Site News  |   Monitor Keywords  |   Monitor Archive  |   Organizer  |   Account Info  |

Microparticles useful as ultrasonic contrast agents and for delivery of drugs into the bloodstream

Microparticles useful as ultrasonic contrast agents and for delivery of drugs into the bloodstream description/claims

This application is a continuation of U.S. application Ser. No. 09/758,988 filed Jan. 11, 2001, currently pending, which is a divisional of U.S. application Ser. No. 09/070,474 filed Apr. 30, 1998, now U.S. Pat. No. 6,193,951, which is a continuation-in-part of U.S. application Ser. No. 08/847,153 filed Apr. 30, 1997, now abandoned, the contents of which are incorporated herein by reference.

Hollow microparticles, sometimes called microbubbles or microspheres, are efficient for back scattering ultrasound energy. Thus, small microbubbles injected into the bloodstream, can enhance ultrasonic echographic imaging to aid the visualization of internal structures, such as the heart and blood vessels. The ultrasound contrast is achieved when acoustic impedance between two materials at an interface is different. Thus, the greater the difference of acoustic impedance between the materials, the greater the intensity of an ultrasound echo from that interface. Since there is a large difference between the acoustic impedance between body tissue and gas, gas containing microparticles circulating within tissue or blood are strong back scatterers of the ultrasound energy. For use in the circulatory system, microparticles should have a diameter of less than about ten microns in order to pass through the capillaries of the circulatory system. The lower limit of sufficient echogenicity of a microparticle is about one to two microns.

In cardiology, microparticles are useful for intravenous injection, thereby providing ultrasound contrast in the right chambers of the heart, enhancing identification of cardiac structures, valve functions and detection of intracardiac shunts. However in order to visualize the left chambers of the heart, the microparticles must first pass through the pulmonary circulation system. Such particles must be small enough to pass through the pulmonary capillaries. Otherwise they are trapped within the lungs. They must also have sufficient structural strength to survive the pressures within the left chambers of the heart.

Microparticles also permit the definition of volumes, wall motion, and other factors that identify diseased states within the heart. The use of contrast agents also facilitates use of Doppler ultrasound techniques because strong echo sources moving in the bloodstream are far more echogenic than red blood cells, which are the usual echo sources used in Doppler ultrasound techniques. Contrast agents in blood may also be used to locate the presence of blood in areas of the body or identify the absence of blood by the lack of echogenicity in areas that should be echogenic. Examples of such uses are the use of microparticles for assessment of perfusion to the myocardium, and for assessment of defects in the coronary septum by the flow of particles through the septum separating the cardiac chambers. Another example is the use of microparticles to identify vascular emboli such as blood clots, and abnormal growths into the vascular chambers by the absence of the ultrasonic contrast.

Other uses of contrast agents are to examine organ perfusion, such as to assess the damage caused by an infarct, to examine organs such as the liver, or to differentiate between normal and abnormal tissues, such as tumors and cysts.

The present invention provides microparticle contrast agents which are delivered intravenously but are capable of passing through the pulmonary circulation system for enhanced examination and diagnosis of both sides of the heart as well as examination of other tissues and organs as described above.

In addition to diagnostic imaging, the microparticles according to the present invention are also used for drug delivery where the drug is released from the particle by diffusion from the microparticle, by degradation of the microparticle, or by rupture of the particle using ultrasonic energy.

The present invention provides compositions of microparticles of which the majority of the microparticles have diameters within the range of about one to ten microns, have an outer layer comprising a biologically compatible material and an inner layer comprising a biodegradable polymer. The microparticles may have a hollow core, containing either a gas or a liquid, or a solid core.

The outer layer may be chosen on the basis of biocompatibility with the blood stream and tissues, whereas the inner layer may be selected on the basis desired mechanical and acoustic properties. The materials of both layers may be selected to predetermine the strength of the microparticle, for example to provide a desired resonant frequency and stability within threshold diagnostic imaging levels of ultrasound radiation. Methods for forming the multi-layered microparticles and the use in ultrasonic diagnostic imaging and drug delivery are also provided. The layers may also be chosen by their capability to contain and deliver drugs.

FIG. 1 is a graph of the time course of the reflected ultrasound intensity in the left atrium in a test of a contrast agent according to example 7.

FIG. 2 is a graph of the time course of the reflected ultrasound intensity in the left atrium of the contrast agent tested in accordance with example 8.

FIG. 3 is a graph of the volumetric size distribution of the unfiltered microcapsules made in example 13, and the size distribution of when the suspension is filtered.

FIG. 4 shows the resonant frequencies of two microcapsule preparations having different wall compositions which were tested in accordance with example 18.

• Provisional Patent
• Utility Patent

• What Is a Patent?
• What Is a Trademark or Servicemark?
• What Is a Copyright?
• Patent Laws