Ultrasound contrast agent dosage formulation
Clinical studies have been conducted and specific dosage formulations developed using polymeric microparticles having incorporated therein perfluorocarbon gases that provide significantly enhanced images of long duration. The dosage formulation includes microparticles formed of a biocompatible polymer, preferably including a lipid incorporated therein, and containing a perfluorocarbon that is a gas at body temperature. The microparticles are provided to a patient in an amount effective to enhance ultrasound imaging in the ventricular chambers for more than 5 minutes or in the mycocardium for more than a minute, in a dose ranging from 0.025 to 8.0 mg microparticles/kg body weight. Preferably the dose ranges from 0.05 to 4.0 mg microparticles/kg body weight. The dosage formulation typically is provided in a vial. A typical formulation is in the form of a dry powder that is reconstituted with sterile water prior to use by adding the water to the vial or syringe of the dry powder and shaking to yield an isosmotic or isotonic suspension of microparticles.
1. A method of evaluating myocardial blood flow in a patient by ultrasound comprising
forming an isosmotic suspension comprising microspheres comprising a poly(hydroxy acid) or copolymer or blend thereof and a hydrophobic compound,
wherein the microspheres are porous spheres with a honeycombed structure or sponge-like structure, and having incorporated therein a perfluorocarbon gas and a pharmaceutically acceptable carrier suitable for injection,
wherein the suspension has a microsphere concentration ranging from 1.0×10 9 to 3.5×10 9 microspheres/mL of suspension or a microsphere mass concentration ranging from 25 to 50 mg microspheres/mL suspension,
intravenously administering to the patient the suspension in a dose ranging from 0.5 to 4.0 mg microspheres/kg body weight, and
imaging the patient's myocardium with ultrasound for more than one minute to produce an enhanced image of the myocardium for more than one minute compared to when no contrast agent is present.
2. The method of claim 1 further comprising administering to the patient an agent to stress the cardiovascular system of the patient and re-imaging the patient.
3. The method of claim 2 , wherein the agent is selected from the group consisting of vasodilators, inotropic agents and chronotropic agents.
4. The method of claim 1 , wherein the suspension has a microsphere concentration ranging from 1.5×10 9 to 2.8×10 9 microspheres/mL of suspension or a microsphere mass concentration ranging from 30 to 45 mg microspheres/mL suspension.
5. The method of claim 1 , wherein the microspheres have a mean particle size of less than 8 microns.
6. The method of claim 5 , wherein the microspheres have a mean particle size ranging from 1.9 to 2.6 microns.
7. The method of claim 1 , wherein the dose is selected from the group consisting of 0.5 mg microspheres/kg body weight, 2.0 mg microspheres/kg body weight and 4.0 mg microspheres/kg body weight.
8. The method of claim 1 , wherein the gas is selected from the group consisting of CF 4 , C 2 F 4 , C 2 F 6 , C 3 F 6 , C 3 F 8 , C 4 F 8 , and C 4 F 10 .
9. The method of claim 8 , wherein the gas is n-perfluorobutane (C 4 F 10 ) provided in an amount between 75 and 500 mg/mL of reconstituted volume of suspension.
10. The method of claim 9 wherein the n-perfluorobutane (C 4 F 10 ) is provided in an amount between 100 and 400 mg/mL of reconstituted volume of suspension.
11. The method of claim 10 wherein the n-perfluorobutane (C 4 F 10 ) is provided in an amount between 150 and 350 mg/mL of reconstituted volume of suspension.
12. The method of claim 8 wherein the gas is n-octafluoropropane (C 3 F 8 ) provided in an amount between 75 and 375 mg/mL of reconstituted volume of suspension.
13. The method of claim 12 wherein the n-octafluoropropane (C 3 F 8 ) is provided in an amount between 120 and 300 mg/mL of reconstituted volume of suspension.
14. The method of claim 1 , wherein the hydrophobic compound is incorporated with the poly(hydroxy acid), or copolymer or blend thereof (“polymer”) at a ratio of between 1 and 12% (weight hydrophobic compound/weight polymer).
15. The method of claim 14 , wherein the hydrophobic compound is a lipid.
16. The method of claim 15 , wherein the lipid is a phospholipid selected from the group consisting of dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC), dipentadecanoylphosphatidylcholine (DPDPC), dilauroylphosphatidylcholine (DLPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), diarachidoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcholine (DBPC), ditricosanoylphosphatidylcholine (DTPC), dilignoceroylphatidylcholine (DLGPC),and phosphatidylethanolamines.
17. The method of claim 16 , wherein the poly(hydroxy acid) copolymer is poly (lactide-co-glycolide) with a lactide to glycolide ratio of 1:1 and a weight average molecular weight ranging from 20 to 40 kDa, and wherein the lipid is diarachidoylphosphatidylcholine incorporated with the polymer in a range of between 5 and 6.6% (weight lipid/weight poly(hydroxy acid) copolymer).
18. The method of claim 1 , wherein the suspension further comprises one or more excipients selected from the group consisting sugars, salts, and surfactants.
19. The method of claim 1 , wherein the poly(hydroxy acid) copolymer is poly (lactide-co-glycolide), wherein the hydrophobic compound is diarachidoylphosphatidylcholine, and wherein the gas is n-perfluorobutane (C 4 F 10 ).