GLYCOPYRRONIUM

CROSS-REFERENCE TO PRIOR APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62/560,892, filed September 20, 2017, which is hereby expressly incorporated by reference in its entirety.

FIELD

The embodiments relate to an inhalable medicament and to a process for preparing inhalable medicaments. The medicaments are for treating respiratory disorders.

BACKGROUND

A range of classes of medicaments have been developed to treat respiratory disorders (e.g. asthma and COPD) 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 p ₂ -agonists.

Anticholinergics (or "muscarinic antagonists" or "antimuscarinics") block the neurotransmitter acetylcholine by selectively blocking its receptor in nerve cells. On topical application, anticholinergics act predominantly on the M ₃ muscarinic receptors located in the airways to produce smooth muscle relaxation, thus producing a bronchodilatory effect. Examples of long-acting muscarinic antagonists (LAMAs) include aclidinium, darifenacin, darotropium, fesoterodine, glycopyrronium, oxitropium, oxybutynin, solifenacin, tiotropium, tolterodine, trospium and umeclidinium. p ₂ -Adrenergic agonists (or "p ₂ -agonists") act upon the p ₂ -adrenoceptors which induces smooth muscle relaxation, resulting in dilation of the bronchial passages. Examples of long-acting p ₂ -agonists (LABAs) include carmoterol, formoterol, indacaterol, olodaterol, salmeterol, tulobuterol and vilanterol.

Another class of medicaments employed in the treatment of respiratory disorders are inhaled corticosteroids (ICSs). Inhaled corticosteroids are steroid hormones used in the long-term control of respiratory disorders. They function by reducing the airway inflammation. Examples of inhaled corticosteroids include budesonide, beclomethasone, ciclesonide, flunisolide, fluticasone, mometasone and triamcinolone.

These classes of active ingredients are administered by inhalation for the treatment of respiratory disorders. A number of approaches have been taken in preparing and 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.

Dry powder inhalable medicaments containing one or a combination of active ingredients, in particular a long-acting muscarinic antagonist or a combination of a long-acting muscarinic antagonist and a long-acting p ₂ -agonist and/or inhaled corticosteroid, are known.

Examples of medicaments containing one or combination of active ingredients are disclosed in the art and set out in WO 2005/105043, WO 2004/019985, WO 2007/071313, WO 2008/102128, WO 201 1/069197 and WO 2015004243.

However, these documents contain little discussion of providing stable and homogenous dry powder formulations.

A dry powder formulation typically contains a micronised active ingredient and a coarse carrier. The active ingredient needs to be in micronised form (typically it should achieve a mass median aerodynamic diameter of 1-10 μηι, more typically 2-5 μηι). 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 typically lactose, usually in the form of a-lactose monohydrate. In order to facilitate delivery into the lung, the micronised active ingredient is adhered 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.

High-energy, micronised active ingredient particles are highly cohesive and form larger unstable agglomerates. The formation of such agglomerates contributes to poor powder flow and homogeneity, accelerated chemical degradation and suboptimal adhesion/dispersion (to/from the carrier).

These factors cause unwanted variations in the blend uniformity of the active ingredients when formulated as inhalable dry powder therapies, and ideally need to be avoided.

Micronised long-acting muscarinic antagonists are particularly cohesive and hygroscopic, and are difficult to formulate as dry powders. Glycopyrronium is a particularly hygroscopic long-acting muscarinic antagonist.

To combat these problems, formulators have typically added a so-called ternary excipient to dry powder inhalable formulations comprising long-acting muscarinic antagonists.

Ternary excipients are used to potentiate problems associated with high-energy active ingredient particles. Including ternary excipients within dry powder formulations protects them from the ingress of moisture, which preserves homogeneity of the mixture, and in turn provides a stabilising effect.

Metal stearates or amino acids are commonly used as ternary excipients within inhalable dry powder formulations, and for formulations containing a long-acting muscarinic antagonist magnesium stearate is most commonly used. Magnesium stearate is commonly used as a ternary excipient in dry powder inhalable formulations containing glycopyrronium. A drawback of ternary excipients is that they are inhaled by the patient. They can build up in the lungs leading to undesirable side effects. They also add to the regulatory burden when seeking approval for the product. There remains a need in the art for formulating dry powder inhalable medicaments comprising long-acting muscarinic antagonists wherein the medicament is stable, homogenous and is resistant to degradation.

SUMMARY OF THE EMBODIMENTS

Accordingly, the embodiments provide a dry powder inhalable medicament comprising glycopyrronium and a coarse carrier, wherein the medicament has a blend uniformity of ±10% of glycopyrronium, and wherein magnesium stearate is not present within the medicament. The embodiments provide a homogenous dry powder inhalable medicament comprising glycopyrronium. The medicament has an advantageous stability profile and does not require a ternary excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

The embodiments will now be described in detail with reference to the accompanying drawings, in which:

Fig. 1 shows entrainment of an inhalable dry powder formulation into an airstream and detachment of micronised active ingredient from a coarse carrier under conditions of strong and weak adhesion (see Particulate Interactions in Dry Powder Formulations for Inhalation, X.M Zeng et al. Taylor & Francis, London, 2000).

Fig. 2 shows the blend uniformity data of the glycopyrronium bromide (GPB) medicament blend, fluticasone propionate, salmeterol xinafoate and glycopyrronium bromide (FSG) medicament blend, and the fluticasone propionate and salmeterol xinafoate (FS) blend.

Fig. 3 shows the maintenance of the aerodynamic particle size distribution of glycopyrronium bromide in a mono product over 3 months under accelerated stability testing conditions, as measured using a next generation impactor. Fig. 4 shows the maintenance of the aerodynamic particle size distribution of fluticasone propionate in a fluticasone/salmeterol/glycopyrronium combination product over 3 months under accelerated stability testing conditions, as measured using a next generation impactor.

Fig. 5 shows the maintenance of the aerodynamic particle size distribution of salmeterol xinafoate in a fluticasone/salmeterol/glycopyrronium combination product over 3 months under accelerated stability testing conditions, as measured using a next generation impactor.

Fig 6 shows the maintenance of the aerodynamic particle size distribution of glycopyrronium bromide in a fluticasone/salmeterol/glycopyrronium combination product mono product over 3 months under accelerated stability testing conditions, as measured using a next generation impactor.

DETAILED DESCRIPTION

The embodiments relate to a dry powder inhalable medicament which contains glycopyrronium and a coarse carrier, where the medicament has a blend uniformity of ±10% without recourse to magnesium stearate or other ternary agents. The embodiments also provide combination products containing a long-acting muscarinic antagonist, such as glycopyrronium, together with a long-acting p ₂ -agonist and/or an inhaled corticosteroid.

The dry powder inhalable medicaments containing glycopyrronium and a coarse carrier and combination products containing a long-acting muscarinic antagonist together with a long-acting p ₂ -agonist and/or an inhaled corticosteroid and a coarse carrier each have advantageous blend uniformity of ±10% of glycopyrronium/LAMA (where appropriate). The formulation of the embodiments advantageously has a high blend uniformity. It also advantageously provides a medicament with a stable (i.e. consistent over time) aerodynamic particle size distribution, and thus provides a medicament capable of maintaining a consistent delivered dose. The delivered dose is dependent upon the aerodynamic particle size distribution (APSD) of the active ingredient particles, and refers to the amount of active ingredient which enters a patient's lung upon actuation of an inhaler device Typically, the APSD is measured using a cascade impactor. Cascade impactors comprise a series of plates each perforated with holes which reduce in size moving from plate to plate. Active ingredient particles enter the impactor in an air stream (typically 60 L/min) and are separated and collected by the plates according to particle size.

Pharmacopoeias recommend the use of several commercially available cascade impactors for determining APSD. Each impactor comprises different plates with different particle size "cut-off diameters. The impactor used in conjunction with the present embodiments is a next generation impactor (NGI).

The NGI apparatus has defined cut-off diameters across seven plates or "stages" of the impactor, and the cut-off diameters are defined relative to a particular flow rate of air. For example, at a defined flow rate of 60 L/min the cut-off diameters for the NGI are, stage 1 (8.06 μηι), stage 2 (4.46 μηι), stage 3 (2.82 μηι), stage 4 (1.66 μηι), stage 5 (0.94 μηι), stage 6 (0.55 μηι), stage 7 (0.34 μηι) (refers to particle size MMAD in μηι). Theoretically, the higher the amount of particles (by weight) of an inhalable size (typically an MMAD of 1-5 μηι or collected at stages 2 to 4 of the NGI) at each stage, the higher the delivered dose.

Advantageously, despite the high-energies associated with dry powder inhalable formulations, the blend uniformity and stability of the present formulation is provided without reliance on magnesium stearate or other ternary agents. High surface energy primarily results from particle size, and hence micronised active ingredients are considered high-energy particles. A secondary contributor to surface energy originates from inherent electrostatic effects, which are a product of the chemical composition and structural architecture of an active ingredient. The electrostatic properties and behaviour of a particular compound result from Van der Waals forces (distance dependent interactions between atoms) which are known to be responsible for inter alia cohesion within powders.

Consequently, the chemical composition and structural architecture of an active ingredient will determine its electrostatic makeup and thus its stability based upon the inter- and intra-particle interactions with neighbouring particles and the broader environment (e.g. atmospheric water vapour). The chemical composition and structure of long-acting muscarinic antagonists is particularly problematic from an electrostatic viewpoint. Long-acting muscarinic antagonists are quaternary ammonium salts and are therefore inherently cohesive and hygroscopic. The moisture absorption associated with this class of compounds is particularly prominent when regions of amorphous character are present on the surface of the particles.

It is difficult for the formulator to control the surface energy of micronised powders. For example, the size reduction step is necessary to break down particles into a smaller size (i.e. inhalable size) but by-products of this step are that the amount of electrostatic energy within the bulk powder is increased, and the surface amorphous character is also increased.

The embodiments potentiate the contribution of electrostatic energy to the total surface energy of the powder, and allows glycopyrronium to be formulated as a stable and homogenous dry powder inhalable medicament without the presence of magnesium stearate or any other ternary excipient.

It has been found that the embodiments protect the long-acting muscarinic antagonist sufficiently such that ternary excipients are not required to stabilise the formulation.

That is, the embodiments provide a dry powder inhalable medicament comprising glycopyrronium and a coarse carrier, wherein the medicament has a blend uniformity of ±10% of glycopyrronium, and wherein a ternary excipient is not present within the medicament.

Ternary excipients are well known in the art. They are also known as force control agents, lubricants and anti-adherents. They use the term "ternary" because they add a third material to the formulation over the active ingredient and the carrier. It should be noted that the coarse carrier inherently contains some fine particles of the same material (e.g. coarse lactose contains fine lactose). Such fine particles composed of the same material as the coarse carrier are not ternary agents.

Typical examples of ternary agents which are not required in the medicament of the present embodiments include metal stearates (such as magnesium and calcium stearate), fatty acids (e.g. stearic acid), amino acids (such as leucine) and phospholipids (such as lecithin). The embodiments also provide a dry powder inhalable medicament consisting of glycopyrronium, optionally one or more additional active ingredients, a coarse carrier and optionally fine particles composed of the same material as the coarse carrier, wherein the medicament has a blend uniformity of ±10% of glycopyrronium.

Fine particles composed of the same material are fine particles that are inherently present and contained within the coarse carrier (as received from a commercial supplier). Such fine particles typically have a particle size of less than 10 μηι in size, more likely 1-5 μηι.

Inherent fine content contained within the coarse carrier can be measured by laser diffraction in air, e.g. with a Sympatec HELOS/BF equipped with a RODOS dispenser and VIBRI feeder unit. Fine particles of same material as the coarse carrier may also be deliberately added to the medicament. They are not considered to be a ternary agent because they do not introduce a third substance beyond the active and the carrier particles.

The embodiments also provide a process for preparing a dry powder inhalable medicament comprising glycopyrronium and a coarse carrier, wherein the glycopyrronium and the coarse carrier are mixed using a low-energy mixing process, and wherein magnesium stearate is not present within the medicament. Again, it is preferable that a ternary excipient is not present within the medicament. The embodiments also provide a process for preparing a dry powder inhalable medicament consisting of glycopyrronium, optionally one or more additional active ingredients, a coarse carrier and optionally fine particles composed of the same material as the coarse carrier, wherein the medicament has a blend uniformity of ±10% of glycopyrronium.

In each instance the process involves mixing micronised glycopyrronium and a coarse carrier using a low-energy mixing process.

It is preferred that the glycopyrronium is micronised using a wet polishing process. Wet polishing is a process used for reducing the particle size of active ingredients, and typically comprises wet milling, specifically by cavitation at elevated pressure. During the process, an active ingredient is preferably suspended in a liquid (water or an organic solvent) in which it is insoluble, the suspension is then spray dried to obtain a dry powder having the desired particle size. Wet polishing is preferred as it is known to avoid imparting amorphous character into the active ingredient which is under-going micronisation.

The process used to prepare the medicament of the embodiments utilises a low- energy mixing process. The process minimises the total amount of kinetic energy being applied to the medicament blend, which reduces electrostatic build up and total surface energy. A reduction in overall energy limits the formation of agglomerates and absorption of water, maximises stability and maintains beneficial inhalable dry powder properties.

Powder mixing is one of the most critical processes in providing a DPI formulation, insofar as the mixing conditions and apparatus can directly influence aerolisation performance. Unlike fluid mixing, wherein the mixing of two components is governed simply by a concentration gradient, powder particles require an input of energy (i.e. kinetic energy) to facilitate mixing. Therefore, a powder mixing apparatus is required to induce motion either by rotational/translational movement of a container in which the powder or medicament is contained, or alternatively the powder or medicament is moved by contact with an impeller or chopper that is contained within the powder mixing vessel.

A mixing technique specific to dry powder inhaler technology is applied. This mixing technique is based upon the use of a tumbling mixer (sometimes referred to as "blenders") (e.g. Turbula® and V-blenders) which are used for low-energy mixing.

For low-energy mixing, a tumbling mixer container is typically mounted within a frame upon a mixing apparatus. The container is supported so that it can be rotated about an axis. In operation, the tumbling action creates circular mixing zones and paths within the container. Thus, tumbling mixers mix powder under the force of gravity as the mixer tumbles (i.e. rotates). The interactions of the powder particles with each other and against the walls of the mixer cause shear mixing to occur. The strength of the shear force experienced by a powder or substrate within a mixture is dependent upon the speed of mixing. The principles of shear mixing are known within the common general knowledge, and for example are discussed in Aulton's Pharmaceutics: The Design and Manufacture of Medicines, M. E. Aulton, Philadelphia, Elsevier Limited, 2007. The speed of mixing contributes to the total amount of energy delivered to a powder during mixing. For low-energy mixing processes (e.g. low-shear mixing) the speed is measured in revolutions per minute (rpm) and refers to rotation of the container in which the powder is held. In accordance with one or more embodiments, low-energy mixing can be achieved with a mixing apparatus having a vessel containing the powder which is rotated to impart a tumbling motion to the powder. These mixers provide efficient powder mixing through the exertion of rotational and translation movement into the bulk powder and thus mix the powder under the force of gravity (i.e. indirect mixing). The mixers are also suitable for the homogenous mixing of powders with differing specific weights and particle sizes. Typical mixers capable of providing this motion are known in the art. The Turbula® is one such example.

The process used to prepare the medicament of the embodiments utilises a low- energy mixing step. It is most preferred wherein the low-energy mixing process is performed in a mixing apparatus operating at below 150 revolutions per minute (rpm). It is also preferred wherein the low-energy mixing process is performed in a mixing apparatus operating at 1-100 rpm. It is also preferred that the low-energy mixing process is conducted for a duration of at least 5 minutes, more preferably 10-60 mins.

The process used to prepare the medicament of the embodiments provides a homogenous dry powder inhalable medicament comprising glycopyrronium with an advantageous stability profile by maintaining low overall energy input into the powder.

The process also provides a dry powder inhalable medicament wherein the glycopyrronium within the mixture displays an advantageous aerodynamic particle size distribution, fine particle fraction and fine particle dose characteristics. The process used to prepare the medicament of the embodiments is particularly advantageous because it obviates the need for including magnesium stearate or any other ternary excipient within the formulation.

The embodiments also provide a dry powder inhalable medicament obtainable by the process as set out herein. The powder medicament is distinguished over powders prepared by other techniques based on the different interaction between the actives and the carrier, as evidenced by the blend uniformity, stability and the maintenance of the aerodynamic particle size distribution. The glycopyrronium is also in a more stable form, with low levels of amorphous character, electrostatic charge and hygroscopicity.

The embodiments also provide a dry powder inhalable medicament comprising glycopyrronium and a coarse carrier, wherein the medicament has a blend uniformity of ±10% of glycopyrronium, and wherein magnesium stearate is not present within the medicament or wherein a ternary excipient is not present within the medicament and wherein the medicament comprises one or more additional active ingredients.

Preferably the one or more additional active ingredients comprise long-acting β ₂ - agonists and/or inhaled corticosteroids.

Owing to the differing energetics, behaviour and stability of active ingredients, the difficulty of providing a stable inhalable dry powder medicament increases as the number of individual active ingredients within a medicament composition increases. It has been found that the process used to prepare the medicament of the embodiments can be advantageously applied to provide double and triple combination dry powder inhalable medicaments. The double and triple combination products comprise a combination of a long-acting muscarinic antagonist together with a long-acting p ₂ -agonist and/or an inhaled corticosteroid. The long-acting muscarinic antagonist is stabilised within the double and triple combinations respectively through using a low-energy mixing step to mix long-acting muscarinic antagonist with coarse carrier and a further low-energy mixing step to mix the long-acting muscarinic antagonist and coarse carrier blend with additional active ingredients. It is preferred that within double and triple combination dry powder inhalable medicaments provided by the embodiments, the glycopyrronium/LAMA (as appropriate) present within said double and triple combination products is micronised using a wet polishing process as described hereinabove.

The embodiments provide medicaments with excellent stability profiles. That is, the physical and chemical stability of glycopyrronium in single active ingredient and combination formulations is maintained on storage. Stability is assessed by wrapping formulations with foil containing a desiccant and placing samples in an accelerated testing chamber at 40°C and 75% RH (relative humidity). These testing conditions have been abbreviated to ACC where appropriate.

The physical stability is assessed by measuring and comparing the aerodynamic particle size distribution over time, for example over three months. The measurement is conducted using a cascade impactor as mentioned hereinabove, preferably a next generation impactor.

The chemical stability is assessed by high-performance liquid chromatography (HPLC) following storage of the product under accelerated testing conditions. Under accelerated stability testing, the total impurity content remains well under the key value of 1.5% i.e. greater than 98.5% glycopyrronium/LAMA (as appropriate) remain. This suggests a shelf-life of at least 24 months at 25°C.

The embodiments also provide a physical stability of the glycopyrronium/LAMA (as appropriate) defined by a decrease in fine particle fraction (FPF) after three months of less than 10%, preferably less than 5%.

The embodiments also provide for a dry powder inhalable medicament comprising glycopyrronium and a coarse carrier, wherein the glycopyrronium is chemically and physically stable after three months ACC wherein magnesium stearate is not present within the medicament, and preferably wherein a ternary excipient is not present within the medicament.

The embodiments also provide a process for preparing a dry powder inhalable medicament comprising a combination of a long-acting muscarinic antagonist and long-acting p ₂ -agonist and/or inhaled corticosteroid, wherein the process comprises the steps of: (i) preparing a mixture of the long-acting p ₂ -agonist and/or the inhaled corticosteroid and a first portion of the coarse carrier to form a first blend using a high-energy mixing process;

(ii) preparing a mixture of the long-acting muscarinic antagonist and a second portion of the coarse carrier to form a second blend using a low-energy mixing process; and

(iii) mixing the first blend and second blend to form the medicament using a low- energy mixing process.

The process provides a double or triple combination dry powder medicament product with an advantageous stability profile and high homogeneity.

It has been found that according to the embodiments the process used to provide a double or triple combination dry powder medicament product comprising a long- acting muscarinic antagonist, protects the long-acting muscarinic antagonist sufficiently such that ternary excipients are not required for stabilisation. Accordingly, in preferred embodiments, the double or triple combination dry powder medicament products comprising a long-acting muscarinic antagonist do not contain a ternary excipient. In more preferred embodiments the double or triple combination dry powder medicament products do not contain a metal stearate. In more preferred embodiments the double or triple combination dry powder medicament products do not contain magnesium stearate.

Preferably, the embodiments provide a process to prepare a dry powder inhalable medicament comprising a combination of a long-acting muscarinic antagonist and long-acting p ₂ -agonist and/or inhaled corticosteroid, wherein the process comprises the steps of:

(i) preparing a mixture of the long-acting p ₂ -agonist and/or the inhaled corticosteroid and a first portion of the coarse carrier to form a first blend using a high-energy mixing process;

(ii) preparing a mixture of the long-acting muscarinic antagonist and a second portion of the coarse carrier to form a second blend using a low-energy mixing process; (iii) mixing the first blend and second blend to form the medicament using a low- energy mixing process; and

wherein the long-acting muscarinic antagonist has a blend uniformity of ±10% of the long-acting muscarinic antagonist, and wherein a ternary excipient is not present within the medicament or a metal stearate is not present within the medicament or wherein magnesium stearate is not present within the medicament. Preferably, the long-acting muscarinic antagonist used within the processes to prepare double and triple combination medicaments is micronised using a wet polishing process as described hereinabove.

High blend uniformity advantageously provides double and triple combination medicaments with stable (i.e. consistent over time) aerodynamic particle size distributions, and thus provides medicaments capable of maintaining a consistent delivered dose.

To prepare combination medicaments two mixing techniques specific to dry powder inhaler technology are applied. These mixing techniques are based upon tumbling mixers (sometimes referred to as "blenders") (e.g. Turbula® and V-blenders) which are used for low-energy mixing, and high-speed mixers (e.g. PharmaConnect®) which use a mixing arm (e.g. an impeller or chopper or combination thereof) for high- energy mixing.

The low-energy mixing step is applied as discussed hereinabove in relation to mixing glycopyrronium and a coarse carrier.

For high-energy mixing, a mixer typically comprises a container having a mixing arm within the container. Typically a mixing arm is an impeller blade or a chopper blade or a combination thereof. Impeller blades are typically centrally mounted within the mixer at the bottom of the container. Chopper blades are typically located on the side wall of the mixing container. In operation, the mixing arm directly contacts the particles of active ingredient and coarse carrier, and imparts force into the powder. The mixing arm rotates at a variable (high) speed, for example in the range of 50-500 revolutions per minute (rpm). In doing so, the mixing arm throws powder from the centre of the mixing bowl towards the wall by centrifugal force. The powder is then forced upwards before resting back towards the centre of the mixing arm. This pattern of particulate movement tends to mix the powders quickly owing to high shear forces generated by the high-speed mixing arm directly contacting with powder particles. Where the mixer has a plurality of mixing arms (typically an impeller and a chopper), the rpm values set out above and below correspond to the cumulative rpm values of both arms. For high-energy mixing processes (e.g. high-shear mixing) the main processing factor is the rotational speed of the mixing arm. The speed of the arm is measured in revolutions per minute (rpm). Thus low- and high-energy mixing modes provide different mixing and a different energy input into the powder.

In accordance with the embodiments, high-energy mixing can be achieved with a mixing apparatus comprising a mixing arm, typically an impeller blade or a chopper blade or a combination thereof. Within such apparatus the impeller blade and/or chopper blade impart kinetic energy into the powder and also generate frictional, inertial and shear force (forces capable of de-agglomerating active ingredients). An example of such a mixer is a PharmaConnect® high-shear mixer. High-energy mixing occurs by contacting of the mixing arm with the powder (i.e. direct mixing) at high speed.

It is most preferred wherein the high-energy mixing process is performed in a mixing apparatus operating at, in the range of 50-500 revolutions per minute (rpm) and wherein the low-energy mixing process is performed in a mixing apparatus operating in the range of 1-100 revolutions per minute (rpm).

It is also preferred wherein the high-energy mixing process is performed in a mixing apparatus operating at 50-5000 rpm and wherein the low-energy mixing process is performed in a mixing apparatus operating at 1-100 rpm. It is also preferred wherein the high-energy mixing process is performed in a mixing apparatus operating at 350- 3500 rpm and wherein the low-energy mixing process is performed in a mixing apparatus operating at 1-100 rpm. It is also preferred wherein the high-energy mixing process is performed in a mixing apparatus operating at 350-2500 rpm and wherein the low-energy mixing process is performed in a mixing apparatus operating at 1-100 rpm.

In accordance with the process to provide a double or triple combination dry powder medicament, it is preferred wherein the high-energy mixing process is conducted for a duration of at least 5 minutes, more preferably 10-90 mins. It is also preferred that the low-energy mixing process is conducted for a duration of at least 5 minutes, more preferably 10-60 mins. Preferably the medicament is prepared by mixing the first and second blends using a low-energy mixing process for a duration of at least 5 minutes, more preferably 10-60 mins.

It is preferred that the total mixing time for providing the first and second blends and the medicament blend does not exceed two hours.

Mixing for extended lengths of time can increase the energy build up within the powder compositions which can have deleterious effects upon the physical properties of the medicament.

Preferably the independent mixing processes of the embodiments are conducted for at least five minutes to allow adequate homogeneity, deagglomeration of active ingredients or adhesion of active ingredient to coarse carrier to occur. The process to provide a double or triple combination dry powder medicament provides a homogenous and stable double or triple combination powder blend and maintains low overall energy input into the powder. The process also provides a dry powder inhalable medicament wherein each of the individual active ingredients within the mixture displays an advantageous aerodynamic particle size distribution, fine particle fraction and fine particle dose characteristics. The administration of a single dose of two or three different classes of active ingredient also increases patient compliance.

The low energy processes conducted in conjunction with the process to provide double or triple combination dry powder medicaments are useful to manage chemically sensitive active ingredients e.g. long-acting muscarinic antagonists, whereas the high energy processes are useful to break down drug agglomerates as well as provide good distribution of active ingredient upon carrier. Upon completion of all of the low-energy mixing process embodiments, the glycopyrronium-containing or long-acting muscarinic antagonist- and long-acting β ₂ - agonist- and/or inhaled corticosteroid-containing medicaments display homogeneous blend uniformity. The term "homogeneous" refers to a powder wherein, upon mixing, the uniformity of distribution of a component, expressed as coefficient of variation (CV) also known as relative standard deviation (RSD), is less than 5.0%. It is usually determined according to known methods, for instance by taking preferably greater than 10 samples from different parts of the powder and testing the component by HPLC or other equivalent analytical methods. A lower RSD of the blend results in a higher uniformity of the delivered dose, which is useful from a clinical and regulatory perspective.

Preferably, the blend uniformity of the medicaments described herein are homogenous. The embodiments achieve a blend uniformity of ±10% of glycopyrronium/LAMA (as appropriate), more preferably ±5% of glycopyrronium/LAMA (as appropriate). The blend uniformity is determined by HPLC or equivalent methods as discussed hereinabove.

The process of the embodiments provides a dry powder inhalable medicament comprising glycopyrronium, preferably glycopyrronium bromide. The process of the embodiments also provide a dry powder inhalable medicament comprising a combination of long-acting muscarinic antagonist, long-acting p ₂ -agonist and/or inhaled corticosteroid. The long-acting muscarinic antagonist is preferably aclidinium (bromide), darifenacin (hydrobromide), darotropium (bromide), fesoterodine (fumarate), glycopyrronium (bromide), oxitropium (bromide), oxybutynin (hydrochloride or hydrobromide), solifenacin (succinate), tiotropium (bromide), tolterodine (tartrate), trospium (chloride) and umeclidinium (bromide). More preferred are glycopyrronium (bromide) and tiotropium (bromide), and most preferred is glycopyrronium (bromide).

The long-acting p ₂ -agonist is preferably carmoterol (hydrochloride), formoterol (fumarate), indacaterol (maleate), olodaterol (hydrochloride), salmeterol (xinafoate), tulobuterol (hydrochloride) and vilanterol (trifenatate). More preferred are formoterol (fumarate) and salmeterol (xinafoate), and most preferred is salmeterol (xinafoate).

The inhaled corticosteroid is preferably budesonide, beclomethasone (dipropionate), ciclesonide, flunisolide, fluticasone (propionate), mometasone (furoate) and triamcinolone (acetonide). More preferred are budesonide, beclomethasone (dipropionate) and fluticasone (propionate), and most preferred is fluticasone (propionate). In each case for the lists of LAMAs, LABAs and ICSs, any preferred salt/ester forms are indicated in parentheses.

More preferably, a triple combination product comprises the long-acting muscarinic antagonist glycopyrronium, the long-acting p ₂ -agonist salmeterol and the inhaled corticosteroid fluticasone. Most preferably, the long-acting muscarinic antagonist is glycopyrronium bromide, the long-acting p ₂ -agonist is salmeterol xinafoate and the inhaled corticosteroid is fluticasone propionate. Preferably, a double combination product comprises the long-acting muscarinic antagonist glycopyrronium and the long-acting p ₂ -agonist salmeterol. Most preferably, the long-acting muscarinic antagonist is glycopyrronium bromide and the long-acting p ₂ -agonist is salmeterol xinafoate. Preferably, a double combination product comprises the long-acting muscarinic antagonist glycopyrronium and the inhaled corticosteroid is fluticasone. Most preferably, the long-acting muscarinic antagonist is glycopyrronium bromide and the inhaled corticosteroid is fluticasone propionate. The process to provide a double or triple combination dry powder medicament provides stable and well-performing inhalable formulations, and comprises mixing a combination of a long-acting muscarinic antagonist and long-acting p ₂ -agonist and/or inhaled corticosteroid, in particular, mixing a long-acting p ₂ -agonist and/or the inhaled corticosteroid and a coarse carrier to form a first blend using a high-energy mixing and a long-acting muscarinic antagonist and coarse carrier using a low-energy mixing process. The long-acting p ₂ -agonist and/or the inhaled corticosteroid and coarse carrier are then combined with the long-acting muscarinic antagonist and coarse carrier and mixed to form a final medicament blend. Preferably the final medicament blends are prepared using low-energy mixing conditions.

The particle sizes (mass median aerodynamic diameter, MMAD) of the long-acting muscarinic antagonist, long-acting p ₂ -agonist and inhaled corticosteroid used within the process of the embodiments are each less than 10 μηι in size, more preferably 1- 4 μηι. MMAD may be measured using a next generation impactor (NGI). This particle size ensures that the particles effectively adhere to the coarse carrier during mixing, and also that the particles disperse and become entrained in the air stream and deposited in the lower lung (i.e. upon actuation of an inhaler device). The volume-based particle size distribution based on the diameter by volume, as measured by laser diffraction, may also be specified.

Preferably, the particle size distribution of the long-acting muscarinic antagonist is d10 = 0.4-1.0 μηι, d50 = 1.0-3.0 μηι, d90 = 2.5-7.5 μηι and NLT99% <10 μηι, when measured by laser diffraction, typically as an aqueous dispersion, e.g. using a Malvern Mastersizer 2000 instrument. The technique is wet dispersion (1 % Tween 80).

Preferably, the particle size distribution of the long-acting p ₂ -agonist is d10 = 0.4-1.0 μηι, d50 = 1.0-3.0 μηι, d90 = 2.5-9.0 μηι and NLT99%, when measured using the same methodology as described for the long-acting muscarinic antagonist.

Preferably, the particle size distribution of the inhaled corticosteroid is d10 = 0.4-1.0 μηι, d50 = 1.0-3.0 μηι, d90 = 2.5-7.5 μηι and NLT99% <10 μηι, when measured using the same methodology as described for the long-acting muscarinic antagonist.

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 of the long-acting β ₂ - agonist and inhaled corticosteroid 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. Preferably the appropriate particle size of glycopyrronium bromide is provided by wet polishing. Examples of coarse grade carriers for preparing an inhalable dry powder according to the embodiments include polysaccharides, e.g. dextrose, fructose, glucose, lactose, mannitol, maltitol, mannose, sorbitol, sucrose, trehalose, xylitol and combinations thereof, preferably lactose and most preferably alpha-lactose monohydrate is used. 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).

Preferably substantially all particles of the coarse grade lactose carrier are less than 300 μηι in size.

It is more preferable, that the particle size distribution of the coarse grade carrier lactose fraction is d10 = 15-50 μηι, d50 = 80-120 μηι, d90 = 120-200 μηι, NLT99% <300 μηι and 1.5-8.5% <10 μηι. Most preferably, the particle size distribution of the coarse grade carrier lactose fraction is d10 = 25-40 μηι, d50 = 87-107 μηι, d90 = 140-180 μηι, NLT99% <300 μηι and 2.5-7.5% <10 μm. The lactose is preferably a- lactose monohydrate (e.g. from DMV Fonterra Excipients).

The coarse grade carrier may contain inherent fine content (i.e. fine lactose). Such lactose has a particle size less than 10 μηι in size, more likely 1-5 μηι. Inherent fine content contained within the coarse carrier can be measured by laser diffraction in air, e.g. with a Sympatec HELOS/BF equipped with a RODOS dispenser and VIBRI feeder unit. In the context of the embodiments, such inherent fine content is not to be understood as a ternary excipient.

In accordance with the process to provide a double or triple combination dry powder medicament it is particularly preferred wherein the first blend and second blend are mixed together in a weight ratio of 0.5-10:1 to form the final blend pre-mix, prior to mixing of the final blend. Preferably the first blend and second blend are mixed together in a weight ratio of 2:1 to form the final blend pre-mix, prior to mixing of the final blend.

It is also particularly preferred that within the final blend, the long-acting muscarinic antagonist is present in an amount of 0.1-0.8 %w/w, the long-acting p ₂ -agonist is present in an amount of 0.1-0.8 %w/w and/or the inhaled corticosteroid is present in an amount of 1.0-5.0 %w/w.

The embodiments also provide a double or triple combination dry powder medicament obtainable by the process as set out herein. The powder medicament is distinguished over powders prepared by other techniques based on the different interaction between the actives and the carrier, as evidenced by the blend uniformity, stability and the maintenance of the aerodynamic particle size distribution over time. The long-acting muscarinic antagonist is also in a more stable form, with low levels of amorphous character, electrostatic charge and hygroscopicity.

The compositions of the embodiments can be useful for treating respiratory disorders (e.g. asthma and COPD).

The dry powder composition may be metered and filled into capsules, e.g. gelatin or hydroxypropyl methylcellulose capsules, such that the capsule contains a unit dose of active ingredient. When the dry powder is in a capsule containing a unit dose of active ingredient, the total amount of composition will depend on the size of the capsules and the characteristics of the inhalation device with which the 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 embodiments 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 dry powder formulation may be presented in an inhaler, e.g. in the reservoir of a multi-dose dry powder inhaler (MDPI), for example the inhalers sold under the brand name Respiclick® or Spiromax® and the inhalers described in WO 92/10229 and WO 201 1/054527. Such inhalers comprise a chassis, a dosing chamber, a mouthpiece and the medicament.

The embodiments will now be described with reference to the following examples which are not intended to be limiting.

Examples

Example 1

A 0.3% w/w glycopyrronium bromide (GPB) blend was produced by first tumble mixing lactose with GPB to produce a 0.9% w/w GPB blend. The lactose and GPB were mixed in a tumbler mixer at 46 rpm for 10 minutes. The obtained 0.9 %w/w GPB blend was then mixed with lactose in the weight ratio of 1 :2 (25 g: 50 g). The lactose and 0.9% w/w GPB blend were mixed in a tumbler mixer at 46 rpm for 10 minutes. The resulting product is a 0.3% w/w GPB blend. The GPB blend was subsequently filled into RespiClick® inhalers for chemical and aerosol performance testing and labelled as GPB mono 15 meg.

Example 2

A 0.6% w/w glycopyrronium bromide (GPB) blend was produced by first tumble mixing lactose with GPB to produce a 1.8% w/w GPB blend. The lactose and GPB were mixed in a tumbler mixer at 46 rpm for 10 minutes. The obtained 1.8% w/w GPB blend was then mixed with lactose in the weight ratio of 1 :2 (25 g: 50 g). The lactose and 1.8% w/w GPB blend were mixed in a tumbler mixer at 46 rpm for 10 minutes. The resulting product is a 0.6% w/w GPB blend. The GPB blend was subsequently filled into RespiClick® inhalers for chemical and aerosol performance testing and labelled as GPB mono 30 meg. Example 3

Fluticasone propionate (Fp) and salmeterol xinafoate (Sx) were blended together with alpha-lactose monohydrate at the concentration of 6.56% w/w Fp and 0.60% w/w Sx using a PharmaConnect™ high shear mixer (process conditions: 1000 rpm chopper speed and 434 rpm impeller speed) for a duration of 15 minutes. Glycopyrronium (glycopyrronium bromide or GPB) was blended together with lactose at the concentration of 0.9 %w/w using a Tumbler mixer (process conditions: 46 rpm) for a duration of 10 minutes. The obtained Fp/Sx blend and GPB blend were then mixed at the weight ratio of 2:1 (50g: 25g) using a tumbler mixer (process conditions: 46 rpm) for a duration of 20 minutes to produce the final triple combination blend containing all three actives (Fp, Sx and GPB) at the concentration of 4.37% w/w, 0.40% w/w and 0.30% w/w respectively. The triple combination blend was subsequently filled into RespiClick® inhalers for chemical and aerosol performance testing and labelled as FSG 232/14/15 meg (containing 232 μg (Fp) 14 μg (Sx) and 15 Mg (GPB)).

Example 4

Fluticasone propionate (Fp) and salmeterol xinafoate (Sx) were blended together with alpha-lactose monohydrate at the concentration of 6.56% w/w Fp and 0.60% w/w Sx using a PharmaConnect™ high shear mixer (process conditions: 1000 rpm chopper speed and 434 rpm impeller speed) for a duration of 15 minutes. Glycopyrronium (Glycopyrronium bromide or GPB) was blended together with lactose at a concentration of 1.8% w/w using a Tumbler mixer (process conditions: 46 rpm) for a duration of 10 minutes. The obtained Fp/Sx blend and GPB blend at the weight ratio of 2:1 (50 g: 20 g) were then mixed using a tumbler mixer (process conditions: 46 rpm) for a duration of 20 minutes to produce the final triple combination blend containing all three actives (Fp, Sx and GPB) at the concentration of 4.37% w/w, 0.40% w/w and 0.60% w/w respectively. The triple combination blend was subsequently filled into RespiClick® inhalers for chemical and aerosol performance testing and labelled as FSG 232/14/30 meg (containing 232 μg (Fp) 14 μg (Sx) and 30 μg (GPB)).

Comparative example

A 1 kg batch of Fp/Sx/lactose (6.56% w/w Fp and 0.60% w/w Sx) was mixed under high-energy high-shear mixing conditions using a PharmaConnect™ high shear mixer (process conditions: 1000 rpm chopper speed and 434 rpm impeller speed) for a duration of 15 minutes. The obtained blend was further mixed with lactose in a tumbler mixer (process conditions: 46 rpm) for a duration of 20 minutes at a ratio of 1 :2 (25 g: 50 g) to obtain an Fp/Sx/lactose blend (4.37% w/w Fp and 0.40%w/w Sx). The formulation was subsequently filled into RespiClick® inhalers for chemical and aerosol performance testing and labelled as FS 232/14 meg (containing 232 μg (Fp) and 14 μg (Sx)).

The blend uniformity profiles of the mono (GPB), combination (FSG) and the comparative (FS) formulations are shown below and demonstrated graphically and numerically by Table 1. Homogeneous GPB mono and FSG triple blends were attained.

In addition to excellent blend uniformity, the process provides mono and combination products with great chemical and physical stability. Table 2 provides the chemical stability data for the mono (GPB), combination (FSG) and the comparative (FS) formulations. Each of the product blends were prepared according to Examples 1 and 2 and stored in a dry powder within an inhaler. In each case the formulations were wrapped with desiccant in foil and placed in an accelerated testing chamber at 40°C and 75% RH (relative humidity). Table 2.1 provides the percentage impurity data for glycopyrronium bromide extracted from the samples in Table 2. These data are particularly impressive because chemical stability is usually very challenging to achieve for glycopyrronium bromide. This particular compound is prone to degradation due to its chemical instability. In this embodiment, excellent chemical stability from GBP mono and FSG triple products was demonstrated up to 2 month ACC condition shown as below.

Tables 3, 4 and 5 demonstrate the aerodynamic particle size data (APSD) for glycopyrronium bromide fluticasone propionate, salmeterol xinafoate and respectively for GPB mono and FSG triple products and FS comparative.

Table 1. Blend uniformity data of the fluticasone propionate, salmeterol xinafoate, glycopyrronium bromide (FSG) triple products, FS control and GPB mono blends

Table 2. Chemical stability data of the GPB mono products, FSG triple products and FS control stored within a Respiclick® inhaler and

Table 2.1. Percentage glycopyrronium bromide impurity as present in the samples submitted to accelerated testing in Table 2

Table 3. GPB APSD stability data of the GPB mono product

Table 4. Fluticasone propionate APSD stability data of the FSG triple products and FS comparative

Table 5. Salmeterol APSD stability data of the FSG triple products and FS comparative