WO2003002111A1

WO2003002111A1 - Inhalation particles

Info

Publication number: WO2003002111A1
Application number: PCT/FI2002/000573
Authority: WO
Inventors: Wiwik Watanabe; Petri Ahonen; Esko Kauppinen; David Brown; Jorma Jokiniemi; Esa Muttonen
Original assignee: Orion Oyj
Current assignee: Orion Oyj
Priority date: 2001-06-28
Filing date: 2002-06-28
Publication date: 2003-01-09
Anticipated expiration: 2003-12-28
Also published as: FI20011386A0

Abstract

Crystalline particles of orazipone having a curved surface with a controlled roughness are useful e.g. for treating asthma, COPD and other respiratory diseases. The particles have a narrow particle size distribution, rough surfaces and an improved stability. The inhalation particles of the invention are particularly useful in the administration of a medicament by inhalation.

Description

INHALATION PARTICLES

Field of the invention

The present invention relates to inhalation particles of orazipone and inhalation compositions of orazipone suitable for pulmonary drug delivery and to methods for the preparation thereof. The compositions are particularly useful to treat asthma, COPD and other respiratory diseases.

Background of the invention

Orazipone or 3-[(4-methylsulfonylphenyl)-methylene]-2,4-pentanedione is a locally acting anti-inflammatory agent that has anti-inflammatory properties complimentary to those of corticosteroids. Orazipone is useful e.g. in the treatment of asthma, COPD and other respiratory diseases. A method for preparing orazipone is described in European Patent No. 440324 B 1.

Inhalation has become the primary route of administration in the treatment of pulmonary and other diseases. This is because, besides providing direct access to the lungs, medication delivered through the respiratory tract provides rapid and predictable onset of action and requires lower dosages when compared to the oral route. To ensure an accurate delivery deeply into the lungs the particles of the active ingredient should be micron-sized, preferably with the aerodynamic particle size from about 1 to 5 μm. A powdered inhalation composition containing conventionally micronized (i.e. milled) orazipone particles is disclosed in US 6,201,027.

It has been found that conventional high energy particle size reduction of large crystallites of orazipone introduces surface and crystallographic damage, which affect powder stability and results in particles with irregular fragments that tend to form strong aggregates. The particle size reduction process also generates flat faceted surfaces that contain many corner sites for condensation to occur, thus increasing adhesion forces and leading to inefficient drug-particle break-up. Furthermore, the particles are highly charged and therefore very cohesive. Thus, there is a need for orazipone particles that are better suited for delivery by inhalation. Summary of the Invention

It has now been found that, by using an aerosol synthesis method, it is possible to prepare uncharged, crystalline inhalation particles of orazipone with curved, preferably substantially spherical, surface and a narrow particle size distribution. The particles provide more controlled delivery of orazipone by inhalation and exhibit improved dispersibility, as well as good stability as a result of their crystalline nature. The particles have a narrow aerodynamic particle size distribution, typically between 1-5 μm that is especially suitable for the preparation of compositions for pulmonary delivery via inhalation. Moreover, as the particles have curved, preferably substantially spherical, and rough, porous surface, significantly less force is required to remove a particle from a surface, to break-up aggregates of particles or detach particles from a coarse carrier material.

Thus, in one aspect, the present invention provides inhalation particles incorporating orazipone, wherein said particles have a curved surface and are in crystalline form. Preferably, the particles are substantially spherical. Preferably, the particles are polycrystalline with rough surface. The mean mass aerodynamic diameter of the particles is typically between about 0.5 - 10 μm, more typically between about 1 - 5 μm. The aerodynamic particle size distribution of said particles is typically between about 0.5 - 10 μm, more typically between 1-5 μm.

In another aspect, the present invention provides an inhalation composition comprising particles incorporating orazipone, wherein said particles have a curved surface and are in crystalline form. The particles may be formulated into an inhalation composition together with one or more pharmaceutically acceptable additives, diluents or carriers. The composition can be in the form of dry inhalation powder for delivery by a dry powder inhaler (DPI). Alternatively, composition can be in the form of suspension for delivery by other means such as pressurized metered dose inhaler (pMDI) or a nebulizer. Preferably, the composition is provided in the form of dry inhalation powder.

In still another aspect the present invention provides a method for preparing orazipone particles, comprising the steps of: providing liquid feed stock comprising orazipone; atomising said liquid feed stock to create droplets; suspending said droplets in a carrier gas; passing said carrier gas and droplets suspended therein through a heated tube flow reactor under predetermined residence time and temperature history; and collecting the orazipone particles produced.

Brief Description of the Drawings

Figures la and lb show scanning electron microscopy images of the orazipone particles produced by a conventional milling process.

Figures 2a and 2b are schematic diagrams showing parts of the apparatus used in the method of the invention.

Figure 3 is a schematic diagram of the electrostatic precipitator.

Figure 4 shows the XRD pattern of orazipone powder of the invention. Figure 5 depicts a scanning electron microscopy image of the orazipone particle of the invention produced at reactor temperature of 50°C.

Figures 6 shows a scanning electron microscopy image of the orazipone particle of the invention produced at reactor temperature of 100°C.

Detailed Description of the Invention

The particles of the present invention are preferably prepared using an aerosol flow reactor method (aerosol synthesis method). It is a one-step continuous process that can directly produce particles in a desirable particle size range. The method has been used to produce various materials, e.g. ceramic powder (US 5,061,682) or zirconia powder (US 4,999,182), at high operation temperatures. However, the method has not been used to produce pharmaceutical materials, which require a significantly lower synthesis temperature (less than 300 °C).

The aerosol flow reactor method comprises generally the following steps:

(a) providing a liquid feed stock comprising one or several active ingredients, (b) atomising said liquid feed stock to create droplets, (c) suspending said droplets in a carrier gas, (d) passing said carrier gas and droplets suspended therein through a heated tube flow reactor under predetermined residence time and temperature history, and (e) collecting the particles produced. The above method differs significantly from the conventional spray-drying process, hi spray-drying hot gas is used as a source of heat to evaporate the solvent. The spray-drying chamber is only used as a place for the heat transfer to occur and chamber itself is not heated or controlled in anyway. The temperature of the gas is changing across the chamber as heat transfer occurs between the cold feed and the hot gas. Furthermore, since the evaporation is very rapid, it is difficult to properly control the temperature history and the residence time of each droplet and product particle. For similar reasons, the crystallization can not be easily controlled and therefore the particles formed are commonly amorphous.

hi the present method, the droplets are already suspended in the carrier gas before they are fed into the tubular flow reactor that is placed in an oven and maintained at a constant temperature. The carrier gas flows evenly in the tubular reactor with a constant rate, controlled temperature field and non-circulating flow. Therefore, the temperature history and the residence time of each droplet and product particle can be properly controlled and the excellent uniformity of the particles can be ensured. Accordingly, the method provides better control of the droplet size distribution (and thus the particle size distribution) such that particles with optimal aerodynamic particle size distribution, typically between about 1-5 μm, can be obtained. Furthermore, in contrast to spray drying, the method allows essentially complete crystallization of the particles. Thus, the method is able to produce consistent and controlled particle properties, including particle size and size distribution, shape, crystallinity, polymorphic phase, surface roughness and chemical purity.

The liquid feed stock of step (a) may be prepared by mixing one or several active ingredients with a suitable solvent to form a solution, suspension, dispersion, gel, emulsion, slurry or the like, and is preferably homogenous to ensure uniform distribution of the components in the mixture. The liquid feed stock in the form of a solution is preferred.

Various solvents maybe employed in the preparation of the a liquid feed stock, including but not limited to, water, hydrocarbons, halogenated hydrocarbons, alchohols, ketones and the like. Examples of suitable solvents include methyl ethyl ketone, acetone, isopropyl alcohol, and combinations thereof.

In case the liquid feed stock is a solution, the active ingredients should be sufficiently soluble in the solvent of the solution so as to obtain, from the atomized droplets of the liquid feed stock, uniform particles with the desired particle size, size distribution and drug ratio. The total solids dissolved may be present in wide range of concentrations, typically from about 0.1 % to about 30 % by weight, for example from about 1 % to about 10 % by weight. A liquid feed stock containing a relatively low concentration of solids results in particles having a relatively small diameter. The finding of suitable liquid feed stock concentrations for each active agent/solvent combinations is considered to be a routine to one skilled in the art. Usually, the liquid feed stock concentration is firstly chosen at its maximum solubility so as to obtain the largest particle size with the atomizer and atomizer conditions used. From the results, a better approximation of the liquid feed stock concentration needed to obtain the desired particle size range with the atomizer and the atomizer conditions used can be easily achieved.

The liquid feed stock is atomized to create droplets in a suitable atomizer, which are well known in the art, such as a spray nozzle (e.g. a two fluid nozzle), an ultrasonic or air assisted nebuliser or a spinning disc, an ultrasonic nebulizer being preferred. Examples of the devices used in this process include ultrasonic generators sold under trademarks Omron NE-U12 and RBI Pyrosol 7901. While there are no special restrictions placed on the atomisers used in the process, it is recommended to use an atomiser that can produce uniform droplets of constant composition and in a specific size range. Such devices are suitable to produce particles with controlled chemical and physical properties suitable for delivery by inhalation.

The droplets of the liquid feed stock are suspended in a carrier gas before passing through a heated tube flow reactor. The carrier gas can be any kind of gas and is preferably inert with respect to the drug molecules and the solvent. It is recommended to use nitrogen gas or other inert gases. The temperature of the carrier gas is typically ambient. To maintain a uniform solution concentration in the droplets in the suspending phase, it is preferred to bubble the carrier gas through a bottle containing the same solvent as the liquid feed stock before entering the atomizer.

Because the droplets are already suspended in the carrier gas when fed into the reactor (i.e. the droplet generation and flow reactor are separated), the temperature history and residence time of each droplet and product particle can be better cont- rolled than in the conventional spray-drying method. Therefore, excellent uniformity of the resulted particles and a narrow particle size distribution can be ensured. The droplets suspended in the carrier gas are passed through a tubular flow reactor that is maintained at a constant temperature. The temperature and the flow rate of the carrier gas are adjusted to evaporate the solvent and to allow the crystallisation process to occur. The particles formed are then collected using an electrostatic precipitator, a cyclone, a planar filter (e.g. nylon) or other particle collecting devices.

The particle size may be controlled to any expected particle size ranges by selection of the atomizer and its operation conditions, and concentration of the liquid feed stock. It is also possible to employ a droplet size modification apparatus (e.g. impactor or virtual impactor, or using size selective collection of particles, e.g. a cyclone) downstream of the flow reactor. Normally, however, this is not required if the atomizer can already produce a sufficient narrow size distribution.

For the tubular flow reactor, while there are no particular restrictions, it is recommended to use a vertical, rather than horizontal configuration in order to minimise buoyancy effects and related losses due to recirculating flow. To ensure uniform temperature and flow fields in the hot zone of the reactor, CFD (Computational Fluid Dynamics) calculations have shown that it is preferable that the aerosol flows against gravity. Flow in any other direction tends to produce undesirable reactor conditions. The reactor tube is preferably placed inside an oven to maintain a uniform reactor wall temperature during the process. The oven can be of any kind that has sufficient temperature control (i.e. ± 1 °C or less) at low temperatures (less than 300 °C). The temperature of the oven is set such that the materials being processed do not decompose. Typically, the selected oven temperature is within the range of about 30 to 300 °C. For orazipone particle production, since the melting point of orazipone is about 134°C, the range of oven temperature used for the particle production may vary between 20 to 120 °C, preferably between 30 to 100 °C.

While there are no particular restrictions placed on the particle collection, it is recommended to use a system that can be heated to prevent re-condensation. Electrostatic precipitators, cyclones and/or filters can be used for this purpose. Accordingly, the particle collection system and the line from the flow reactor outlet to the particle collection system are preferably heated to a temperature above the boiling point of the solution to prevent the re-condensation process to occur. However, the tempera- ture should not be too high so as to cause material degradation. For example, for the orazipone dissolved in methyl ethyl ketone, the temperature of the collection system and the line may be kept constant at a temperature between 30 to 120 °C. To further prevent the re-condensation process to occur, dry carrier gas may be introduced to the particle collection system. The carrier gas is preferably heated at a temperature the same as that of reactor.

It is preferred that the aerosol flow reactor conditions are selected such that crystalline substantially spherical particles of homogeneous constituents having a narrow particle size distribution and rough surfaces are formed. The particle size of the resulting orazipone powder is such that the mean mass aerodynamic diameter of said particles is between about 0.5 - 10 μm, more typically between about 1 - 5 μm. Particularly it is preferred that more than 98 % of the mass is in particles having a diameter of 5 μm or less, and less than about 5 % of the mass being in particles having a diameter of 0.5 μm or less. It is particularly preferred that the aerodynamic particle size distribution of said particles is between about 0.5 - 10 μm, more preferably between about 1 - 5 μm.

The orazipone particle of the invention is in a crystalline form, i.e. has a relative degree of crystallinity preferably 90 % or higher, more preferably 95 % or higher, most preferably 99 % or higher. Preferably the aerosol flow reactor conditions are selected such that the resulting particles are in a crystalline form. The relative degree of crystallinity can be determined based on the x-ray powder diffraction patterns. The value of the relative degree of crystallinity can be estimated by a known method of broadening of the diffraction maxima (FWHM- values).

The particles are typically polycrystalline, i.e. an individual particle consists of a plurality of smaller crystallites.

The orazipone particles of the invention have curved surface. The term "particle with curved surface" means herein a regular shaped particle with rounded, dragee-like, nearly spherical or substantially spherical form such form being consistent and apparent when examined under a scanning electron microscope. In particular, it is preferred that the majority of the particles are as rounded as possible and substantially devoid of sharp or broken edges or flat faceted surfaces. Most preferably, the particles are substantially spherical. The curved surface reduces the contact areas between particles and thereby improves aerosolization and deagglomeration of the particles upon inhalation. Generally, the surface of the particles of the invention is rough, i.e. the roughness is consistent over the entire surface of the particle, apparent when examined under the scanning electron microscope, and the ratio of the maximum and minimum diameter of the particle is between 1.01 - 1.5, preferably between 1.02 - 1.3, more preferably between 1.03 - 1.2. The rough surface of the particles appears typically as porous, filled consistently with dimples and cavities. A rough surface is advantageous since it increases the effective separation distance of the particles, and thus improves aerosolization and deagglomeration properties of the particles. The surface roughness can be controlled by controlling the primary crystallite size of the partic- les.

If desired, various additives known in the art maybe additionally incorporated in the particles together with the active ingredient or ingredients. Such additives include e.g. diluents such as lactose, carriers and stabilizers and the like, hi such a case the additives are included in the liquid feed stock of the process together with the active ingredients. Also such additives incorporated in the particle are preferably in crystalline form. It is particularly preferred that at least about 90 w-% of the total weight of the particle is in crystalline form.

However, in order to reduce the amount of material other than the active ingredients potentially reaching the lungs, it is preferred that the active ingredients constitute at least 90 w-%, preferably at least 95 w-%, more preferably at least 99 w- %, of the total weight of particles. Most preferably the particles are free from other material than the active ingredients.

The particles of the invention may be formulated into an inhalation composition together with one or more pharmaceutically acceptable additives, diluents or carriers. Examples of suitable solid diluents or carriers comprise lactose, dextran, mannitol and glucose, lactose being preferred. Examples of aerosol carriers include non-chlorofluorocarbon-based carriers such as HFA (hydrofluoroalkane). The use of aqueous carriers is also possible. Typical additives include solubilizers, stabilizers, flavouring agents, colorizing agents and preserving agents.

The particles of the invention are preferably administered in the form of a dry powder composition. The particles obtained are generally in the form of individual (unagglomerated) particles which are well suited for pulmonary drug delivery by inhalation as such, e.g. they can be filled directly into capsules, cartridges, blister packs or reservoirs of dry powder inhalers. However, if desired the particles maybe adapted to form loose agglomerates of several individual particles, said agglomerates breaking into individual particles upon dispersion in the inhaled air stream. The particles may also be combined with pharmaceutically acceptable carrier materials or excipients typically used in dry inhalation powders. Such carriers may be used simp- ly as bulking agents or to improve the flowability of the powder. For example, the particles may be used in admixture with carrier particles, e.g. lactose, having larger particle size than the active ingredients, typically in the range of 5 to 100 μm. If the composition contains a carrier, the total amount of the active ingredients is typically about 0.1 - 50 % (w/w), preferably about 1 - 10 % (w/w), based on total weight of the composition. Such compositions can be prepared by methods known in the art.

The particles of the invention can be also administered in the form of pressurized metered dose inhalation suspension, where the particles are suspended in pressurized aerosol carrier and delivered using pressurized metered dose inhaler (pMDI). Alternatively, the particles can be administered in the form of a suspension used in the delivery via a nebulizer.

The invention is further illustrated by the following experiments, which are not meant to limit the scope of the invention.

Experiments

Example 1 (Reference). SEM images ofmicronized orazipone particles

Figure la to lb show scanning electron microscopy (SEM) images of orazipone particles micronized by conventional high energy milling. It can be seen that the particles are irregular in shape, have flat faceted surfaces and have large crystallites, which neck strongly together forming large aggregates.

Example 2. Inhalation particles incorporating orazipone

Preparation of the liquid feed stock

The orazipone liquid feed stock was prepared by dissolving 1 g of orazipone powder in 50 ml of methyl ethyl ketone at room temperature. Aerosol Synthesis

Figure 2a shows the experimental set-up of the particle synthesis, and Fig. 2b show optional configuration used for particle analysis. The liquid feed stock described above was atomised using an ultrasonic atomizer (2), sold under trade mark RBI Pyrosol 7901. The resulted droplets, which were suspended into a carrier gas, were then passed through a heated tube flow reactor (4). Nitrogen gas was used as a carrier gas, with a constant flow rate of 1.5 1/min. To maintain a uniform solution concentration in the atomizer, the carrier gas was bubbled through methyl ethyl ketone in a saturation bottle (1) before entering the atomizer. A vertical tube, which was inserted into an oven (3), was used to evaporate the solvent from the droplets. The oven used was a WTB Binder FD/FED 400 that has temperature variations of ± 1 and + 2°C for temperature at 70 and 150°C, respectively. The tube was made of stainless steel, with an inner diameter and a heated length of 30 and 800 mm, respectively. The oven temperature was set at 50 °C. The minimum particle residence time in the heated zone under the selected process conditions was approximately 3.3 seconds. From the CFD calculation, it is shown that temperature field is uniform and the velocity is fully developed and non-circulating in the heated zone.

The resulted particles were then collected using an electrostatic precipitator (ESP) (5) connected to a high voltage generator (6). The exhaust gas was led from ESP via a dripping bottle (7) to exit (9). Figure 3 shows the schematic diagram of ESP having inlet (16) and exit for exhaust gas (19). The ESP was made of a tubular stainless steel collection plate (20) with inside diameter and length of 47 and 300 mm, respectively. A 0.05 mm diameter tungsten wire was placed on the center axis of the collection plate and a high voltage (18) was applied between the wire and the plate. The high electric field formed a corona discharge (17) on the wire and charged the gas molecules. The gas ions were then formed. These ions migrated across the space between the wire and the plate under the influence of the applied electric field. During the migration, the ions collided with the aerosol particles, which thus acquired charge. The charged particles then migrated toward the grounded surface electrode. When the particles struck the grounded plate, they lost their charges and adhered to the plate surface via surface forces. Therefore, the particles collected were not charged. Temperature in the ESP and in the line from tubular tube outlet to the ESP, were maintained at a constant temperature of 50 °C to avoid condensation of organic vapours and moisture to occur. Condensation particle counter (CPC) model 3022, shown as (8) in Fig. 2a, was used to determine efficiency of the ESP. Particles collected were then removed from the plate surface of ESP by scraping, and then placed in an airtight glass bottle to avoid moisture penetration or other contamination.

Characterisation

i. Particle size analysis

Referring now to Fig. 2b, the particle size distribution was measured by an electrical low pressure impactor (12) (ELPI) connected to a vacuum (13). The particles exiting the tubular tube were passed into two diluters (10a and 10b), with a dilution ratio of 1 : 10, before entering the ELPI. The first diluter (10a) was heated at 50°C and the nitrogen gas entering the first diluter is also heated at the same temperature. Some particles exiting from the first diluter were sampled directly into a TEM grid (11) via a combination electrostatic precipitator connected to a vacuum, for morphology analysis. To minimize temperature gradient, and thus to reduce the moisture condensation, the diluter, the line to the diluter and the gas line into the diluter were layered with heating elements that were kept also at 50°C. The gravimetric measurement shows that a narrow particle size distribution within the range of aerodynamic size of interest, i.e. at around 1-5 μm, was obtained.

ii. Particle crystallinity analysis

Crystallinity of the sample was studied by X-ray powder diffraction (Diffractometer D500, Siemens GmbH, Karlsruhe, Germany). A copper target X-ray (wavelength 0.1541nm) tube was operated with the power of 40 kV x 40 mA.

For x-ray powder diffraction analysis, 500 mg of the sample was mounted to a specific cylindrical single crystal mini sample stage, which has a diameter of 20 mm and height of approximately 2 mm.

The relative degree crystallinity of the powder was determined based on the x-ray powder diffraction patterns shown in Figure 4. The estimation was based on the broadening of the diffraction maxima (FWHM-values) positioned at 2Θ range 3- 53°. It is noticed that the powder was well crystallised. The maximum intensities were sharp and well above background intensities. iii. Particle shape and surface structure

As explained above, individual particles were collected on the surface of a holey carbon film TEM grid (11) connected to a vacuum after particle collection. The morphology of the particles were then imaged using a field emission low voltage scanning electron microscope (FE-SEM) operated at a 2 kV acceleration voltage. Figure 5 is a scanning electron microscope image of the particle. It is shown that the particles are polycrystalline and have curved and rough surfaces with diameter of about 1-3 μm. It is not possible to produce such spherical polycrystalline particles via size reduction of large crystallites by conventional size reduction prosesses.

iv. Chemical analysis

The product purity was analysed using Hewlett-Packard HP 1090 Liquid Chromatograph equipped with diode array detector (wavelength 277). The column used was a Hewlett-Packard Hypersil ODS, 5 μm, 100x2.1 mm. The quantitative analyses were carried using the external standard method (four different standard concentrations). 15 mM phosphate buffer (pH 2 with H₃PO₄) : methanol at the ratio of 60:40 (v/v) was used as a mobile phase. The powder samples were first dissolved into methanol and diluted with a 15 mM phosphate buffer (pH 2 with H₃PO₄) : methanol (50:50). The liquid samples were then diluted with a 15 mM phosphate buffer (pH 2 with H₃PO₄) : methanol (50:50). The analysis results showed that the purity of resulted powder is 100%

Example 3. Inhalation particles comprising Orazipone with controlled primary crystallite size

The liquid feed preparation and aerosol synthesis process are the same as example 2 except that the process temperatures are set at 100°C. The minimum particle residence time in the heated zone under the selected process conditions was approximately 3.8 seconds.

It is found that the particle size distribution is the same as that of example 2 but the primary crystallite sizes are smaller, as shown in Figure 6. Thus, it is possible to control primary crystallite size, and thus particle surface roughness, by varying the process conditions.

Claims

Claims:

1. Inhalation particles incorporating orazipone, wherein said particles have a curved surface and are in crystalline form.

2. Inhalation particles according to claim 1, wherein the particles are substantially spherical.

3. Inhalation particles according to claim 1 or 2, wherein the particles are polycrystalline.

4. Inhalation particles according to any of claims 1 to 3, wherein the particles have a rough surface.

5. Inhalation particles according to any of claims 1 to 4, wherein the particles are substantially spherical polycrystalline particles.

6. Inhalation particles according to any of claims 1 to 5, wherein the mean mass aerodynamic diameter of the particles is between 1 - 5 μm.

7. Inhalation particles according to any of claims 1 to 6, wherein the aerodynamic particle size distribution of said particles is between 0.5 - 10 μm, preferably between 1 - 5 μm

8. Inhalation particles according to any of claims 1 to 7, wherein the particles are uncharged.

9. Inhalation composition comprising particles according to any of claims 1 to 8.

10. Inhalation composition according to claim 9, additionally comprising one or more pharmaceutically acceptable additives, diluents or carriers.

11. Inhalation composition according to claim 9 or 10 in the form of dry inhalation powder.

12. Inhalation composition according to claim 9 or 10 in the form of suspension for a pressurized metered dose inhaler or a nebulizer.

13. An inhaler device comprising inhalation composition according to any of claims 9 to 12.

14. A method for preparing orazipone particles, comprising the steps of: providing liquid feed stock comprising orazipone; atomising said liquid feed stock to create droplets; suspending said droplets in a carrier gas; passing said carrier gas and droplets suspended therein through a heated tube flow reactor under predetermined residence time and temperature history; and collecting the orazipone particles produced.

15. A method of claim 14 wherein the liquid feed stock is in the form of a solution.

16. A method according to claim 14 or 15, wherein the carrier gas is nitrogen gas or other inert gas.

17. A method according to any of claims 14 to 16, wherein the orazipone particles are collected using a particle collection system, which is an electrostatic precipitator, a cyclone or a filter.

18. A method according to claim 17, wherein the particle collection system is heated to prevent solvent re-condensation.

19. A method according to claim 18, wherein the liquid feed stock comprises methyl ethyl ketone as a solvent.

20. Inhalation particles incorporating orazipone, prepared using a method according to any of claims 14 to 19.