WO2019060604A1 - Inhalable medicament - Google Patents

Abstract

The embodiments provide a process for preparing a product range containing at least a first and second inhalable dry powder medicament. The first and second inhalable medicament contain the same active ingredient at different doses, although the active ingredient is always within the range of 0.1-5.5% w/w, based on the total weight of the medicament. The amounts of the active ingredient in the first and second medicament define a dose ratio, and the delivered doses of the active ingredient in the first and second medicament define a delivered dose ratio. The medicament also contains a coarse carrier and a fine excipient. The dose ratio is substantially the same as the delivered dose ratio, and this is achieved by adjusting the amount of the fine excipient in the first and second medicament. The amount of the active ingredient and the fine excipient in total does not exceed 15% w/w, based on the total weight of the medicament.

Description

INHALABLE MEDICAMENT

CROSS-REFERENCE TO PRIOR APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 62/560,917, filed September 20, 2017, which is hereby expressly incorporated by reference in its entirety.

FIELD

The embodiments relate to an inhalable medicament, and in particular to preparing independent inhalable dry powder medicaments of different dosage strengths. The inhalable dry powder medicaments preferably comprise a corticosteroid, or a combination of a corticosteroid and a long-acting p₂-agonist.

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 p2-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 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 aclidinium, darifenacin, darotropium, fesoterodine, glycopyrronium, oxitropium, oxybutynin, solifenacin, tiotropium, tolterodine, trospium and umeclidinium. p₂-Adrenergic agonists (or "p₂-agonists") act upon the p₂-adrenoceptors which induces smooth muscle relaxation, resulting in dilation of the bronchial passages. Examples of long-acting p₂-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.

Fluticasone propionate is a corticosteroid indicated for the treatment of asthma and allergic rhinitis. It is also used to treat eosinophilic esophagitis. It is named as S- (fluoromethyl)-6a,9-difluoro-1 i p, 17-dihydroxy-16a-methyl-3-oxoandrosta-1 ,4-diene- 17p-carbothioate-17-propanoate, the structure of which is well-known in the art.

Salmeterol is a long-acting p₂-adrenergic receptor agonist that is indicated for the treatment of asthma and chronic obstructive pulmonary disease (COPD). It is named as (RS)-2-(hydroxymethyl)-4-{1 -hydroxy-2-[6-(4-phenylbutoxy)

hexylamino]ethyl}phenol. Salmeterol is typically administered as the xinafoate salt, the structure of which is well-known in the art.

An inhalable dry powder medicament containing fluticasone propionate as the sole active ingredient (i.e. mono-product) is marketed in the EU by GlaxoSmithKline UK as Flixotide® using the Accuhaler® dry powder inhaler (DPI). The Accuhaler® uses blisters filled with a mixture of microfine fluticasone propionate (50 micrograms, 100 micrograms, 250 micrograms or 500 micrograms) and larger particle size lactose.

An inhalable dry powder medicament containing a combination of fluticasone propionate and salmeterol (as the xinafoate salt) is marketed in the EU by Allen & Hanburys as Seretide®, this product also uses the Accuhaler®. Seretide® is marketed at three dosage strengths, each providing 50 micrograms of salmeterol xinafoate and 100, 250 or 500 micrograms of fluticasone propionate. The delivered doses (i.e. the amount of drug which reaches the lungs) are lower. In the US, the product is called Advair® and the inhaler is called Diskus®. Similar combination products containing fluticasone propionate, salmeterol xinafoate and lactose are marketed in the EU by Teva Pharma BV as Aerivio® using the Spiromax® device, and by Sandoz Limited as AirFluSal® using the Forspiro® device. A dry powder medicament 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 (MMAD) of 1-10 μηι, more typically 1-5 μηι. This size of particle is able to penetrate into the lung on inhalation. However, such particles have a high surface energy and require a coarse carrier in order to allow metering of the medicament. The coarse carrier is often lactose, usually 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.

The amount of active ingredient dissociating from the carrier is primarily dependent upon the strength of adhesion between the carrier and the active ingredient. Adhesion strength is known to be variable owing to energy variance across the surface of the carrier. The energy differences can be inherently present or introduced during mixing processes (e.g. micronisation). The presence of excessive adhesion forces between carrier and active ingredient are known in the art. Several mechanisms have been postulated that describe how the interparticulate carrier/active ingredient forces may operate and potentially be managed.

One particular management technique describes adding a fine excipient, for example fine lactose. The technique relies upon fine particle excipient occupying the high- energy surfaces upon the carrier instead of active ingredient. Therefore, any excessive adhesion forces exist between the carrier and fine excipient. Consequently, following mixing (of carrier, fine excipient and active ingredient) the active ingredient should be able to dissociate from the carrier with a consistent release profile. WO01/78695 discloses powders for use in a dry powder inhaler comprising a fraction of fine particles constituted by a mixture of excipient and additive (a fraction of coarse particles and an active ingredient).

Various inhalable dry powder medicaments comprising active ingredient(s), coarse carrier and fine excipient are able to provide consistent release profiles of the active ingredient into the lung.

When preparing the medicament, the formulator must consider the aerodynamic particle size distribution (APSD) of the formulation. The APSD determines the delivered dose of the drug, and therefore requires optimisation to provide a distribution of particles with a size suitable for inhalation into the lung.

The mixing process used to produce the formulation can affect the APSD, and once optimised, the mixing process is kept constant (in accordance with regulatory guidelines) such that the APSD is unchanged between batches. If the formulator is required to provide different dosage strengths of the same formulation, the formulator must re-optimise the mixing process (to take account of the additional active ingredient) in order to obtain an equally advantageous APSD. There remains a need in the art to provide multiple independent medicaments of the same active ingredient at different dosage strengths, wherein the mixing process used to prepare each medicament is unchanged and does not require independent optimisation. Thus, there is a need in the art for providing safe, stable and consistent approaches for the delivery of independent inhalable dry powder medicaments of the same active ingredient(s) at different dose strengths.

SUMMARY OF THE EMBODIMENTS

Accordingly, the embodiments provide a process for preparing a first and second inhalable dry powder medicament containing the same active ingredient having different doses, wherein the first and second medicament comprise 0.1-5.5% w/w of the active ingredient, based on the total weight of the medicament, a coarse carrier and a fine excipient,

wherein the amounts of the active ingredient in the first and second medicament define a dose ratio, and the delivered doses of the active ingredient in the first and second medicament define a delivered dose ratio, and the dose ratio is substantially the same as the delivered dose ratio,

and wherein the amount of the fine excipient in the first and second medicament is adjusted in order to achieve the delivered dose ratio,

and wherein the amount of the active ingredient and the fine excipient in total does not exceed 15% w/w, based on the total weight of the medicament.

The process provides of a range of medicaments of the same active ingredient having different doses. It is advantageous because it does not require changes to be made to the mixing process.

BRIEF DESCRIPTION OF THE DRAWINGS

The embodiments will now be described 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., London, Taylor & Francis, 2000). Fig. 2 shows the aerodynamic particle size distributions and dose proportionality of fluticasone propionate across three dosage strengths within three independent mono-products as measured using a next generation impactor. Fig. 3 shows the aerodynamic particle size distributions and proportionality of fluticasone propionate across three dosage strengths within three independent combination products as measured using a next generation impactor.

Fig. 4 shows the aerodynamic particle size distributions and of the dose consistency of salmeterol xinafoate within three independent combination products containing different strength fluticasone propionate as measured using a next generation impactor.

DETAILED DESCRIPTION The embodiments relate to a process for preparing a product range containing at least a first and second inhalable dry powder medicament. The first and second inhalable medicament contain the same active ingredient at different doses, although the active ingredient is always within the range of 0.1 -5.5% w/w, based on the total weight of the medicament. The amounts of the active ingredient in the first and second medicament define a dose ratio, and the delivered doses of the active ingredient in the first and second medicament define a delivered dose ratio. The medicament also contains a coarse carrier and a fine excipient. The dose ratio is substantially the same as the delivered dose ratio, and this is achieved by adjusting the amount of the fine excipient in the first and second medicament. The amount of the active ingredient and the fine excipient in total does not exceed 15% w/w, based on the total weight of the medicament.

Preferably, the total amount of active ingredient and fine excipient does not exceed 12% w/w, based on the total weight of the medicament.

Inhalable medicaments are typically provided in a range of product strengths so that the patient and clinician are able to escalate or deescalate dose as required. Accordingly, the embodiments provide a first and second inhalable dry powder medicament containing the same active ingredient having different doses. The product range may also have further inhalable medicaments. Provision of these medicaments is not straightforward owing to the aforementioned variations in the release profile. Combination products are even more problematic, as control over the dose of the individual active ingredients is reduced. For a p₂-agonist (e.g. salmeterol xinafoate), it is of particular concern since the therapeutic window is narrow and p₂-agonists are associated with serious adverse effects, including cardiac side-effects. Advantageously, the process of the embodiments allows for the preparation of multiple independent dry powder medicaments of the same active ingredient having different doses, where the delivered doses vary proportionally with the actual or predefined doses. This is termed "dose proportionality". That is, the amounts of the active ingredient in the first and second medicament are present in a defined dose ratio (e.g. the dose of the active ingredient in the second medicament is double that of the first). And the delivered doses of the active ingredient have the same delivered dose ratio (in this example the delivered dose of the active ingredient in the second medicament is also double that of the first). One way of achieving such dose proportionality is to adjust the mixing conditions when preparing the medicaments so that the delivered dose ratio matches the dose ratio. This is a time-consuming process and adds to the regulatory burden. Surprisingly, it has now been found that the required dose proportionality can be achieved by varying the amount of fine excipient between the first and second medicaments. This is a much more straight forward approach.

An inhalable dry powder medicament contains a defined amount of the active ingredient in the formulation. The formulation may be a bulk formulation in a reservoir, from which an aliquot is metered out. Alternatively, the formulation may be single, discrete amounts in a capsule or a blister in a blister strip. Either way, the aliquot or single, discrete amount contains a predetermined amount of active ingredient, which is the "dose" of the active ingredient. On inhalation by the patient, the formulation containing the dose of the active ingredient is entrained in the patient's breath and leaves the inhaler. The amount of the active ingredient released from the inhaler on inhalation is termed the "emitted dose". Of that emitted dose, some of the active ingredient impacts in the patient's throat and is swallowed, and some enters the lung, which is the active site for these active ingredients. The amount of the active ingredient which enters the lung is termed the "delivered dose". The goal of the embodiments is for the ratio of the dose of the first and second medicaments to be as close as possible to the ratio of the delivered dose of the first and second medicaments, whilst using the same mixing process for the two medicaments. It is achieved by varying the amount of fine excipient.

The independent medicaments provided by the process of the embodiments, allow for an increase or decrease in the amount of active ingredient reaching the lung of a patient, corresponding to the increase or decrease in the amount of active ingredient contained across two or more medicament dosage strengths. Thus doubling the amount of active ingredient used in the process to prepare a medicament will essentially double the amount of active ingredient reaching a patient's lungs.

As defined hereinabove, the amount of the active ingredient which enters the lung is termed the "delivered dose" and the delivered dose is dependent upon the aerodynamic particle size distribution (APSD) of the active ingredient particles. 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 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) at each stage, the higher the delivered dose.

For a pre-defined dose of active ingredient, it is possible to separate the active ingredient particles using the NGI apparatus. Following separation, the APSD of the pre-defined dose can be established which provides a close approximation of the delivered dose (based on the amount by weight of particles collected at stages with cut-off diameters suitable for reaching a patient's lungs i.e. 1-5 μηι or stages 2 to 4 of the NGI).

In accordance with the embodiments, it is preferred that following separation of the particles of each of the first and second medicament using a next generation impactor, the ratio of the sum of the particles (by weight) at each stage of the impactor is substantially the same as the dose ratio between the first and second medicament. Preferably, the ratio of the sum of the particles (by weight) collected at stages 1 to 5 of the impactor for the first and second medicament is substantially the same as the dose ratio between the first and second medicament.

Advantageously, maintenance of the aerodynamic particle size distribution between the first and second medicament ensures accurate dosing of different dosage strengths.

In a preferred embodiment, the dose ratio and the delivered dose ratio are within ±15% of one another, in a more preferred embodiment the dose ratio and the delivered dose ratio are within ±10% even more preferably they are within ±5% of one another.

The difference in the doses between the first and second medicaments will depend on the dosages strengths required for treating patients. Examples of dose ratios include 1.5, 2 and 3 and the corresponding delivered dose ratios are 1.4-1.6, 1.8-2.2 and 2.7-3.3. It is preferable wherein the dose ratio and the delivered dose ratio are each of from 1.8-2.2.

It is preferable wherein each of the dosage strengths of the medicaments each comprise an amount of active ingredient of 0.1-5.5% w/w, as this provides an appropriate dose of an inhalable active ingredient.

The process of the embodiments is amenable to preparing both mono-products and combination products. That is, the dry powder inhalable medicament of the embodiments may contain a single active ingredient or two or more active ingredients (usually two or three). Hence, the first and second medicament each contains an active ingredient and optionally an additional active ingredient. The additional active ingredient usually has the same dose in the first and second medicament, but it could vary in the same manner as the principle active ingredient.

The active ingredient may be a long-acting p₂-agonist, an inhaled corticosteroid or a long-acting muscarinic antagonist, and preferably a long-acting p₂-agonist or an inhaled corticosteroid. The additional active ingredient may also be a long-acting β₂- agonist, an inhaled corticosteroid or a long-acting muscarinic antagonist, and preferably a long-acting p₂-agonist or an inhaled corticosteroid.

The long-acting p₂-agonist may be 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).

The long-acting muscarinic antagonist is preferably clidinium (bromide), darifenacin (hydrobromide), darotropium (bromide), fesoterodine (fumarate), glycopyrronium (bromide), ipratropium (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). In each case for the lists of LABAs, ICSs and LAMAs, any preferred salt/ester forms are indicated in parentheses.

The particle sizes (mass median aerodynamic diameter, MMAD) of the active ingredients (e.g. LABA, LAMA, ICS) 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 p₂-agonist is d10 = 0.4-1.0 μηι, d50 = 1.0-3.0 μηι, d90 = 2.5-9.0 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 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.

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, again when measured using the same methodology as described for the long-acting muscarinic antagonist.

See J. P. Mitchell and M.W. Nag el 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.

Upon completion of the preparation protocol the blend uniformity is homogeneous.

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.

A preferred mono-product produced by the process of the embodiments is a first and second inhalable medicament of the same active ingredient at different dosage strengths comprising a corticosteroid. The most preferred corticosteroid is fluticasone propionate.

A preferred combination produced by the process of the embodiments is a first and second inhalable medicament of the same active ingredient at different dosage strengths comprising a corticosteroid and a long-acting p₂-agonist. The most preferred corticosteroid is fluticasone propionate and the most preferred long-acting p₂-agonist is salmeterol xinafoate. The additional active ingredient typically has the same dose in the first and second medicament. That is, the active ingredient has a variable dose, but the additional active ingredient has the same dose between the first and second medicaments.

It is preferred wherein the first and second inhalable medicament comprises at least two doses wherein the dosage strength of fluticasone propionate in μg is of 40-70, 100-130 or 215-250. It is even more preferred wherein the dosage strength of fluticasone propionate in μg is 55, 1 13 or 232. It is preferred wherein the first and second inhalable medicament comprises at least two doses wherein the dosage strength of fluticasone propionate to salmeterol xinafoate in μg is 40-70: 1-20, 100-130:1-20 or 215-250:1-20 respectively. It is even more preferred wherein the dosage strength of fluticasone propionate to salmeterol xinafoate in μg is 55/14, 1 13/14 or 232/14 respectively.

Particularly preferred dosage strengths of fluticasone propionate (Fp), salmeterol xinafoate (Sx) and fine excipient provided by the process of the embodiments can be selected from:

A coarse carrier and fine excipient are used in the process of the embodiments.

Examples of coarse carriers and fine excipients for preparing an inhalable dry powder are lactose, glucose, or mannitol, preferably lactose and most preferably alpha lactose monohydrate.

In general, the particle size of the coarse 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 coarse carrier preferably has a mean particle size of 40 microns or more, more preferably the carrier particles have a VMD of 50-250 microns. It is also preferable that substantially all particles of the coarse carrier are less than 300 μηι in size. The particle size distribution of the lactose provided herein is measured by laser diffraction in air, e.g. with a Sympatec HELOS/BF equipped with a RODOS dispenser and VIBRI feeder unit. The fine excipient has a d90 of less than 10 μηι. Intrinsic fines contained within the coarse carrier were measured by laser diffraction in air, e.g. with a Sympatec HELOS/BF equipped with a RODOS dispenser and VIBRI feeder unit.

Most preferably the coarse carrier and fine excipient are lactose monohydrate.

The embodiments also provide for the use of a fine excipient in the preparation of a first and second inhalable dry powder medicament containing the same active ingredient having different doses, wherein the first and second medicament comprise 0.1 -5.5% w/w of the active ingredient, based on the total weight of the medicament, a coarse carrier and the fine excipient,

wherein the amounts of the active ingredient in the first and second medicament define a dose ratio, and the delivered doses of the active ingredient in the first and second medicament define a delivered dose ratio, and the dose ratio is substantially the same as the delivered dose ratio,

and wherein the amount of the fine excipient in the first and second medicament is adjusted in order to achieve the delivered dose ratio,

and wherein the amount of the active ingredient and the fine excipient in total does not exceed 15% w/w, based on the total weight of the medicament.

The preferred features of the process described herein apply mutatis mutandis to this use. The process requires no substantial modification of the process used to prepare (mix) each medicament. In fact, the first and second medicaments are prepared using substantially the same mixing conditions.

Two mixing techniques specific to dry powder inhaler technology are generally applied in the art. 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. 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. Mixing speed is typically less than 150 rpm, e.g. 1-100 rpm.

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 at least 150 revolutions per minute (rpm), e.g. 150-5000 rpm or 350-3500 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 correspond to the cumulative rpm values of both arms.

The mixer used in accordance with the embodiments is preferably a high speed, high-shear mixer, (e.g. PharmaConnect®). Mixing time is usually at least 5 minutes, more preferably 10-90 mins.

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 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 rotations per minute (rpm). For low-energy mixing processes (e.g. low- shear mixing) the speed is also measured in rpm, however in comparison to high- energy mixing, the rpm refers to rotation of the container in which the powder is held.

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.

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. Both high- and low-energy mixing processes are suitable for producing medicaments in accordance with the embodiments.

Preferably the first and second medicaments are prepared using substantially the same mixing conditions. That means, they both use either a tumbling mixing or they both use a mixing apparatus having a mixing arm. Also, the rotation speeds and mixing times should be within ±10% of one another, more preferably within ±5% of one another, ideally the rotation speeds and mixing times should be the same. Ideally, the mixing processes are the same. The embodiments also provides a first and second inhalable medicament obtainable by the process of the embodiments. The embodiments also provides a product range containing at least the first and second inhalable medicament obtainable by the process of the embodiments.

Examples of some medicaments prepared by the process of the embodiments are selected from:

0.1-1.7 %w/w fluticasone propionate, 7.0-10.0 %w/w fine excipient and a coarse carrier;

1.7-2.5 %w/w fluticasone propionate, 5.5-8.5 %w/w fine excipient and a coarse carrier;

0.1-1.7 %w/w fluticasone propionate, 0.20-0.50 %w/w salmeterol xinafoate, 4.0-8.5 %w/w fine excipient and a coarse carrier;

1.8-3.0 %w/w fluticasone propionate, 0.20-0.50 %w/w salmeterol xinafoate, 3.0-7.0 %w/w fine excipient and a coarse carrier; and

3.1-5.0 %w/w fluticasone propionate, 0.20-0.50 %w/w salmeterol xinafoate, 1.0-4.5 %w/w fine excipient and a coarse carrier. The fine excipient and coarse carrier of the medicaments is preferably composed of lactose.

The medicaments provided by the process of the embodiments can be provided in an inhaler or a capsule.

The dry powder medicaments 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 medicaments may also be presented in a blister strip of unit doses within the inhaler, such as the dry powder nebuliser from MicroDose Therapeutx Inc. and the inhalers described in WO 2005/081833 and WO 2008/106616. The dry powder medicaments may alternatively be metered and filled into capsules, e.g. gelatin or hydroxypropyl methylcellulose capsules, such that the capsule contains a unit dose of fine active ingredient, fine excipient and coarse carrier lactose. 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.

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

Examples

Example 1 Dry powder medicament formulations were prepared by combining the following ingredients:

- fluticasone propionate having a particle size of d10 = 0.5-0.9 μηι, d50 = 1 .5-2.4 μηι, d90 = 3.3-6.0 μηι, and NLT99% <10 μηι;

- salmeterol xinafoate having a particle size of d10 = 0.6-1 .1 μηι, d50 = 1 .75-2.65 μηι, d90 = 2.7-5.5 μηι, and NLT99% <10 μηι; and

- a-lactose monohydrate (DMV Fonterra Excipients) having a particle size of d10 = 25-40 μηι, d50 = 87-107 μηι, d90 = 140-180 μηι, NLT99% <300 μηι and 3-9% <10 μηι.

The aerodynamic particle size distribution (APSD) measurements for the Fp and Fp/Sx (as shown in Figs 2-4) were recorded using a next generation impactor (USP/Ph Eur - recommended). Example 2

Three formulation strengths containing fluticasone propionate (Fp) with coarse and fine lactose were prepared. To account for the variation in the quantity of active ingredient present in each formulation, the quantity (%w/w) of fine lactose (< 10 μηι) was varied across the three strengths. The quantity of coarse lactose remained unchanged. Table 1. Composition per fluticasone propionate formulation (55, 1 13 and 232 meg):

The formulations were prepared using a high shear mixer (i.e. PharmaConnect with 60 L bowl size) with the impeller speed and chopper speed set to 120 and 1 ,000 rpm respectively (i.e. a total rpm value of 1 ,200). The APIs and excipient were charged into the blender in the following sequence forming multiple layers: Firstly, charge about 1/3 of the sieved lactose, then charged the pre-mixed salmeterol xinafoate- lactose followed by another 1/3 of the sieved lactose monohydrate, then charge the sieved fluticasone propionate and followed by the final 1/3 of the sieved lactose monohydrate. The total mixing time was 10 minutes. Upon completion of the preparation protocol the blend uniformity was demonstrated to be homogeneous according to the following acceptance criteria:

Stage 1

Assay 10 blend samples from Set 1 (n=10) the formulation blend is deemed homogenous if:

Mean (n = 10 samples from Set 1): 90.0 - 1 10.0% of target blend strength; Relative standard deviation (n = 10 samples): < 5.0%;

Individual results within 10% (absolute) of the mean of the results; and

If the blend fails to meet any one of the above acceptance criteria, then go to Stage 2.

Stage 2

Assay additional 20 blend samples from Set 2 and Set 3, followed by computing the mean and RSD of all 20 samples, the formulation blend is deemed homogenous if:

Mean (n = 30 samples from Set 1 - 3): 90.0 - 1 10.0% of target blend strength; Relative standard deviation (n = 30 samples): < 5.0%; and

Individual results within 10% (absolute) of the mean of the results.

Proportionality and consistency of dose across the three strengths were recorded. The proportionality in term of aerodynamic particle size distribution (APSD) for the Fp drug component within the Fp MDPI formulation is provided in Fig. 2. In Fig. 2, the lines correspond to bottom 55 μg, middle 1 13 μ9 and top 232 μg.

It can be seen that, as the dose doubles from 55 to 1 13 to 232 μg, the delivered dose (as determined by the amount of Fp reaching stages 2-6) also doubles and the shape of the particle size distribution stays substantially the same. The dose proportionality was achieved using the same mixing conditions for each product, with the only variable, other than the amount of drug, being the amount of fine lactose present.

Example 3

Three formulation strengths containing fluticasone propionate (Fp) and salmeterol xinafoate (Sx) with coarse and fine lactose were prepared. As per Example 2, to account for the variation in the quantity of active ingredient present in each formulation, the quantity (%w/w) of fine lactose (< 10 μηι) was varied across the three strengths. The quantity of coarse lactose remained unchanged.

Table 2. Composition per fluticasone propionate/salmeterol xinafoate formulation (55/14, 1 13/14 and 232/14 meg):

The formulations were prepared in using a high shear mixer (i.e. PharmaConnect with 60 L bowl size) with the impeller speed and chopper speed set to 160 and 1000 rpm respectively. The APIs and excipient were charged into the blender in the following sequence forming multiple layers: Firstly, charge about 1/3 of the sieved lactose, then charged the pre-mixed salmeterol xinafoate-lactose followed by another 1/3 of the sieved lactose monohydrate, then charge the sieved fluticasone propionate and followed by the final 1/3 of the sieved lactose monohydrate. The total mixing time was 15 minutes. Blend homogeneity was measured according to the established methods discussed under Example 2.

Proportionality and consistency of dose across the three strengths were recorded. The proportionality in terms of aerodynamic particle size distribution (APSD) for the Fp and Sx drug components within the Fp/Sx MDPI formulation is provided in Fig. 3, with Fp in the top graph and Sx in the lower graph. In the top graph for Fp, the lines correspond to bottom 55/14 μg, middle 1 13/14 μg and top 232/14 μg. In the bottom graph for Sx, the lines correspond to bottom 55/14 μg, middle 1 13/14 μg and top 232/14 μg (where top/middle/bottom are as observed at stage 4). Again, dose proportionality of the Fp was maintained, even in the presence of a second active, Sx. The doses and delivered doses for Sx are constant. In other words, the dose ratio and delivered dose ratio are both unity.

Claims

Claims

1. A process for preparing a first and second inhalable dry powder medicament containing the same active ingredient having different doses, wherein the first and second medicament comprise 0.1-5.5% w/w of the active ingredient, based on the total weight of the medicament, a coarse carrier and a fine excipient,

wherein the amounts of the active ingredient in the first and second medicament define a dose ratio, and the delivered doses of the active ingredient in the first and second medicament define a delivered dose ratio, and the dose ratio is substantially the same as the delivered dose ratio,

and wherein the amount of the fine excipient in the first and second medicament is adjusted in order to achieve the delivered dose ratio,

and wherein the amount of the active ingredient and the fine excipient in total does not exceed 15% w/w, based on the total weight of the medicament.

2. A process as claimed in claim 1 , wherein the first and second medicaments are prepared using substantially the same mixing conditions.

3. A process as claimed in claim 1 or 2, wherein the aerodynamic particle size distributions of the first and second medicament are substantially the same, and that following separation of the particles of each of the first and second medicament using a next generation impactor, the ratio of the sum of the particles (by weight) at each stage of the impactor is substantially the same as the dose ratio between the first and second medicament.

4. A process as claimed in any preceding claim, wherein the dose ratio and the delivered dose ratio are within ±15% of one another.

5. A process as claimed in any preceding claim, wherein the dose ratio and the delivered dose ratio are each of from 1.8-2.2.

6. A process as claimed in any preceding claim, wherein the total amount of active ingredient and fine excipient does not exceed 12% w/w, based on the total weight of the medicament.

7. A process as claimed in any preceding claim, wherein the active ingredient is or a long-acting p₂-agonist, an inhaled corticosteroid or a long-acting muscarinic antagonist, preferably a long-acting p₂-agonist or an inhaled corticosteroid.

8. A process as claimed in any preceding claim, wherein the first and second medicament contains an additional active ingredient.

9. A process as claimed in claim 8, wherein the additional active ingredient has the same dose in the first and second medicament.

10. A process as claimed in any preceding claim, wherein the fine excipient and coarse carrier are composed of lactose.

1 1. A first and second inhalable dry powder medicament obtainable by the process as claimed in any of the preceding claims.

12. An inhalable dry powder medicament selected from:

0.1-1.7 %w/w fluticasone propionate, 7.0-10.0 %w/w fine excipient and a coarse carrier;

1.7- 2.5 %w/w fluticasone propionate, 5.5-8.5 %w/w fine excipient and a coarse carrier;

0.1-1.7 %w/w fluticasone propionate, 0.20-0.50 %w/w salmeterol xinafoate, 4.0-8.5 %w/w fine excipient and a coarse carrier;

1.8- 3.0 %w/w fluticasone propionate, 0.20-0.50 %w/w salmeterol xinafoate, 3.0-7.0 %w/w fine excipient and a coarse carrier; and

3.1-5.0 %w/w fluticasone propionate, 0.20-0.50 %w/w salmeterol xinafoate, 1.0-4.5 %w/w fine excipient and a coarse carrier.

13. A medicament as claimed in claim 12, wherein the fine excipient and coarse carrier are composed of lactose.

14. Use of a fine excipient in the preparation of a first and second inhalable dry powder medicament containing the same active ingredient having different doses, wherein the first and second medicament comprise 0.1 -5.5% w/w of the active ingredient, based on the total weight of the medicament, a coarse carrier and the fine excipient,

wherein the amounts of the active ingredient in the first and second medicament define a dose ratio, and the delivered doses of the active ingredient in the first and second medicament define a delivered dose ratio, and the dose ratio is substantially the same as the delivered dose ratio,

and wherein the amount of the fine excipient in the first and second medicament is adjusted in order to achieve the delivered dose ratio,

and wherein the amount of the active ingredient and the fine excipient in total does not exceed 15% w/w, based on the total weight of the medicament.