Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Reexamination Certificate
2000-02-14
2002-09-03
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
C516S011000, C516S077000
Reexamination Certificate
active
06444193
ABSTRACT:
The present invention relates to a process for the preparation of gas-containing vesicles, e.g. ultrasound contrast agents or precursors therefore.
For ultrasound diagnostic imaging it has been widely proposed to use a contrast agent comprising vesicles (e.g. microballoons, liposomes or micelles) which comprise a gas or gas mixture entrapped within a membrane. For this purpose, the membrane may be a mono-layer or a multilayer, e.g. of an amphiphilic material such as a lipid.
Such gas-containing vesicles may readily be produced by shaking or sonicating a liquid containing a membrane-forming material in the presence of a suitable gas or gas mixture. (By gas or gas mixture is included a material which is gaseous at body temperatures, e.g. at 37° C.).
However, the vesicles produced by such techniques have a broad size distribution which may vary from batch to batch and moreover the yield, ie. the percentage of membrane forming material which ends up in appropriately sized gas-containing vesicles, may also vary from batch to batch.
Desirably the vesicles produced will have a narrow size distribution about the desired vesicle size, generally 1 to 7 &mgr;m, e.g. 3±1 &mgr;m.
We have now found that yield can be improved and undue production of oversized vesicles avoided if vesicle production is effected using a rotor-stator mixer, ie. a mixer in which the starting mixture is passed through a zone in which shear forces are exerted upon it by relative rotation of two surfaces, one on an element referred to as a rotor and the other on an element referred to as a stator.
Rotor-stator mixers are commonly used to produce emulsions from a mixture of immiscible liquids and a schematic drawing of a standard laboratory scale rotor-stator is shown in
FIG. 1
of the accompanying drawings. Such a rotor-stator, with a rotor external diameter of 15 mm was used at a rotation rate of 23000 rpm to produce the gas-containing vesicles described in Example 2(b) of W097/29783 (Nycomed).
However we have now found that the yield of appropriately sized gas-containing vesicles is improved if the relative speed of the rotor and stator surfaces is at least 20 m/s.
Thus viewed from one aspect the invention provides a process for the preparation of gas-containing vesicles wherein a mixture of gas or gas-precursor, liquid and vesicle membrane forming material is passed through a zone in which it is subject to shear forces exerted by surfaces moving relative to each other at a speed of at least 20 m/s, preferably at least 25 m/s, especially preferably at least 30 m/s, and more especially preferably at least 35 m/s, e.g. up to 100 m/s, more particularly up to 60 m/s, and especially up to 50 m/s.
We have also found that the vesicle size distribution is improved if the vesicle forming mixture is passed successively through a plurality of shear force zones (e.g. rotor:stator stages), e.g. at least two such zones, preferably at least three and more preferably at least four such zones, especially preferably at least 12 such zones e.g. up to 90, more particularly up to 44 such zones, e.g. up to 20 or up to 12 such zones. In this way the range of residence times within the shear force zone(s) will have a narrower distribution and the occurrence of over-sized vesicles is reduced. Indeed having a plurality of sequential shear force zones through which the mixture passes avoids the need to recirculate the mixture through an open shear force zone and so ensures that adequate mixing occurs with the entirety of the mixture experiencing substantially the same mixing conditions, e.g. residence time and temperature profile. Such uniform and definable mixing parameters result in a product with significantly lower batch to batch variation in properties and is of great importance in a mixing process upscaled from the laboratory bench to pilot plant or commercial manufacture.
Thus viewed from a further aspect the invention also provides a process for the preparation of gas-containing vesicles wherein a mixture of gas or gas-precursor, liquid and vesicle membrane forming material is passed sequentially through a plurality of different zones in which it is subject to shear forces exerted by surfaces moving relative to each other. In this second process, the mixture is advantageously passed through at least one such zone in which the relative speed of the surfaces is at least 10 m/s, preferably at least 15 m/s, especially at least 30 m/s, more especially up to 50 m/s and especially preferably is in accordance with the first process of the invention. Using a 110 mm diameter outer zone, it has been found advantageous to operate at a relative surface speed of 46 m/s.
In the processes of the invention, the surfaces moving relatively to each other to create the shear force zones are desirably separated from each other by less than 2 mm, preferably less than 1 mm, especially preferably less than 500 &mgr;m, e.g. 100 to 300 &mgr;m. The optimum separation will depend upon the viscosity of the mixture passing through the shear force zones and the minimum separation may be imposed by manufacturing constraints. Generally however for an aqueous-mixture the separation will desirably be in the range 200 to 300 &mgr;m. As some deformation may occur while the surfaces are moving, such separations refer to values measurable when the surfaces are not moving.
For convenience sake, the shear force zones will generally be created-between a moving surface and a static surface, preferably a rotating surface and a static surface, ie. as in a rotor-stator mixer.
Where the mixture passes through a plurality of shear force zones, this may for example be provided by a plurality of rotor-stator devices, with successive such devices receiving the mixture produced by the previous device. Such devices may have separate rotation drives or may share a common drive, ie. be arranged coaxially about a common drive shaft. However, it is more efficient to use one or more rotor-stator combinations each of which provides a plurality of radially separated shear force zones.
Thus viewed from a further aspect the invention provides a process for the preparation of gas-containing vesicles wherein a mixture of gas or gas-precursor, liquid and vesicle membrane forming material is passed sequentially through a plurality of different zones in which it is subject to shear forces exerted by at least one rotor moving relative to at least one stator, preferably exerted by two or more (e.g. 2 to 20, for example 2 to 10) coaxial rotors each preferably providing two or more (e.g. 2 to 20, for example 2 to 10 but conveniently higher, e.g. 13) radially separated said zones.
The relative speeds of the rotor and stator surfaces in the third process of the invention will preferably be such that in at least one zone the rotor and stator surfaces move at a relative speed of at least 10 m/s, preferably at least 15 m/s more preferably at least 30 m/s, e.g. up to 50 m/s, and especially preferably in accordance with the first process of the invention.
Rotor-stator mixer apparatus suitable for use in this third process of the invention is novel and forms a further aspect of the invention.
Viewed from this aspect the invention provides a rotor-stator mixer apparatus comprising a mixing chamber having gas and liquid inlet ports and a mixture outlet port, with disposed in said chamber a rotor and drive means therefore, said mixer having in facing relationship to said rotor a stator, said stator and rotor having axially extending interlocking ridges and grooves provided with radially extending fluid transit means whereby to define a plurality of shear force zones for fluid passing radially between said rotor and said stator from said inlet ports.
In the mixer apparatus of the invention, the inlet ports are preferably located radially inwardly of the shear force zones, preferably at or near the rotation, axis of the rotor. Desirably the inlet ports are adjacent a mixing means, e.g. an axially extending flange or “propeller”, provided on a drive shaft for the rotor, so that the gas and liquid are mixed b
Haugseter Bjorn
Omtveit Tore
Pete Tony
Chisholm Robert F.
Hartley Michael G.
Nycomed Imaging AS
Ronning, Jr. Royal N.
Ryan Stephen G.
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