid powder is obtained, and    d) dispersing the resulting lipid powder into a low salt aqueous solvent at a temperature of less than about 30° C.    
   
   
       33 . The method of  claim 31  wherein said processing step is by high energy manipulation.  
   
   
       34 . The method of  claim 33  wherein said high energy manipulation is selected from the group consisting of microfluidization, sonication, high speed shearing, extrusion, sonication and homogenization.