WO2015181360A1

WO2015181360A1 - An inhalable medicament

Info

Publication number: WO2015181360A1
Application number: PCT/EP2015/061977
Authority: WO
Inventors: Ullmann MICHIEL
Original assignee: Teva Pharmaceuticals Europe B.V.
Priority date: 2014-05-30
Filing date: 2015-05-29
Publication date: 2015-12-03
Also published as: GB201409603D0; AR100687A1

Abstract

This invention relates to an inhalable medicament and in particular to a new solid-state form, namely solid amorphous particles comprising an intimate admixture of two or three active ingredients selected from a long-acting muscarinic antagonist (LAMA), a long-acting β₂- agonist (LABA) and an inhaled corticosteroid (ICS), together with a pharmaceutically acceptable co-solid having a glass transition temperature of at least −50ºC.

Description

AN INHALABLE MEDICAMENT

This invention relates to an inhalable medicament and in particular to a combination product for treating respiratory disorders.

The present invention is directed to the treatment of respiratory disorders such as asthma and COPD. A range of classes of medicaments have been developed to treat respiratory disorders and each class has differing targets and effects. Bronchodilators are employed to dilate the bronchi and bronchioles, decreasing resistance in the airways, thereby increasing the airflow to the lungs. Bronchodilators may be short-acting or long-acting. Short-acting bronchodilators provide a rapid relief from acute bronchoconstriction, whereas long-acting bronchodilators help control and prevent longer- term symptoms.

Different classes of bronchodilators target different receptors in the airways. Two commonly used classes are anticholinergics and ₂-agonists.

Anticholinergics (or "antimuscarinics") block the neurotransmitter acetylcholine by selectively blocking its receptor in nerve cells. On topical application, anticholinergics act predominantly on the M₃ muscarinic receptors located in the airways to produce smooth muscle relaxation, thus producing a bronchodilatory effect. Examples of long-acting muscarinic antagonists (LAMAs) include tiotropium (bromide), aclidinium (bromide), glycopyrronium (bromide), oxybutynin (hydrochloride or hydrobromide) and darifenacin (hydrobromide). 2-Adrenergic agonists (or ¾-agonists") act upon the ₂-adrenoceptors which induces smooth muscle relaxation, resulting in dilation of the bronchial passages. Examples of long- acting ₂-agonists (LABAs) include formoterol (fumarate) and salmeterol (xinafoate). Another class of medicaments employed in the treatment of respiratory disorders are inhaled corticosteroids (ICSs). ICS are steroid hormones used in the long-term control of respiratory disorders. They function by reducing the airway inflammation. Examples include budesonide, beclomethasone (dipropionate) and fluticasone (propionate). These classes of active ingredients are administered by inhalation for the treatment of respiratory disorders. A number of approaches have been taken in formulating these classes of active ingredients for delivery by inhalation, such as via a dry powder inhaler (DPI), a pressurised metered dose inhaler (pMDI) or a nebuliser. The active ingredients may be administered in combination and both combination therapies and combination products have been proposed.

Examples of combination treatments and products disclosed in the art are set out in WO 2004/019985, WO 2007/071313, WO 2008/102128 and WO 201 1/069197. However, these documents contain minimal discussion of suitable formulations for the combinations.

In the case of pMDI and nebuliser formulations, the active ingredients may be present in solution or in suspension in the liquid carrier (a propellant for pMDIs and water for nebulisers). When they are in solution, the active ingredients tend to be susceptible to chemical degradation and it is particularly difficult to stabilise combination products on account of the different requirements of the different active ingredient types. Suspension formulations are less prone to chemical degradation, but the suspensions have a tendency to physical instability, typically particle growth and particle agglomeration. The degree of particle agglomeration is dependent on, inter alia, the nature of the active ingredient.

DPI formulations are dry formulations and hence there is less of a concern over chemical and physical instability. However, dry powder formulations tend to be prone to absorption of water which can affect the stability of the active ingredients. Moreover, the interaction between the active ingredients and the powder carrier can be unpredictable.

A dry powder formulation typically contains a micronised active ingredient and a coarse carrier. The active ingredient needs to be in micronised form (typically a mass median aerodynamic diameter of 1-10 μιτι, more typically 2-5 μιτι). This size of particle is able to penetrate the lung on inhalation. However, such particles have a high surface energy and require a coarse carrier in order to be able to meter the formulation. The coarse carrier is often lactose, usually olactose monohydrate.

The micronised active ingredient adheres to the surface of the coarse carrier and, on inhalation, the active ingredient separates from the coarse carrier and is entrained into the lung. The coarse carrier particles are of a size that, after inhalation, most of them remain in the inhaler or deposit in the mouth and upper airways. In order to reach the lower airways, active ingredient particles must therefore dissociate from the carrier particles and become redispersed in the air flow. This process is shown diagrammatically in Fig. 1 (reproduced from Particulate Interactions in Dry Powder Formulations for Inhalation, Zeng, X. M., Martin, M. P., Marriott, C, London: Taylor & Francis, 2000).

It is apparent that the amount of active ingredient dissociating from the carrier is dependent on the strength of the adhesion between the carrier and the active ingredient. It has been found that some regions of the carrier surface are higher in energy than others and so different active ingredients will adhere differently depending on their specific interaction with the carrier. This can also be dependent on the order in which the active ingredients contact the surface. This causes an unwanted variation in the release profile of the active ingredients when in combination.

In each of the formulation types discussed, there is a need in the art for more stable and more consistent approaches for delivery of combination products.

Accordingly, the present invention provides solid amorphous particles comprising an intimate admixture of two or three active ingredients selected from a long-acting muscarinic antagonist (LAMA), a long-acting ₂-agonist (LABA) and an inhaled corticosteroid (ICS), together with a pharmaceutically acceptable co-solid having a glass transition temperature of at least -50°C.

In a particularly preferred embodiment, the present invention provides solid amorphous particles comprising an intimate admixture of a LAMA, a LABA and optionally an ICS, together with a pharmaceutically acceptable co-solid having a glass transition temperature of at least -50°C.

The present invention is described with the reference to the accompanying drawings, in which Fig. 1 shows the known interaction between active ingredient and carrier in a dry powder formulation.

The present invention therefore provides a new solid-state form for double or triple LAMA LABA ICS combination products. The particles are an intimate admixture of the active ingredient combination and a co-solid defined by its glass transition temperature, such as a sugar, a sugar derivative or a combination thereof. That is, substantially all of the individual particles are composed of both/all the active ingredients and the co-solid. The active ingredients and the co-solid are in the amorphous state and the active ingredients are dispersed at a molecular level as opposed to a mechanical mixture of amorphous active ingredient and amorphous co-solid in which the active ingredients are not dispersed at a molecular level. Preferably the particles consist essentially of the active ingredients and the co-solid. Reference is made to substantially all of the particles because it is possible from a purely statistical stand point that a small number of the particles might contain only the co- solid or only one active ingredient if such particles solidify in the absence of a particular active ingredient.

The active ingredients are a combination of a LAMA, a LABA and an ICS. That is, they may be a double combination of a LAMA and a LABA, a LAMA and an ICS or a LABA and an ICS; or a triple combination of a LAMA, a LABA and an ICS. A combination of a LAMA and a LABA, optionally with an ICS is preferred. The present invention also provides solid amorphous particles consisting of an intimate admixture of the active ingredients, together with a pharmaceutically acceptable co-solid having a glass transition temperature of at least -50°C. In an embodiment, the present invention provides solid amorphous particles as defined herein, comprising: an intimate admixture of a LAMA and a LABA as the sole active ingredients present, together with a pharmaceutically acceptable co-solid having a glass transition temperature of at least -50°C; or an intimate admixture of a LAMA and an ICS as the sole active ingredients present, together with a pharmaceutically acceptable co-solid having a glass transition temperature of at least -50°C; or an intimate admixture of a LABA and an ICS as the sole active ingredients present, together with a pharmaceutically acceptable co-solid having a glass transition temperature of at least -50°C.

The LAMA is preferably tiotropium (bromide), aclidinium (bromide), glycopyrronium (bromide), oxybutynin (hydrochloride or hydrobromide) or darifenacin (hydrobromide). The LABA is preferably formoterol (fumarate), salmeterol (xinafoate), indacaterol (maleate) olodaterol (hydrochloride) or carmoterol (hydrochloride), more preferably formoterol (fumarate), salmeterol (xinafoate), olodaterol (hydrochloride) or carmoterol (hydrochloride), and most preferably formoterol (fumarate) or salmeterol (xinafoate). The ICS is preferably budesonide, beclomethasone (dipropionate) or fluticasone (propionate). In each case, particularly preferred salt/ester forms are indicated in parentheses.

Particularly preferred combinations are:

oxybutynin (hydrochloride or hydrobromide) and formoterol (fumarate)

darifenacin (hydrobromide) and formoterol (fumarate)

oxybutynin (hydrochloride or hydrobromide), formoterol (fumarate) and beclomethasone (dipropionate)

darifenacin (hydrobromide), formoterol (fumarate) and beclomethasone (dipropionate) oxybutynin (hydrochloride or hydrobromide) and salmeterol (xinafoate)

darifenacin (hydrobromide) and salmeterol (xinafoate)

oxybutynin (hydrochloride or hydrobromide), salmeterol (xinafoate) and fluticasone (propionate)

darifenacin (hydrobromide), salmeterol (xinafoate) and fluticasone (propionate)

glycopyrronium (bromide) and indacaterol (maleate)

glycopyrronium (bromide) and formoterol (fumarate)

tiotropium (bromide) and formoterol (fumarate)

tiotropium (bromide) and carmoterol (hydrochloride)

tiotropium (bromide) and olodaterol (hydrochloride)

tiotropium (bromide) and indacaterol (maleate)

budesonide and formoterol (fumarate) Particular problems arising from combinations of these active ingredients are that they are very different in terms of their structures and physical properties. The result is that they behave markedly differently when formulated. For example, in a suspension formulation, they tend to have different agglomeration behaviours. In a dry powder formulation, they interact differently with the carrier leading to variation in the release characteristics. This results in a reduced consistency of delivery. By forming the particles of the present invention, the surface of the active ingredient particles which is presented to the formulation is consistent and the particles behave consistently. Moreover, the co-solid protects the active ingredient from the ingress of moisture and the effect of solvents.

The particles of the active ingredients of the present invention are an amorphous solid, i.e. a glass. That is, the particles are a solid in which there is no long-range order in the positions of the molecules. The amorphous solid is obtained by processes in which a solid is formed before the molecules can crystallise into a more thermodynamically favourable crystalline state.

The solid particles of the present invention present essentially the same surface to the one another and, in the case of a DPI formulation, to the coarse carrier. This leads to a more consistent profile. It also provides a higher fine particle fraction compared to the amorphous active ingredient and amorphous fine lactose when present as a mechanical mixture rather than an intimate admixture. The particles of the present invention are also stable and have a reduced tendency to absorb moisture from the environment. This is an important property for an inhalable medicament, particularly when formulated as a dry powder. In addition, the co- solid provides additional bulk to the active ingredients. A number of LAMAs and LABAs are highly potent and are typically used in microgram doses. Such small quantities of active ingredients can be difficult to handle and can hinder accurate metering. However, incorporation of the co-solid allows for easier handling and more accurate metering of the active ingredients.

The co-solid used in the particles must be pharmaceutically acceptable which has its standard meaning in the art, namely that it may be incorporated into a medicament. That is, the co- solid will be non-toxic, biodegradable and biocompatible. It will ideally be physicochemically stable and non-hygroscopic.

The co-solid must also have a glass transition temperature of at least -50°C, more preferably at least -25°C and most preferably at least 0°C. This lower limit on the glass transition temperature ensures that the amorphous (i.e. glass) state is stable at ambient temperature (i.e. 20°C), and preferably at elevated temperatures that the medicament may experience during storage, e.g. 50°C or above and even 75°C or above. By stable is meant that the amorphous state does not crystallise or otherwise degrade. The upper limit to the glass transition temperature is less relevant and is only limited by the practicalities of the lyophilisation process and the co-solids available. The glass transition temperature may be measured by differential scanning calorimetry (DSC), for example using a Q200 DSC from TA Instruments, at a heating rate of 10 K min.

The co-solid is preferably water soluble and more preferably has a water solubility of at least 20 mg per 100 mL at 20°C, more preferably at least 50 mg per 100 mL at 20°C and most preferably at least 80 mg per 100 mL.

The co-solid used in the particles of the present invention is typically a sugar or a sugar derivative, or a combination thereof. The derivative may be a sugar polyol or an amino sugar. Sugars, sugar alcohols and amino sugars are well known in the art and the present invention is not restricted to any particular sugar, sugar alcohol or amino sugar. Any sugar, sugar alcohol or amino sugar which is capable of forming an amorphous solid in the presence of the active ingredients may be used. Preferably the sugar is a mono or disaccharide, or the derivative is based on a mono or disaccharide. The sugar alcohol is a sugar in which at least one of the carboxyl groups (aldehyde or ketone) in the sugar has been reduced to an alcohol (primary or secondary alcohol). Sugar polyols are sometimes referred to in the art simply as sugar alcohols. The amino sugar is a sugar in which at least one of the hydroxyl groups has been replaced with an amino group. Specific examples of sugars used in the present invention are dextrose, fructose, glucose, lactose, mannose, sucrose and trehalose. Particularly preferred sugars are glucose, lactose, mannose, sucrose and trehalose. Specific examples of sugars alcohols used in the present invention are mannitol, maltitol, sorbitol and xylitol. A particularly preferred sugar alcohol is mannitol. A particularly preferred amino sugar alcohol is glucosamine. Other examples of suitable co-solids include PEG, HMPC and PLC Of all of the co-solids, lactose is the most preferred. The solid amorphous particles of the present invention may be prepared by lyophilising (freeze drying), by spray-freeze-drying or by any other method known in the art, for example, spray drying, of an aqueous solution of the active ingredients and the co-solid, usually the sugar and/or sugar derivative. Accordingly, the present invention provides a process for preparing the solid amorphous particles described herein comprising lyophilising or spray- freeze drying an aqueous solution of two or three of the LAMA, LABA and ICS, together with the pharmaceutically acceptable co-solid. Preferably the aqueous solution is prepared by forming an aqueous solution of the co-solid, dissolving the active ingredients therein and optionally adjusting the pH, typically to a value from 4 to 6. The process may further comprise micronising the particles. The aqueous solution may be prepared simply by dissolving the components in water or a mixture of water and a water-miscible pharmaceutically acceptable co-solvent. A suitable co- solvent is an alcohol and preferably methanol, ethanol, n-propanol, iso-propanol, n-butanol, tert-butanol iso-butanol or combinations thereof. However, other solvents may be used, such as acetonitrile, which is particularly useful for dissolving the ICS (although if acetonitrile is used, it should be removed under vacuum on account of its toxicity). In a preferred embodiment, the co-solid, e.g. sugar and/or sugar derivative, is added to an aqueous solvent and the solution is optionally heated to dissolve the co-solid. Once dissolved, the aqueous solution is allowed to cool to provide a hyper-saturated solution. The active ingredients are then added thereto. The mixture may be heated and/or sonicated to dissolve the active ingredients and a surfactant, such as oleic acid, may also be employed, if required. The resulting solution may be filtered if required and the pH may be adjusted. The preferred pH is from 4 to 6. The solution is then lyophilised using standard techniques in the art, such as for example, by methods disclosed in Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, Mack Publishing Co., Easton, PA 1990 and Remington: The Science and Practice of Pharmacy, Lippincott, Williams & Wilkins, 1995, and references cited therein. There are typically three stages in the lyophilisation process, namely freezing, primary drying, and secondary drying.

The freezing step may be performed in a shell freezer by placing the aqueous solution in a freeze-drying flask and rotating the flask in a bath cooled, for example, by mechanical refrigeration, dry ice, methanol or liquid nitrogen. Alternatively, the freezing step may be performed using a freeze-drying machine. In the freeze drying machine, fine droplets of the aqueous solution are sprayed into the refrigerant, e.g. liquid nitrogen. The freeze drying machine is preferred for the industrial preparation of the material.

During the primary drying step the pressure is lowered and enough heat is supplied to the material for the aqueous solution to sublimate. The secondary drying step may be used if required to sublimate the solvent molecules that are adsorbed during the freezing step.

The mean particle diameter of the solid amorphous particles of the present invention is preferably 1-10 microns and more preferably 1-5 microns. The particles size of the particles disclosed herein is the mass median aerodynamic diameter. See J. P. Mitchell and M.W. Nagel in "Particle size analysis of aerosols from medicinal inhalers" KONA No. 2004, 22, 32 for further details concerning the measurement of particles sizes. The appropriate particle size may be provided by the lyophilisation process described hereinabove although further micronisation may be performed by grinding in a mill, e.g. an air jet, ball or vibrator mill, by sieving, by crystallization, by spray-drying or by further lyophilisation. The weight ratio of active ingredients (i.e. the total amount of LAMA/LABA/ICS) to co-solid in the particles is from 1 : 1 to 1 : 1000, preferably from 1 :10 to 1 :500 (measured as a property of the bulk material). The ratio between the active ingredients will be dictated by the required dose of each active ingredient present.

The present invention also provides a method for the treatment of respiratory disorders, such as COPD and/or asthma, which method comprises administering a non-toxic, pharmaceutically acceptable amount of the inhalable medicament of the present invention to a patient in need thereof.

The invention further provides an inhalable medicament comprising the particles described herein and one or more pharmaceutically acceptable excipients, and in particular for use in the treatment of respiratory disorders, such as COPD and/or asthma. That is, the present invention provides inhalable medicament as defined herein for treating respiratory disorders, such as asthma or COPD.

The present invention also provides an inhalable medicament comprising the particles described herein and one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients include carriers, including diluents, propellants, surfactants, and flavourings (see Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, Mack Publishing Co., Easton, PA 1990 and Remington: The Science and Practice of Pharmacy, Lippincott, Williams & Wilkins, 1995). The pharmaceutical composition may be a dry powder for a dry-powder inhaler in which the one or more pharmaceutically acceptable excipients includes an inert carrier, or an aerosol for a pressurised metered-dose inhaler in which the one or more pharmaceutically acceptable excipients includes a propellant. Accordingly, the present invention provides an inhaler containing the inhalable medicament as defined herein. The inhaler is preferably a dry powder inhaler (DPI) or a pressurised metered dose inhaler (pMDI). The present invention also provides a kit comprising an inhaler and the inhalable medicament as defined herein.

Examples of particulate carriers for preparing an inhalable dry powder include lactose, glucose, or sodium starch glycolate, preferably lactose and most preferably alpha lactose monohydrate. In general, the particle size of the carrier should be such that it can be entrained in an air stream but not deposited in the key target sites of the lung. Accordingly, the carrier preferably has a mean particle size of 40 microns or more, more preferably the carrier particles have a VMD of 50-250 microns. The particle size may be determined using laser light scattering (Sympatec GmbH, Claasthal-Zellerfeld, Germany).

The dry powder composition may be metered and filled into blisters, e.g. a plastic/aluminium laminate base with a thermoplastic formable web, or capsules, e.g. gelatin or hydroxypropyl methylcellulose capsules, such that the blister or capsule contains a unit dose of active ingredient. When the dry powder is in a blister or capsule containing a unit dose of active ingredient, the total amount of composition will depend on the size of the blister cavities/capsules and the characteristics of the inhalation device with which the blister pack/capsules are being used. However, typical examples of total fill weights of dry powder per capsule are 1-25 mg. Alternatively, the dry powder composition according to the invention may be filled into the reservoir of a multi-dose dry powder inhaler (MDPI), for example of the type disclosed in WO 92/10229. Such inhalers comprise a chassis, a dosing chamber, a mouthpiece and the medicament. The formulation is also particularly suited for use in a dry powder nebuliser, e.g. from MicroDose Therapeutix Inc, see WO 2005/081833 and WO 2008/106616.

The particles of the present invention may also be formulated as an aerosol. Examples of a propellant gas for preparing an aerosol formulation include HFA134a, HFA227 or mixtures thereof. See EP 0 372 777, EP 0 616 525 and WO 98/05302 for further details of aerosol formulations. Pressured metered-dose inhalers of this type typically comprise a chassis, a mouthpiece and a canister comprising the medicament as described in the aforementioned documents. The present invention will now be described with reference to the following examples which are not intended to be limiting.

Examples Example 1

Lactose is added to water and the solution is heated to dissolve the lactose. Once dissolved, the aqueous solution is allowed to cool to provide a hyper-saturated solution. Oxybutynin hydrochloride and formoterol fumarate are separately added such that the ratio of lactose to total active is 100 parts by weight lactose to one part by weight total active. The mixture is sonicated to dissolve the active ingredients. The resulting solution is then filtered through filter paper and the pH is adjusted to 5.

The solution is then transferred to a round-bottomed flask and the flask is submerged in liquid nitrogen. The flask is swirled such the inside wall of the flask becomes coated in a thin layer of a solid material. The flask is then placed under vacuum at a temperature of -20°C for 24 hours to produce fluffy particles. The particles are collected and micronised so that they are suitable for inhalation. Example 2

An aqueous solution of oxybutynin hydrochloride, formoterol fumarate and lactose is formed as set out in Example 1. The solution is placed into a freeze-drier which sprays small droplets (about 10 μιτι) into liquid nitrogen. The particles are collected and placed in a vacuum freezer for 24 hours. The resulting particles are suitable for inhalation and do not require micronisation. The particles may, however, be micronised if desired.

Example 3

An inhalable medicament is formed by combining the particles formed in Examples 1 or 2 with coarse lactose using techniques described in, for example, WO 2004/017942.

Example 4

Examples 1-3 are repeated using tiotropium bromide and formoterol fumarate. Example 5 Examples 1-3 are repeated using glycopyrronium bromide and indacaterol maleate. Example 6

Examples 1-3 are repeated using glycopyrronium bromide and formoterol fumarate.

Example 7

Examples 1-3 are repeated using tiotropium bromide and indacaterol maleate. Example 8

Examples 1-3 are repeated using tiotropium bromide and formoterol fumarate. Example 9

Examples 1-3 are repeated using tiotropium bromide and olodaterol hydrochloride.

Example 10 Examples 1-3 are repeated using glucose instead of lactose.

Claims

1. Solid amorphous particles comprising an intimate admixture of two or three active ingredients selected from a long-acting muscarinic antagonist (LAMA), a long-acting β₂- agonist (LABA) and an inhaled corticosteroid (ICS), together with a pharmaceutically acceptable co-solid having a glass transition temperature of at least -50°C.

2. Solid amorphous particles as claimed in claim 1 , comprising an intimate admixture of a LAMA, a LABA and optionally an ICS, together with a pharmaceutically acceptable co-solid having a glass transition temperature of at least -50°C.

3. Solid amorphous particles as claimed in claim 1 or 2, comprising an intimate admixture of a LAMA and a LABA as the sole active ingredients present, together with a pharmaceutically acceptable co-solid having a glass transition temperature of at least -50°C.

4. Solid amorphous particles as claimed in claim 1 , comprising an intimate admixture of a LAMA and an ICS as the sole active ingredients present, together with a pharmaceutically acceptable co-solid having a glass transition temperature of at least -50°C.

5. Solid amorphous particles as claimed in claim 1 comprising an intimate admixture of a LABA and an ICS as the sole active ingredients present, together with a pharmaceutically acceptable co-solid having a glass transition temperature of at least -50°C.

6. The particles as claimed in any preceding claim, wherein the co-solid has a water solubility of at least 20 mg per 100 mL at 20°C.

7. The particles as claimed in any preceding claim, wherein the co-solid is a sugar and/or a sugar derivative.

8. The particles as claimed in claim 7, wherein the sugar derivative is a sugar polyol or an amino sugar.

9. The particles as claimed in any preceding claim, wherein the co-solid is selected from dextrose, fructose, glucosamine, glucose, lactose, mannitol, maltitol, mannose, sorbitol, sucrose, trehalose, xylitol and combinations thereof.

10. The particles as claimed in claim 9, wherein the co-solid is lactose.

11. The particles as claimed in any preceding claim, wherein the particle size is 1-10 μιτι.

12. The particles as claimed in any preceding claim, wherein the weight ratio of the total amount of LAMA, LABA and ICS to co-solid is from 1 : 1 to 1 :1000.

13. The particles as claimed in claim 12, wherein the weight ratio is from 1 : 10 to 1 :500.

14. The particles as claimed in any preceding claim, wherein the LAMA, when present, is selected from tiotropium, aclidinium, glycopyrronium, oxybutynin and darifenacin, the LABA, when present, is selected from formoterol, salmeterol, indacaterol olodaterol and carmoterol, and the ICS, when present, is selected from budesonide, beclomethasone and fluticasone.

15. The particles as claimed in any preceding claim, wherein the particles contain:

oxybutynin and formoterol;

darifenacin and formoterol;

oxybutynin, formoterol and beclomethasone;

darifenacin, formoterol and beclomethasone;

oxybutynin and salmeterol;

darifenacin and salmeterol;

oxybutynin, salmeterol and fluticasone;

darifenacin, salmeterol and fluticasone;

glycopyrronium and indacaterol;

glycopyrronium and formoterol;

tiotropium and formoterol;

tiotropium and carmoterol;

tiotropium and olodaterol;

tiotropium and indacaterol; or

budesonide and formoterol.

16. A process for preparing the solid amorphous particles as claimed in any preceding claim comprising lyophilising or spray-freeze drying an aqueous solution of the active ingredients, together with the pharmaceutically acceptable co-solid.

17. A process as claimed in claim 16, further comprising the step of micronising the particles.

18. An inhalable medicament comprising the particles as claimed in any of claims 1 to 15 and one or more pharmaceutically acceptable excipients.

19. An inhalable medicament as claimed in claim 18, wherein the medicament is a dry powder and the one or more pharmaceutically acceptable excipients includes an inert carrier.

20. An inhalable medicament as claimed in claim 18, wherein the medicament is a pMDI formulation and the one or more pharmaceutically acceptable excipients includes a propellant.

21. The inhalable medicament as claimed in any of claims 18 to 20 for treating asthma.

22. The inhalable medicament as claimed in any of claims 18 to 21 for treating COPD.

23. An inhaler containing the inhalable medicament as claimed in any of claims 18 to 22.

24. A blister pack or capsule containing the inhalable medicament as claimed in any of claims 18, 19, 21 or 22.

25. A kit comprising an inhaler and the inhalable medicament as claimed in any of claims 18 to 22.