Liposomal formulations, and methods of using and preparing thereof
The disclosure provides phosphorylated carbohydrate replacement therapies (CRT) that include compositions of phosphorylated carbohydrates and phospholipids, as well as methods for preparing such compositions. Such compositions are suitable for pharmaceutical delivery of phosphorylated carbohydrates to cell interior, endoplasmic reticulum, and Golgi, and can be used for treating CDG type I and CDG type II diseases as well as other metabolic disorders.
1 . A pharmaceutical composition comprising:
a liposome comprising:
i) 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), or a salt thereof, present in an amount between about 30 mol % and about 50 mol %;
ii) 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), or a salt thereof, present in an amount between about 45 mol % and about 75 mol %; and
iii) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), or a salt thereof, conjugated to polyethylene glycol (PEG), present in an amount between about 0.1 mol % and about 10 mol %; and
mannose-1-phosphate or a salt thereof encapsulated in the liposome.
2 . A method for delivering mannose-1-phosphate or a salt thereof to a human in need thereof, comprising administering to the human the pharmaceutical composition of claim 1 .
3 . A method for delivering mannose-1-phosphate or a salt thereof to a cell interior of a subject in need thereof, comprising administering to the subject a pharmaceutical composition of claim 1 , wherein at least a portion of the administered composition traverses the cell plasma membrane to deliver the mannose-1-phosphate or a salt thereof to the cell interior.
4 . A method for treating a congenital disorder of glycosylation (CDG) in a human in need thereof, comprising administering to the human a pharmaceutical composition of claim 1 .
5 . The method of claim 4 , wherein the congenital disorder of glycosylation (CDG) is a CDG-Ia disorder.
6 . A kit comprising:
a pharmaceutical composition of claim 1 ;
a container; and
a label or package insert on or associated with the container.
7 . The pharmaceutical composition of claim 1 , wherein the DSPE conjugated to PEG is DSPE-PEG 2000 .
8 . The pharmaceutical composition of claim 1 , wherein the liposome does not comprise cholesterol or a cholesterol ester.
9 . The pharmaceutical composition of claim 1 , wherein the concentration of mannose-1-phosphate or a salt thereof in the liposome is from about 2.5 mM to about 5 mM.
10 . The pharmaceutical composition of claim 1 , wherein the concentration of mannose-1-phosphate or a salt thereof in the liposome is from about 5 mM to about 10 mM.
11 . The pharmaceutical composition of claim 1 , wherein the liposome has an average particle size of about 0.1 microns.
12 . The method of claim 4 , wherein the CDG is CDG-1a, CDG-Ie, CDG-Ii, CDG-Ik, CDG-Io, GDG-Ip, or DPM2-CDG.
13 . The pharmaceutical composition of claim 1 , wherein DOPE, or a salt thereof, is present in an amount between about 40 mol % and about 50 mol %.
14 . The pharmaceutical composition of claim 1 , wherein DOPC, or a salt thereof, is present in an amount between about 50 mol % and about 75 mol %.
15 . The pharmaceutical composition of claim 1 , wherein DSPE-PEG, or a salt thereof, is present in an amount between about 1 mol % and about 6 mol %.
16 . The pharmaceutical composition of claim 1 , wherein the molar ratio of DOPE, or a salt thereof; DOPC, or a salt thereof; and DSPE-PEG, or a salt thereof, is about 30:67:3.