Reference to any prior art in the specification is not, and should not be taken as, an acknowledgement of any form of suggestion that this prior art forms part of the common general knowledge in Australia or any other jurisdiction or that his prior art would reasonably be expected to be ascertained, understood and regarded as relevant by a person skilled in the art.
Conventional techniques for production of fine particulate preparations (also called particulate products) suffer from many disadvantages. These conventional methods involve either mechanical comminution (crushing, grinding, and milling), or precipitation or recrystallisation of the solute from liquid solutions. The production of particles of less than 5 μm is most usually achieved by comminution of larger crystal material.
Micronisation by high energy processes such as grinding and milling can result in mechanically induced damage to the crystal structure manifesting as amorphous regions on the surface of the particles. As a result the particles are usually highly charged, hygroscopic and/or cohesive.
Conventional recrystallisation (eg U.S. Pat. No. 6,221,398) of solutes from liquid solutions exploits the dependence of a compound's solubility on temperature and/or mixture composition. Crystallisation by either solvent evaporation or solvent extraction of a solute usually requires the use of toxic organic antisolvents and surfactants, and yields wet particles that require further drying to remove traces of adsorbed solvent residues. Furthermore there is limited scope to control the precipitation process, and thus the particles produced are commonly larger than required, and of a broad particle size range distribution.
Freeze drying is another technique for the production of solid preparations and products. A solution or suspension of pharmaceutical ingredients is snap-frozen, and then the solvent is removed by sublimation under conditions of low pressure and/or temperature. However, this process usually results in a product that is described as an amorphous cake, which does not normally comprise discrete particles which would be required, for example, for effective inhalational delivery.
Another alternative method is spray drying, where a solution or suspension of pharmaceutical ingredients is sprayed into a chamber, the particles being produced though evaporation of the solvent in a hot air-fluidized bed. The high temperatures can degrade sensitive drugs and polymers, and the technique does not lend itself to the close control of product morphology during process scale-up. The method may also produce amorphous particles, which may have stability problems and a high tendency towards moisture re-absorption.
Supercritical Fluid (SCF) Technologies have advanced over the last decade, driven by the need for high purity drugs with controlled morphology. The most frequently used SCF process is the Aerosol Solvent Extraction System (ASES) process. The typical ASES process involves a continuous flow of solution containing a substance to be precipitated and the supercritical fluid being co-introduced into a particle formation vessel. This leads to simultaneous dispersion and mixing of the solution, rapid supersaturation and particle nucleation and formation of particles. Process conditions such as temperature, pressure, flow rates and type of solvent and antisolvent determine the morphology of the resulting particles. An example of an antisolvent commonly used in this process is carbon dioxide and the solvent may be chosen from a wide range of solvents in which the drug is soluble, and where the solvent is miscible with the antisolvent.
The simplest approach for the preparation of a particulate product containing two or more pharmaceutical ingredients is to mix the individual components by physical blending. Physical blending is commonly used to prepare particulate preparations for inhalation by dry powder inhalers. The difficulty in achieving consistent, homogenous mixtures using this approach is well recognised by the pharmaceutical industry and regulatory bodies.
Furthermore, the individual components of a physical mixture may separate over time; especially with processing, handling and administration, because of differences in particle morphology of the different ingredients. Such separation of components within a bulk mixture may lead to dosage inconsistencies and is therefore problematic.
An example of an existing method for the production of a combination particulate product is contained in US patent application no 20040028619. Therein a method is described where two drugs were dissolved in a mutual solvent in the desired ratio and the resultant liquid feed stock was atomised using an ultrasonic atomiser. The resultant droplets were suspended in a nitrogen carrier gas which was passed through a heated flow reactor. The particles that formed were collected using an electrostatic precipitator. However, there was evidence that the particles were of inconsistent morphology which is not desirable for many drug delivery applications.
Accordingly, it would be an advance in the art if a process could be developed for the production of particles of a combination product (ie, a product containing two or more pharmaceutically active compounds); the particles preferably having a small particle size, a narrow particle size distribution, and the active compounds in a crystalline form. It would be a further advance in the art if the combination product could be produced in essentially one step, and, for example, have superior aerodynamic properties over a combination product for inhalation produced by physical mixing.