Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Reexamination Certificate
2001-03-21
2004-04-06
Travers, Russell (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
C424S009500, C424S009510, C424S450000, C604S021000, C604S058000, C514S04400A, C600S437000
Reexamination Certificate
active
06716412
ABSTRACT:
FIELD OF THE INVENTION
The present invention describes, among other things, the surprising discovery that gaseous precursor filled compositions are profoundly more effective as acoustically active contrast agents when the compositions are thermally preactivated to temperatures at or above the boiling point of the instilled gaseous precursor prior to their in vivo administration to a patient. Further optimization of contrast enhancement is achieved by administering the gaseous precursor filled compositions to a patient as an infusion. Enhanced effectiveness is also achieved for ultrasound mediated targeting and drug delivery.
BACKGROUND OF THE INVENTION
Previously, gaseous precursor filled contrast agents had limited effectiveness because high doses of gaseous precursor materials were required to be intravascularly injected into a patient to produce contrast enhancement. Even after IV injection into a patient, not all of the gaseous precursor materials converted into stable gaseous vesicles. Gaseous precursor materials that did not convert to a gas were much less effective as a contrast agent. Sonication, agitation and hypobaric activation were developed to activate gaseous precursor filled contrast agents; however, these methods were incompletely effective and ineffective for sustained infusions of the contrast agents.
More effective methods of converting gaseous precursor materials to a gas are necessary to overcome the problems associated with the prior art. The invention is directed to these, as well as other, important ends.
SUMMARY OF THE INVENTION
The present invention describes methods of providing images of regions of a patient comprising heating a composition comprising a gaseous precursor to a temperature at or above the boiling point of the gaseous precursor; administering the composition to the patient; and scanning the patient using diagnostic imaging to obtain visible images of regions of the patient. Preferably, the gaseous precursor is a fluorinated compound. If desired, the composition may be administered to the patient as an infusion. The compositions may comprise a wide variety of additional components, including, for example, one or more of gases, gaseous precursors, liquids, oils, stabilizing materials, diagnostic agents, targeting ligands and/or bioactive agents.
The present invention also describes methods of diagnosing the presence of diseased tissues in a patient comprising heating a composition comprising a gaseous precursor to a temperature at or above the boiling point of the gaseous precursor; administering the composition to the patient; and scanning the patient using diagnostic imaging to obtain visible images of any diseased tissues in the patient. Preferably, the gaseous precursor is a fluorinated compound. If desired, the composition may be administered to the patient as an infusion. The composition may comprise a wide variety of additional components, including, for example, one or more of gases, gaseous precursors, liquids, oils, stabilizing materials, diagnostic agents, targeting ligands and/or bioactive agents.
The present invention also describes methods of delivering bioactive agents to a patient comprising heating a composition comprising a bioactive agent and a gaseous precursor to a temperature at or above the boiling point of the gaseous precursor; and administering the composition to the patient. If desired, the methods may further comprise imaging the patient to monitor the location of the composition and/or conducting ultrasound imaging on the patient to facilitate delivery of the bioactive agents. Preferably, the gaseous precursor is a fluorinated compound. The composition may be administered to the patient as an infusion, if desired. The composition may comprise a wide variety of additional components, including, for example, one or more of gases, gaseous precursors, liquids, oils, stabilizing materials, diagnostic agents, targeting ligands and/or bioactive agents.
These and other aspects of the invention will become more apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
As employed above and throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings.
“Lipid” refers to a naturally-occurring, synthetic or semi-synthetic (i.e., modified natural) compound which is generally amphipathic. The lipids typically comprise a hydrophilic component and a hydrophobic component. Exemplary lipids include, for example, fatty acids, neutral fats, fluorinated lipids, phosphatides, oils, fluorinated oils, glycolipids, surface active agents (surfactants and fluorosurfactants), aliphatic alcohols, waxes, terpenes and steroids. The phrase semi-synthetic (or modified natural) denotes a natural compound that has been chemically modified in some fashion.
“Surfactant” refers to a surface active agent, which is a compound that alters surface tension. Surface active agents include, for example, detergents, wetting agents and emulsifiers. “Fluorosurfactant” refers to a surfactant in which at least one hydrogen atom of the surfactant is replaced with a fluorine atom.
“Polymer” or “polymeric” refers to molecules formed from the chemical union of two or more repeating units. Accordingly, included within the term “polymer” may be, for example, dimers, trimers and oligomers. The polymer may be synthetic, naturally-occurring or semisynthetic. In a preferred form, “polymer” refers to molecules which comprise 10 or more repeating units.
“Protein” refers to molecules comprising, and preferably consisting essentially of, &agr;-amino acids in peptide linkages. Included within the term “protein” are globular proteins such as albumins, globulins and histones, and fibrous proteins such as collagens, elastins and keratins. Also included within the term “protein” are “compound proteins,” wherein a protein molecule is united with a nonprotein molecule, such as nucleoproteins, mucoproteins, lipoproteins and metalloproteins. The proteins may be naturally-occurring, synthetic or semi-synthetic.
“Amphiphilic moiety” or “amphiphile” refers to a synthetic, semi-synthetic (modified natural) or naturally-occurring compound having a water-soluble, hydrophilic portion and a water-insoluble, hydrophobic portion. Preferred amphiphilic compounds are characterized by a polar head group, for example, a phosphatidylcholine group, and one or more nonpolar, aliphatic chains, for example, palmitoyl groups. “Fluorinated amphiphilic moiety” refers to an amphiphilic compound in which at least one hydrogen atom of the amphiphilic compound is replaced with a fluorine atom. In a preferred form, the fluorinated amphiphilic compounds are polyfluorinated. “Polyfluorinated amphiphilic moiety” refers to amphiphilic compounds which contain two or more fluorine atoms. “Perfluorinated amphiphilic moiety” refers to amphiphilic compounds in which all the hydrogen atoms have been replaced with a fluorine atom. “Amphipathy” refers to the simultaneous attraction and repulsion in a single molecule or ion containing one or more groups having an affinity for the phase or medium in which they are dissolved, emulsified and/or suspended, together with one or more groups that tend to be expelled from the involved phase or medium.
“Vesicle” refers to an entity which is generally characterized by the presence of one or more walls or membranes which form one or more internal voids. Vesicles may be formulated, for example, from a stabilizing material such as a lipid, including the various lipids described herein, a proteinaceous material, including the various proteins described herein, and a polymeric material, including the various polymeric materials described herein. Vesicles may also be formulated from carbohydrates, surfactants, and other stabilizing materials, as desired. The lipids, proteins, polymers, surfactants and/or other vesicle forming stabilizing materials may be natural, synthetic or semi-synthetic. Preferred vesicles are those which comprise walls or membranes formulated from lipids. The walls or me
Imarx Therapeutics Inc.
Sharareh S
Travers Russell
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