Aggregates with increased deformability, comprising at least three amphipats, for improved transport through semi-permeable barriers and for the non-invasive drug application in vivo, especially through the skin

Abstract

The invention describes combinations of at least three amphipatic substances forming aggregate suspensions in a polar liquid. Judicious choice of system components, which differ at least 2-times to 10-times in solubility, ensures said aggregates to have extended, unusually adaptable surfaces. This is probably due to simultaneous action on said aggregates of at least two more soluble substances amongst said three system components, at least one of which is an active ingredient and preferably a drug; the third component, alternatively, can take the role of a drug. The patent further deals with the use of said combinations in pharmaceutical preparations capable of transporting drugs into the body of warm blood creatures. This is made possible by the drug loading capability of said aggregates with the highly flexible and deformable coating, which renders the resulting drug carriers highly adaptable. The patent finally reveals suitable methods and favourable conditions for carrier manufacturing and application.

1 - 92 . (canceled)  
   
   
       93 . A vesicular composition comprising: 
 a phosphatidylcholine;    a polyhydroxyethylene-long fatty chain ether, a polyhydroxyethylene-long fatty chain ester, or a polyoxyethylene-sorbitan long fatty chain ester;    bupivacaine; and    a pharmaceutically acceptable polar liquid medium, wherein the pH of the liquid medium is between pKa−2 and pKa+1.5 of bupivacaine.    
   
   
       94 . The composition of  claim 93 , wherein the polyhydroxyethylene-long fatty chain ether is a polyhydroxyethylene oleoyl ether.  
   
   
       95 . The composition of  claim 94 , wherein the polyhydroxyethylene oleoyl ether is Brij 98.  
   
   
       96 . The composition of  claim 93 , wherein the polyhydroxyethylene-long-chain fatty ester is a polyhydroxyethylene-oleate.  
   
   
       97 . The composition of  claim 96 , wherein the polyhydroxyethylene-oleate is polyhydroxyethylene-8-oleate.  
   
   
       98 . The composition of  claim 93 , wherein the polyhydroxyethylene-long fatty chain ester is Myrj 45.  
   
   
       99 . The composition of  claim 93 , wherein the polyoxyethylene-sorbitan long fatty chain ester is polyethyleneglycol-sorbitan-monooleate.  
   
   
       100 . The composition of  claim 93 , wherein the polyoxyethylene-sorbitan long fatty chain ester is Tween 80.  
   
   
       101 . A vesicular composition comprising: 
 a phosphatidylcholine;    a polyhydroxyethylene-long fatty chain ether, a polyhydroxyethylene-long fatty chain ester, or a polyoxyethylene-sorbitan long fatty chain ester;    clonidine; and    a pharmaceutically acceptable polar liquid medium, wherein the pH of the liquid medium is between pKa−2 and pKa+1.5 of clonidine.    
   
   
       102 . The composition of  claim 101 , wherein the polyhydroxyethylene-long fatty chain ether is a polyhydroxyethylene oleoyl ether.  
   
   
       103 . The composition of  claim 102 , wherein the polyhydroxyethylene oleoyl ether is Brij 98.  
   
   
       104 . The composition of  claim 101 , wherein the polyhydroxyethylene-long fatty chain ester is a polyhydroxyethylene-oleate.  
   
   
       105 . The composition of  claim 104 , wherein the polyhydroxyethylene-oleate is polyhydroxyethylene-8-oleate.  
   
   
       106 . The composition of  claim 101 , wherein the polyhydroxyethylene-long fatty chain ester is Myrj 45.  
   
   
       107 . The composition of  claim 101 , wherein the polyoxyethylene-sorbitan long fatty chain ester is polyethyleneglycol-sorbitan-monooleate.  
   
   
       108 . The composition of  claim 101 , wherein the polyoxyethylene-sorbitan long fatty chain ester is Tween 80.  
   
   
       109 . A vesicular composition comprising: 
 (a) a phosphatidylcholine;    (b) a polyhydroxyethylene-long fatty chain ether, a polyhydroxyethylene-long fatty chain ester, or a polyoxyethylene-sorbitan long fatty chain ester;    (c) an amphipathic anaesthetic; and    (d) a pharmaceutically acceptable polar liquid medium, wherein the composition's adaptability exceeds, by at least 20% or by at least twice the standard deviation (whichever is smaller), the adaptability of: 
 a second vesicular composition comprising (a), (b), and (d), but not (c); or  
 a third vesicular composition comprising (a), (c), and (d), but not (b),  
 wherein the combined molar concentration of both (b) and (c) in the vesicular composition is equal to or less than the molar concentration of (b) in the second vesicular composition, or of (c) in the third vesicular composition, at the same molar concentration of (a) in all three vesicular compositions.  
   
   
   
       110 . The composition of  claim 109 , wherein the composition's adaptability exceeds, by at least 30%, the adaptability of: 
 a second vesicular composition comprising (a), (b), and (d), but not (c); or    a third vesicular composition comprising (a), (c), and (d), but not (b),    wherein the combined molar concentration of both (b) and (c) in the vesicular composition is equal to or less than the molar concentration of (b) in the second vesicular composition, or of (c) in the third vesicular composition, at the same molar concentration of (a) in all three vesicular compositions.    
   
   
       111 . The composition of  claim 109 , wherein the amphipathic anesthetic is bupivacaine.  
   
   
       112 . The composition of  claim 109 , wherein the polyhydroxyethylene-long fatty chain ether is a polyhydroxyethylene oleoyl ether.  
   
   
       113 . The composition of  claim 112 , wherein the polyhydroxyethylene oleoyl ether is Brij 98.  
   
   
       114 . The composition of  claim 109 , wherein the polyhydroxyethylene-long fatty chain ester is a polyhydroxyethylene-oleate.  
   
   
       115 . The composition of  claim 114 , wherein the polyhydroxyethylene-oleate is polyhydroxyethylene-8-oleate.  
   
   
       116 . The composition of  claim 109 , wherein the polyhydroxyethylene-long fatty chain ester is Myrj 45.  
   
   
       117 . The composition of  claim 109 , wherein the polyoxyethylene-sorbitan long fatty chain ester is polyethyleneglycol-sorbitan-monooleate.  
   
   
       118 . The composition of  claim 109 , wherein the polyoxyethylene-sorbitan long fatty chain ester is Tween 80.  
   
   
       119 . A vesicular composition comprising: 
 (a) a phosphatidylcholine;    (b) a polyhydroxyethylene-long fatty chain ether, a polyhydroxyethylene-long fatty chain ester, or a polyoxyethylene-sorbitan long fatty chain ester;    (c) an antihypertensive having an imidazoline structure; and    (d) a pharmaceutically acceptable polar liquid medium, wherein the composition's adaptability exceeds, by at least 20% or by at least twice the standard deviation (whichever is smaller), the adaptability of: 
 a second vesicular composition comprising (a), (b), and (d), but not (c); or  
 a third vesicular composition comprising (a), (c), and (d), but not (b),  
 wherein the combined molar concentration of both (b) and (c) in the vesicular composition is equal to or less than the molar concentration of (b) in the second vesicular composition, or of (c) in the third vesicular composition, wherein the molar concentration of (a) is the same in all three vesicular compositions.  
   
   
   
       120 . The composition of  claim 119 , wherein the composition's adaptability exceeds, by at least 30%, the adaptability of: 
 a second vesicular composition comprising (a), (b), and (d), but not (c); or    a third vesicular composition comprising (a), (c), and (d), but not (b),    wherein the combined molar concentration of both (b) and (c) in the vesicular composition is equal to or less than the molar concentration of (b) in the second vesicular composition, or of (c) in the third vesicular composition, at the same molar concentration of (a) in all three vesicular compositions.    
   
   
       121 . The composition of  claim 119 , wherein the antihypertensive having an imidazoline structure is clonidine.  
   
   
       122 . The composition of  claim 119 , wherein the polyhydroxyethylene-long fatty chain ether is a polyhydroxyethylene oleoyl ether.  
   
   
       123 . The composition of  claim 122 , wherein the polyhydroxyethylene oleoyl ether is Brij 98.  
   
   
       124 . The composition of  claim 119 , wherein the polyhydroxyethylene-long-chain fatty ester is a polyhydroxyethylene-oleate.  
   
   
       125 . The composition of  claim 124 , wherein the polyhydroxyethylene-oleate is polyhydroxyethylene-8-oleate.  
   
   
       126 . The composition of  claim 119 , wherein the polyhydroxyethylene-long fatty chain ester is Myrj 45.  
   
   
       127 . The composition of  claim 119 , wherein the polyoxyethylene-sorbitan long fatty chain ester is polyethyleneglycol-sorbitan-monooleate.  
   
   
       128 . The composition of  claim 119 , wherein the polyoxyethylene-sorbitan long fatty chain ester is Tween 80.  
   
   
       129 . A vesicular composition comprising: 
 (a) a phosphatidylcholine;    (b) a polyhydroxyethylene-long fatty chain ether, a polyhydroxyethylene-long fatty chain ester, or a polyoxyethylene-sorbitan long fatty chain ester;    (c) an amphipathic antimycotic; and    (d) a pharmaceutically acceptable polar liquid medium, wherein the composition's adaptability exceeds, by at least 20% or by at least twice the standard deviation (whichever is smaller), the adaptability of: 
 a second vesicular composition comprising (a), (b), and (d), but not (c); or  
 a third vesicular composition comprising (a), (c), and (d), but not (b),  
 wherein the combined molar concentration of both (b) and (c) in the vesicular composition is equal to or less than the molar concentration of (b) in the second vesicular composition, or of (c) in the third vesicular composition, at the same molar concentration of (a) in all three vesicular compositions.  
   
   
   
       130 . The composition of  claim 129 , wherein the composition's adaptability exceeds, by at least 30%, the adaptability of: 
 a second vesicular composition comprising (a), (b), and (d), but not (c); or    a third vesicular composition comprising (a), (c), and (d), but not (b),    wherein the combined molar concentration of both (b) and (c) in the vesicular composition is equal to or less than the molar concentration of (b) in the second vesicular composition, or of (c) in the third vesicular composition, at the same molar concentration of (a) in all three vesicular compositions.    
   
   
       131 . The composition of  claim 129 , wherein the polyhydroxyethylene-long fatty chain ether is a polyhydroxyethylene oleoyl ether.  
   
   
       132 . The composition of  claim 131 , wherein the polyhydroxyethylene oleoyl ether is Brij 98.  
   
   
       133 . The composition of  claim 129 , wherein the polyhydroxyethylene-long fatty chain ester is a polyhydroxyethylene-oleate.  
   
   
       134 . The composition of  claim 133 , wherein the polyhydroxyethylene-oleate is polyhydroxyethylene-8-oleate.  
   
   
       135 . The composition of  claim 129 , wherein the polyhydroxyethylene-long fatty chain ester is Myrj 45.  
   
   
       136 . The composition of  claim 129 , wherein the polyoxyethylene-sorbitan long fatty chain ester is polyethyleneglycol-sorbitan-monooleate.  
   
   
       137 . The composition of  claim 129 , wherein the polyoxyethylene-sorbitan long fatty chain ester is Tween 80.  
   
   
       138 . A vesicular composition comprising: 
 a first amphipathic component being phosphatidylcholine;    a second amphipathic component being a surfactant selected from a polyhydroxyethylene-long fatty chain ether, a polyhydroxyethylene-long fatty chain ester, or a polyoxyethylene-sorbitan long fatty chain ester; and    a third amphipathic component selected from an antimycotic, an anaesthetic or an antihypertensive;    in a liquid medium, wherein the ratio of the phosphatidylcholine to surfactant is in the range of 1/1 to 9/1, wherein the first, second, and third amphipathic components are present in a vesicle.    
   
   
       139 . The composition of  claim 138 , wherein the ratio of the phosphatidylcholine to surfactant is in the range of 7/1.  
   
   
       140 . The composition of  claim 138 , wherein the ratio of the phosphatidylcholine to surfactant is in the range of 4/1.  
   
   
       141 . The composition of  claim 138 , wherein the anaesthetic is bupivacaine.  
   
   
       142 . The composition of  claim 141 , further comprising a fourth amphipathic component that is an antihypertensive.  
   
   
       143 . The composition of  claim 142 , wherein the antihypertensive is clonidine.  
   
   
       144 . The composition of  claim 138 , wherein the antihypertensive is clonidine.  
   
   
       145 . The composition of  claim 138 , wherein the third component is between 0.1 rel. % and 60 rel. % compared to total mass of all three components.  
   
   
       146 . The composition of  claim 138 , wherein the third component is between 0.5 rel. % and 50 rel. % compared to total mass of all three components.  
   
   
       147 . The composition of  claim 138 , wherein the third component is between 1.0 rel. % and 40 rel. % compared to total mass of all three components.  
   
   
       148 . The composition of  claim 138 , having an average surface curvature corresponding to an average radius between 15 nm and 5000 nm.  
   
   
       149 . The composition of  claim 138 , having an average surface curvature corresponding to an average radius between 30 nm and 1000 nm.  
   
   
       150 . The composition of  claim 138 , having an average surface curvature corresponding to an average radius between 40 nm and 300 nm.  
   
   
       151 . The composition of  claim 138 , having an average surface curvature corresponding to an average radius between 50 nm and 150 nm.  
   
   
       152 . The composition of  claim 138 , wherein the second component is at least 10 times more soluble than the first component in the liquid medium.  
   
   
       153 . The composition of  claim 138 , wherein the third component is at least 10 times more soluble than the first component in the liquid medium.