Modified drugs for use in liposomal nanoparticles

Abstract

Drag derivatives are provided herein which are suitable for loading into liposomal nanoparticle carriers. In some preferred aspects, the derivatives comprise a poorly water-soluble drag derivatized with a weak-base moiety that facilitates active loading of the drag through a LN transmembrane pH or ion gradient into the aqueous interior of the LN. The weak-base moiety can optionally comprise a lipophilic domain that facilitates active loading of the drag to the inner monolayer of the liposomal membrane. Advantageously, LN formulations of the drag derivatives exhibit improved solubility, reduced toxicity, enhanced efficacy, and/or other benefits relative to the corresponding free drags.

1 - 21 . (canceled) 
     
     
         22 . A compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein D is a drug selected from the group consisting of: tacrolimus, cyclosporine, and azathioprine; 
         wherein Z is a Liposome Solubilization Unit of formula IIA: 
       
       
         
           
           
               
               
           
         
         wherein [S] is a “spacer” comprising:
 (a) a chain of the type (CH 2 ) n , where n may range from 1 to 10, or 
 (b) a derivative of the above (CH 2 ) n  where one or more H atoms are replaced by: a linear, branched, or cyclic alkyl group containing from 1 to 10 C atoms, a heteroatom such as N, O, S, Si, which may be further connected to H atoms; or to heteroatoms such as N, O, S; or to linear, branched, or cyclic alkyl groups containing from 1 to 10 C atoms and facultatively incorporating one or more halogen atoms, a halogen atom; or 
 (c) a derivative of the above (CH 2 ) n  where one or more CH 2  groups are replaced by: a heteroatom such as N, O, S, Si, which may be further connected to H atoms; or to heteroatoms such as N, O, S; or to linear, branched, or cyclic alkyl groups containing from 1 to 10 C atoms and facultatively incorporating one or more halogen atoms, a ring structure consisting of 3 to 10 carbon atoms and facultatively incorporating one of more heteroatoms such as N, O, S, Si, or halogen, as well as multiple bonds among pairs of atoms; or 
 (d) a derivative of the above (CH 2 ) n  where one or more pairs of adjacent C atoms share a double bond of E- or Z-geometry, or a triple bond; and 
 
         wherein [N] is a Solubilization Domain of any of the following:
 (a) [N] is of the general formula III: 
 
       
       
         
           
           
               
               
           
         
         wherein R and R′ together with the nitrogen atom to which they are attached form a heterocyclic ring having four to five carbon atoms, which may comprise one of multiple rings within a ring system; or
 (b) [N] is selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         wherein:
 A is selected from the group consisting of: carbonyl, methylene, and NR—C═O, where R is H or C 1 -C 5  alkyl; 
 R 1  and R 2  are independently selected from the group consisting of: linear or branched C 1 -C 30  alkyl, C 2 -C 30  alkenyl, and C 2 -C 30  alkynyl; and 
 R 3  and R 4  are independently selected from the group consisting of: H; C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, each optionally substituted with halo; and cycloalkyl, heterocyclyl, aryl, and heteroaryl, each optionally substituted with halo; or 
 R 3  and R 4  together with the nitrogen atom to which they are attached form a heterocyclic ring having four to five carbon atoms, which may comprise one of multiple rings within a ring system; or 
 (c) [N] is selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 22  or a pharmaceutically acceptable salt thereof, wherein [S] is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 22  or a pharmaceutically acceptable salt thereof, wherein the Solubilization Unit is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 22  having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         26 . The compound of  claim 22  having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         27 . The compound of  claim 22  having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein R and R′ together with the nitrogen atom to which they are attached form a heterocyclic ring having four to five carbon atoms, which may comprise one of multiple rings within a ring system. 
       
     
     
         28 . A composition comprising a compound of  claim 22  or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier. 
     
     
         29 . The composition of  claim 28 , wherein said pharmaceutically acceptable carrier comprises a liposome. 
     
     
         30 . The composition of  claim 29 , having a liposome particle size of from about 80 nm to about 120 nm. 
     
     
         31 . A liposome composition comprising the compound of  claim 22  or a pharmaceutically acceptable salt thereof, a phosphatidyl choline lipid, and cholesterol. 
     
     
         32 . The liposome composition of  claim 31 , wherein said phosphatidyl choline lipid is selected from the group consisting of: C 14  to C 22  saturated fatty acid phosphatidyl choline lipids. 
     
     
         33 . The liposome composition of  claim 32 , wherein said phosphatidyl choline lipid is selected from the group consisting of: distearoylphosphatidyl choline, dipalmitoylphosphatidyl choline, and dimyristoylphosphatidyl choline. 
     
     
         34 . The liposome composition of  claim 31 , wherein the molar ratio of cholesterol:phosphatidyl choline lipid is from 0.1 to 1.0. 
     
     
         35 . The liposome composition of  claim 31 , further comprising a negatively or positively charged lipid. 
     
     
         36 . The liposome composition of  claim 35 , wherein said negatively charged lipid is selected from the group consisting of: dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, di stearoylphosphatidylglycerol, dimyristoylphosphatidic acid, dipalmitoylphosphatidic acid, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, and cardiolipin. 
     
     
         37 . The liposome composition of  claim 35 , wherein said positively charged lipid is selected from the group consisting of: N,N′-dimethyl-N,N′-dioctacyl ammonium bromide (DDAB) and N,N′-dimethyl-N,N′-dioctacyl ammonium chloride (DDAC), N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), 3β-[N—(N′,N′-dimethylaminoethyl)carbamoyl) cholesterol (DC-chol), 1,2-dioleoyloxy-3-[trimethylammonio]-propane (DOTAP), 1,2-dioctadecyloxy-3-[trimethylammonio]-propane (DSTAP), and 1,2-dioleoyloxypropyl-3-dimethyl-hydroxyethyl ammonium chloride (DORI). 
     
     
         38 . The liposome composition of  claim 31 , further comprising a polymer layer coating for said liposomes. 
     
     
         39 . The liposome composition of  claim 38 , wherein said liposomes comprise poly(ethylene glycol)-conjugated lipids. 
     
     
         40 . The liposome composition of  claim 39 , wherein said poly(ethylene glycol)-conjugated lipids are selected from the group consisting of: 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-350] (mPEG 350 PE); 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-550] (mPEG 550 PE); 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-750] (mPEG 750 PE); 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-1000] (mPEG 1000 PE); 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (mPEG 2000 PE); 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-3000] (mPEG 3000 PE); 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-5000] (mPEG 5000PE); N-acyl-sphingosine-1-[succinyl(methoxy polyethylene glycol) 750] (mPEG 750 Ceramide); N-acyl-sphingosine-1-[succinyl(methoxy polyethylene glycol) 2000] (mPEG 2000 Ceramide); and N-acyl-sphingosine-1-[succinyl(methoxy polyethylene glycol) 5000] (mPEG 5000 Ceramide). 
     
     
         41 . The liposome composition of  claim 31 , having a liposome particle size of from about 80 nm to about 120 nm. 
     
     
         42 . A pharmaceutical formulation comprising the liposome of  claim 31 .