Composition of matter comprising liposomes embedded in a polymeric matrix and methods of using same

Abstract

The present disclosure provides a composition of matter comprising liposomes encapsulating in their intraliposomal aqueous compartment at least one active agent, the liposomes having a diameter of at least 200 nm and being embedded in a water insoluble, water absorbed cross-linked polymeric matrix. In one embodiment, the composition of matter is held within an aqueous medium, preferably being in iso-osmotic equilibrium with the intraliposomal aqueous compartments of the liposomes. The present disclosure also provides a method of removal of non-encapsulated active agent from the composition of matter, a method of preparing said composition of matter, a pharmaceutical composition comprising said composition of matter, use of such composition of matter; a method of providing prolonged delivery of a active agent to a subject in need thereof by administering to said subject the composition of matter disclosed herein as well as a package comprising said composition of matter held within said aqueous medium and instructions for use thereof.

1 . A composition of matter comprising liposomes encapsulating in their intraliposomal aqueous compartment at least one active agent, the liposomes having a diameter of at least 200 nm and being embedded in a water insoluble, water absorbed cross-linked polymeric matrix. 
     
     
         2 . The composition of matter as claimed in  claim 1 , comprising an aqueous medium holding said polymeric matrix. 
     
     
         3 . The composition of matter as claimed in  claim 1 , wherein said liposomes are multilamellar vesicles (MLVs) or multivesicular vesicles (MVVs). 
     
     
         4 . The composition of matter as claimed in  claim 1 , wherein the polymer of said matrix is a fully cross-linked polymer or partially cross-linked polymer. 
     
     
         5 . The composition of matter as claimed in  claim 1 , wherein the polymeric matrix is a hydrogel, said hydrogel comprises at least one cross-linked polysaccharide, the polysaccharide being selected from the group consisting of alginate and chitosan. 
     
     
         6 . The composition of matter as claimed in  claim 2 , wherein said aqueous medium holding the polymeric matrix is in iso-osmotic equilibrium with the intraliposomal aqueous compartment of said liposomes. 
     
     
         7 . The composition of matter as claimed in  claim 5 , wherein said aqueous medium and said intraliposomal aqueous compartment of the liposomes have an osmolarity between 50 to 600 mOsm/kg. 
     
     
         8 . The composition of matter as claimed in  claim 2 , wherein said aqueous medium and said intraliposomal aqueous compartment have an osmolarity difference of no more than 50 mOsmole. 
     
     
         9 . The composition of matter as claimed in  claim 2 , wherein said aqueous medium comprises an amount of said at least active agent in free form. 
     
     
         10 . The composition of matter as claim in  claim 1 , wherein said liposomes have a diameter of between 200 nm to 25 mm. 
     
     
         11 . The composition of matter as claimed in  claim 1 , being stable during storage at 4° C. for a period of at least 3 months, said stability is measured by the amount of active agent present in the aqueous medium, an amount of less than 30% of said active agent out of the total amount thereof in the composition of matter being indicative that said composition of matter is stable. 
     
     
         12 . A method of preparing a composition of matter comprising liposomes encapsulating in their intraliposomal aqueous compartment at least one active agent, the liposomes having a diameter of at least 200 nm and being embedded in a cross-linked water insoluble and water absorbed polymeric matrix, the method comprising mixing (i) liposomes encapsulating in their intraliposomal aqueous compartment at least one active agent, the liposomes having a diameter of at least 200 nm; (ii) at least one cross-linkable polymer; and (iii) an aqueous solution comprising a cross-linker capable of forming with said cross-linkable polymer a water insoluble, water absorbed cross-linked polymer having embedded therein said liposomes. 
     
     
         13 . The method as claimed in  claim 12 , comprising washing said composition of matter to remove excess amount of said cross-linker. 
     
     
         14 . The method as claimed in  claim 12 , comprising adding to said composition of matter an aqueous medium being in an iso-osmotic equilibrium with the intraliposomal aqueous compartment of said liposomes. 
     
     
         15 . A method for removal of non-encapsulated active agent from a composition of matter comprising liposomes encapsulating in their intraliposomal aqueous compartment at least one such active agent, the liposomes having a diameter of at least 200 nm and being embedded in a cross-linked water insoluble and water absorbed polymeric matrix, the composition of matter being held in an aqueous medium, the method comprising decanting at least part of said aqueous medium from said composition of matter, thereby removing from said composition of matter at least part of non-encapsulated active agent. 
     
     
         16 . The method as claimed in  claim 15 , wherein removal provides a composition of matter comprising less than 10% non-encapsulated active agent. 
     
     
         17 . The method as claimed in  claim 16 , wherein said composition of matter comprising less than 7% non-encapsulated active agent. 
     
     
         18 . The method as claimed in  claim 15 , for removal of non-encapsulated active agent after storage of said composition of matter in said aqueous medium, said storage being at 4° C. for a period of at least 3 months. 
     
     
         19 . A method of providing prolonged delivery of an active agent to a subject in need thereof, the method comprising administering to said subject a pharmaceutical composition as claimed in  claim 1 .