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(12) United States Patent (10) Patent No.: US 6,261,537 B1 Klaveness Et Al

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(12) United States Patent (10) Patent No.: US 6,261,537 B1 Klaveness Et Al USOO626.1537B1 (12) United States Patent (10) Patent No.: US 6,261,537 B1 Klaveness et al. (45) Date of Patent: *Jul.17, 2001 (54) DIAGNOSTIC/THERAPEUTICAGENTS 5,632,983 5/1997 Tait et al.. HAVING MICROBUBBLES COUPLED TO 5,643,553 * 7/1997 Schneider et al. .................. 424/9.52 ONE OR MORE VECTORS 5,650,156 7/1997 Grinstaff et al. ..................... 424/400 5,656.211 * 8/1997 Unger et al. .......................... 264/4.1 5,665,383 9/1997 Grinstaff et al. (75) Inventors: Jo Klaveness; Pál Rongved; Anders 5,690,907 11/1997 Lanza et al. .......................... 424/9.5 Høgset; Helge Tolleshaug, Anne 5,716,594 2/1998 Elmaleh et al. Naevestad; Halldis Hellebust; Lars 5,733,572 3/1998 Unger et al.. Hoff, Alan Cuthbertson; Dagfinn 5,780,010 7/1998 Lanza et al. Levhaug, Magne Solbakken, all of 5,846,517 12/1998 Unger. Oslo (NO) 5,849,727 12/1998 Porter et al.. 5,910,300 6/1999 Tournier et al. .................... 424/9.34 (73) Assignee: Nycomed Imaging AS, Oslo (NO) FOREIGN PATENT DOCUMENTS (*) Notice: This patent issued on a continued pros ecution application filed under 37 CFR 2 145 505 4/1994 (CA). 19 626 530 1/1998 (DE). 1.53(d), and is subject to the twenty year 0 727 225 8/1996 (EP). patent term provisions of 35 U.S.C. WO91/15244 10/1991 (WO). 154(a)(2). WO 93/20802 10/1993 (WO). WO 94/07539 4/1994 (WO). Subject to any disclaimer, the term of this WO 94/28873 12/1994 (WO). patent is extended or adjusted under 35 WO 94/28874 12/1994 (WO). U.S.C. 154(b) by 0 days. WO95/03356 2/1995 (WO). WO95/03357 2/1995 (WO). (21) Appl. No.: 08/960,054 WO95/07072 3/1995 (WO). WO95/15118 6/1995 (WO). (22) Filed: Oct. 29, 1997 WO 96/39149 12/1996 (WO). WO 96/40277 12/1996 (WO). Related U.S. Application Data WO 96/40285 12/1996 (WO). WO 96/41617 12/1996 (WO). (63) Continuation-in-part of application No. 08/958.993, filed on WO 97/23855 7/1997 (WO). Oct. 28, 1997. (60) Provisional application No. 60/049.264, filed on Jun. 7, WO 97/33474 9/1997 (WO). 1997, provisional application No. 60/049,265, filed on Jun. WO 97/41898 11/1997 (WO). 7, 1997, and provisional application No. 60/049.268, filed WO 98/OO172 1/1998 (WO). on Jun. 7, 1997. WO 98/04293 2/1998 (WO). WO 98/19705 5/1998 (WO). (30) Foreign Application Priority Data WO 98/20856 5/1998 (WO). Oct. 28, 1996 (GB) .................................................. 9622366 WO 98/42384 10/1998 (WO). Oct. 28, 1996 (GB) ... ... 9622367 OTHER PUBLICATIONS Oct. 28, 1996 (GB) ... ... 9622368 Jan. 15, 1997 (GB) ... ... 97OO699 Worthington Enzyme Manual, enzymes, enzyme reagents, Apr. 24, 1997 (GB) .................................................. 9708265 Jun. 6, 1997 (GB) .................................................. 9711842 related biochemicals; Worthington Biochemical Corpora Jun. 6, 1997 (GB) .................................................. 9711846 tion, 1972. Thomas Fritzsch, et al., “Microparticle Prepartions Made (51) Int. Cl." ............................. A61B 8/00; A61 B 5/055; From Biodegradable Copolymers”, Apr. 1999. A61K 51/00; A61K 49/04; A61K 9/14 U.S. application No. 08/640,464, Unger, filed May 1, 1996. Muzykantov et al., J. Nuclear Medicine, 35(8): 1358–1365 (52) U.S. Cl. ......................... 424/9.52; 424/9.32; 424/9.4; (1994). 424/1.29; 424/9.6; 424/489 Klibanov et al., Acta Radiologica, 38(Supp. 412): 113-120 (58) Field of Search .................................. 424/9.52, 9.51, (1997). 424/489, 490, 498, 502, 450, 9.3, 9.32, * cited by examiner 9.4, 1.29, 9.6; 264/4, 4.1, 5; 427/213, 213.3, 213.36; 428/402, 402.21; 530/300, 326, Primary Examiner Michael G. Hartley 328; 600/458, 441 (74) Attorney, Agent, or Firm-Bacon & Thomas; Richard (56) References Cited E. Fichter U.S. PATENT DOCUMENTS (57) ABSTRACT 4,927,916 5/1990 Matsueda et al. Targetable diagnostic and/or therapeutically active agents, 5,013,556 5/1991 Woodle et al. e.g. ultrasound contrast agents, having reporters comprising 5,154,924 10/1992 Friden. gas-filled microbubbles stabilised by monolayers of film 5,198.424 3/1993 McEver. forming Surfactants, the reporter being coupled or linked to 5,356,633 10/1994 Woodle et al.. at least one vector. 5,505,932 4/1996 Grinstaff et al. 5,534.241 7/1996 Torchillin et al. 5,612,057 3/1997 Lanza et al. 22 Claims, 2 Drawing Sheets U.S. Patent Jul. 17, 2001 Sheet 1 of 2 US 6,261,537 B1 256 Gm: 15.62 CW. 3439 144-1023) 18430 (92.2/) U.S. Patent Jul. 17, 2001 Sheet 2 of 2 US 6,261,537 B1 18880 (94.4/) FIT Clog F. G. 2. US 6,261,537 B1 1 2 DIAGNOSTIC/THERAPEUTICAGENTS chosen target, or it may bind only Selectively, having affinty HAVING MICROBUBBLES COUPLED TO also for a limited number of other molecules/structures, ONE OR MORE VECTORS again creating possible background problems. There is a limited body of prior art relating to targeted Applicants hereby claim benefit under 35 U.S.C. S119(e) 5 ultrasound contrast agents. Thus, for example, US-A- of provisional application No. 60/049,264 filed Jun. 7, 1997, 553 1980 is directed to systems in which the reporter com provisional application No. 60/049,265 filed Jun. 7, 1997 prises an aqueous Suspension of air or gas microbubbles and provisional application No. 60/049,268 also filed Jun. 7, Stabilised by one or more film-forming Surfactants present at 1997 and is a continuation-in-part of application Ser. No. least partially in lamellar or laminar form, said Surfactant(s) 08/958,993, filed Oct. 28, 1997, pending. being bound to one or more vectors comprising “bioactive This invention relates to diagnostic and/or therapeuti Species designed for Specific targeting purposes'. It is Stated cally active agents, more particularly to diagnostic and/or that the microbubbles are not directly encapsulated by therapeutically active agents incorporating moieties which Surfactant material but rather that this is incorporated in interact with or have affinity for sites and/or structures liquid-filled liposomes which stabilise the microbubbles. It within the body So that diagnostic imaging and/or therapy of 15 will be appreciated that lamellar or laminar Surfactant mate particular locations within the body may be enhanced. Of rial Such as phospholipids present in Such liposomes will particular interest are diagnostic agents for use in ultrasound inevitably be present in the form of one or more lipid imaging, which are hereinafter referred to as targeted ultra bilayers with the lipophilic tails “back-to-back” and the Sound contrast agents. hydrophilic heads both inside and outside (see e.g. It is well known that ultrasound imaging comprises a Schneider, M. on "Liposomes as drug carriers: 10 years of potentially valuable diagnostic tool, for example in Studies research” in Drug targeting, Nyon, Switzerland, Oct. 3-5, of the vascular System, particularly in cardiography, and of 1984, Buri, P. and Gumma, A. (Ed), Elsevier, Amsterdam tissue microvasculature. A variety of contrast agents has 1984). been proposed to enhance the acoustic images So obtained, EP-A-0727225 describes targeted ultrasound contrast including Suspensions of Solid particles, emulsified liquid 25 agents in which the reporter comprises a chemical having a droplets, gas bubbles and encapsulated gases or liquids. It is Sufficient vapour pressure Such that a proportion of it is a gas generally accepted that low density contrast agents which at the body temperature of the subject. This chemical is are easily compressible are particularly efficient in terms of asSociated with a Surfactant or albumin carrier which the acoustic backScatter they generate, and considerable includes a protein-, peptide- or carbohydrate-based cell interest has therefore been shown in the preparation of adhesion molecule ligand as vector. The reporter moieties in gas-containing and gas-generating Systems. Such contrast agents correspond to the phase shift colloid Gas-containing contrast media are also known to be systems described in WO-A-9416739; it is now recognised effective in magnetic resonance (MR) imaging, e.g. as that administration of Such phase shift colloids may lead to susceptibility contrast agents which will act to reduce MR generation of microbubbles which grow uncontrollably, Signal intensity. Oxygen-containing contrast media also rep 35 possibly to the extent where they cause potentially danger resent potentially useful paramagnetic MR contrast agents. ouS embolisation of, for example, the myocardial vascula Furthermore, in the field of X-ray imaging it has been ture and brain (see e.g. Schwarz, Advances in Echo-Contrast observed that gases Such as carbon dioxide may be used as 1994(3)], pp. 48–49). negative oral contrast agents or intravascular contrast WO-A-9320802 proposes that tissue-specific ultrasonic agents. 40 image enhancement may be achieved using acoustically The use of radioactive gases, e.g. radioactive isotopes of reflective oligolamellar liposomes conjugated to tissue inert gases Such as Xenon, has also been proposed in Specific ligands Such as antibodies, peptides, lectins etc. The Scintigraphy, for example for blood pool imaging. liposomes are deliberately chosen to be devoid of gas and So Targeted ultrasound contrast agents may be regarded as will not have the advantageous echogenic properties of comprising (i) a reporter moiety capable of interacting with 45 gas-based ultrasound contrast agents. Further references to ultrasound irradiation to generate a detectable signal; (ii) one this technology, e.g. in targeting to fibrin, thrombi and or more vectors having affinity for particular target Sites atherosclerotic areas are found in publications by and/or structures within the body, e.g.
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