Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-04-15
2002-06-18
Bawa, Raj (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C552S632000, C552S638000, C552S639000
Reexamination Certificate
active
06406718
ABSTRACT:
The present invention relates to particulate products which may be prepared by using supercritical fluids. More particularly, the invention relates to novel crystalline forms of fluticasone propionate, which is S-fluoromethyl 6&agr;,9&agr;-difluoro-11&bgr;-hydroxy-16&agr;-methyl-3-oxo-17&agr;-propionyloxyandrosta-1,4-diene-17&bgr;-carbothiate.
Fluticasone propionate is described and claimed in British Patent No. 2088877 (see Example 14 thereof). This compound has proven anti-inflammatory activity and is particularly useful for the treatment of respiratory disorders, particularly asthma. Fluticasone propionate has been obtained in a crystalline form, designated Form 1, by dissolving the crude product (obtained, e.g. as described in British Patent No. 2088877) in ethyl acetate and then recrystallising. Standard spray-drying techniques have also been shown to lead only to the known Form 1 of fluticasone propionate. According to the present invention, fluticasone propionate may be prepared in a new polymorphic form, designated Form 2. Form 2 may be characterised for example by its X-ray powder diffraction (XRPD) pattern (see infra).
The particulate products of the present invention are produced according to a supercritical fluid technique which we have developed.
The use of supercritical fluids (SCFs) and the properties thereof have been extensively documented, see for instance, J. W. Tom and P. G. Debendetti, “Particle Formation with Supercritical Fluids—A Review”,
J. Aerosol. Sci.,
22 (5), 555-584 (1991). Briefly, a supercritical fluid can be defined as a fluid at or above its critical pressure (P
c
) and critical temperature (T
c
) simultaneously. Supercritical fluids have been of considerable interest, not least because of their unique properties. These characteristics include:
High diffusivity, low viscosity and low surface tension compared with liquids.
Large compressibility of supercritical fluids compared with the ideal gas implies large changes in fluid density for slight changes in pressure, which in turn results in highly controllable solvation power. Supercritical fluid densities typically range from 0.1-0.9 g/ml under normal working conditions. Thus, selective extraction with one supercritical fluid is possible.
Many supercritical fluids are normally gases under ambient conditions, which eliminates the evaporation/concentration step needed in conventional liquid extraction.
Most of the commonly used supercritical fluids create non-oxidising or non-degrading atmospheres for sensitive and thermolabile compounds, due to their inertness and moderate temperatures used in routine working conditions. Carbon dioxide is the most extensively used SCF due to its cheapness, non-toxicity, non-flammability and low critical temperature.
These characteristics have led to the development of several techniques of extraction and particle formation utilising supercritical fluids. In particular, two particle formation methods have been identified:
Rapid expansion of supercritical solution (RESS) (see, for instance, J. W. Tom and P. G. Debendetti, supra) involves the dissolution of the solute of interest in a supercritical fluid, followed by rapid expansion of the resulting supercritical solution to atmospheric pressure, resulting in the precipitation of solute particles.
Gas Anti Solvent (GAS) recrystallisation (P. M. Gallagher et al, Supercritical Fluid Science and Technology, ACS Symp. Ser. 406, 134 (1989)) is particularly useful in situations when the solvent of interest does not dissolve in, or has a very low solubility in, a supercritical fluid or a modified supercritical fluid. In this technique, the solute is dissolved in a conventional solvent. A supercritical fluid such as carbon dioxide is introduced into the solution, leading to a rapid expansion of its volume. As a result, the solvent power decreases dramatically over a short period of time, triggering the precipitation of the particles.
There is a need for techniques whereby a product may be obtained with consistent and controlled physical criteria, including control of particle size and shape, quality of the crystalline phase, chemical purity and enhanced handling and fluidising properties.
In addition, it would be advantageous to prepare micron-sized particles directly without the need to mill products to this size range. Such milling leads to associated problems such as increased static charge and enhanced particle cohesiveness, as well as reduced yield of product. It also leads to highly stressed particles, which stress may affect the particles, dissolution after administration.
Described in WO95/01324 is an apparatus for the formation of a particulate product in a controlled manner utilising a supercritical fluid particle formation system. The disclosure of WO95/01324 is incorporated herein by this reference. The apparatus comprises a particle formation vessel with means for controlling the temperature of said vessel and means for controlling the pressure of said vessel, together with a means for the co-introduction into said vessel of a supercritical fluid and a vehicle containing at least one substance in solution or suspension, such that dispersion and extraction of the vehicle occur substantially simultaneously by the action of the supercritical fluid.
As used herein, the term “supercritical fluid” means a fluid at or above its critical pressure (P
c
) and critical temperature (T
c
) simultaneously. In practice, the pressure of the fluid is likely to be in the range 1.01 P
c
-7.0 P
c
, and its temperature in the range 1.01 T
c
-4.0 T
c
.
The term “vehicle” means a fluid which dissolves a solid or solids, to form a solution, or which forms a suspension of a solid or solids which do not dissolve or have a low solubility in the fluid. The vehicle can be composed of one or more fluids.
As used herein, the term “supercritical solution” means a supercritical fluid which has extracted and dissolved the vehicle.
The term “dispersion” means the formation of droplets of the vehicle containing at least one substance in solution or suspension.
The term “particulate product” includes products in a single-component or multi-component (e.g. intimate mixtures of one component in a matrix of another) form.
It will be appreciated that, where necessary, the apparatus may additionally comprise a means for the collection of the particulate product, for example, a means for the retention of the product in the particle formation vessel, such as a filter, thus reducing loss of the product together with the resultant supercritical solution. An alternative means may involve a cyclone separating device.
The apparatus mentioned above and its use provide the opportunity for manufacturing dry particulate products with controlled particle size and shape by offering control over the working conditions, especially the pressure, utilising, for example, an automated back-pressure regulator such as model number 880-81 produced by Jasco Inc. Such an improved control eliminates pressure fluctuation across the particle formation vessel and ensures a more uniform dispersion of the vehicle (containing at least one substance in solution or suspension) by the supercritical fluid with narrow droplet size distribution during the particle formation process. There is little or no chance that the dispersed droplets will reunite to form larger droplets since the dispersion occurs by the action of the supercritical fluid which also ensures thorough mixing with the vehicle and rapidly removes the vehicle from the substance(s) of interest, leading to particle formation.
The simultaneous co-introduction of the vehicle containing at least one substance in solution or suspension and the supercritical fluid, according to the method described herein, allows a high degree of control of parameters such as temperature, pressure and flow rate, of both vehicle fluid and supercritical fluid, at the exact point when they come into contact with one another.
Further advantages for particles formed as described herein include control over the quality of the crystalline and polym
Bawa Raj
SmithKline Beecham Corporation
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