Micronized lipids
The present invention relates to drug delivery vehicles comprising micronized particles that include an active lipid agent, and in particular to micronized lipid particles that comprise an ether lipid such as sn-1-O-eicosanyl-sn-2-palmitoyl-glycerol and its isomers.
1. A lipid particle composition comprising crystalline solid non-polar lipid particles having an average particle size of less than 50 microns stably suspended in a buffered aqueous vehicle suitable for topical administration, wherein the crystalline solid non-polar lipid particles comprise lipids selected from the group consisting of:
wherein
R 1 is an unsubstituted C6 to C30 alkyl or alkenyl;
R 2 is an unsubstituted C5 to C29 alkyl or alkenyl; and
R 3 is a hydrogen;
wherein
R 1 is a hydrogen;
R 2 is an unsubstituted C5 to C29 alkyl or alkenyl; and
R 3 is an unsubstituted C6 to C30 alkyl or alkenyl;
wherein
R 1 is an unsubstituted C6 to C30 alkyl or alkenyl;
R 2 is an unsubstituted C5 to C29 alkyl or alkenyl; and
R 3 is a hydrogen
wherein
R 1 is an unsubstituted C6 to C30 alkyl or alkenyl;
R 2 is a hydrogen; and
R 3 is an unsubstituted C5 to C29 alkyl or alkenyl;
wherein
R 1 is an unsubstituted C5 to C29 alkyl or alkenyl;
R 2 is a hydrogen; and
R 3 is an unsubstituted C6 to C30 alkyl or alkenyl; and
wherein
R 1 is an unsubstituted C6 to C30 alkyl or alkenyl;
R 2 is a hydrogen; and
R 3 is an unsubstituted C5 to C29 alkyl or alkenyl.
2. The lipid particle composition of claim 1 , wherein the crystalline solid non-polar lipid particles have a melting point of less than 80 degrees C.
3. The lipid particle composition of claim 1 , wherein the crystalline solid non-polar lipid particles have a melting point of from 20 to 80 degrees C.
4. The lipid particle composition of claim 1 , wherein the crystalline solid non-polar lipid particles have a melting point of from 30 to 60 degrees C.
5. The lipid particle composition of claim 1 , wherein the crystalline solid non-polar lipid particles have an average particle size of less than 20 microns.
6. The lipid particle composition of claim 1 , wherein the crystalline solid non-polar lipid particles have an average particle size of less than 10 microns.
7. The lipid particle composition of claim 1 , wherein the active lipid agent is a non-polar ether lipid.
8. The lipid particle composition of claim 1 , wherein the crystalline solid non-polar lipid particles comprise an active lipid agent selected from the group consisting of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG), sn-1-O-eicosanyl-2-palmitoyl-glycerol, sn-2-palmitoyl-3-O-eicosanyl-glycerol, 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG), sn-1-O-eicosanyl-3-palmitoyl-glycerol, sn-1-palmitoyl-3-O-eicosanyl-glycerol and mixtures thereof.
9. The lipid particle composition of claim 8 , wherein the crystalline solid non-polar lipid particles comprise an active lipid agent selected from the group consisting of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) or 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) and mixtures thereof.
10. The lipid particle composition of claim 9 , wherein the mixture of ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized in comprising greater than 95% (mole percent) of the 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomer or greater than 95% (mole percent) of the 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomer.
11. The lipid particle composition of claim 9 , wherein the mixture of ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized in comprising greater than 98% (mole percent) of the 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomer or greater than 98% (mole percent) of the 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomer.
12. The lipid particle composition of claim 9 , wherein the mixture of ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized in comprising greater than 99% (mole percent) of the 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomer or greater than 99% (mole percent) of the 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomer.
13. The lipid particle composition of claim 9 , wherein the mixture of ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized in comprising greater than 95% (mole percent) of the 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomer and no greater than 5% (mole percent) of the 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomer.
14. The lipid particle composition of claim 9 , wherein the mixture of ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized in comprising greater than 98% (mole percent) of the 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomer and no greater than 2% (mole percent) of the 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomer.
15. The lipid particle composition of claim 9 , wherein the mixture of ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized in comprising greater than 99% (mole percent) of the 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomer and no greater than 1% (mole percent) of the 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomer.
16. The lipid particle composition of claim 1 , wherein the crystalline solid non-polar lipid particles further comprise one or more additional lipids selected from the group consisting of a nonpolar mono-, di-or tri-glyceride, a wax ester including cholesterol esters, a sterol, a free fatty acid and combinations thereof.
17. The lipid particle composition of claim 1 , wherein the aqueous buffered vehicle comprises phosphate buffered saline (PBS), 3% or less (w/w of the vehicle) polysorbate 80 and 0.3% or less (w/w of the vehicle) xanthan gum and has a pH of from 6.5-8.0 and an osmolality of from 260 to 320 mOsm/L.
18. The lipid particle composition of claim 1 , wherein the suspended particles are stable to phase separation from the suspension for 6 months at room temperature.
19. The lipid particle composition of claim 18 , wherein the suspended particles are chemically stable to <5% isomerization of 1,2-EPRG to the isomeric 1,3-EPRG during storage at room temperature for 6 months.
20. The lipid particle composition of claim 1 , wherein the suspended particles are stable to phase separation from the suspension for 24 months at room temperature.
21. The lipid particle composition of claim 20 , wherein the suspended particles are chemically stable to <5% isomerization of 1,2-EPRG to the isomeric 1,3-EPRG during storage at room temperature for 24 months.
22. The lipid particle composition of claim 1 , wherein the composition is sterile.
23. The lipid particle composition of claim 1 , wherein the composition comprises a preservative.
24. The lipid particle composition of claim 1 , wherein the suspension is preservative-free.
25. The lipid particle composition of claim 1 , wherein the aqueous buffered vehicle is an ophthalmologically acceptable carrier.
26. The lipid particle composition of claim 1 , wherein the aqueous buffered vehicle further comprises an agent selected from the group consisting of a buffering agent, a tonicity agent, a wetting agent, a thickening and viscosity agent, a density adjusting agent and combinations thereof.
27. The lipid particle composition of claim 1 , wherein the active lipid agent in the crystalline solid non-polar lipid particles is released from the crystalline solid non-polar lipid particles as individual molecules for a period of time after administration as an ophthalmic drop.
28. The lipid particle composition of claim 27 , wherein the individual molecules are released for a period of from 1 up to 24 hours.
29. The lipid particle composition of claim 1 , wherein the suspension is provided in a drop dispenser.
30. A method of treating a disease or disorder of the eye selected from the group consisting of evaporative dry eye, meibomian gland dysfunction and symptoms or conditions associated therewith, an unstable tear film resulting in rapid aqueous tear evaporation and keratoconjunctivitis sicca and symptoms or clinical signs associated therewith, in an animal or human subject in need of such treatment, comprising topically administering a lipid particle composition according to claim 1 comprising an effective amount of the active lipid agent to the eye of the subject.