PARTICULATE DRUG COMPOSITIONS AND THEIRUSES

The present invention relates to particulate drug compositions, including the method of formation and the use of such compositions. In particular the present invention relates to the use of combination drug particles, which may be capable of exerting synergistic effects, in the treatment of pulmonary diseases and the use of the lung as a portal for systemic therapy with inhaled compositions.

There are many known respiratory diseases, the most common of which include diseases such as emphysema, respiratory distress syndrome, asthma, COPD

(Chronic Obstructive Pulmonary Disease) and Cystic Fibrosis. These diseases place common symptoms upon the patient, such as the irritation and narrowing of the airways. Consequently, air is trapped in the lungs and obstructive lung diseases follow, causing shortness of breath on exertion, chest tightness and hyperventilation, for example.

Although applicable to a wide range of different pulmonary diseases, particular reference will hereinafter be made to the application of the present invention in the treatment of asthma. It will be understood, however, that the description is provided without prejudice to the generality of the invention, and its range of applications.

Inhalation has become the primary route of administration for the treatment of asthma. Due to the common occurrence of asthma and other related diseases, vast amounts of research has been undertaken to find the most effective and efficient inhalation devices which can promptly administer medicaments to the lungs. The Metered Dose Inhaler (MDI) has more than a 45 year history of being used as a device for drug delivery. The Metered Dose Inhaler often comprises a suspension of fine micronised drug particles in a propellant gas. Other forms of drug delivery to the lungs include Dry Powder Inhalers (DPI) and nebulisers. Recent particle engineering has, therefore, been directed towards MDI and DPI platforms, either as the active pharmaceutical ingredient in a suspension based pressurised MDI form, or a carrier based DPI formulation or within an agglomerated DPI formulation.

Pharmaceutical issues such as chemical and physical stability and therapeutic and clinical performance are often related to the solid state properties of active pharmaceutical ingredients. Current industrial approaches for their preparation are via a molecule to crystal, crystal to particle and particle to dosage form strategy. There are, however, limitations to this approach in that conventional crystallisation techniques, typically, require the use of mechanical comminution techniques, such as micronisation, for the processing of respirable sized particles. These destructive based techniques are severely limited by long processing times, low yields, high polydispersity in particle size and can adversely affect a whole range of highly important physicochemical properties. Such properties include the formation of amorphous regions which may render particles thermodynamically unstable under elevated conditions of relative humidity and temperature.

An amorphous state can be classified by the absence of three-dimensional long- range order in comparison to that observed in a crystal. It is possible that amorphous materials, as described above, may recrystallise if the molecular mobility within the region is high enough to allow such reordering.

In the pharmaceutical industry, especially with regard to suspension based MDI and DPI formulations, the amount of amorphous material present within a processed bulk powder is often unpredictable. This can lead to batch-to-batch variation in material performance during a product's lifespan.

The present invention therefore aims to provide a single droplet to particle approach with specific control of the surface characteristics and surface geometry of the colloidal and nanometre-sized crystalline particles.

The treatment of asthma usually involves more that one type of required medication, for example a corticosteroid and a /5 ₂ -agonist. The reason for treating asthma by use of two different medications is because only in combination can these medications overcome the symptoms caused by asthma. A corticosteroid does not relieve the symptoms of asthma instantly, but is instead a preventative medication which helps to suppress inflammation and reduce the swelling of the lining in anyone who has frequent need of relievers or who has severe symptoms. Corticosteroids may be broken down into two sub groups, namely glucocorticoids and mineralocorticoids, however, mainly glucocorticoids are of interest in the regulation of inflammation.

Conversely, the fø-agoiiist is used in order to relieve the symptoms brought on by asthma in a patient. Although a /3 ₂ -agonist is able to relieve the symptoms of asthma, it does not however cure asthma. fø-agonists can also be broken down into two sub groups, namely short-acting /3 ₂ -agonists and long-acting /3 ₂ -agonists.

Short-acting /3 ₂ -agonists are bronchodilators. They provide quick relief of symptoms of acute asthma episodes. They do this by relaxing the muscles lining of the airways that carry air to the lungs (bronchial tubes), usually within five minutes, increasing airflow and making it easier to breathe. They can relieve asthma symptoms for up to six hours. They do not, however, control inflammation of the bronchial passages.

Long-acting /3 ₂ -agonists, as their name suggests, are long-acting bronchodilators for long-term use. Unlike short-acting bronchodilators, their effects usually last for twelve hours, and are used to give a smooth symptomatic effect. Although patients have reported improved symptom control, these drugs do not replace the need for routine preventers, and their slow onset means that short-acting bronchodilators may still be required.

To improve the practice of dual therapy for the treatment of asthma, inhalers have

been developed which combine both corticosteroids and /3 ₂ -agonists, thereby reducing the number of inhalers that an asthma patient would normally require. These inhalers, however, combine the corticosteroids and /3 ₂ -agonists only as far as creating a physical mixture of the two separate drugs with or without excipients.

The resultant inhalation powder is then loaded into the inhaler device. With regard to DPI formulations, this method of mechanically mixing two different drugs to produce the final composition has certain drawbacks. For example, some powder manufacturing methods may produce dry powders that are highly charged and therefore very cohesive. It is therefore difficult to maintain the ratio of drugs in each dose constant, which may have serious consequences if a very potent drug is delivered in a much higher yield than expected. Another problem encountered, which the present invention aims to address, is the difficulty in calculating and delivering the correct ratios of bronchodilators and antiinflammatories, due to factors which affect the effects of the respective drugs. Such factors include, the size or consistency of the drug particles in each dose which cannot easily be controlled and issues relating to stability of the actives and subsequent effects on their delivery within a suspension formulation or in a carrier based dry powder formulation.

In this way, the respective drug particles may come into contact with the same target cell in their different proportions and at different temporal periods, thereby preventing the synergistic effects of the two different drugs (which may influence the processing and dispersion of the APIs via an inhaler device). For example, a conventional label dose variation between budesonide, a corticosteroid and formoterol, a long-acting /^-agonist, is 400μg to 12μg. Due to the high proportion of corticosteroid compared to the /3 ₂ -agonist, the probability of both active ingredients being delivered to the same target cell simultaneously, via a physical mixture, may be low. Furthermore, the corticosteroid dose is usually varied while

the /3 ₂ -agonist dose is kept constant. This gives rise to further variability in the likelihood of co-delivery of the two active agents.

Accordingly, the present invention aims to address the aforementioned problems associated with this type of drug delivery.

An alternative use of the present invention may be made by administering medication for, not only pulmonary diseases, but also for systemic diseases and therapy. In this way the lung may be used as a portal for systemic drug therapy. For example, a bifunctional combination particle medicament for the treatment of two factors, such as thrombosis and pain, may be inhaled for systemic therapy via the lung.

According to an aspect of the present invention, there is provided a combination drug particle for use as a pharmaceutical composition, wherein the drug particle has a crystalline form and is a combination of at least two different active agents.

The at least two different active agents may be crystalline with well defined polymorphic forms.

Known combination particles, as disclosed in WO 02/28377 for example, are formed from processes which do not allow effective control of the crystallisation process. WO 02/28377 describes a method of preparing particles incorporating a combination of two or more active ingredients which includes the step of providing

a temperature gradient within an aerosol flow reactor to induce crystallisation of the particles. Due to the uncontrolled nature of the crystallisation process, it is probable that a significant proportion of amorphous particles may result, which is highly undesirable for pharmaceutical particles intended for administration by inhalation. This is caused by different active ingredients having different optimum crystallisation temperatures. Consequently, where the different active ingredients are crystallised under the same conditions, the combination particle may include both a crystalline active ingredient and an amorphous active ingredient.

The behaviour of amorphous phases may directly influence manufacturability, stability, shelf-life and delivery characteristics of a formulated drug product. Amorphous solids are thermodynamically unstable and experience a continuous driving force towards a more stable crystalline state. The activation energy barrier towards recrystallisation may be continually lowered on exposure to water vapour and/or heat, absorption and induction of which respectively, may lead to physicomechanical instability due to increased molecular motion and greater free volume within the amorphous solid. This possible transformation will directly affect product performance particularly under varying storage conditions of humidity and temperature.

The method of forming a combination drug particle, described herein, involves the application of ultrasonication to induce nucleation and crystal growth of the particles. Unlike the methods already known, as described above, this method

allows greater control over the crystallisation process thereby generating significantly less undesirable amorphous particles than methods of the prior art.

The combination drug particle of the present invention may further comprise an excipient. The excipient may affect the active ingredient by enhancing its therapeutic effect, modifying its stability properties and allow avoidance of alveolar macrophage uptake. The excipient may be a lung surfactant, for example.

By combining multiple active ingredients (for example a bronchodilator and an anti-inflammatory substance) into a single particle it is possible to attain synergistic effects. Combination drug particles can be brought into contact with bronchial cells of a patient, when the combination drug particle is inhaled, to administer the effects of each agent to individual cells simultaneously.

The combination drug particle has a crystalline form. The particle size of the final combination drug particle may be controlled by modification of the conditions during the formation of the particle. More details are provided below in the description.

The active agents forming a solution in a solvent, may comprise one or more β%- agonists. Such fø-agonists may be at least one selected from salbutamol, formoterol, fenoterol, procaterol, salmeterol, clenbuterol, bitolterol, broxaterol, picumeterol, mabuterol, terbutaline, isoprenaline, orciprenaline, metaprotereuol, pirbuterol, bambuterol and pharmaceutically acceptable esters, acetals and salts

thereof. The combination drag particle may therefore comprise a long-acting bronchodilator and/or a short-acting bronchodilator.

The active agents forming a solution in a solvent, may comprise a corticosteroid. Further, the corticosteroid may be a glucocorticoid. The corticosteroid may be at least one selected from betamethasone, fluticasone, budesonide, tipredane, dexamethasone, bectomethasone prednisolone, mometasone, rofleponide, flumethasone, flunisolide, ciclesonide, deflazacort, cortivazol and pharmaceutically acceptable esters, acetals and salts thereof.

The combination drug particle may therefore comprise at least two different substances, such as two different corticosteroids for example. Alternatively, the combination drag particle may comprise two different corticosteroids and a β ₂ - agonist. hi another embodiment, the combination drag particle may comprise one corticosteroid and one fø-agonist. The combination will depend upon the requirements of the individual patient, which may be determined by symptoms as diagnosed by a doctor for example, as will the proportions of the active agents contained within the combination drag particle.

The active agents forming the solution from a solvent, may comprise an anticholinergic. More particularly, the anticholinergic may be a muscarinic antagonist. The muscarinic antagonist may be at least one selected from ipratropium, atropine, oxitropium and pharmaceutically acceptable esters, acetals and salts thereof. An anticholinergic agent is a member of a class of

pharmaceutical compounds which serve to reduce the effects mediated by acetylcholine in the central nervous system and peripheral nervous system. When used with a fø-agonist bronchodilator for the therapy of asthma, some anticholinergics appear to provide bronchodilation beyond that achieved by either agent used alone. Narrowing of the airways in an asthma sufferer, is enhanced by the action of a specific group of nerves, called cholinergic nerves, which release the capital transmitter acetylcholine from the nerve endings to exert their effects. By blocking the effects of acetylcholine at these nerve endings, anticholinergic agents cause bronchodilation. Muscarinic antagonists work by inhibiting muscarinic receptors in the bronchial airways which lead to muscle relaxation, bronchodilation and improving lung function. ^" Muscarinic antagonists are particularly effective in the treatment of COPD.

Both muscarinic antagonists and fe-agonists have a similar function, in that they cause bronchodilation, but they differ in their mechanistic routes of action in performing this function. Accordingly, the combination drug particle of the present invention may comprise active agents, such as a /3 ₂ -agonist and a muscarinic antagonist, thereby providing dual therapy. In addition, the combination drug particle may also comprise an additional active agent type, such as a corticosteroid, thereby providing a triple therapy action. Alternatively, the combination- drug particle may simply comprise a combination of two different types of muscarinic antagonists.

The active agents forming a solution from a solvent, may comprise a leukotriene antagonist. More particularly, the leukotriene antagonist may be a montelukast. Leukotrienes are autocrine and paracrine eicosanoide lipid mediators derived from arachidonic acid by 5-lipoxygenase. The cysteinyl-leukotrienes act at their cell surface receptors CysLTl and CysLT2 on target cells to contract bronchial and vascular smooth muscle, to increase permeability of small blood vessels, to enhance secretion of mucus in the airway and gut, and to return leukocytes to sites of inflammation. As well as mediating inflammation, these receptors are able to induce asthma, whereby reducing the airflow to the alveoli. Accordingly, montelukast is a leukotriene receptor antagonist for the maintenance treatment of asthma, as well as to relieve symptoms of seasonal allergies. As is the case with muscarinic antagonists, a montelukast is not able to treat acute asthma attacks and therefore a patient should also be supplied with reliever medication, such as a /3 ₂ - agonist. Montelukasts are able to block the action of leukotriene D4 on the cysteinyl-leukotriene receptor CysLTl, thus inhibiting bronchoconstriction.

The active agents forming the solution from a solvent, may comprise a methylxanthine. More particularly, the methylxanthine may be theophylline. Xanthines are a group of alkaloids that may be commonly used for their effects as mild stimulants and bronchodilaters. Theophylline is a derivative of methylated xanthine. Theophylline may be used to treat mild to moderate persistant asthma. For example, sustained-release methylxanthine medications may be used to control inflammation in the airways in the lungs (bronchial tubes). In addition, short- acting methylxanthine medications may be used to control narrowing of the

bronchial tubes, thereby relieving asthma symptoms. As with all the other active agents described herein, it will be understood that theophylline may also be provided in combination with any other active agent to form the final combination drug particle.

In a particular embodiment of the present invention, the combination drug particle may comprise a corticosteroid and a ^-agonist. The predetermined ratio of corticosteroid to /? ₂ -agonist may be dependant upon each individual patient. For example, the proportions of the active agents may range from 1:1 to 3000:1, preferably from 1:1 to 50:1 for the corticosteroid to the ^-agonist. Typically, the corticosteroid dosage is varied, whilst the fø-agonist dosage is kept constant to maintain control over patient exacerbations.

It is possible that the combination drug particle may comprise any combination of its racemates, single enantiomers, or their single disastereomeric forms.

The mean mass aerodynamic diameter of the particles may range from 50nm to 7μm. The lung tree is a good size separator and may therefore be utilised in delivering a specific particle size to a specific site in the lungs. For example, particles with a mean mass aerodynamic diameter ranging from 2μni to 7μm may be preferred for use in treating asthma. Conversely, nanoparticulate matter may be capable of being delivered deeper into the lung than, for example, micro particulate matter. In. the case of COPD patients, who have lungs that are particularly deteriorated, they may find it difficult to exhale nanoparticulate matter which had

been carried deep into the lungs, when compared to a person with normal breathing capabilities. Particles with a mean mass aerodynamic diameter ranging from 50nm to 500nm may therefore be preferred for use in treating COPD. Accordingly, due to the sedimentation and diffusion properties of nanoparticulate matter in the lungs of COPD patients, it may be possible to provide an effective delivery, to achieve the necessary effects in overcoming such a disease. Recent studies have shown that only 70% of particles which are inhaled with a mean mass aerodynamic diameter of 100 nanometres or less, are exhaled by COPD patients. This is in comparison to a person with normal breathing, who is able to re-breathe up to 90% of the 100 nanometre particles. Accordingly, the 30% of the 100 nanometre (or less) nanoparticles which are being collected, may be used as a source for treating diseases such as COPD and asthma in patients who have deteriorated lungs.

A composition of the present invention may be provided in combination with any method of formation or mean mass aerodynamic diameter of the particle described herein.

In another aspect of the present invention, there is provided a method of forming a crystalline combination drug particle from at least two different active agents, comprising the steps of: a) formation of a solution of the said at least two different active agents in a solvent; b) generation of an aerosol from the solution of said at least two different active agents; c) collection of the aerosol droplets in a vessel contaiiήng a non-solvent of said at least two different active agents; and d)

application of a nucleation step as a means to induce controlled crystallisation of said at least two different active agents into a combined drug particle.

The method may comprise a solvent, which may be at least one selected from acetone, dimethylacetamide, a low alkyl alcohol, water, an ester, dimetleylsulfoxide or a mixture thereof. A low alkyl alcohol may comprise, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, sec- butanol or tert-butanol. The selection of the solvent may depend on factors such as the solubility of the active agents in a particular solvent or the volatility, in that vapour pressure, of the solvent. For example, a highly volatile solvent may evaporate more readily upon aerosol formation and therefore is likely to give rise to a highly supersaturated solution of solute which may provide the conditions for primary nucleation and crystal growth. Furthermore, the related increase in viscosity of highly supersaturated droplets has been shown to provide a means of controlling the degree of sphericity of crystalline particles.

The method may comprise a non-solvent or anti-solvent within the crystallisation vessel, which may be at least one selected from, water, n-hexane, cyclohexane, isooctane (2, 2, 4 trimethylpentane), fluorinated ethers, perfluorocarbons and isopropanol. The choice of solvent may be dependant on the solubility and stability of the actives. For example, in the case of proteins and peptides, the preferred carrier solvent includes fluorinated ethers and perfluorocarbons.

Fluorinated ethers comprise liquids in which one component comprises a hydrofluoroether, perfluoroether, hydrofluoroamine, perfluoroamine, hydrofluorothioether, perfiuorothioether, hydrofluoropolyether, perfluoropolyether or a general formula R ¹ -X-R ² , R ^l -X (CF ₂ Y) _n (CF ₂ CF ₂ Z) _1n -R ² or R ¹ [(X-CF-R ² ) _n - (X-CF ₂ ) _m ]OR ³ ; where X,Y,Z are defined as oxygen, an ether, an alkyl amine, an amine or sulphur; and each of R ¹ , R ² and R ³ are defined as a non-fluorinated, partially fluorinated or fully fluorinated alkyl, cycloalkyl, aryl or arylatkyl group, or an organic functional group, halogen group or cyano group.

Perfluorocarbons may include perfluorodecalin or perfluorophenanthrene, for example. Perfluorocarbons are a group of extremely stable gases containing only fluorine and carbon atoms, and may often be found as a compressed liquid.

The non-solvent may be a carrier solvent, thereby not reacting with the active agents to dissolve them. Instead, when suitable nucleation means are applied to the non-solvent containing the active agents, nucleation and crystal growth of the combination drug particle may be obtained. The solvent and the non-solvent of the present invention, may be miscible. In this way any solvent that has not completely evaporated from the aerosol droplet before reaching the vessel containing the non- solvent, may dissolve in the non-solvent, thereby preventing adverse effects to the crystallinity of the combination drug particle.

The method may comprise an aerosol which may be generated by means of electrohydiOdynamic spraying, a high air pressure atomiser, a pneumatic system, a

rotary system, spray nozzles, nebulisers, propellant evaporation systems, piezoelectric transducers and ultrasonic transducers. The aerosol is a combination of the fine particulate active agents dissolved in a solvent, forming the initial solution, with pressurised air.

The nucleation means of the method of the present invention may be high intensity ultrasound. The high intensity ultrasound may be applied to the active agent/anti- solvent mix, temporarily, when in a supersaturated state. This may act to induce crystallisation of the combination drug particles.

Due to the specific way that the combination drug particle is produced, the proportions of the individual substances, in that either the bronchodilator or the /S ₂ - agonist, may be controlled effectively so that the correct proportions of each type of active agent is present within each combination drug particle, and consequently administered to the patient in the correct proportions that the patient requires.

The method of forming the combination drug particle may be achieved in a single droplet to particle operation or via a droplet-to-crystal and crystal to particle operation. For example, combination particles may be formed as larger than dose sized particles and subsequently harvested for milling to a smaller particle size. The mean mass aerodynamic diameter of the larger than dose sized particle may be equal to or greater than lOOμm, for example. The milling process may be performed by means of micronisation, for example. This approach may allow bulk

crystallisation of particles before being milled down to a required particle size for correct dose requirements.

The proportions within each individual combination drug particle may be selected by addition of the appropriate amount of the respective active agent in the formation of the initial solution in a solvent. Li other words, the concentrations of the active agent in the initial solution may determine the proportions of the final combination drug particle.

In addition to this, the size of the final combination drug particle may be controlled by varying the diameter of the nozzle through which the aerosol droplets are ejected. Further, the size of the final combination drug particle may also be controlled by varying the concentrations of the active agents in the initial solution containing a solvent.

The particle shape characteristics of the final combination drug particle may be controlled by varying the distance between, for example, the separation distance between the nozzle which ejects the aerosol droplets, and the vessel which collects the aerosol droplets. The distance between these points may determine the degree of evaporation which may occur from the aerosol droplets, which may influence the degree of supersaturation of the solute in the aerosol droplet and as a result its viscosity. Ideally, significant evaporation will occur thereby leaving a droplet containing a high concentration of the active agents required to form the final combination drug particle. The crystalline form of the combination drug particle

may be critical in providing the particle with thermal and moisture induced stability i.e. to prevent the particle from being thermally labile.

Any aspect of the method described hereinbefore may be used to provide any aspect of the combination particle described herein.

In another aspect of the present invention, there is provided the use of a combination drug particle as described herein, in the manufacture of a medicament for use in the treatment of a disease. The disease may be a pulmonary disease, such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, emphysema, respiratory distress syndrome and other pulmonary diseases.

Respiratory distress syndrome is caused by a lack of, in the immature lung, a lung surfactant. Without such a lung surfactant, smaller alveoli would tend to collapse upon expiration forcing air into larger alveoli, thereby inducing over inflation. The lungs are therefore not able to function efficiently because they are not able to inflate to their maximum. The film pressure generated by surfactants, however, act to neutralise the differences and therefore stabilise the lung. When an insufficient amount of lung surfactant is present in the body, thereby inhibiting normal breathing, this is known as respiratory distress syndrome. This is a common occurrence in premature babies who have been unable to develop a sufficient amount of lung surfactant to prevent the effects of respiratory distress syndrome. To this end, the present invention may also be used to treat the symptoms of respiratory distress syndrome by delivery of the surfactant, as an excipient in

combination with the active agents, to the lungs for systemic therapy. This may provide a dual response in terms of preventing macrophage uptake and possible protection to the conducting airway.

The combination drug particle for use, as described above, may be formed in accordance with any aspect of a method as described herein.

The use of the combination drug particle of the present invention may include the patient requiring only one daily dose of the medicament.

The use of the combination drug particle of the present invention may be for the treatment of a systemic disease. In this way systemic treatment may be provided.

The present invention therefore provides a way of alternative administration of medication. For example, small peptides and proteins are absorbed more rapidly after inhalation than after subcutaneous injection. Inhalation drug delivery provides the option of treating the lung locally or utilising the lung as an organ for drug absorption to the systemic circulation.

Li another aspect of the present invention, there is provided a combination drug particle in the manufacture of a medicament for use by non-invasive pulmonary delivery in the treatment of a systemic disease. This medicament may be formed in accordance with any aspect of the combination drug particle as described herein. Further, the combination drug particle may be provided in combination with any aspect of a method of forming a particle described herein. Accordingly the lung

may be used as a portal for systemic delivery. The medicament may be suitable for delivery by inhalation.

A particular group of molecules that are relevant to the ability of utilising the lung as a portal for systemic delivery, are the opioids. Opioids may include morphine and analogues thereof, for example. Molecules of this type are required so that they are able to cross the blood/brain barrier. Most systemic drugs are administered to a patient in a soluble form, in that, a salt form. The salt form must then be converted to the base, which is the active form of the drug, in order to attain the maximum effects. The conversion of the salt to the base would normally occur in the liver. Conversely, the present invention allows opioids to be administered to a patient directly in an active form via systemic circulation due to inhalation. The combination drug particles are sufficiently small in size to provide good solubility of the base, which may be directly administered to the lungs. This would remove the requirement of a conversion step in the liver which may include, for example, a dealkylation or demethylation step of the inactive drug to the active drug form. This may include a surfactant which avoids clearance from macrophages, thus allowing sustained release.

Various embodiments of the present invention will now be described more particularly, by way of example.

Example 1

The preparation of a composition containing fluticasone propionate and salmeterol xinafoate combination particles.

Salmeterol xinafoate and fluticasone propionate are dissolved in the ratios 1:1.379, 1:3.448 and 1:6.897 in acetone (a suitable solvent). These ratios are equivalent to a 1:2, 1:5 and 1:10 for salmeterol base and fluticasone propionate. These ratios are chosen to replicate the dose requirements for a dry powder inhalation power formulation. For a pressurised metered dose inhaler preparation, the two actives may be dissolved as a 1:13.77 ratio, equivalent to a 1:24 salmeterol base and fluticasone propionate.

It must be noted that these ratios can be altered according to any dose ratio required, of the long-acting j8 ₂ -agonist and the corticosteroid.

The solution is subsequently atomised via a flow through an ultrasonic atomiser. The flow rate is at a well defined flow rate, thus the atomiser is able to generate a distribution of aerosol droplets in a well defined size range. The mean droplet size of the atomiser can be modified by adjustment of the ultrasonic frequency of the atomiser. Alternatively, the atomiser may be pneumatic or rotary based.

The resulting aerosol droplets are ejected from the atomiser to a collection vessel containing a carrier solvent, in this case water. By controlling the separation distance between the atomiser and the collection vessel, together with the flow

behaviour, it is possible to ensure that sufficient evaporation of the solvent occurs to give rise to highly supersaturated droplets of the active agents prior to collection.

The suspended particles are subsequently collected in the carrier solvent which is sonicated by high intensity ultrasound. The application of the ultrasound induces the nucleation and crystal growth of the two active ingredients as a combination drug particle. If the particles contained within the non-solvent/carrier (water) were in a suitably supersaturated or viscous state, then spherical crystalline particles may result.

The resultant combination particles may then be collected and either mixed with a carrier, such as lactose, to form a dry powder inhaler composition or a suspension based pressurised metered dose inhaler or nebuliser formulation.

A scanning electron micrograph of a combination drug particle of salmeterol xinafoate and fluticasone propionate produced in a respirable size range in the ratio 1:5 is shown in Figure 1. The differential scanning calorimetery thermogram in Figure 2, shows two distinctive melting endotherms of salmeterol xinafoate and fluticasone propionate indicative of two well defined polymorphic forms of the respective active ingredients within the combination drug particle.

Example 2

Budesonide and Formoterol Fumarate

Budesonide and formoterol fumerate is solubilised in the ratios 17.77:1 and 35.55:1 in methanol or a mixture of methanol/ethanol. The process of forming the combination drug particle is the same as described in Example 1, up to the point at which the supersaturated particles are collected in the collection vessel, containing the non-solvent. In this example, the non-solvent/carrier is either water or n- hexane. High intensity ultrasound was applied to induce the formation of stable nuclei for crystal growth of the combination particles.

Example 3 Butesonide and Salmeterol Xinafoate

Formed according to any aspect of any method described herein. The solvent is either methanol or methanol/ethanol mix. The carrier solvent/anti solvent is water, cyclohexane or n-hexane.

Example 4

Fluticasone Propionate and Formoterol Fumarate

The combination particle may be formed according to any aspect of any method described herein. The solvent is acetone. The carrier solvent/anti solvent is either water, n-hexane or cyclohexane.

Example 5

Once-dailv Combination Products

Ciclesonide and Formoterol Fumarate.

Example 6

Combination of short-acting broiichodilaters such as anticholinergics and fø- agonist.

Ipratropium bromide and salbutamol.

Example 7

Combination of long-acting broncholdilaters such as anticholinergics and long- acting /32-agonists. Tiotropium bromide and salmeterol.

Example 8

Triple therapy

A bi-functional muscarinic (ipratropium bromide), a /3 ₂ -agonist (salmeterol, salbuterol or bambuterol) and a corticosteroid (budesonide).