LIPID ENCAPSULATED GAS MICROSPHERE COMPOSITIONS AND RELATED METHODS
The invention provides improved compositions relating to lipid-encapsulated gas microspheres and methods of their use.
1 . A composition used to form an ultrasound contrast agent, comprising
a lipid solution comprising DPPA, DPPC and PEG5000-DPPE, and
a perfluorocarbon gas, in a container,
wherein the perfluorocarbon gas occupies about 60-85% of the container volume, and wherein when activated the composition comprises microspheres having an average diameter of about 1 micron to about 2 microns.
2 . A composition for use as an ultrasound contrast agent, comprising
lipid-encapsulated gas microspheres having an average diameter ranging from about 1.0 micron to about 2.0 microns in a mixture of a lipid solution comprising DPPA, DPPC and PEG5000-DPPE and a perfluorocarbon gas in a container, wherein the perfluorocarbon gas occupies about 60-85% of the container volume.
3 . A composition used to form an ultrasound contrast agent, comprising
a lipid solution comprising DPPA, DPPC and PEG5000-DPPE, and
a perfluorocarbon gas, in a container,
wherein the perfluorocarbon gas occupies about 60-85% of the container volume.
4 . A composition for use as an ultrasound contrast agent, comprising
lipid-encapsulated gas microspheres in a mixture of a lipid solution comprising DPPA, DPPC and PEG5000-DPPE and a perfluorocarbon gas in a container, wherein the perfluorocarbon gas occupies about 60-85% of the container volume.
5 . A composition used to form an ultrasound contrast agent, comprising
a lipid solution comprising DPPA, DPPC and PEG5000-DPPE, and
a perfluorocarbon gas, in a container,
wherein the perfluorocarbon gas occupies about 60-85% of the container volume, and wherein when activated the composition comprises about 0.5×10 9 to about 3.5×10 9 microspheres per mL.
6 . A composition for use as an ultrasound contrast agent, comprising
about 0.5×10 9 to about 3.5×10 9 lipid-encapsulated gas microspheres per mL in a mixture of a lipid solution comprising DPPA, DPPC and PEG5000-DPPE and a perfluorocarbon gas in a container, wherein the perfluorocarbon gas occupies about 60-85% of the container volume.
7 . The composition of any of the foregoing claims, wherein the microspheres have an average diameter ranging from about 1.2 microns to about 1.8 microns.
8 . The composition of any of the foregoing claims, wherein the microspheres have an average diameter of about 1.6 microns.
9 . The composition of any of the foregoing claims, wherein at least 50% of the microspheres have a diameter of about 1.0 to about 2.0 microns.
10 . The composition of any of the foregoing claims, wherein at least 70% of the microspheres have a diameter of about 1.0 to about 2.0 microns.
11 . The composition of any one of the foregoing claims, wherein the lipid solution comprises DPPA, DPPC and PEG5000-DPPE in a mole % ratio of 10:82:8.
12 . The composition of any one of the foregoing claims, wherein the PEG500-DPPE is MPEG5000-DPPE.
13 . The composition of any one of the foregoing claims, wherein the perfluorocarbon gas is perfluoropropane.
14 . The composition of any one of the foregoing claims, wherein the perfluorocarbon gas occupies about 65%, about 70%, about 75%, about 80% or about 85% of the volume of the container.
15 . The composition of any one of the foregoing claims, wherein the lipid solution further comprises propylene glycol, glycerol, and saline.
16 . The composition of any one of the foregoing claims, wherein the lipid solution further comprises propylene glycol, glycerol, buffer, and saline.
17 . The composition of any one of the foregoing claims, wherein the lipid solution further comprises propylene glycol, glycerol, phosphate buffer, and saline.
18 . The composition of any one of the foregoing claims, wherein the lipid solution further comprises saline, glycerol and propylene glycol in a weight ratio of 8:1:1.
19 . The composition of any one of the foregoing claims, comprising about 1 ml lipid solution and about 2.75 ml of perfluorocarbon gas.
20 . The composition of any one of the foregoing claims, wherein the lipid solution comprises about 0.75 to about 1.0 mg of lipids per ml of solution.
21 . A composition used to form an ultrasound contrast agent, comprising
a lipid solution comprising about 0.1 mg to about 0.6 mg combined of DPPA, DPPC and PEG5000-DPPE per ml of solution, and
a perfluorocarbon gas, in a container,
wherein when activated the composition comprises microspheres having an average diameter of about 1 micron to about 2 microns.
22 . A composition for use as an ultrasound contrast agent, comprising
lipid-encapsulated gas microspheres having an average diameter ranging from about 1.0 micron to about 2.0 microns in a mixture of a lipid solution and a perfluorocarbon gas in a container, wherein the lipid solution comprises about 0.1 to about 0.6 mg DPPA, DPPC and PEG5000-DPPE (combined) per ml of solution.
23 . A composition used to form an ultrasound contrast agent, comprising
a lipid solution comprising about 0.1 mg to about 0.6 mg combined of DPPA, DPPC and PEG5000-DPPE per ml of solution, and
a perfluorocarbon gas, in a container.
24 . A composition for use as an ultrasound contrast agent, comprising
lipid-encapsulated gas microspheres in a mixture of a lipid solution and a perfluorocarbon gas in a container, wherein the lipid solution comprises about 0.1 to about 0.6 mg DPPA, DPPC and PEG5000-DPPE combined per ml of solution.
25 . A composition used to form an ultrasound contrast agent, comprising
a lipid solution comprising about 0.1 mg to about 0.6 mg combined of DPPA, DPPC and PEG5000-DPPE per ml of solution, and
a perfluorocarbon gas, in a container,
wherein when activated the composition comprises about 0.1×10 9 to about 3.5×10 9 microspheres per mL.
26 . A composition for use as an ultrasound contrast agent, comprising
about 0.1×10 9 to about 3.5×10 9 lipid-encapsulated gas microspheres per mL in a mixture of a lipid solution and a perfluorocarbon gas in a container, wherein the lipid solution comprises about 0.1 to about 0.6 mg DPPA, DPPC and PEG5000-DPPE combined per ml of solution.
27 . The composition of any one of claims 21 - 26 , wherein the microspheres have an average diameter ranging from about 1.2 microns to about 1.8 microns.
28 . The composition of any one of claims 21 - 26 , wherein the microspheres have an average diameter of about 1.6 microns.
29 . The composition of any one of claims 21 - 28 , wherein at least 50% of the microspheres have a diameter of about 1.0 to about 2.0 microns.
30 . The composition of any one of claims 21 - 28 , wherein at least 70% of the microspheres have a diameter of about 1.0 to about 2.0 microns.
31 . The composition of any one of claims 21 - 30 , wherein the lipid solution comprises DPPA, DPPC and PEG5000-DPPE in a mole % ratio of 10:82:8.
32 . The composition of any one of claims 21 - 31 , wherein the PEG500-DPPE is MPEG5000-DPPE.
33 . The composition of any one of claims 21 - 32 , wherein the perfluorocarbon gas is perfluoropropane.
34 . The composition of any one of claims 21 - 33 , wherein the lipid solution further comprises propylene glycol, glycerol, and saline.
35 . The composition of any one of claims 21 - 33 , wherein the lipid solution further comprises propylene glycol, glycerol, buffer, and saline.
36 . The composition of any one of claims 21 - 33 , wherein the lipid solution further comprises propylene glycol, glycerol, phosphate buffer, and saline.
37 . The composition of any one of claims 16 - 26 , wherein the lipid solution further comprises saline, glycerol and propylene glycol in a weight ratio of 8:1:1.
38 . The composition of any one of claims 21 - 37 , comprising about 1.76 ml lipid solution and about 2.03 ml of perfluorocarbon gas.
39 . The composition of any one of claims 21 - 38 , wherein the lipid solution comprises about 0.2 to about 0.5 mg of lipids per ml of solution.
40 . The composition of any one of claims 21 - 38 , wherein the lipid solution comprises about 0.3 to about 0.4 mg of lipids per ml of solution.
41 . The composition of any one of claims 21 - 38 , wherein the lipid solution comprises about 0.4 to about 0.5 mg of lipids per ml of solution.
42 . The composition of any one of the foregoing claims, wherein the container is a vial, a tube, or a syringe.
43 . The composition of any one of the foregoing claims, wherein the container is a rubber-less container.
44 . The composition of any one of the foregoing claims, wherein the container is a plastic container.
45 . The composition of any one of the foregoing claims, wherein the container is a plastic syringe having a rubber-less plunger.
46 . The composition of any one of the foregoing claims, wherein the container is a plastic syringe having a substantially flat-end plunger.
47 . A composition used to form an ultrasound contrast agent, comprising
a lipid solution comprising DPPA, DPPC and PEG5000-DPPE, and
a perfluorocarbon gas, in a container having an actual internal volume of less than 3 mL,
wherein the perfluorocarbon gas occupies about 50-55% of the actual internal volume, and wherein when activated the composition comprises microspheres having an average diameter of about 1.0 micron to about 2.0 microns.
48 . The composition of claim 47 , wherein the actual internal volume is in the range of 1 mL to less than 3 mL.
48 . A composition for use as an ultrasound contrast agent, comprising
lipid-encapsulated gas microspheres having an average diameter ranging from about 1.0 micron to about 2.0 microns in a mixture of a lipid solution comprising DPPA, DPPC and PEG5000-DPPE and a perfluorocarbon gas in a container having an actual internal volume of less than 3 mL, wherein the perfluorocarbon gas occupies about 50-55% of the actual internal volume.
49 . The composition of claim 48 , wherein the actual internal volume is 1 mL to less than 3 mL.
50 . A composition used to form an ultrasound contrast agent, comprising
a lipid solution comprising DPPA, DPPC and PEG5000-DPPE, and
a perfluorocarbon gas, in a rubber-less plastic container, optionally having an adjustable or fixed flat end,
wherein the perfluorocarbon gas occupies about 50-55% of the container volume, and wherein when activated the composition comprises microspheres having an average diameter of about 1.0 micron to about 2.0 microns.
51 . A composition for use as an ultrasound contrast agent, comprising
lipid-encapsulated gas microspheres having an average diameter ranging from about 1.0 micron to about 2.0 microns in a mixture of a lipid solution comprising DPPA, DPPC and PEG5000-DPPE and a perfluorocarbon gas in a rubber-less plastic container, optionally having an adjustable or fixed flat end, wherein the perfluorocarbon gas occupies about 50-55% of the container volume.
52 . A composition used to form an ultrasound contrast agent, comprising
a lipid solution comprising DPPA, DPPC and PEG5000-DPPE, and
a perfluorocarbon gas, in a glass container having a v-shaped bottom,
wherein the perfluorocarbon gas occupies about 50-55% of the container volume, and wherein when activated the composition comprises microspheres having an average diameter of about 1.0 micron to about 2.0 microns.
53 . A composition for use as an ultrasound contrast agent, comprising
lipid-encapsulated gas microspheres having an average diameter ranging from about 1.0 micron to about 2.0 microns in a mixture of a lipid solution comprising DPPA, DPPC and PEG5000-DPPE and a perfluorocarbon gas in a glass container having a v-shaped bottom, wherein the perfluorocarbon gas occupies about 50-55% of the container volume.
54 . A method for producing an ultrasound contrast agent, comprising
activating the composition of any one of the foregoing claims to form a population of lipid-encapsulated microspheres.
55 . The method of claim 54 , wherein the composition is activated for less than 1 minute.
56 . The method of claim 54 , wherein the composition is activated for about 20 to about 50 seconds.