Use of biodegradable microspheres labeled with imaging energy constrast materials

• US 5,186,922 A
• Filed: 01/08/1990
• Issued: 02/16/1993
• Est. Priority Date: 03/15/1985
• Status: Expired due to Fees

• Current Assignee: David Summers, Endovasc Ltd., Inc.
• Original Assignee: See/Shell Biotechnology Incorporated
• Inventors: Shell, William E., See, Jackie R.
• Primary Examiner(s): Yasko, John D.
• Assistant Examiner(s): Polutta, Mark O.
• Application Number:
  US07/462,740
• Time in Patent Office: 1,135 Days
• Field of Search: 128/653 CA, 128/645, 660/1, 660/3, 660/9, 604/20, 424/1.1, 424/4, 424/9, 424/489, 424/5, 424/490, 514/5
• US Class Current: 424/9.4
• CPC Class Codes: A61K 49/0419 Microparticles, microbeads, microcapsules, microspheres, i.e. having a size or diameter higher or equal to 1 micrometer
• CPC Class Codes: A61K 9/1658 Proteins, e.g. albumin, gelatin

Abstract

The invention relates to an inexpensive and easy to use method of visualizing an arterial circulation, using biodegradable microspheres which are permeated with an imaging energy absorbent contrast material, such as an X-ray absorbent material, which enables the diagnosis of pulmonary embolism. The microspheres may be comprised of a variety of materials, including human albumin, and may be dyed with a number of X-ray absorbent materials, or other imaging energy absorbent materials. The microspheres are injected into the bloodstream at a particular location such that they travel through the desired circulation, e.g. an arterial circulation and ultimately become lodged in the capillaries of a tissue of interest. Upon exposure of the arterial circulation to X-rays, blood vessels therein containing the microspheres will absorb the X-rays, causing them to show on a developed X-ray film in contrast to other blood vessels and body tissue which do not contain the microspheres that transmit the X-rays. The microspheres are designed to dissolve into the bloodstream within fifteen to thirty minutes after their introduction, the X-ray dye or other contrast material being ultimately excreted from the body via the urine or metabolized by the liver.

Claims

1. A non-toxic method of visualizing circulation in the bloodstream of a subject comprising the steps of:

a) selecting a quantity of contrast agent laden microspheres which will enable generation of an image and for a desired duration when injected into the bloodstream of a subject and which microspheres are laden with a non-toxic amount of a non-metallic imaging energy responsive material but which is nevertheless sufficient to enable imaging when subjected to an imaging energy;

b) injecting the selected quantity of non-metallic biodegradable imaging energy responsive microspheres into the bloodstream of the subject at a point in the subject'"'"'s circulatory system such that said microspheres are carried to a bloodstream circulation area sought to be visualized, said microspheres being sold and having the contrast agent inculcated throughout the microspheres, said microspheres also having a size with respect to the bloodstream circulatory system which is to be imaged such that the microspheres will lodge within the bloodstream circulatory system, and said microspheres further being sufficiently cross-linked so that they will not readily dissolve in the bloodstream in a short time and which will thereby remain in that circulatory system for a time sufficient to be subjected to imaging;

c) subjecting said bloodstream circulation area to electromagnetic wavelength imaging energy of a type which is absorbed by said microspheres to form an image of said bloodstream circulation area without resulting in toxicity to the subject; and

d) examining said image for the presence of said microspheres, which will enable visualization of said circulation area by response of said microspheres to the imaging energy, and thereafter enabling said microspheres to be absorbed in the bloodstream without resulting in toxicity to the subject.

2. A method as set forth in claim 1 wherein said imaging energy responsive material is absorptive of the imaging energy.

3. A method as set forth in claim 1 wherein said bloodstream circulation is an arterial circulation.

4. A method as set forth in claim 1 wherein said microspheres are comprised of human albumin.

5. A method as set forth in claim 1 wherein said microspheres are X-ray absorbent by virtue of their being laden with an X-ray opaque material.

6. A method as set forth in claim 1 wherein said microspheres are X-ray absorbent by virtue of their being laden with potassium iodide.

7. A method as set forth in claim 1 wherein said microspheres are X-ray absorbent by virtue of being laden with hypaque-sodium.

8. A method as set forth in claim 1 wherein said microspheres have a size on the order of about 9 u to about 100 u in diameter and are thereby sized to become lodged in capillaries and arteries of the bloodstream circulatory system.

9. A method as set forth in claim 1 wherein said microspheres have a size on the order of about 10 u to about 50 u in diameter and are thereby sized to become lodged in capillaries and arteries of the bloodstream circulatory system.

10. A method as set forth in claim 1 wherein said arterial circulation is a pulmonary circulation.

11. A method as set forth in claim 1 wherein said biodegradable microspheres are dissolved in said bloodstream within about 15 to about 30 minutes after introduction into said bloodstream and which time is sufficient to obtain an imaging of a portion of the bloodstream circulatory system.

12. A non-toxic method of diagnosing pulmonary embolism in the bloodstream of a subject comprising the steps of:

a) selecting a quantity of non-metallic microspheres and which are laden with a non-toxic amount of a non-metallic imaging energy absorbent material but with an amount which is nevertheless sufficient to enable imaging when subjected to imaging energy, and which will thereby enable generation of an image and for a desired duration when injected into the bloodstream of a subject;

b) injecting the imaging energy absorbent non-metallic microspheres into the bloodstream of said subject at a point in the circulatory system such that said microspheres will be carried to the pulmonary circulation, and having the imaging energy material inculcated throughout the microspheres, said microspheres also having a size with respect to the pulmonary circulation such that the microspheres will become lodged in the pulmonary circulation, and said microspheres further being sufficiently cross-linked so that they will not readily dissolve in the bloodstream in a short time and which will thereby remain in the pulmonary circulation of the subject for a time sufficient to be subjected to imaging;

c) subjecting said pulmonary circulation to imaging energy of a type which is absorbed by said microspheres to form an image of said pulmonary circulation without resulting in toxicity to the subject;

d) conducting an examination of said image for the presence of said microspheres and thereafter enabling said microspheres to be absorbed in the bloodstream of the subject;

without resulting in toxicity to the subject and

e) determining from said examination whether a pulmonary embolism is present.

13. A method as set forth in claim 12 wherein said pulmonary circulation is a pulmonary arterial circulation.

14. A method as set forth in claim 13 wherein said imaging energy is X-ray energy.

15. A method as set forth in claim 14 wherein said microspheres are comprised of human albumin.

16. A method as set forth in claim 15 wherein said microspheres are X-ray opaque by virtue of their being laden with hypaque-sodium.

17. A method as set forth in claim 15 wherein said microspheres are X-ray opaque by virtue of their being dyed with potassium iodide.

18. A method as set forth in claim 13 wherein said microspheres have a size on the order of about 9 u to about 100 u in diameter and are thereby sized to become lodged in arteries and capillaries of the pulmonary circulation.

19. A method as set forth in claim 13 wherein said microspheres have a size on the order of about 10 u to about 50 u in diameter and are thereby sized to become lodged in arteries and capillaries of the pulmonary circulation.

20. A method as set forth in claim 13 wherein said biodegradable microspheres dissolve in said bloodstream within about 15 minutes to about 30 minutes after introduction into said bloodstream and which time is sufficient to obtain an imaging of a portion of the pulmonary circulation.

21. A non-toxic method of visualizing an arterial circulation in the bloodstream of a subject comprising the steps of:

a) selecting a quantity of non-metallic microspheres and which are laden with a non-toxic amount of non-metallic X-ray absorbent material but with an amount which is nevertheless sufficient to enable imaging when subjected to X-ray energy, and which will enable generation of an X-ray image and for a desired duration when injected into the bloodstream of a subject;

b) injecting biodegradable X-ray absorbent microspheres into the bloodstream of the subject at a point in the subject'"'"'s circulatory system such that said microspheres are carried in the bloodstream to a bloodstream circulation area sought to be visualized, said microspheres being solid and having the X-ray absorbent material inculcated throughout the microspheres, said microspheres also having a size with respect to the bloodstream circulatory system which is to be visualized such that the microspheres will lodge within the bloodstream circulatory system, and said microspheres further being sufficiently cross-linked so that they will not readily dissolve in the bloodstream in a short time and which will thereby remain in the circulatory system for a time sufficient to be subjected to X-ray imaging;

c) subjecting said circulation area to X-rays to form an X-ray image of said circulation area ans causing the microspheres to absorb the X-rays to render them X-ray opaque for contrast against surrounding or adjacent tissue without resulting in toxicity to the subject;

d) examining said X-ray image for the presence of white areas on an X-ray film to represent the presence of said microspheres, which will enable visualization of said circulation by means of the absorption of X-rays by said microspheres; and

e) thereafter permitting the microspheres to become degraded in the body after a period of time for visualization which is sufficient to enable X-ray imaging but which is not sufficiently long to create damage to the tissue in which the visualization of the circulation is taking place and which will not result in toxicity to the individual.