Contrast agents

• US 20070003485A1
• Filed: 06/06/2006
• Published: 01/04/2007
• Est. Priority Date: 03/28/1991
• Status: Abandoned Application

• Current Assignee: Jo Klaveness, Pal Rongved, Per Strande
• Original Assignee: Jo Klaveness, Pal Rongved, Per Strande
• Inventors: Klaveness, Jo, Strande, Per, Rongved, Pal
• Application Number:
  US11/448,601
• Publication Number:
  US 20070003485A1
• Time in Patent Office: Days
• US Class Current: 424/9.520
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 49/225 Microparticles, microcapsules gas-filled to be classified in A61K49/223
• CPC Class Codes: C07C 69/96 Esters of carbonic or haloformic acids

Abstract

The invention relates to ultrasound contrast agents comprising vesicles comprising a protein capable of formation of gas-containing vesicles, wherein the vesicles contain gas which comprises sulphur hexafluoride or a low molecular weight fluorinated hydrocarbon. These contrast agents exhibit stability in vivo upon administration so as to permit ultrasound visualization while allowing rapid subsequent elimination from the system.

Claims

1. Contrast agents for use in diagnostic ultrasound studies comprising microbubbles of gas or a gas precursor encapsulated in a protein shell characterised in that the said protein is crosslinked with crosslinking groupings containing biodegradable linkages.

2. Contrast agents as claimed in claim 1 wherein the crosslinking groupings contain biodegradable linkages selected from amide, imide, imine, ester, anhydride, acetal, carbamate, carbonate, carbonate ester and disulphide groups.

3. Contrast agents as claimed in claim 2 wherein the crosslinking groups contain biodegradable linkages of formula

—

(Y)_n—

CO—

O—

C(R¹R²)—

O—

CO-(Z)_n-

(where Y and Z, which may be the same or different, are —

O—

, —

S—

or —

NR³ —

;

R¹ and R², which may be the same or different, are hydrogen atoms or carbon-attached monovalent organic groups or together represent a carbon-attached divalent organic group;

R³ is a hydrogen atom or an organic group; and

the symbols n, which may be the same or different, are zero or

     1).

4. Contrast agents as claimed in any of the preceding claims wherein the protein is albumin, gelatin or globulin.

5. Contrast agents as claimed in claim 4 wherein the protein is human serum albumin.

6. Contrast agents as claimed in any of the preceding claims further containing an inorganic particulate stabiliser.

7. A process for the preparation of a contrast agent as claimed in claim 1 which comprises encapsulating a gas or gas precursor in a protein and crosslinking the protein with crosslinking groups containing biodegradable linkages before, during or after said encapsulation.

8. A process as claimed in claim 7 wherein crosslinking is effected after encapsulation.

9. A process as claimed in claim 7 or claim 8 wherein crosslinking is effected using a crosslinking agent of formula (I)

A¹-X-A²  

 

(I)

(where X is a linking group containing one or more biodegradable linkages as defined in claim 2 or claim 3 and A¹ and A², which may be the same or different, are functional groups reactive with proteins).

10. A process as claimed in claim 9 in which A¹ and A² are both aldehyde groups.

11. A process as claimed in any of claims 8 to 10 wherein encapsulation is effected by agitation or sonication of the protein in an aqueous medium to yield a protein foam which is dried and thereafter suspended in a solution of the crosslinking agent in a polar organic solvent 12. A process as claimed in claim 11 in which the crosslinking agent is a compound of formula (I) as defined in claim 9 in which A¹ and A² are both O-linked sulphonated N-hydroxysuccinimidyl residues.