Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Reexamination Certificate
1999-07-16
2001-07-03
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
Reexamination Certificate
active
06254852
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to targeted ultrasound contrast agents having porous particles of an inorganic material containing an entrapped gas or liquid and having an average particle diameter of about 0.05 to 500 microns. The outer surfaces of the particles incorporate a targeting ligand to target delivery of the contrast agent.
BACKGROUND OF THE INVENTION
Techniques for ultrasound imaging various parts of the body are well known. An ultrasonic scanner is placed on the body surface overlying the area to be imaged. The sound waves generated by the scanner are directed toward the area to be imaged. The scanner then detects sound waves reflected from the underlying area and translates the signal into images.
The acoustic properties of a substance, such as an organ system, will depend upon the velocity of the ultrasonic transmissions and the density of the substance. Changes in the substance's acoustic properties will be most prominent at the interface of components of the substance differing in density, such as solid, liquid, and gas components. When ultrasonic energy is transmitted through a substance, the changes in acoustic properties (e.g., density) of the substance cause changes in the reflection characteristics, resulting in a more intense sound reflection signal received by the ultrasonic scanner.
Ultrasound contrast agents are introduced into the body organ system being imaged using ultrasound, and there act to influence the ultrasound signal in a way that enhances the ultrasound image. The contrast agent may be ingested or injected into and perfuse the microvasculature of the tissue desired to be imaged, to provide clearer images of the tissue. Such ultrasound contrast agents may be useful in helping to diagnose diseases earlier and more accurately.
Liquid and solid contrast agents containing entrapped gas are known in the art. The microbubbles provided by these contrast agents act as sound wave reflectors because of the acoustic differences between the gas microbubble and surrounding liquid.
Feinstein, U.S. Pat. No. 4,572,203, describes “microbubbles” of about 6-20 microns diameter produced by sonication of certain viscous solutions, as ultrasound contrast agents. Feinstein also describes solid or semi-solid metal-containing microparticles, such as glass or graphite, not containing trapped air, small enough to pass through capillaries, as ultrasound contrast agents. Also illustrated are microspheres formed from an amino acid polymer matrix, such as albumin, with magnetic particles, such as magnetite (Fe
3
O
4
) embedded therein.
Tickner, U.S. Pat. No. 4,265,251, depicts the use of certain saccharide composition “microbubble” particles with a hollow gas-filled interior space as ultrasound enhancing agents.
Rasor and Tickner, U.S. Pat. Nos. 4,442,843, 4,657,756, and 4,681,119, illustrate aggregates of microparticles (of 1-50 micron diameter) of a solid material, which are soluble in blood, containing gas in the voids between the particles, or with gas adsorbed on the surface of the particle, or containing gas as an integral part of the internal structure of the particle, for use in ultrasound imaging. The following solid materials are used: various saccharides, NaCl, sodium citrate, sodium acetate, sodium tartrate, CaCl
2
and AlCl
3
.
Hilmann et al., European Patent Application Publication Number 122,624, contains microparticles comprised of a solid surface-active substance, including various organic lipophilic compounds, with enclosed air, as ultrasound contrast agents. Also described is the combination of particles of the surface-active material and particles of a non-surface active material, such as sodium chloride, sodium citrate, sodium acetate, sodium tartrate, and various saccharides.
Glajch et al, U.S. Pat. No. 5,147,631, discloses porous particles of an inorganic material containing an entrapped gas or liquid. The materials disclosed include monomeric or polymeric borates, monomeric or polymeric aluminas, monomeric or polymeric carbonates, monomeric or polymeric silicas, monomeric or polymeric phosphates; and pharmaceutically acceptable organic or inorganic cationic salts thereof.
Unger, U.S. Pat. No. 5,088,499, describes the preparation of gas filled liposomes and their use as ultrasound contrast agents. These include materials which contain gases, gaseous precursors which can be activated by pH, temperature, or pressure and other solid and liquid contrast agents.
Quay, U.S. Pat. No. 5,558,094, describes the use of microbubbles comprised of specially selected gases. These gases included specific halocarbons which were alleged to have longer persistence in solution as free microbubbles and therefore could be useful as ultrasound contrast agents.
The contrast agents described above are proposed for general ultrasound contrast imaging of the vasculature and especially for heart imaging. In addition, the imaging of specific organs, systems, or other areas of the body would be useful for a variety of diagnosing specific disease states. Examples of this include the specific imaging or tumors, blood clots, and areas of infection in a directed manner.
Quay, et al., European Patent Application Number 96630007.1 ilustrates the use of compositions including a cell adhesion molecule (CAM) ligand which is incorporated into a desired molecule to form a conjugate. The CAM is incoporated in a surfactant or albumin carrier and also comprises a chemical with sufficiently high vapor pressure to be a gas at body temperature.
The present invention relates to targeted ultrasound contrast agents comprising inorganic porous particles useful for ultrasound imaging and a targeting ligand that directs the particles to a body organ or disease site. Such contrast agents may be an important adjunct in ultrasound diagnostic procedures, for example, for cardiovascular, oncologic, and gastrointestinal uses. The inorganic porous particles of the invention provide contrast for ultrasound imaging; i.e., the particles act to reflect ultrasound waves and thereby enhance the ultrasound signal when introduced into the organ system being imaged using ultrasound.
SUMMARY OF THE INVENTION
The present invention provides novel targeted ultrasound contrast agents, comprising: a pharmaceutically acceptable carrier and porous particles of an inorganic material having an average particle diameter of about 0.05 to 500 microns and containing entrapped gas or liquid, and containing, on the outside surface of the particle, a targeting ligand to target delivery of the contrast agent. The entrapped gas or liquid provides a suitable echogenic interface to enhance an ultrasound image.
The targeting ligand is attached to the porous inorganic particles by coating, adsorbing, layering, or reacting the outside surface of the particle with the targeting ligand. Representative targeting ligands include RGD-containing peptides, other compounds that bind to members of the integrin, selectin, and IgG receptor superfamilies as well as cell surface substances which cause white blood cells to move towards sites of infection/inflammation, i.e., fMLF and leukotriene receptors (LTA, B, C, D
4
).
The porous inorganic particles of the invention may be coated with a variety of organic polymeric and lipid materials to control the stability, pharmacokinetics, targeting, and biological effects of the particles in vivo.
The porous inorganic particles of the invention are administered parentally or nonparentally with a pharmaceutically acceptable carrier to a person, to thereby enhance the ultrasound image of a tissue or organ system of that person.
DETAILED DESCRIPTION OF THE INVENTION
[1] In a first embodiment, the present invention provides a novel targeted ultrasound contrast agent, comprising: a pharmaceutically acceptable carrier and a particle of the formula:
P—L—T
wherein;
P is a porous particle of an inorganic material having an average particle diameter of about 0.05 to 500 microns and containing an entrapped gas or liquid,
L is absent or is a linker, and
T is a targeting ligand.
Carpenter Jr. Alan P.
Cheesman Edward H.
Glajch Joseph L
Dolan Peter L.
DuPont Pharmaceuticals Company
Hartley Michael G.
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