Delivery of Urea to Cells of the Macula and Retina Using Liposome Constructs

Abstract

Provided are liposome constructs for delivery of urea to the vitreoretinal interface of the eye. The liposome constructs are agglomerates of small lamellar vesicles (SUVs) and have a greater density than the vitreal fluid, such that they sink to the back of the eye rather than dispersing throughout the vitreous.

1 . A pharmaceutical composition comprising a liposome construct and a pharmaceutically acceptable carrier, wherein the liposome construct comprises an agglomerate of small unilamellar vesicles (SUVs), wherein the SUVs comprise urea encapsulated within the SUVs, wherein the SUVs have a specific gravity that is greater than about 1.05, a z-average diameter of less than about 220 nm, and a polydispersity index value (PdI) of less than about 0.150. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the SUVs have a z-average diameter of less than about 200 nm. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the SUVs comprise a lamella comprising one or more phospholipids and no cholesterol. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the SUVs comprise a lamella comprising one or more phospholipids and 1-9 mol % cholesterol. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the SUVs comprise a lamella comprising one or more phospholipids and 42-69 mol % cholesterol. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the SUVs comprise a lamella comprising one or more of cholesterol, dioleoyl phosphatidylcholine (DOPC), dioleyl phosphatidylethanolamine (DOPE), dioleoyl trimethylammonium propane (DOTAP), dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylglycerol (DPPG), distearoyl phosphatidylcholine (DSPC), phosphatidylcholine (PC), and palmitoyl oleoyl phosphatidylcholine (POPC). 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the SUVs comprise a lamella consisting essentially of:
 58 mol % DPPC and 42 mol % cholesterol;   58 mol % DOPC and 42 mol % cholesterol;   58 mol % POPC and 42 mol % cholesterol;   29 mol % DPPC, 42 mol % cholesterol, and 29 mol % DPPG;   80 mol % POPC and 20 mol % DOTAP;   67 mol % DMPC and 33 mol % DMPG, or   33 mol % DPPC, 13 mol % DSPC, 32 mol % DOPC, 17 mol % 18:2 PC, 5 mol % 20:4 PC.   
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the SUVs comprise a lamella consisting essentially of 58 mol % DOPC and 42 mol % cholesterol. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the SUVs comprise a surface modifying group. 
     
     
         10 . The pharmaceutical composition of  claim 7 , wherein the surface modifying group is polyethylene glycol (PEG). 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the SUVs have an encapsulation efficiency of at least 20%. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein a packed pellet of the SUVs comprises at least about 100 mg encapsulated urea per mL of packed pellet. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable carrier comprises urea. 
     
     
         14 . The pharmaceutical composition of  claim 1 , which is in the form of an emulsion or a suspension. 
     
     
         15 . A method for delivering urea to the vitreoretinal interface, the method comprising administering to the vitreous of a subject the pharmaceutical composition of  claim 1 . 
     
     
         16 . A method of inducing posterior vitreous detachment (PVD) in a subject having or susceptible to a disease or disorder of the macula or retina, the method comprising administering to the vitreous of the subject the pharmaceutical composition of  claim 1 . 
     
     
         17 . A method of treating diabetic retinopathy or vitreomacular adhesion (VMA) in a subject, the method comprising administering to the vitreous of the subject the pharmaceutical composition of  claim 1 . 
     
     
         18 . The method of  claim 15 , wherein the administering is via intravitreal injection. 
     
     
         19 . The method of  claim 15 , wherein the subject is in a supine position during administration of the pharmaceutical composition. 
     
     
         20 - 22 . (canceled) 
     
     
         23 . The method of  claim 16 , wherein the administering is via intravitreal injection. 
     
     
         24 . The method of  claim 17 , wherein the administering is via intravitreal injection. 
     
     
         25 . The method of  claim 16 , wherein the subject is in a supine position during administration of the pharmaceutical composition. 
     
     
         26 . The method of  claim 17 , wherein the subject is in a supine position during administration of the pharmaceutical composition.