Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Patent
1993-03-15
1996-05-21
Lovering, Richard D.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
106124, 106125, 12866001, 12866002, 12866005, 12866104, 12866202, 252314, 2523635, A61K 4900, A61B 800, A61B 802
Patent
active
055187099
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the preparation of diagnostic agents comprising hollow proteinaceous microcapsules used to enhance ultrasound imaging.
The fact that air bubbles in the body can be used for echocardiography has been known for some time. Bubble-containing liquids can be injected into the bloodstream for this purpose (see Ophir et al (1980) "Ultrasonic Imaging" 2, 67-77, who stabilised bubbles in a collagen membrane, U.S. Pat. No. 4,446,442 (Schering) and EP-A-131 540 (Schering)) and EP-A-224934 and EP-A-324938 disclose the use of bubbles prepared by sonicating an albumin solution. However, the size distribution of the bubbles is apparently uncontrollable and the bubbles disappear when subjected to pressure experienced in the left ventricle (Shapiro et al (1990) J. Am. Coll. Cardiology, 16(7), 1603-1607).
EP-A-52575 discloses, for the same purpose, solid particles which have gas entrained in them, the gas being released from the particles in the bloodstream.
EP 458 745 (Sintetica) discloses a process of preparing air- or gas-filled microballoons by interfacial polymerisation of synthetic polymers such as polylactides and polyglycolides. WO 91/12823 (Delta) discloses a similar process using albumin. Wheatley et al (1990) Biomaterials 11, 713-717 discloses ionotropic gelation of alginate to form microbubbles of over 30 .mu.m diameter. WO 91/09629 discloses liposomes for use as ultrasound contrast agents.
We have now found that a process of atomising a solution of microcapsule-forming agent and then insolubilising the microcapsules which are formed leads to an improved product. Przyborowski et al (1982 Eur. J. Nucl. Med. 7, 71-72) disclosed the preparation of human serum albumin (HSA) microspheres by spray-drying for radiolabelling and subsequent use in scintigraphic imaging of the lung. The microspheres were not said to be hollow and, in our repetition of the work, only solid microspheres are produced. Unless the particles are hollow, they are unsuitable for echocardiography. Furthermore, the microspheres were prepared in a one step process which we have found to be unsuitable for preparing microcapsules suitable for echocardiography; it was necessary in the prior process to remove undenatured albumin from the microspheres (which is not necessary in our process); and a wide size range of microspheres was apparently obtained, as a further sieving step was necessary. Hence, not only was the Przyborowski et al process not an obvious one to choose for the preparation of microcapsules useful in ultrasonic imaging but the particles produced were unsuitable for that purpose. We have devised a considerable improvement over that prior process. The Przyborowski et al article refers to two earlier disclosures of methods of obtaining albumin particles for lung scintigraphy. Aldrich & Johnston (1974) Int. J. Appl. Rad. Isot. 25, 15-18 disclosed the use of a spinning disc to generate 3-70 .mu.m diameter particles which are then denatured in hot oil. The oil is removed and the particles labelled with radioisotopes. Raju et al (1978) Isotopenpraxis 14(2), 57-61 used the same spinning disc technique but denatured the albumin by simply heating the particles. In neither case were hollow microcapsules mentioned and the particles prepared were not suitable for echocardiography.
One aspect of the present invention provides a process comprising a first step of atomising a solution or dispersion of a wall-forming material in order to obtain microcapsules.
Preferably, the product obtained thereby is subjected to a second step of reducing the water-solubility of at least the outside of the said microcapsules.
The said two steps may be carried out as a single process or the intermediate product of the first step may be collected and separately treated in the second step. These two possibilities are referred to hereinafter as the one step and two step processes.
The wall-forming material and process conditions should be so chosen that the product is sufficiently non-toxic and non-immunogenic in the conditions of use, whic
REFERENCES:
patent: 2797201 (1957-06-01), Veatch et al.
patent: 3501419 (1970-11-01), Bridgeford
patent: 3937668 (1976-02-01), Zolle
patent: 4089800 (1978-05-01), Temple
patent: 4107288 (1978-08-01), Oppenheim et al.
patent: 4127622 (1978-11-01), Watanabe et al.
patent: 4147767 (1979-04-01), Yapel, Jr.
patent: 4247406 (1981-01-01), Widder et al.
patent: 4276885 (1981-07-01), Tickner et al.
patent: 4316391 (1982-04-01), Tickner
patent: 4349530 (1982-09-01), Royer
patent: 4357259 (1982-11-01), Senyei et al.
patent: 4420442 (1983-12-01), Sands
patent: 4466442 (1984-01-01), Hilmann et al.
patent: 4774958 (1988-10-01), Feinstein
patent: 4957656 (1990-06-01), Cerny et al.
patent: 4960351 (1990-03-01), Kendall, Jr. et al.
patent: 4981625 (1991-02-01), Rhim et al.
patent: 5137928 (1992-08-01), Erbel et al.
patent: 5190982 (1993-03-01), Erbel et al.
patent: 5205287 (1993-04-01), Erbel et al.
Rettenmaier et al. J. Clin Lab Immunol vol. 17, pp. 99-103 (1985).
Ellison Ann Occup Hyg vol. 10, pp. 363-367 (1967).
Gupta & Hung J. Microencap vol. 6, pp. 427-462 (1989).
Galyean et al, J. Food Sci. vol. 44 pp. 1345-1349 (1979).
Parkinson, J. Sci Fd Agric. vol. 26, pp. 1625-1637 (1975).
Modler et al. J. Dairy Sci vol. 61 pp. 249-299 (1979).
Raju et al. Isopenpraxis, vol. 14, pp. 57-61 (1978).
Buchanan et al. J. Nucl. Med., vol. 10, pp. 487-490 (1969).
Scheffel et al. J. Nucl. Med., vol. 13, pp. 498-503 (1972).
Kramer J. Phar Sci, vol. 63 pp. 1646-1647 (1974).
Schroeder et al J. Pharm Sci, vol. 67, pp. 504-507 (1977).
Widder et al Adv Pharm Chemotherap vol. 16, pp. 213-269 (1979).
Takenaka et al. Chem Pharm Bull vol. 30, pp. 2189-2195.
Wheatly et al Biomaterials, vol. 11, pp. 713-717, 1990.
Kawashima et al. J. Controlled Release, vol. 16, 279-290 (1991).
Aldrich et al. Int. J. App. Rad. & Isotop, vol. 25, pp. 15-18 (1974).
Ophir et al Ultrasonic Imaging vol. 2 pp. 67-77 (1980).
Przyborowski et al. J. Nucl. Med., vol. 7, pp. 71-72 (1982).
Shapiro et al, JACC, vol. 16, No. 7, pp. 1603-1607, 1990.
Feinstein et al, JACC, vol. 4, No. 3, pp. 595-600, 1984.
Schneider et al. Invest. Radiol., vol. 27, pp. 134-139, 1992.
Ophir et al. Ultrasonic Imaging vol. 1, pp. 256-279, 1979.
Sato et al. Pharm Res vol. 5, pp. 21-30, 1988.
Heath David
Johnson Richard A.
Senior Peter J.
Sutton Andrew D.
Andaris Limited
Lovering Richard D.
LandOfFree
Preparation of diagnostic agents does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Preparation of diagnostic agents, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Preparation of diagnostic agents will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2035922