Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Reexamination Certificate
2000-06-26
2003-05-13
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
C424S009500, C424S009510
Reexamination Certificate
active
06562320
ABSTRACT:
This invention relates to thermally stabilized freeze-dried vesicle containing ultrasound contrast agents and a process for their preparation.
Vesicles (the term is used herein to denote unilamellar and multilamellar structures, eg. structures referred to variously as liposomes, micelles, microbubbles and micro-balloons) are frequently used as a means for delivering therapeutically or diagnostically active agents. In the field of ultrasound imaging contrast media, vesicles containing materials (herein referred to as vesicular materials) which are gaseous at body temperatures may be used as echogenic contrast agents, particularly for administration into the vasculature.
Vesicular contrast media will generally be administered in the form of an aqueous dispersion containing a low concentration of the vesicles relative to the aqueous carrier medium. Accordingly storage and transportation of such vesicular contrast agents is made significantly more efficient if the vesicles can be stored in a dried form.
Freeze-drying of vesicular compositions is possible and, for this, formulation excipients are generally included in the composition to aid the drying technique. Such excipients generally serve one of two functions. Bulking agents are added to increase the total solids content in order to achieve a mechanically more robust product. Stabilizers, otherwise referred to as cryoprotectants or lyoprotectants, are added to aid the formation of the glassy state produced during dehydration and to provide physical strength in the dried product. Examples of stabilizers used in this way include mannitol and glucose.
Freeze-dried vesicular ultrasound contrast agents while providing advantages for transport and storage due to the reduction in bulk relative to the aqueous ready-to-use dispersions, also provide problems since the freeze-dried product is not thermally stable in the range of ambient temperatures normally encountered during transportation and storage and as a result must be maintained, prior to secondary production, in an environment in which the temperature is maintained below ambient (eg. at 5 to 10° C.).
It has now surprisingly been found that by appropriate choice of the stabilizer used for freeze-drying it is possible to produce freeze-dried vesicular ultrasound contrast agents which are thermally stable at ambient temperatures and above, and indeed at all temperatures normally encountered during transportation and storage.
The thermally stable freeze-dried product may then be stored and transported without need of temperature control of its environment and in particular may be supplied to hospitals and physicians for on site formulation into an administrable dispersion without requiring such users to have special storage facilities.
Thus viewed from one aspect the invention provides a freeze-dried vesicle containing ultrasound contrast agent containing a freeze-drying stabilizer and thermally stable at temperatures in excess of 20° C., preferably at least 22° C., especially 22° C., at least 25° C., more preferably at least 30° C. and especially preferably at least 40° C., eg. up to 65° C. or higher. Alternatively viewed the invention provides a freeze-dried vesicle containing ultrasound contrast agent containing a freeze-drying stabilizer and having a glass transition temperature (Tg) above 20° C., preferably 22° C., especially preferably at least 25° C., more preferably at least 30° C. and especially preferably at least 40° C., eg. up to 65° C. or higher.
Viewed from a further aspect the invention provides a process for the preparation of a thermally stable freeze-dried vesicle containing ultrasound contrast agent, which process comprises freeze-drying an aqueous dispersion comprising a vesicular ultrasound contrast agent and a freeze-drying stabilizer or mixture of stabilizers, characterised in that said stabilizer or mixture of stabilizers has a Tg value of at least 20° C. (preferably at least 22° C., especially at least 25° C., more preferably at least 30° C. and especially preferably at least 40° C., eg. up to 65° C. or higher) and a Tg′ value of −37° C. or above (preferably above −36° C., especially preferably above −35° C., eg. −10 to −37° C.).
Viewed from a still further aspect the invention provides an ultrasound contrast medium comprising an aqueous carrier medium, a freeze-drying stabilizer or mixture of stabilizers and an echogenic vesicular ultrasound contrast agent, characterised in that said stabilizer or mixture of stabilizers has a Tg value of at least 20° C., (preferably at least 22° C., especially at least 25° C., more preferably at least 30° C. and especially preferably at least 40° C., eg. up to 65° C. or higher) and a Tg′ value of −37° C. or above (preferably above −36° C., especially preferably above −35° C., eg. −10 to −37° C.).
Viewed from a yet still further aspect the invention provides the use of a freeze-drying stabilizer or mixture of stabilizers having a Tg value of at least 20° C., (preferably at least 22° C., especially at least 25° C., more preferably at least 30° C. and especially preferably at least 40° C., eg. up to 65° C. or higher) and a Tg′ value of −370° C. or above (preferably above −36° C., especially preferably above −35° C., eg. −10 to −37° C.) for the manufacture of a vesicle containing ultrasound contrast medium for use in diagnosis involving diagnostic ultrasound imaging.
Viewed from a further aspect the invention provides a process for the storage or transportation of a vesicular ultrasound contrast agent, characterized in that said agent is in freeze-dried form, contains a freeze-drying stabilizer and has a glass transition temperature (Tg) of at least 20° C. (preferably at leat 22° C., etc.), and in that storage and transportation takes place without cooling.
Viewed from a still further aspect the invention provides a process for the preparation of a vesicle containing ultrasound contrast medium, said process comprising dispersing a freeze-dried contrast agent according to the invention in physiologically tolerable aqueous dispersion medium.
For any material, Tg is the glass transition temperature of the dried material while Tg′ is the glass transition temperature of the maximally freeze-concentrated pure aqueous solution of the material.
Besides the improved thermal stability, the freeze-dried vesicular contrast agents according to the invention also surprisingly enhance the ability of the vesicles to retain the halocarbon gases and gas precursors commonly used in ultrasound contrast agents.
In the invention, the ultrasound contrast agent may be any physiologically tolerable echogenic vesicular agent, preferably however the vesicles will contain a gas or gas precursor (eg. a compound or compound mixture which is substantially in gaseous (including vapour) form at normal human body temperatures (37° C.)). Any biocompatible gas, gas precursor or mixture may be employed. The gas may thus, for example, comprise air; nitrogen; oxygen; carbon dioxide; hydrogen; nitrous oxide; an inert gas such as helium, argon, xenon or krypton; a sulphur fluoride such as sulphur hexafluoride, disulphur decafluoride or trifluoromethylsulphur pentafluoride; selenium hexafluoride; an optionally halogenated silane such as tetramethylsilane; a low molecular weight hydrocarbon (e.g. containing up to 7 carbon atoms), for example an alkane such as methane, ethane, a propane, a butane or a pentane, a cycloalkane such as cyclobutane or cyclopentane, an alkene such as propene or a butene, or an alkyne such as acetylene; an ether; a ketone; an ester; a halogenated low molecular weight hydrocarbon (e.g. containing up to 7 carbon atoms); or a mixture of any of the foregoing. At least some of the halogen atoms in halogenated gases advantageously are fluorine atoms. Thus biocompatible halogenated hydrocarbon gases may, for example, be selected from bromochlorodifluoro-methane, chlorodifluoromethane, dichlorodifluoromethane, bromotrifluoromethane, chlor
Braenden Jorunn Undheim
Fahlvik Anne Kjersti
Gulliksen Per Helge
Swaerd-Nordmo Marit
Amersham Health AS
Chisholm Robert F.
Hartley Michael G.
Ronning, Jr. Royal N.
Ryan Stephen G.
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