Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-03-08
2003-06-10
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S490000
Reexamination Certificate
active
06576262
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the controlled formation of particulate products using supercritical fluids. It provides methods and apparatus for the formation of substances in particulate form, and also particulate products of the methods.
BACKGROUND TO THE INVENTION
It is known to form particles of a substance of interest (a “target substance”) by dissolving or suspending it in a suitable vehicle and then using a supercritical fluid anti-solvent to extract the vehicle to cause particle precipitation.
One particular technique for doing this is known as “SEDS” (Solution Enhanced Dispersion by Supercritical fluids). This is described in WO-95/01221 and (in a modified form) in WO-96/00610. The essence of SEDS is that a solution or suspension of a target substance, in an appropriate vehicle, is co-introduced into a particle formation vessel with a supercritical fluid anti-solvent having a relatively high flow rate, in such a way that two things happen substantially simultaneously and substantially immediately on introduction of the fluids into the vessel: the solution or suspension is “dispersed” into separate fluid elements (such as droplets) by the mechanical action of the supercritical fluid (ie, by the transfer of kinetic energy from the supercritical fluid to the solution or suspension), and at the same time the vehicle is extracted from the solution or suspension, again by the supercritical fluid, to cause particle formation.
SEDS allows a high degree of control over conditions such as pressure, temperature and fluid flow rates, and over the physical dispersion of the solution/suspension, at the exact point where particle formation occurs (ie, at the point where the vehicle is extracted into the supercritical fluid). It therefore allows excellent control over the size, shape and other physicochemical properties of the particles formed.
Processes such as SEDS are not however suitable for all types of target substance. If the target is to any degree soluble in the chosen supercritical fluid, then when the supercritical fluid extracts the vehicle it will also dissolve some or all of the target substance. This can lead to reduced product yield, not to mention engineering problems when the solute later precipitates out of the supercritical fluid outside the particle formation vessel.
The same considerations apply to all particle formation processes in which a supercritical fluid is used as an anti-solvent to cause precipitation of a target substance from a solution or suspension. If the substance is at all soluble in the supercritical fluid, whether simply because of the chemical natures of the substance and the fluid (which may also contain modifiers), or because of the particular operating conditions (such as temperature and pressure) being used, problems can arise. Such techniques are thus restricted in application to substances which are poorly soluble or completely insoluble in the chosen supercritical fluid.
A supercritical fluid which is commonly used in particle formation techniques is supercritical carbon dioxide, which is relatively inexpensive, non-toxic and has convenient critical temperature and pressure values. For this particular supercritical fluid, it is generally non-polar or low polarity substances which cause problems, being either very or at least reasonably soluble in it. Thus, for instance, low molecular weight lipophilic materials cannot easily be formed into particles using supercritical carbon dioxide.
In the past, such problems have been overcome either by altering the operating conditions to reduce solubility of the target substance in the supercritical fluid (it is not always possible, however, to alter the conditions sufficiently to achieve that), or by using a different technique altogether for particle formation. A process known as RESS (Rapid Expansion of Supercritical Solution), for instance, may be used to precipitate a substance of interest by dissolving it in a supercritical fluid and then rapidly expanding the resulting solution. However, RESS is generally a less accurate and reliable technique than techniques such as SEDS, allowing less control over the characteristics of the particles formed.
Alternatively, one might attempt to use a different supercritical fluid as the anti-solvent, but it can often be very difficult to select a supercritical fluid which is not only an anti-solvent for the target substance but also capable of dissolving the solvent vehicle—both requirements need to be met for the fluid to be useable. Supercritical nitrogen, for instance, would act as an anti-solvent for the low molecular weight lipophilic materials which cannot be processed using supercritical carbon dioxide, but most conventional organic solvents are insoluble in supercritical nitrogen, so the choice of vehicle would be extremely limited.
It would therefore be advantageous if SEDS, and other similar supercritical fluid particle formation processes, could be modified to be used under conditions where the target substance is soluble in the chosen supercritical fluid. In particular, it would be desirable to be able to use supercritical carbon dioxide in the production of lipophilic and other low polarity materials. The present invention thus aims to facilitate the use of supercritical anti-solvents for an even greater number of target substances, and hence to overcome a technical problem in, and widen the field of application for, an already very useful technology.
STATEMENTS OF THE INVENTION
According to a first aspect of the present invention, there is provided a method for forming particles of a target substance, the method involving:
(a) preparing a solution or suspension of the target substance in a vehicle which is or includes either a near-critical fluid or a first supercritical fluid;
(b) introducing the solution or suspension into a particle formation vessel; and
(c) contacting the solution or suspension, in the particle formation vessel, with a second supercritical fluid, under conditions which allow the second supercritical fluid to cause precipitation of particles of the target substance from the solution or suspension;
wherein the second supercritical fluid is miscible or substantially miscible with the vehicle and is a fluid in which the target substance is insoluble or substantially insoluble.
The vehicle should be soluble or at least partially, preferably substantially, soluble in the second supercritical fluid. The fluids can then dissolve in one another by a rapid diffusion process, causing the target substance to “crash out” from its solution or suspension. The second supercritical fluid must not be capable, to any significant degree, of dissolving the substance itself as the particles are formed. In other words, it must be chosen so that the target substance is for all practical purposes insoluble (preferably having a solubility below 10
−3
mole %, more preferably below 10
−5
mole %) in it, under the chosen operating conditions and taking into account any supercritical fluid modifiers present.
By “miscible” is meant generally that the two fluids are miscible in all proportions under the operating conditions used, and “substantially miscible” encompasses the situation where the two fluids can mix sufficiently well, under those operating conditions, as to achieve the same or a similar effect, ie, dissolution of the fluids in one another and precipitation of the target substance.
Using the method of the invention, particles can be formed even of substances which are soluble in a chosen supercritical fluid, by using that supercritical fluid as the vehicle for the substance, and making use of another supercritical fluid (the second supercritical fluid) as the anti-solvent to cause particle precipitation. The target substance is able to dissolve or be suspended in the vehicle, but to precipitate out of it when the vehicle and the second supercritical fluid mix, without product loss into the second supercritical fluid.
In previous literature relating to similar particle formation techniques (such as SEDS), it ha
Hanna Mazen Hermiz
York Peter
Cagan Felissa H.
Nektar Therapeutics
Page Thurman K.
Pulliam Amy E
Rafa Michael J.
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