WO2001087277A2

WO2001087277A2 - Method of manufacturing particles

Info

Publication number: WO2001087277A2
Application number: PCT/GB2001/002137
Authority: WO
Inventors: David Alexander Vodden Morton
Original assignee: Vectura Limited
Priority date: 2000-05-15
Filing date: 2001-05-15
Publication date: 2001-11-22
Also published as: AU2001254995A1; WO2001087277A3

Abstract

Powders of pharmaceutically active material are prepared by providing a solution comprising the active material and a low-boiling fraction and expelling the solution through an orifice to form droplets, allowing the low-boiling fraction to evaporate and collecting the particles formed. The powders may be used in medicinal powders for inhalation.

Description

Method of Manufacturing Particles

The present invention relates to particles and to methods

5 of making particles. In particular, the invention relates to methods of making particles comprising a pharmaceutical substance .

It is known to administer to patients drugs in the form of fine particles, for example, in pulmonary administration a

-0 particulate medicament composition is inhaled by the patient. In order that the particles be carried deep into the lungs, the particles must be very fine, for example having an aerodynamic diameter of less than lOμm. Pulmonary administration is particularly suitable for medicaments which

.5 are intended to cure or alleviate respiratory conditions such as asthma and for medicaments which are not suitable for oral ingestion such as certain biological macromolecules.

Medicament compositions in the form of particles may also be administered via needle-less injection.

!0 Fine medicament particles suitable for pulmonary administration have been prepared by milling. However, it is difficult to control the morphology, size distribution, shape, density and other physical properties of the particles during the milling process.

'5 Fine medicament particles have also been prepared by spray drying. W09741833 describes a method for the manufacture of fine particles comprising biological macromolecules in which the biological macromolecules are slurried or dissolved in a liquid medium, usually an aqueous 0 medium, which is then atomised in a heated gas stream so that the liquid evaporates to form particles.

Supercritical fluids have been used in the production of aerosols for the precipitation of fine solid particles. Such methods have relied on the increased solubilising ability of compressed fluids above their critical temperature and pressure and the loss of that property upon reduction in pressure below the critical point . Fluids used include those which are gases at standard temperature and pressure and the most commonly used fluid is carbon dioxide. US5639441 discloses a method wherein a supercritical fluid and a solution of an active substance are mixed to give an immiscible mixture. That mixture is passed through an orifice into a low pressure region causing the precipitation of the active substance as fine particles.

The present invention provides a method of preparing a powder comprising particles comprising an active substance, the method comprising the steps of providing a solution comprising the active substance and a low-boiling fraction, expelling the solution through an orifice to form droplets, allowing the low-boiling fraction to evaporate, particles comprising the active substance being formed and collecting the particles as a powder.

The powder may be used directly as a medicament or may be subject to further treatment steps. For example, the powder may be combined with other materials such as flow aids.

Prior to expulsion of the solution through the -orifice, the major part and preferably substantially all of the active substance will be dissolved.

Preferably, the powders will be dry powders, that is the water content will be less than about 20%, preferably 10% and more preferably 5% by weight of the powder immediately after collection.

The term low-boiling fraction will be understood to refer to any compound having a boiling point below 20 °C at atmospheric pressure or to any combination of such compounds. Furthermore, the low boiling fraction will be understood not to be heated and pressurised above its critical point, that is, it will not be supercritical. The use of such a low- boiling fraction allows the evaporation and consequent formation of the particles to be carried out at ambient temperatures or at temperatures only slightly above ambient temperatures, for example at temperatures of 20 to 25°C or slightly above. Such temperatures are particularly suitable for the manufacture of powders comprising temperature- sensitive substances such as proteins, although the invention is not limited to such powders. In contrast, in conventional spray drying from aqueous solutions the air inlet temperature will generally be more than 50°C and often in excess of 100°C to ensure full evaporation. A further advantage over conventional spray drying of aqueous solutions is that the solutions used in the method of the invention will often have a comparatively low surface tension and/or viscosity and in consequence the method of the invention will often require a comparatively low amount of energy and deliver smaller particles with less degradation of the active substance due to shear forces .

When the solution of the active substance is expelled from the orifice, the low-boiling fraction will rapidly boil or evaporate off. Preferably the orifice is located in a nozzle, for example, a nozzle suitable for use in a spray dryer. The rapid generation of vapour will assist in dispersing the solution stream into droplets and it is therefore possible to operate the method of the invention using simple apparatus . Preferably, the orifice is a single fluid nozzle. The more complex nozzles commonly used in spray drying, for example, two fluid nozzles (which expel, for example, an aqueous liquid and a stream of air, the air being required to disperse the aqueous liquid into droplets) , spinning disc nozzles and ultrasonic nozzles are not always required but may be advantageously used in some cases. For example, a two fluid nozzle may be employed where it is desired to have a carrier gas to provide additional dilution.

It is believed that, as the solution approaches the orifice, the low-boiling fraction starts to vapourise, such that a proportion of the low-boiling fraction forms vapour bubbles within the liquid. Those bubbles expand rapidly and coalesce to form a high pressure and high velocity vapour stream which accompanies the liquid on exit from the nozzle. That vapour stream performs, at least to some extent, the same function as the driving gas of a two fluid nozzle, that is, it creates the shear force at the nozzle to provide the primary break-up of the solution. As the solution passes through the orifice, it forms into films which extend from the surfaces of the nozzle around the orifice. Droplets, known as primary droplets, are formed by vapour flow stripping liquid from the films. Secondary droplets are subsequently formed in the vapour stream, from suspended liquid filaments which are shattered by the high velocity vapour flow, and from bubbles bursting from liquid droplets of larger size. Assuming further fragmentation does not occur, and no solid condensation or particle-particle collisions occur, the resulting particle mass from a drying droplet is dependent on the non-volatile solute and solid mass contained within the droplet. The above description of the formation of the droplets and particles is for the purpose of illustration only and is not to be taken as limiting the invention.

The aerosol cloud formed from the spray is very dynamic and rapidly evolving. The evolution includes dramatic shrinkage in size of the droplets and changes in velocity over a relatively short time period. Surprisingly, it has been observed that, despite the complex nature of this process, the reproducibility is remarkably consistent, so that a given set of conditions will consistently provide particles of similar mass on different 5 occasions.

Preferably, the low-boiling fraction comprises at least 10%, advantageously at least 30% and more preferably at least 50%, more advantageously at least 70% and most preferably at least 90% of the solution by weight. The solution preferably

LO comprises less than 99.99% by weight of the low boiling fraction.

The low-boiling fraction consists of one or more compounds having a boiling point (at atmospheric pressure) below 20°C, advantageously below 10°C and preferably below 0 C.

L5 For example, the low-boiling fraction may consist of one or more compounds having a boiling point (at atmospheric pressure) in the range of -100°C to 20°C, advantageously in the range of -60 °C to 20 °C, preferably in the range of -50°C to 10°C and especially between -45°C and -10°C. ϋ0 Advantageously, the low-boiling fraction comprises a propellant suitable for use in aerosol formation and preferably the low-boiling fraction comprises a propellant suitable for use in an aerosol can device or a pressurised metered dose inhaler. Examples of suitable propellants and

25 their boiling points are given in Table 1. Such propellants have low viscosities and low surface energies which allow the solution to disperse easily into fine droplets. Generally each droplet will produce one particle and therefore in general terms the finer the droplets, the finer are the

50 particles produced. The low-boiling fraction is preferably non-toxic. However, the low boiling fraction may comprise pharmaceutically unacceptable compounds as long as those compounds fully evaporate so that the particles are essentially free of those compounds. Preferably the low- boiling fraction is non-flammable. The low-boiling fraction may comprise a halogenated hydrocarbon, especially a hydrofluoroalkane such as HFA 134a or HFA 227 or a mixture thereof .

The solution may comprise only the active substance and the low-boiling fraction. In that case, the solution may be prepared simply by dissolving the active substance in the low- boiling fraction.

Table 1 - Suitable Propellants

Propellants Boiling Point/ °C

Chlorofluorocarbon 12 -30

Hydrofluorocarbon 134a -26

Hydrofluorocarbon 227 -17

HCFC-22 Difluorochloromethane -41

HCFC-124 Chlorotetrafluoroethane 10 Dimethyl ether -25

Propane -42 n-butane -1 isobutane -12

HFA-125 Pentafluoroethane -55 HFA-152 Difluoroethane -25

The solution may also comprise one or more co-solvents. The term "co-solvent" is to be understood as including any solvent or solvent system which enhances the solubility of the active substance in the low-boiling fraction. Co-solvents will normally be polar liquids. Suitable co-solvents include, for example water, any one of or combination of organic solvents such as alcohols (e.g. methanol , ethanol) , ethers, halogenated hydrocarbons (dichloromethane, chloroform etc) , which provide a variable solvation capability, altering the polarity of the liquid appropriate to allow the solvation of the active substance. Many suitable solvents are non-toxic and physiologically tolerable. Co-solvents which are toxic or otherwise pharmaceutically unacceptable may, however, be used as long as they may be fully evaporated from the particles, either during the spray process or in a post-process conditioning. A co-solvent will be required where the active substance is not soluble to the required degree in the low- boiling fraction alone. For example, where the low-boiling fraction consists of HFA 134a or HFA 227 or a mixture thereof, it will sometimes be necessary to add a co- solvent such as ethanol and/or water. Whilst the co-solvent will not be as volatile as the low-boiling fraction it is preferred for the co-solvent to have a vapour pressure which is such that it evaporates from the droplets relatively quickly. In particular, the co-solvent should preferably be semi-volatile, that is, it should have a boiling point of between 2Tj°C and 110°C at atmospheric pressure. The co-solvent may be any organic or inorganic compound which has the required solvation and vapour pressure characteristics.

Appropriate co-solvents are, in particular, semi-volatile solvents or solvent systems which are suitable for adjusting the polarity of the solution in order to alter the solvation properties. Preferably, the selected co-solvent or co- solvents is/are non-combustible in the combined vapour/gas system generated in the course of the method of the invention. Preferred co-solvents are alcohols, such as ethanol and methanol, water, acetone, dichloromethane and other semi- volatile halogenated hydrocarbons, diethyl ether, acetonitrile, tetrahydrofuran, and aliphatic and aromatic hydrocarbon solvents having appropriate properties. Ethanol, dichloromethane, diethyl ether and water are especially preferred co-solvents. The co-solvent or co-solvents will preferably be present in the solution in a proportion of less than 30%, more preferably less than 20% by weight. Semi- volatile substances which are not co-solvents may also be included in the solution, for example, to influence the particle morphology as described below.

In the method of the invention it is possible by appropriate selection of the process parameters to produce particles having a desired morphology. The morphology of the particles is thought to depend on the nature of the droplet evaporation process. As the low-boiling fraction and any co- solvent evaporate the concentration of the dissolved solids increases to saturation point, after which the dissolved solids will be forced to precipitate. The process may be controlled by selection of the compounds comprising the low- boiling fraction and of any semi-volatile substance such as a co-solvent which will each evaporate at a respective rate dependent upon their respective vapour pressures and upon any heat transferred to the spray plume from gas surrounding the spray plume. Where a particular composition of low-boiling fraction (and co-solvents, if present) is used, a substantially reproducible morphology is observed, other factors being equal. A different composition of low-boiling fraction (and co-solvent, if present) will in general produce particles of a different morphology.

The general types of morphologies are summarised as follows. The first type is obtainable under conditions of very rapid evaporation, where particle formation is dominated by the boiling of the low-boiling fraction. The boiling phenomena produces many bubbles in the precipitating material (which may be a wet slurry or gel/glass) . These can result in very porous and sponge-like solid particles. The second type occurs where evaporation occurs less rapidly from the surface of the droplet. A solute gradient is created across the diameter of the droplet as a result. The solute precipitates at the more highly supersaturated surface if solute diffusion within the droplet is insufficient to cancel the gradient. Often this surface crust is permeable to subsequent evaporation, or a portal is left for evaporation. If not, vapour pressure may build up and the crust may shatter. Consequently, either hollow cenospheres are produced or crust fragments.

The third case occurs where evaporation occurs still less rapidly from the surface of the droplet. In this case growth is allowed (generally by a slower process) to occur to produce a substantially solid particle that is, a particle containing no or few voids. Generally this is observed where high solubility systems and low evaporation rates are involved. Low evaporation rates may occur where the solution contains particular excipients or active substances. It is believed that the vapour pressure of the low boiling fraction or co- solvents may, in those cases, be reduced by association with the excipient or active substances.

In method of the invention, these conditions are controlled by providing the correct evaporation rate and solution nature, and by correct choice of the composition of the low-boiling fraction the co-solvents and other liquids. Again, despite the complex nature of this phenomena, we have surprisingly shown consistent behaviour for a given set of conditions (e.g. solution composition, orifice type and temperature) . The solution may also comprise one or more non-volatile substances (in addition to the active substance or active substances which will themselves be non-volatile) . The term non-volatile substance is to be understood as referring to any substance having a vapour pressure at 20°C of not more than 0.5 kPa, more preferably not more than 0.1 kPa and most preferably not more than 0.05 kPa. Such a component will not evaporate or will evaporate only slowly from the droplets and will therefore be present at least to some extent in the particles. The inclusion of one or more non-volatile substances in addition to the active substance will therefore generally lead to the formation of larger particles than would otherwise be the case. The purpose of the non-volatile substance (s) may essentially be to influence the particle morphology, and/or to act to stabilise the active substance during spray-drying and/or during storage, pH modifiers or spray nozzle valve lubricants. Preferably, the non-volatile substance is an excipient, that is, a material which in combination with the powder forms a solid product at room temperature and which is not pharmaceutically active. The excipient may act as a solubilising aid for the active substance or for any other excipients, for example, the excipient may be oligolactic acid or polylactic acid (as described in Respiratory Drug Delivery VII, 2000, pages 83- 89) , a polyoxyethylene-based dispersant, a polyester-based dispersant, oleic acid, a bile acid, an ethoxylate of oleyl alcohol or polyvinylpyrrolidone .

Where the particles are for pulmonary administration, the excipient may be a dispersal agent for the promotion of the dispersal of the particles, upon actuation of the inhaler device. Advantageously the dispersal agent includes one or more compounds selected from amino acids and derivatives thereof, and peptides and polypeptides having molecular weight from 0.25 to 1000 KDa, and derivatives thereof. It is particularly advantageous for the dispersal agent to comprise an amino acid. Alternatively, the dispersal agent may comprise a phospholipid or a derivative thereof for example, - li the dispersal agent may be a lecithin such as soya lecithin. The dispersal agent may comprise one or more surface active materials, in particularly materials that are surface active in the solid state, which may be water soluble, for example lecithin, in particular soya lecithin, or substantially water insoluble, for example solid state fatty acids such as lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid, or derivatives (such as esters and salts) thereof. Specific examples of such materials are: magnesium stearate; sodium stearyl fumarate; sodium stearyl lactylate; phospatidylcholines, phosphatidylglycerols and other examples of natural and synthetic lung surfactants; Liposomal formulations; lauric acid and its salts, for example, sodium lauryl sulphate, magnesium lauryl sulphate; triglycerides such as Dynsan 118 and Cutina HR; and sugar esters in general. Magnesium stearate is a preferred dispersal agent. Other possible additive materials include talc, titanium dioxide, aluminium oxide, silicon dioxide and starch.

The excipient may be an agent having a strong taste or flavour such as menthol.

The excipient may be lactose, poloxamer, PEG 2000, or polyvinylpyrrolidone (PVP) . Other suitable excipients include polyglycolic acid, polylactic-polygylcolic acid copolymer, hydroxy propyl methyl cellulose and other modified celluloses, fatty acids and fatty acid derivatives including fluorinated fatty acids, amino acids and derivatives, polyamino acids, peptides (e.g. albumen), sugars for example, mannitol, sorbitol and trehalose, PEG especially higher molecular weight-PEGs, ascorbic acid, citric acid, phospholipids and derivatives, inorganic salts, Carbopol , cyclodextrins, surfactants such as the Spans, Tweens and Pluronics and saccharin. The solution may include substances known as stabilisers which stabilise proteins for example, glycerol , PEG, PVP and amino acids. Excipients such as magnesium stearate, amino acids e.g. leucine, fatty acids or fatty acid derivatives and phospholipids such as lecithin may, individually or in combination, form a protective layer around the active particles, protect the active particles from moisture, make the active particles more easily disaggregated and/or impart controlled release properties on the active material . Any non-volatile components will preferably be pharmaceutically acceptable.

It will be apparent from the above that a single nonvolatile substance may have more than one function when included in the solution. For example, an amino acid may stabilise a protein active material during the drying process, promote the dispersal of the particles when the particles are dispensed from an inhaler, and form a protective layer around the particles .

The solution will preferably be substantially free of suspended particles and emulsified liquids. However, it may be advantageous to include particular excipients or dispersal agents, for example, magnesium stearate in the form of particles suspended in the solution of the active substance.

In order to prevent the solution from boiling (with consequent loss of the low-boiling fraction) before the solution is expelled from the orifice, the solution may be maintained unpressurised at a temperature below its boiling point. However, that will lead to a lower rate of evaporation and it is preferred to maintain the solution at or around ambient temperature under sufficient pressure to prevent boiling. When the solution is maintained under pressure, that pressure will act to expel it from the orifice and it will often not be necessary to pump the solution through the orifice. A valve or other flow regulating system may be used to control the rate of expulsion from the orifice. Additionally, an expansion chamber such as that present in a pressurised metered dose inhaler actuator or the like may be present as part of the nozzle system.

Preferably, the orifice communicates with a chamber. The chamber may be of the type used in conventional spray drying having for example, an approximately cylindrical upper section and a tapering lower section. The dimensions and shape of the chamber will preferably be such that the droplets may circulate within it and dry to form particles whilst keeping impacts with the walls of the chamber to a minimum. The evaporation of the low-boiling fraction and any co-solvent present in the droplets will require the input of heat energy corresponding to at least the heat of vaporisation of those substances . In order to supply this heat energy and to prevent an undesirable drop in the temperature of the chamber, a current of carrier gas may be injected into the chamber. Preferably, the current of carrier gas, which is preferably air, serves to promote a swirling motion of the droplets and increases the rate of drying and keeps them airborne whilst they dry. The current of gas may also serve to carry the particles through the apparatus to a separator, where the particles are separated from the gas. The current of gas may be at ambient temperature or alternatively, where it is desired to increase the rate of evaporation, the current of carrier gas may be of a heated gas. Advantageously the flow of the gases in the chamber is substantially laminar in order to minimise agglomeration. The pressure in the chamber may be maintained at below atmospheric pressure. This increases the rate of evaporation and also prevents leaks of the vapour from the chamber.

The word "vapour" as used herein refers to the products of the evaporation of the volatile components of the solution, that is the low-boiling fraction, any co-solvents and any other volatile components. The word "gas" as used herein refers to gases, such as air or nitrogen, which have not been derived from evaporation or boiling of the liquids of the solution.

5 After the droplets have dried to form the particles, the particles will be in the form of a cloud or dispersion entrained with the vapours of the evaporated low-boiling fraction and co-solvents, if present, and optionally with a carrier gas such as air or nitrogen. It is then necessary to

.0 separate the particles from those vapours and gases. The separation may be a settling process in which the particles fall under gravity. However, where the aerodynamic diameter of the particles is very small, for example, less than lOμm, such settling processes will be slow and it is therefore

-5 preferred to use a separation device which is especially suitable for the collection of very fine particles . The step of collecting the particles may involve a filter, for example, a bag filter, a cartridge filter or a sintered metal filter. Preferably, the filter is a reverse jet filter to enable

JO easier recovery of the collected particles. The step of collecting the particles preferably involves a cyclone, and advantageously involves an impactor or virtual impactor. In some cases it will be desirable to use a combination of two or more of those methods of separation, for example the

J5 gas/vapour/particle mixture may be passed through one or more cyclones and then through a bag filter. This may be conducted to selectively fractionate and collect more than one size fraction, where a specifically narrow or selected size fraction is required.

SO It will often be desirable to produce particles having a selected range of sizes. As noted above, the size of the particles produced will to some extent depend on the droplet size which will in turn be determined by such variables as the size and configuration of the orifice, the properties (such as surface tension, viscosity, and concentration of the active substance) of the solution, the vapour pressure of the liquid, the size and shape of the orifice and design of the nozzle,

5 and the rate of expulsion of the solution from the orifice. In practice the rate of expulsion of the solution from the orifice, the size and configuration of the orifice and the concentration of active substance in the solution may be most conveniently adjusted. Those variables will desirably be

.0 selected so as to maximise the proportion of the particles produced which fall within the desired range of sizes. For example, where it is intended that the particles be used as drug particles in a medicament formulation for pulmonary administration, at least 50% and preferably 90% by weight of

.5 the particles should in general have an aerodynamic diameter of less than lOμm, preferably less than 5μm and more preferably less than 2μm (in order that they penetrate to the lower lung) . The lower limit of the diameter may be as small as lnm but is advantageously greater than O.Olμm (particles of

JO diameter less than O.Olμm tend to be exhaled rather than retained in the lung) .

Where the particles are intended for use in needle-less injections, that is, to be carried through the skin by a blast of propellant gas, they will desirably have diameters of not

!5 more than 50μm.

The composition of the solution and the conditions of evaporation may be selected so as to produce hollow or porous particles. Such particles will have a lower aerodynamic diameter than a particle of the same mass which is not hollow

SO or porous and therefore such particles may be advantageous for pulmonary administration. Agglomerates of primary particles of diameter 0.5μm or below may be formed. Those agglomerates may be fractal agglomerates, chain agglomerates or spherical agglomerates. Advantageously, the solution also comprises a non-volatile substance, for example, an excipient which, as the agglomerate forms, provides a whole or partial coating on the surface of the agglomerates which increases the texturing or roughness of the surface.

Preferably, the solution of the active substance and/or the particles of the active substance are not liposomal formulations .

Preferably at least some of the low-boiling fraction is recycled, for example, by feeding the vapours after separation of the particles into compression or refrigeration apparatus which will condense the low-boiling fraction. The co-solvents may also be recycled.

Preferably, the method of the invention is run as a continuous process over a period of at least one minute, advantageously at least 5 minutes, more preferably at least one hour. Preferably, within that time, the process produces at least 0.5g of particles, more preferably at least 5g of particles . The active substance is a medicinal substance, that is, a substance which has therapeutic or prophylactic effects. Active substances which may advantageously be included in the formulation include those products which are usually administered orally by inhalation for the treatment of disease such as respiratory disease, for example, β-agonists.

The active substances may be a β₂-agonist, for example, terbutaline, salbuta ol, salmeterol and formoterol. If desired, the solution may comprise more than one of those active substances, provided that they are compatible with one another under conditions of storage and use. Preferably, the active substance is salbutamol sulphate. The active substance may be ipratropium bromide. References herein to any active substance is to be understood to include any physiologically acceptable derivative. In the case of the β₂-agonists mentioned above, physiologically acceptable derivatives include salts, especially sulphates.

The active substance may be a steroid, which may be beclomethasone dipropionate, budesonide, or fluticasone. The active substance may include a cromone which may be sodium cromoglycate or nedocromil . The active substance may include a leukotriene receptor antagonist.

The active substance may be a carbohydrate, for example heparin.

Active particles for pulmonary administration may advantageously comprise an active substance for systemic use provided that it is capable of being absorbed into the circulatory system via the lungs. The particles may be suitable for use for the local administration of other active substances, for example, pain relief agents, anti -cancer agents, anti-viral agents or antibiotics. Preferably, the active substance is a biological macromolecule, for example, a polypeptide, a protein, or a DNA fragment. The active substance may be selected from the group consisting of insulin, human growth hormone, cytokines, cyclosporin, interferon, gonadotrophin agonists and antagonists, erythropoietin, leptin, antibodies, vaccines, antisense oligonucleotides, calcitonin, somotastatin, parathyroid hormone, alpha-1-antitrypsin, Factor 7, Factor 8, Factor 9, and estradiol . Advantageously the active substance is selected from the group consisting of insulin, human growth hormone, cytokines, cyclosporin, interferon, gonadotrophin agonists and antagonists, erythropoietin, leptin, antibodies, vaccines and antisense oligonucleotides.

The invention also provides a powder comprising particles comprising an active substance obtainable by the method described above. Such particles may be porous or hollow or may have surface projections or wrinkles. It is believed that the presence of surface projections or wrinkles reduces the forces of attraction between the particles and thereby reduces the cohesiveness of the particles and enables those particles to be dispersed more easily, for example during pulmonary administration. Pollen grains are known to have surface projections and it is believed that those projections similarly aid in the dispersal of pollen into the air. The process of the invention may provide particles having a pollen-like surface morphology. The powder may advantageously have a density which is less than 70%, for example less than 50%, preferably less than 25%, most preferably less than 10% of the density of the solid material having the same composition as the powder. The density of the powder as referred to herein will be understood to be the density of a sample of a powder consisting of the particles and may be measured by pouring a known weight, for example 50g, of the powder into a measuring cylinder, tapping the cylinder until the powder settles to constant volume and measuring the volume of the powder. The density of the solid material will, in general, be known but may be measured by any suitable method.

The particles according to the invention may be suitable for subsequent use in any administration form, but are especially advantageous for use in pressurised metered dose inhalers, dry powder inhalers or needle-less injection devices. If appropriate or if desired, the particles may undergo subsequent processing and formulation steps before their use in such applications.

Accordingly, the invention also provides a pharmaceutical composition, for example, a composition for inhalation comprising a powder according to the invention. The composition for inhalation may be a dry powder for use in a dry powder inhaler. In that case, the powder according to the invention may be used alone or may be mixed with other dry materials such as excipients, flavour modifiers and flow aids.

Alternatively, the composition for inhalation may comprise a propellant and be suitable for use in a pressurised 5 metered dose inhaler. In that case the powder will be present as a suspension in the propellant. Such formulations may contain other materials such as dispersents, and surfactants.

The powders according to the invention can, in general, be included in compositions for inhalation in the same way as -0 for currently known milled icronised drug powders and therefore the development of appropriate formulations will be within the ability of the skilled person.

Certain embodiments of the invention will now be described by way of example only with reference to the -5 accompanying drawing, in which:

Figure 1 is a schematic representation of an apparatus for carrying out a method according to the invention;

Figure 2 is a scanning electron micrograph (SEM) image of particles of beclomethasone diproprionate made using one form JO of method according to the invention,

Figure 3 is a SEM image of particles of beclomethasone dipropionate similar to those of Figure 2 but at higher magnification; and

Figure 4 is a SEM image of particles of budesonide . J5 With reference to Figure 1, a system for manufacturing the particles comprises a reservoir 1 for holding the solution. The reservoir 1 is equipped with means 2 for stirring the solution. The reservoir and its immediate location are within a temperature control zone 3 , in which a SO constant temperature is maintained (including the reservoir and contents) . The solution is introduced into the reservoir through an inlet pipe (not shown) and leaves the reservoir via an outlet pipe 4, which leads to a single fluid nozzle 5. A valve 6 or other flow regulating system may be used to control the rate of expulsion from the orifice. An expansion chamber (not shown) may be present as part of the nozzle system. The nozzle 5 is located in the upper region of a spray chamber 7 5 and is surrounded by carrier gas which has been heated to the required temperature and introduced into the chamber via carrier gas line 8 and gas inlets 9. The reservoir 1 and the nozzle system 5, and the drying chamber 7 may be independently maintained at different temperatures.

-0 As the solution is expelled from the nozzle 5 it generates a spray plume of droplets. The low-boiling fraction and the co-solvents, if present, evaporate inside the chamber 7 to form particles. Those particles are carried via line 10 into a particle classification and collection system, which in

-5 the embodiment shown is a cascade of cyclones 11 which separates the majority of the particles from the gas/vapour stream. If desired, an inertial classifier or a virtual impactor may be used as well as or instead of the cyclones. The gas/vapour stream then passes through a high efficiency

JO filter 12 where the remainder of the particles are separated. The vapour/gas mixture then passes into a refrigerated zone 13 where the vapours are condensed and collected for recycling. The gases and residual vapour are then fed to an exhaust. Reference numeral 14 designates a pump. The reservoir 1,

!5 chamber 7, cyclones 11, filter 12 and connecting transport lines are within a second temperature control zone 15, which is insulated from the surroundings. Temperature control zone 3 is wholly contained within temperature control zone 15 and may be maintained independently at a different temperature

SO therefrom.

Where it is desired to maintain the system at a pressure greater than atmospheric pressure, the carrier gas will be fed into the chamber inlet under positive pressure, driven by, for example, a fan. Where it is desired to maintain the system at a pressure lower than atmospheric pressure, a gas pump will be provided in the region of the exhaust. The suction of the gas pump will draw the carrier gas through the system. In either case, the carrier gas carries the vapour and particles through the system.

Example 1

Beclamethasone diproprionate (BDP) was dissolved in an 85:15 by weight hydrofluorocarbon 134a: ethanol mixture to form a 0.5% w/w solution. That composition was maintained at 25°C in a reservoir at about 7 bar and sprayed at a spray rate of 50μl/sec through a nozzle having a circular orifice into a 2 litre vessel. The vessel was maintained at approximately 25°C by heating carrier air, which was pumped into the vessel at a flow rate of 50 1pm. The particles formed were separated from the air/vapour steam by means of drawing them onto a filter using a pump. The particles so obtained are shown in Figure 2. The particles were substantially in the size range of 0.5 to lOμm and had a highly porous structure. Figure 3 shows at higher magnification than Figure 2 particles of beclamethasone diproprionate made by a similar method.

A powder for inhalation was then prepared by mixing lg of the beclamethasone diproprionate powder with 9g of a coarse carrier lactose in a tumbling mixer for 5 minutes at 42rpm. The resulting powder was suitable for firing from a suitable inhaler device such as the Cyclohaler. In vitro tests, for example in a twin stage impinger, gave a fine particle fraction (i.e. having a diameter of less than 5μm) of greater than 50%. Example 2

Insulin is dissolved in a mixture of hydroflurocarbon 227 with ethanol and water as co-solvents (85:7.5:7.5) to give a 0.5% w/w solution of insulin. The solution is maintained at 25°C in a reservoir and sprayed from the reservoir into a vessel maintained at approximately 35°C by heating the carrier air. Dry particles of insulin are produced.

A powder for inhalation comprising the insulin particles is produced in the same way as for Example 1.

Example 3

Budesonide was dissolved in a mixture of 85 parts of hydrofluorocarbon 134a and 15 parts of ethanol. The concentration of budesonide was approximately 0.1% w/w. The solution was maintained at 25°C and sprayed from the reservoir into a vessel maintained at approximately 25°C by heating the carrier air. Dry particles were produced. The particles, shown in Figure 4, were substantially in the size range of from 0.5 to 3μm, and visibly more dense than the particles obtained in Example 1.

In one experiment, the solution was sprayed over a period of 1 hour with approximately 5g of the powder being collected in a cyclone. A powder for inhalation comprising the budesonide powder may be prepared by the method of Example 1.

Example 4

Cyclosporin is dissolved in a mixture (85:15) of hydrofluorocarbon 227 with ethanol as co-solvent. The composition is maintained at 25°C and sprayed from the reservoir with a vessel maintained at approximately 35°C by heating the carrier air. Dry particles are produced.

The cyclosporin powder may be included in a powder for inhalation by the same method as in Example 1.

Claims

5 1. A method of preparing a powder comprising particles comprising an active substance, the method comprising the steps of providing a solution comprising the active substance, and a low-boiling fraction, LO expelling the solution through an orifice to form droplets, allowing the low-boiling fraction to evaporate, particles comprising the active substance being formed and collecting the particles as a powder. L5

2. A method as claimed in claim 1, wherein the low-boiling fraction is present in the solution in a proportion of at least 50% by weight.

3. A method as claimed in claim 1 or in claim 2, wherein the low-boiling fraction consists of compounds having a boiling

JO point in the range of -100°C to 20°C.

4. A method as claimed in any of claims 1 to 3 , in which the low-boiling fraction comprises a propellant suitable for use in an aerosol can device or a pressurised metered dose inhaler.

!5 5. A method as claimed in any of claims 1 to 4 , in which the low-boiling fraction comprises a halogenated hydrocarbon.

6. A method as claimed in claim 5, in which the low-boiling fraction comprises HFA 134a, HFA 227 or a mixture of both.

7. A method as claimed in any of claims 1 to 6 , in which the 10 solution also comprises one or more co-solvents.

8. A method as claimed in claim 7, in which the solution comprises one or more co-solvents selected from alcohols, water, acetone, semi -volatile halogenated hydrocarbons, diethyl ether, acetonitrile, tetrahydrofuran and semi-volatile

_'5 aliphatic and/or aromatic hydrocarbon solvents.

9. A method as claimed in any of claims 1 to 8, in which the solution comprises at least one non-volatile substance.

10. A method as claimed in any of claims 1 to 9 , in which the solution is maintained under pressure prior to being expelled from the orifice.

11. A method as claimed in any of claims 1 to 10, in which the orifice is a single fluid nozzle.

12. A method as claimed in any of claims 1 to 11, in which the orifice communicates with a chamber via a valve or flow regulator.

13. A method as claimed in claim 12, in which a current of carrier gas is supplied to the chamber.

14. A method as claimed in claim 12, in which the current is of heated air or nitrogen.

15. A method as claimed in any of claims 12 to 14, in which the pressure in the chamber is below atmospheric pressure.

16. A method as claimed in any of claims 1 to 15, in which the step of collecting the particles involves a filter.

17. A method as claimed in any of claims 1 to 16, wherein the step of collecting the particles involves one or more cyclones .

18. A method as claimed in any of claims 1 to 17, in which the step of collecting the particles involves an impactor or a virtual impactor.

19. A method as claimed in any of claims 1 to 18, in which the step of collecting the particles involves size selection.

20. A method as claimed in any of claims 1 to 19, in which at least some of the low-boiling fraction is recycled.

21. A method as claimed in any of claims 1 to 20, in which at least 50% of the particles by weight have an aerodynamic diameter of less than lOμm.

22. A method as claimed in any of claims 1 to 21, in which the composition of the solution and the conditions of evaporation are selected so as to produce porous or hollow particles .

23. A method as claimed in any of claims 1 to 22, in which the active substance is a product which may be administered

5 orally by inhalation for the treatment of respiratory diseases .

24. A method as claimed in claim 23, in which the active substance is selected from the group consisting of β-agonists, steroids, cromones, and leukotriene receptor agonists.

10 25. A method as claimed in any of claims 1 to 24, in which the active substance is a biological macromolecule. 26. A method as claimed in claim 25, in which the active substance is selected from the group consisting of polypeptides, proteins and nucleic acid fragments.

L5 27. A method as claimed in claim 25, in which the active substance is selected from the group consisting of insulin, human growth hormone, cytokines, cyclosporin, interferon, gonadotrophin agonists and antagonists, erythropoietin, leptin, antibodies, vaccines, antisense oligonucleotides,

20 calcitonin, somotastatin, parathyroid hormone, alpha-1- antitrypsin, Factor 7, Factor 8, Factor 9, and estradiol .

28. A method of making particles substantially as described herein with reference to Figures 1 to 4.

29. A powder comprising particles comprising an active

25 substance obtainable by the method of any of claims 1 to 28.

30. A powder as claimed in claim 29, having a density which is less than 70% of the density of a solid material having the same composition as the particles.

31. A powder comprising particles comprising an active 30 material substantially as described herein.

32. A composition for inhalation comprising a powder as claimed in claim 29.

33. A composition as claimed in claim 32 which is a dry powder for use in a dry powder inhaler.

34. A composition as claimed in claim 32 which also comprises a propellant and is suitable for use in a pressurised metered dose inhaler.

35. A composition for inhalation substantially as described herein with reference to Figures 1 to 4.