Classifying – separating – and assorting solids – Fluid suspension – Liquid
Reexamination Certificate
1999-12-14
2001-03-20
Walsh, Donald P. (Department: 3653)
Classifying, separating, and assorting solids
Fluid suspension
Liquid
C209S172500, C209S173000, C209S155000
Reexamination Certificate
active
06202855
ABSTRACT:
This invention relates to a process for size selection of particulate pharmaceuticals, in particular contrast agents for use in diagnostic imaging procedures such as for example magnetic resonance, X-ray (eg. CT), scintigraphy and ultrasound imaging.
In many diagnostic imaging modalities substances, contrast agents, are administered to the subject to enhance image contrast, for example to facilitate differentiation between different tissues or organs or between healthy and unhealthy tissues. While particulate materials have long been used as contrast agents for the gastrointestinal tract, more recently the parenteral administration of particulate contrast agents has been proposed.
While for administration into the GI tract the particle size and size distribution has not generally been considered to be particularly important, the same is not true of parenterally administered particulate agents, for example because of the risk of embolisation by overly large particles.
Accordingly in the preparation of particulate contrast agents for parenteral administration there is a need to ensure that the mean particle size and the particle size distribution are within desired limits.
The present invention provides a particularly straightforward solution to this problem.
Thus viewed from one aspect the present invention provides a process for the selection from a particulate pharmaceutical product of particles of a preselected size (eg. a substantially monodisperse fraction), said process comprising
(i) obtaining a substantially homogeneous suspension of said particulate pharmaceutical product in a fluid suspension medium which is immiscible with said product and is of different density to said product,
(ii) carrying out a size selection procedure to set an effective lower or upper size limit on the particles in the final particulate product, and
(iii) where required carrying out a further size selection procedure to produce a particulate product containing particles of the preselected size,
wherein step (ii) comprises either
(iv) allowing said suspension to settle for a predetermined period,
(v) separating said suspension into a first and a second component in a predetermined volume ratio, said first component deriving from an upper layer of said suspension and said second component deriving from a lower layer of said suspension,
(vi) adding further suspension medium to said first component where said medium is more dense than the pharmaceutical product or to said second component where said medium is less dense than the pharmaceutical product and mixing to produce a substantially homogeneous suspension of particulate pharmaceutical product in said fluid suspension medium, and
(vii) repeating steps (iv) to (vi) at least once, optionally omitting the last repeat of step (vi), adding the fluid suspension medium in the repeat of step (vi) to the first component or the second component where the substantially homogeneous suspension produced in the first operation of step (vi) derives from the first component or the second component respectively, whereby to set an effective lower size limit on the particles in the final particulate product,
or
(viii) allowing said suspension to settle for a predetermined period,
(ix) separating said suspension into a third and a fourth component in a second predetermined volume ratio, said third component deriving from an upper layer of said suspension and said fourth component deriving from a lower layer of said suspension, and retaining said third component where said medium is less dense than the pharmaceutical product or said fourth component where said medium is more dense than said product, whereby said second predetermined volume ratio is such as to set an effective upper size limit on the particles in the retained component, and optionally
(x) adding further suspension medium to the non-retained component and mixing to produce a substantially homogeneous suspension,
(xi) repeating steps (viii), (ix) and (x) one or more times, optionally omitting the last repeat of step (x), and collecting the retained components from step (ix) and repeats thereof.
Where step (ii) is effected so as to set a lower size limit, ie. by operation of steps (iv) to (vii), step (iii) may advantageously comprise operation of steps (viii) to (xi) after a final repetition of step (vi) .
In effect therefore the process of the invention may involve removal of particles below a desired lower size limit from a polydisperse particulate, followed by removal and retention of particles below a desired upper size limit from the remaining particulate mixture. The retained particulate mixture then contains particles within a desired size range. Alternatively the removal of over-sized particles may be effected analogously to steps (viii) to (xi) prior to or during removal of under-sized particles by steps (iv) to (vii).
The starting material for the process of the invention may thus be a particulate product in which the upper or the lower size limit or neither the upper nor the lower size limit has been set. While the process may be used to set both size limits, it is especially preferred to use a starting material for which the upper size limit has been set, e.g. by the removal of over-sized particles or by the use of a particle creation technique which does not produce over-sized particles, e.g. the use of a rotor-stator for the production of particles which are vesicles or emulsion droplets. Alternatively the process of the invention may be used simply to set a lower particle size limit for a particle product in which the incidence of over-sized particles is acceptably low, or from which the over-sized particles may subsequently be removed, e.g. by skimming or decanting. It will be noted that while steps (viii) to (xi) can be used to remove essentially all over-sized particles, the extent to which under-sized particles are removed by steps (iv) to (vii) will depend upon the number of repetitions. For this reason the lower size limit is referred to as an “effective” size limit.
The use of a rotor-stator to generate a particle mixture from which under-sized particles are removed using the process of the invention is novel and especially advantageous and forms a further aspect of the invention. Viewed from this aspect the invention provides a process for the production of a particulate pharmaceutical product, said process comprising:
(A) generating with a rotor-stator a particulate pharmaceutical product,
(B) obtaining a substantially homogeneous suspension of the particulate product generated in step (A) in a fluid suspension medium which is immiscible with and of different density to the particulate product,
(C) allowing said suspension to settle for a predetermined period,
(D) separating said suspension into a first and a second component in a predetermined volume ratio, said first component deriving from an upper layer of said suspension and said second component deriving from a lower layer of said suspension,
(E) adding further suspension medium to said first component where said medium is more dense than the pharmaceutical product or to said second component where said medium is less dense than the pharmaceutical product and mixing to produce a substantially homogeneous suspension of particulate pharmaceutical product in said fluid suspension medium, and (F) repeating steps (C) to (E) at least once, optionally omitting the last repeat of step (E), adding the fluid suspension medium in the repeat of step (E) to the first component or the second component where the substantially homogeneous suspension produced in the first operation of step (E) derives from the first component or the second component respectively, whereby to set an effective lower size limit on the particles in the final particulate product.
The particulate product of the process of the invention can subsequently be concentrated and if desired dried to yield a size selected powder, suspension or dispersion.
Where the particulate material is less dense than the fluid suspension medium, following homogenisation of the suspe
Haugseter Bjørn
Omtveit Tore
Bacon & Thomas
Miller Jonathan R.
Nycomed Imaging AS
Walsh Donald P.
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