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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2017/033032 Al 2 March 2017 (02.03.2017) P O P C T

(51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 9/14 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/GB20 16/052680 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 30 August 2016 (30.08.2016) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 15 15310.9 27 August 2015 (27.08.2015) GB TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: JAGOTEC AG [CH/CH]; Eptingerstrasse 61, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, CH-4132 Muttenz (CH). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventors: MUELLER-WALZ, Rudi; Eptingerstrasse 61, GW, KM, ML, MR, NE, SN, TD, TG). 4132 Muttenz (CH). FRD3EZ, Morgan; Eptingerstrasse 61, 4132 Muttenz (CH). BALAXI, Maria; Eptingerstrasse Published: 61, 4132 Muttenz (CH). — with international search report (Art. 21(3)) (74) Agent: BERESFORD CRUMP LLP; 16 High Holborn, — before the expiration of the time limit for amending the London Greater London WC1V 6BX (GB). claims and to be republished in the event of receipt of (81) Designated States (unless otherwise indicated, for every amendments (Rule 48.2(h)) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,

o o o (54) Title: PHARMACEUTICAL COMPOSITION FOR INHALATION (57) Abstract: The present invention provides a pharmaceutical composition for inhalation comprising a first active agent and a second active agent, wherein the aerodynamic particle size distribution of the first and second active agents relative to their delivered doses is substantially the same. PHARMACEUTICAL COMPOSITION FOR INHALATION

The present invention relates to a pharmaceutical composition for inhalation comprising a first active agent and a second active agent, wherein the aerodynamic particle size distribution of the first and second active agents relative to their delivered doses is substantially the same.

Drugs for the treatment of respiratory diseases and disorders, such as beta-2 , , muscarinic antagonists and inhibitors are frequently administered directly to the lungs via inhalation. The inhalation route may also be used for the delivery of systemically acting drugs. Administration via inhalation can increase the therapeutic index, reduce side effects of the drugs compared to administration by other routes (such as orally or intravenously), can result in a rapid speed of onset of the drugs, and in improved patient compliance. Administration by inhalation may be in the form of either dry powders or aerosol formulations, which are inhaled by the patient either through use of an inhalation device or nebuliser.

While single active agents may be employed to treat a specific disease or disorder, the use of combinations of drugs is often advantageous. For example low-dose therapy using one drug may not be sufficient to control symptoms, but adding treatment with another drug having a different mechanism of action may significantly improve symptoms compared with simply increasing a patient's dose of a single drug, while also reducing side effects. A combination of drugs may also have a synergistic effect, leading to enhanced patient treatment. Alternatively, the two drugs may act to treat two different symptoms; for example one drug may treat the airway constriction while the other may reduce or prevent of the airways. Formulating two active agents in a single formulation for administration from a single inhalation device is particularly advantageous for improving patient compliance.

In order that a medicinal formulation is suitable for use with an inhalation device, the particle size of the deployed formulation must be small enough that it can be inhaled into the lungs of the users. Therefore, the particles of the formulation need to be in the micrometer size range, i.e. having a mean aerodynamic particle diameter (measured as Mass Median Aerodynamic Diameter (MMAD)) of about 1 to Ι Οµ , in order to be capable of penetrating into the lungs and exerting its intended pharmacological effect. The particle size of the active agents should not be larger than 1Οµηι and preferably not larger than 5µ η.

Various methods may be used to form such fine particles for inhalation which are known to the skilled person. The most widely used method of producing particles of a drug compound in the micrometer size range is a particle reduction technique called micronisation, using an air jet mill. Jet milling is a highly effective technology for reducing the particle size of drugs where the size of the particles is relevant to the effective delivery.

Air jet mills grind materials by using a high speed jet of compressed air or inert gas which accelerates particles fed into the grinding chamber. Particle reduction is achieved by the impact of particles colliding into each other at high speed and reducing themselves by attrition and collision. Air jet mills are usually designed to output particles below a certain size; the compressed air or gas jet exits the mill through an outlet at the center of the grinding chamber and draws the micronised particles with it. Larger, i.e. oversized particles are held in the grinding chamber by centrifugal force and continue the milling process until the desired micrometer size is achieved, allowing them to escape the grinding chamber. Particles leaving the mill can eventually be separated from the gas stream by c3/clonic separation. Due to this design, a narrow particle size distribution of the resulting product can be achieved. The resulting particle size distribution of micronised drug compound depends on several parameters, such as the diameter of the air jet mill, the grinding gas pressure, the feeding gas pressure and the feeding rate. Furthermore, drug compound specific characteristics are also important for the result and need to be considered, such as the starting particle size range of the un-micronised compound, hardness, friability, temperature sensitivity (softening at higher temperature), or polymorph stability. Oxygen or moisture sensitivity of the drug compound may also demand the use of inert gas as a feeding and grinding media.

The above described compound specific parameters usually require that micronisation trials are performed to establish the suitable set of process parameters with control ranges needed to yield micronised particles of the requested target particle size. The skilled person would also understand that each specific drug compound may require its defined individual set of process parameters. In the case of a combination drug product, the different microfine drug powders as constituents of the combination drug product are therefore normally manufactured and micronised separately, and only combined at a later stage of preparation of the finished drug product. However, separate preparation of the two active agents may result in differing behaviour in the finished drug product and therefore different delivery or deposition at different locations in the lungs may well occur.

It would therefore be advantageous to formulate a pharmaceutical combination product in which the two active agents deliver to and deposit at the same site in the lungs.

According to a first aspect of the present invention there is provided a pharmaceutical composition for inhalation comprising a first active agent and a second active agent, wherein the aerodynamic particle size distribution (APSD) of the first and second active agents relative to their delivered doses is substantially the same. The aerodynamic particle size distribution relative to the delivered dose is preferably substantially the same within ± 25% on each impactor stage, preferably within ± 20% on each impactor stage, more preferably within ± 15% on each impactor stage, more preferably within ±10% on each impactor stage.

It has been found that by ensuring that the first and active agents have an APSD relative to their delivered doses that is substantially the same, co-deposition of the active agents occurs. This is particularly useful when co-deposition of both drugs in the same target area is required to exert a synergistic pharmacological effect, for allowing targeted treatment of a small area of infected lung or for targeting a specific region of the lungs (for example, the central airways to treat asthma, or the alveoli for a drug intended for systemic administration).

It is well established that cascade impactors may be used as an instrument to determine the aerodynamic particle size distribution of airborne drug particles delivered from inhaled formulations. Cascade impactors separate the drug particles contained in the formulation into fractions on the basis of differences in inertia, which is a function of particle density, shape, and velocity. Two types of cascade impactors widely used in the pharmaceutical development of inhaled formulations are the Andersen Cascade Impactor (ACI) and the Next Generation Impactor (NGI). Both types of cascade impactors include a number of stages, each with a specified number of nozzles of known diameter, with nozzle size and total nozzle area decreasing with stage number. A vacuum pump draws the inhaled formulation isokinetically through the stages. At each stage, particles with sufficient inertia break out of the air stream and impact on a surface located beneath the stage where they are collected, while the remainder of the particles remain entrained in the air stream, passing onto the next stage. The volumetric air flow through the apparatus remains constant, so velocity through the nozzles increases at each stage, meaning that smaller and smaller particles achieve sufficient inertia to reach the collection surface. Any residual material is captured on a terminal filter. The material captured on each stage of the apparatus and the filter are dissolved in an appropriate solvent and analysed. Each sample thus represents the amount of drug deposited on a specific impactor stage which relates to a defined particle size range.

Cascade impactors thus segregate the drug dose delivered by an inhaled formulation into several size classes and give the Aerodynamic Particle Size Distribution (APSD) of the inhaled formulation. The APSD represents an in-vitro surrogate of the particulate aerosol delivered to the lungs, and it is agreed that inhaled formulations with similar APSD will behave similarly in-vivo and are delivered to the same regions of the lung. In reverse, for two drug compounds that are intended to exhibit a synergistic pharmacological effect it is imperative for them to be targeted to the same region in the lung by having the same or at least similar APSD.

Measurement of the APSD with a cascade impactor also determines the amount of active drug deployed in fine, inhalable particles which is the fine particle dose (FPD) or the fine particle fraction (FPF), defined as the percentage of the fine particle dose relative to the total amount of released active compound. The measurement of the FPD and FPF is carried out by routine tests for which the methods and apparatus are described in the pharmacopeias. For example, formulations of the present invention meet the requirement set out in Chapter <601> of the United States Pharmacopeia (USP) 32 or in the monograph 2.9. 18 of the European Pharmacopeia (Ph.Eur.), 6th edition 2009.

In a preferred aspect, the first and second active agents belong to different classes of pharmacological active agents. In other words, the first and second active agents exert their effects via different pharmacological mechanisms. For example, a formulation according to the first aspect of the invention may comprise the combination of a long acting beta 2 and a long acting . Alternatively, a formulation according to the first aspect of the invention may comprise the combination of a long acting beta 2 agonist and a . A further option for a formulation according to the first aspect of the invention comprises the combination of a long acting muscarinic antagonist and a corticosteroid. Another option comprises the combination of a muscarinic antagonist- beta 2 agonist in combination with a corticosteroid. Other combinations of classes of drugs commonly used in the treatment of respiratory diseases may also be used in a formulation according to the first aspect of the invention, such as phosphodiesterase IV inhibitors, phosphodiesterase V inhibitors, or antagonists, each in combination with a corticosteroid. Preferably, a formulation according to the first aspect of the invention comprises a methylxanthine and a corticosteroid.

Preferably the methylxanthine is selected from the group consisting of , , oxtriphylline, IBMX (3-isobutyl-1-methylxanthine), , , , isbufylline, acepifylline, , bufylline, cafaminol, , , dihydroxypropyltheophylline, , , etophylline, , suxamidofylline, furaphylline, 7-propyl-theophylline-, , denbufylline, , cipamfylline, HWA 448, SDZ MKS 492, BB-1052, and or a pharmaceutically acceptable salt or derivative thereof.

Preferably the inhaled corticosteroid is selected from the group consisting of , beclomethasone dipropionate, , , , , , , , , methyl prednisolone, , , acetate, acetonide, , , , , dipropionate, , rimexalone, propionate, triamcinolone, , , desoxycorticosterone, , etiprendnol dicloacetate, GW-685698, GW-799943, NCX-1010, NCX-1020, NO-, PL-2146, NS-126, ZK- 216348 or a pharmaceutically acceptable salt or derivative thereof. Preferably the long acting beta 2 agonist is selected from the group consisting of , , , , , , , , or a pharmaceutically acceptable salt thereof.

Preferably the long acting muscarinic antagonist is selected from the group consisting of glycopyrronium, tiotropium, aclidinium, umeclidinium, oxitropium, ipratropium, or a pharmaceutically acceptable salts or derivatives thereof.

Preferably the muscarinic antagonist- beta 2 agonist is selected from the group consisting of THRX-198321 or GSK961081 or pharmaceutically acceptable salts or derivatives thereof.

Preferably the phosphodiesterase IV inhibitor is selected from the group consisting of , ciclamilast, , , , , BAY 19-8004, CI-1044, SCH 351591 or a pharmaceutically acceptable salt or derivative thereof. Preferably the phosphodiesterase V inhibitor is selected from the group consisting of , , , , , , , , , T-1032, or a pharmaceutically acceptable salt or derivative thereof.

Preferably the leukotriene is selected from the group consisting of , and zilueton or a pharmaceutically acceptable salt or derivative thereof.

Particularly preferred combinations of active agents comprise theophylline and ; fluticasone propionate and formoterol fumarate; fluticasone propionate and salmeterol xinafoate; budesonide and formoterol fumarate; and beclometasone dipropionate and formoterol fumarate.

In a preferred embodiment, the first and second active agents have a synergistic pharmacological effect. The present invention is particularly advantageous in relation to synergistic combinations, because the co-deposition of the two drugs ensures that the synergistic effect is maximised. For example a synergistic effect may occur between theophylline and inhaled corticosteroids or between long acting beta 2 agonists and corticosteroids and result in enhanced pulmonary efficacy. This synergy can be achieved using doses of the drugs which were less effective when administered alone, but which are formulated such that they co-deposit in the lungs to maximise the synergistic effect between the two drugs.

In a preferred aspect the pharmaceutical composition of the first aspect may also include a third active agent. Examples of third active agents which may be included in the composition are long-acting beta 2 agonists, muscarinic antagonists or muscarinic antagonist- beta 2 agonists. Preferably, the third active agent belongs to a different class of pharmacological active agents, i.e. the first, second and third active agents all exert their effects via different pharmacological mechanisms.

The pharmaceutical composition of the first aspect of the invention may be formulated as a dry powder for inhalation. Such a formulation may optionally include a carrier. Suitable examples of carriers to be used in a pharmaceutical composition according to a first aspect are mono or di saccharides, such as glucose, lactose, lactose monohydrate, sucrose or trehalose, sugar alcohols such as mannitol or xylitol, polylactic acid or cyclodextrin, glucose, trehalose. Preferably the carrier is alpha lactose monohydrate. The dry powder may be formulated for administration by a dry powder inhaler. A dry powder inhaler may be a multi dose dry powder inhaler which comprises a reservoir from which individual therapeutic dosages can be withdrawn on demand through actuation of the device. Alternatively multi dose dry powder inhalers may contain a plurality of capsules or blisters containing single or multiple pre-dosed units.

Optionally, stearate may be included in a pharmaceutical composition according to the first aspect of the invention, which may improve the flowability of the formulation. This is particularly useful if the composition is a dry powder formulation for inhalation. The amount of magnesium stearate used is preferably in the range of 0.001 to 10% by weight, more preferably 0.01 to 5% by weight, more preferably 0.1 to 2% by weight, more preferably 0.5% to 1% by weight, based on the total formulation.

Alternatively, the composition may be formulated as a suspension formulation for inhalation. Such a formulation may include a propellant, preferably a HFA propellant, such as HFA134a or HFA227. Suspension formulations according to the invention may be formulated for administration by a pressurised metered dose inhaler. A metered dose inhaler typically consists of a canister for storing an aerosol formulation under pressure, which is sealed at one end with a metering valve. The canister and valve are held in an actuator, which comprises means for actuating the metering valve through which may be dispensed a precisely fixed dose of the aerosol formulation, and a mouth-piece through which a dispensed dose of the aerosol formulation is directed into the mouth of a patient.

A wetting agent and a co-solvent or either one of those may also be included in a suspension formulation. A suitable wetting agent or co-solvent is an , more particularly , diols or polyols, such as propylene glycol, glycerol, butandiol or mixtures thereof. Preferably the wetting agent is ethanol and more preferably dehydrated ethanol. The amount of ethanol used within the formulation is typically adjusted according to its role. For example, if the wetting agent is a solvent for one or both of the drug substances, the wetting agent should be employed in an amount that avoids solubilisation or partial solubilisation of the drug substances or any excipients intended to be held in suspension.

In a further alternative option, the suspension formulation may be formulated for delivery by a nebuliser. The formulation is therefore formulated as an aerosol liquid, which is dispersed in a gas phase (typically, air).

In a second aspect of the invention, the pharmaceutical composition of the first aspect is obtainable or obtained by co-micronising the two active agents. It has been found that a perfectly superimposing APSD or near perfectly superimposing APSD of the delivered doses of both drugs can be achieved when both drugs are co-micronised rather than prepared separately. Co-micronisation of two active drugs to achieve co-deposition in the lungs for exerting a synergistic effect or to target a specific area of the lungs for treatment is particularly advantageous.

The first and second active agents may be mixed prior to co-micronisation, or may be mixed and co-micronised as a one step process. Both the first and second active agents are preferably co- micronised starting from an unmicronised form, or in some instances one active agent may be provided already in micronised form and then co-micronised together with the other active agent. Where the first and second active agents are mixed prior to co-micronisation, this blending step provides an important way of ensuring that the same ratio of the two active agents is micronised as is required to deliver the correct safe and efficacious dose of either drug and to achieve an ordered mixture, and is particularly useful when the two active agents are cohesive and so do not easily mix. The mixing may be carried out by sieving or blending (for example using a tumble blender or high shear mixer). The homogeneity of the blend of the two active agents is ensured by the interparticulate adhesive forces and the blending process may be more or less complex depending on the physicochemical characteristics of the drug entities. When the first and second active agents are co-micronised as a one step process, preferably pre-defined ratios of the amounts of each active agent may be fed (either via one feeder or separate feeders) and directly mixed in a micronisation chamber.

The co-micronisation as described above surprisingly results in a formulation in which the two active agents have substantially the same ASPD relative to their delivered doses and co-deposit in the lungs. The micronisation may be carried out using mechanical grinding, preferably using an air jet mill. Manipulation of the process parameters set for the micronisation in the air jet mill results in the desired particle size of the micronised particles of both drugs to target the site of action being obtained. These process parameters can be determined by the skilled person to provide the appropriate results.

Pharmaceutical compositions which include a first active agent, second active agent and third active agent are obtainable by co-micronising all three active agents. Alternatively, two of the active agents may be co-micronised in a first step and the other active agent may be added subsequently, for example co-micronisation of the first and second active agents and subsequent addition of micronised third active agent; co-micronisation of the first and third active agents and subsequent addition of the micronised second active agent; or co-micronisation of the second and third active agents and subsequent addition of the micronised first active agent. In an alternative option, two of the active agents are co-micronised to form a co-micronised mixture, and the third active agent is then co-micronised with the mixture. Co-micronising only two of the active agents together may be particularly advantageous if they have a synergistic action but the other does not, or if two are required for targeting one area of the lung and the other is required in a different part of the lung. The skilled person would be able to determine the appropriate order for co-micronisation of the three active agents depending on the particle size, shape, hardness, roughness and/or friability of each active agent. When a carrier is present in the formulation, this is preferably mixed or blended with the co- micronised first and second active agents, i.e. the carrier is added in a separate step subsequent to micronisation.

When magnesium stearate is included in the formulation of the invention, the magnesium stearate is preferably co-micronised with the first active agent and the second active agent. The invention therefore includes a pharmaceutical composition which is obtainable or obtained by co-micronising a first active agent, second active agent and magnesium stearate. When a third active agent is present, the magnesium stearate is preferably co-micronised with the first, second and third active agents. However, in a method in which two of the active agents are co- micronised first and the other is co-micronised with this mixture, the magnesium stearate is preferably co-micronised at the same time as the two active agents.

In a third aspect of the invention there is provided a method of making a pharmaceutical composition for inhalation, comprising co-micronising a first active agent, a second active agent and optionally magnesium stearate. Preferably the co-micronised first and second active agents and optional magnesium stearate are mixed with a carrier. Preferably the co-micronised first and second active agents and optional magnesium stearate are co-micronised with a third active agent.

In a fourth aspect of the invention, there is provided a pharmaceutical composition of the first aspect of the invention for use in the treatment of a respiratory disease, preferably a respiratory disease selected from the group consisting of asthma, severe asthma, paediatric asthma, COPD, cystic fibrosis, pulmonary hypertension, pulmonary arterial hypertension, interstitial lung disease, alveolar hypoventilation disorders, respiratory distress syndrome, asthma- COPD overlap syndrome (ACOS) or idiopathic pulmonary fibrosis. There is also provided a method of treating a respiratory disease comprising administering an effective amount of a pharmaceutical composition of the first aspect of the invention to a patient in need of treatment, preferably wherein the respiratory disease is selected from e group consisting of asthma, severe asthma, paediatric asthma, COPD, cystic fibrosis, pulmonary hypertension, pulmonary arterial

10

SUBSTITUTE SHEET RULE 26 hypertension, interstitial lung disease, alveolar hypoventilation disorders, respiratory distress syndrome, asthma- COPD overlap syndrome (ACOS) or idiopathic pulmonary fibrosis.

Preferred features of the second, third and fourth aspects of the invention are as defined for the first aspect mutatis mutandis.

The following is a description by way of example only with reference to the accompanying drawings of embodiments of the present invention.

Figures

Figure 1 shows theophylline co-micronisation

Figure 2 shows Grinding principle of the spiral jet mill (Alpine Hosokawa AS). Picture from http://www.hosokawamicron.co.jp.

Figure 3 shows the jet mill working area.

Figure 4 shows process manufacture No. 4 (process for comparison).

Figure 5 shows process manufacture No. 5 (process for comparison).

Figure 6 shows process manufacture No. 9 (example process according to the invention).

Figure 7 shows process manufacture No. 10 (example process according to the invention).

Figure 8 shows process manufacture No. 12 (process for comparison).

Figure 9 shows the particle size distribution of theophylline (TP) & fluticasone propionate (FP) co-micronised with the optimized settings, measured with Malvern Mastersizer Micro Plus.

Figure 10 shows particle size distribution of TP & FP co-micronised with the optimized settings, measured with Malvern Mastersizer Micro Plus.

Figure 11 shows the fine particle fraction (FPF) results of the different batches.

Figure 12 shows the aerodynamic particle size distribution of TP and FP, measured by NGI for batch 010AG01, which was manufactured by micronising TP alone (for comparison). Figure 3 shows the aerodynamic particle size distribution, measured by NGI for batch 014AG01, which was manufactured by co-micronising TP and FP.

Figure 14 shows the aerodynamic particle size distribution, measured by NGI for batch 015AG01, which was manufactured by co-micronising TP, FP and magnesium stearate (MgS).

Figure 15 shows the aerodynamic particle size distribution, measured by NGI for batch Oil AGO1, which was manufactured by micronising TP alone (for comparison).

Figure 16 shows the aerodynamic particle size distribution, measured by NGI, for batch 019AG01, which was manufactured by co-micronising TP with FP and MgS.

Figure 17 shows the aerodynamic particle size distribution, measured by NGI, for batch 080AG01, which was manufactured by co-micronising TP with FP and MgS.

Figure 18 shows the aerodynamic particle size distribution, measured by NGI, for batch 081AG01, which was manufactured by co-micronising TP with FP and MgS.

Figure 19 shows the aerodynamic particle size distribution, measured by NGI, for batch 082AG01, which was manufactured by co-micronising TP with FP and MgS.

Figure 20 shows the aerodynamic particle size distribution, measured by NGI during stability storage for batch 080AG02, manufactured by co-micronising TP with FP and MgS.

Figure 2 1 shows the aerodynamic particle size distribution, measured by NGI during stability storage for batch 081 AG02, manufactured by co-micronising TP with FP and MgS.

Figure 22 shows the aerodynamic particle size distribution, measured by NGI during stability storage for batch 082AG02, manufactured by co-micronising TP with FP and MgS.

Figure 23 shows the particle size distribution by laser diffraction with Sympatec Helos of batch 076ABO1before co-micronisation of TP with FP and MgS.

Figure 24 shows the particle size distribution by laser diffraction with Sympatec Helos of batch 076A301 after co-micronisation of TP with FP and MgS. Examples

The examples are based on the combination of anhydrous theophylline (TP) and the inhaled corticosteroid fluticasone propionate (FP) and the co-micronisation of these two active agents. Theophylline is a drug given orally in the treatment of asthma and is therefore not commercially available as microfine particles suitable for inhalation. However, the methods and procedures used can be applied to any combination of two or three active agents according to the invention.

Example 1: Preparation of formulations containing 250µ fluticasone propionate and either 500 or 3000u.g theophylline and APSD testing

The following two formulations of different strengths were prepared, comprising theophylline anhydrous, fluticasone propionate, magnesium stearate (MgS) and lactose monohydrate, in the amounts shown in Table 1 below.

Table 1 formulations Target 50 g TP / 25(^g FP 3000 g TP / 250 g FP dosage strength

Quantity Quantity Quantity Quantity per % per batch, per % per capsule, w/w capsule, w/w g batch, g mg mg Theophylline 0.500 2.00 20.00 3.000 12.00 120.00 anhydrous Fluticasone propionate 0.250 1.00 10.00 0.250 1.00 10.00 Magnesium stearate 0.250 1.00 10.00 0.250 1.00 10.00 Lactose monohydrate 24.000 96.00 960.00 21.500 86.00 860.00

Total 25.000 100.00 1000.00 25.000 100.00 1000.00 The above formulations were manufactured in batches either according to the present invention, or according to prior art processes (for comparison).

Theophylline anhydrous was micronised alone for use in comparative blends in a process comprising sieving followed by jet milling. The micronised theophylline was then blended with fluticasone propionate, lactose and (optionally) magnesium stearate.

Co-micronisation of theophylline, fluticasone propionate (and optionally magnesium stearate) for use in blends according to the invention was performed as shown in Figure 1, in which theophylline anhydrous, fluticasone propionate (compound B) and magnesium stearate (compound C) were first sieved and then mixed prior to jet milling. The co-micronised combination was then blended with lactose. More specific details of the preparation of the formulations in accordance with the invention are given below.

Micronisation was carried out using an Alpine Hosokawa 50 AS spiral air jet mill with a Fritsch vibratory feeder added. The jet milling was operated at the range shown in Table 2.

Table 2: Jet mill operating range

Injector pressure p(injector) 1 -- 8 bar Grinding pressure p(grind) 0 -- 3 bar (= f(p injector)) Powder feeding rate 1 -- 4 g/min Number of milling runs 1 -- 2

The ratio of the injector pressure to the grinding pressure was kept high enough to avoid the powder being blown back to the feeding funnel. The working area is shown in Figure 3.

All blending steps were performed by low shear mixing.

Capsule filling was done manually (25mg ± 8%) under controlled laboratory conditions. Filled capsules were stored into 30ml HDPE bottles. Stability samples were packed into Alu/Alu blisters. Table 3 provides details of the batches manufactured, including details of whether theophylline was micronised alone (with optional magnesium stearate) or co-micronised with fluticasone propionate (again, with optional magnesium stearate) and the subsequent blending process used.

Table 3: Blends manufactured. Processes 4, 5, 9, 10 and 12 are detailed in Figures 4, 5, 6, 7 & 8.

, Dosage strength . . Batch No. Micronisation Process

TP 010AG0I* 500µg / 250 g 4 008 TP+FP 014AG01** 500µg / 250µ 9 (x=50) 0 11 TP+FP+MgS 015AG01** 500µg / 250µg 10 (x=50) 015 TP 0 11AG01* 3000µg / 50µg 5 008 TP+MgS 018AG01* 3000µg / 250µg 1 (x=50) 017 TP+FP+MgS 019AG01** 3000µg / 250µg 10 (x=50) 018 * =blend for comparison **= blend according to the invention

Specific details of preparation of formulations i accordance with the invention

Preparation of batch 014AG01 involved pre-blending theophylline anhydrous with fluticasone propionate in the ratio 2:1 (see table 4).

Table 4 : batch 014AG01 Designation Lot number Quantity

Theophylline anhydrous KN 14079 4 g Fluticasone propionate KN 13140 2 g

The co-micronisation was performed according to the process described in Figure 1 and with the jet milling parameters shown in Table 5. Table 5: Jet milling parameters Setting Value

Feed rate 1 g/min Injector pressure 8 bar Grinding pressure 3 bar Number of milling runs 1

Preparation of batches 015AG01 and 019AG01 involved pre-blending of theophylline with fluticasone propionate in the 2 ratios corresponding to the 50(^g TP /25(^g FP and to the 300(^g TP 25( g FP strengths (see Table 6).

Table 6: batches 015AG01 and 019AG01 Quantity Quantity 2 Designation Lot number 1 (015) (019) Theophylline anhydrous KN 14079 10.0 g 34.4 g Fluticasone propionate KN 13141 5.0 g 2.8 g Magnesium stearate KN 12041 5.0 g 2.8 g

The co-micronisation was performed according to the process described in Figure 1 and with the jet milling parameters shown in Table 7.

Table 7: Jet milling parameters

Setting Value

Feed rate 1 g/min Injector pressure 8 bar Grinding pressure 3 bar Number of milling runs 1

Analytical testing of all formulations was performed by Skyepharma AG. For all testing, the analytical monographs valid at the time of testing were used. Particle size distribution of formulations according to the invention

Particle size distribution was measured with a Malvern Mastersizer Micro Plus.

The particle size distribution batch 014AG01 (co-micronised TP and FP) co-micronised with optimised settings is shown in Figure 9. The particle size distribution of batches 015AG01 and 0 19AG01(co-micronised TP, FP and MgS) co-micronised with optimised settings is shown in Figure 10.

APSD and FPD

A Next Generation Impactor (NGI) with pre-separator (Apparatus E Ph. Eur. 2.9.18 current edition) was used to determine aerodynamic particle size distribution. The NGI is a cascade impactor with 7 stages and a micro-orifice collector (MOC) that takes the place of a final filter. The NGI consists of a lid, body, nozzle pieces, collection cups, cup tray, and bottom frame. Major accessories include the NGI induction port and pre-separator.

With an empty inhaler in place, a flowmeter was connected to the induction port. The vacuum was turned on and the air flow through the apparatus adjusted by the flow control valve to achieve steady flow at the required rate defined by the device resistance. With the inhaler in place and the test flow rate established the absolute pressure on both sides of the control valve P2 and P3 was measured to confirm that the ratio P3/P2 is not more than 0.5 indicating critical flow conditions. For the test the vacuum was applied for drawing 4 litres of air with the adjusted flow rate from the mouthpiece of the inhaler, using a timer acting on a two-way solenoid valve. With the inhaler in place and actuated, a dose is drawn by the air flow from the mouthpiece into the NGI apparatus. The adequate number of doses as defined by the sensitivity of the detection method is delivered from the inhaler into the NGI apparatus.

The active substance was recovered from each of the 7 stage collection cups and from the MOC with a suitable amount of recovery solvent and these sample solutions were analyzed by UPLC, using a gradient, reversed-phase method with UV detection and external standard calibration for quantification.

17

SUBSTITUTE SHEET RULE 26 The fine particle dose (less than 5 µη ) of active (in was determined using a cumulative mass-weighed, quadratic calculation model in accordance with Ph. Eur. 2.9.18. The fine particle fraction was calculated as percentage of the total dose delivered.

The aerodynamic particle size results for TP and FP are presented in Table 8 below.

Table 8: APSD results of the different batches manufactured, measured by NGI

atc or compar son **batch according to the invention

A surprisingly significant performance increase can be observed for blends manufactured with TP co-micronised with FP, with or without MgS, compared to blends manufactured with TP micronised alone. The FPF results of the different batches are also shown in Figure 11.

Tables 9 and 10 below show the percentage difference between the percentage delivered dose for TP and FP for the different batches. Table 9: % difference between % delivered dose for TP and FP for the 500 g 125(^g batches manufactured.

Batch 010AG01 015AG01 Impactor Average [%DD] Average [%DD] stage TP FP % Diff TP FP % Diff RA 2.46% 2.22% 10.51% 1.32% 1.34% 1.43%

IP 32.70% 23.35% 33.38% 11.41% 10.80% 5.49%

S 25.95% 34.09% 27.09% 38.76% 41.14% 5.96%

Stage 1 12.04% 9.01% 28.83% 4.12% 4.00% 2.88%

Stage 2 15.10% 12.02% 22.74% 8.67% 7.09% 20.09%

Stage 3 6.62% 8.13% 20.46% 12.99% 10.91% 17.38%

Stage 4 3.66% 7.68% 7D.81% 12.76% 12.72% 0.30%

Stage 5 0.96% 2.83% 99.11% 6.57% 7.54% 13.72%

Stage 6 0.35% 0.58% 50.51% 2.47% 3.14% 23.90%

Stage 7 0.15% 0.10% 38.17% 0.82% 1.10% 0.00%

MOC 0.00% 0.00% 0.00% 0.12% 0.23% 0.00%

Sum 100.00% 100.00% 0.00% 100.00% 100.00% 0.00% Table 10: % difference between % delivered dose for TP and FP for the 3000µg / 250 g batches manufactured.

Batch 0 11AG01 019AG01

Impactor Average [%DD] Average [%DD] stage TP FP % Diff TP FP % Diff

RA 2.05% 1.84% 10.63% 1.12% 1.07% 5.10%

IP 39.93% 29.75% 29.20% 13.28% 11.89% 11.03%

PS 23.73% 27.30% 13.99% 25.24% 24.62% 2.48%

Stage 1 12.94% 11.01% 16.10% 5.58% 5.24% 6.35%

Stage 2 12.78% 12.86% 0.67% 13.04% 11.70% 10.87%

Stage 3 5.55% 7.84% 34.15% 14.48% 14.43% 0.33%

Stage 4 2.22% 5.84% 89.93% 12.96% 14.52% 11.34%

Stage 5 0.66% 2.80% 123.28% 7.12% 8.28% 14.98%

Stage 6 0.15% 0.77% 132.70% 4.06% 4.63% 13.26%

Stage 7 0.00% 0.00% 0.00% 2.11% 2.45% 14.53%

MOC 0.00% 0.00% 0.00% 1.00% 1.18% 16.45%

Sum 100.00% 100.00% 0.00% 100.00% 100.00% 0.00%

It can be seen that the percentage difference for the batches 010AG01 and 0 11AG01 is greatly increased compared to the percentage difference for the batches 0 15AGO1 and 019AG01 of the present invention and the values for 010AG01 and 0 11AG01 do not fall within the 25% difference in APSD relative to delivered doses for TP and FP of the present invention. In contrast the results for 015AG01 and 019AG01 do fall within this percentage difference.

Figures 12, 13, 14, 15 and 16 show the APSD profiles of both actives overlaid. It is evident that the profiles for theophylline and fluticasone are similar when the APIs are co-micronised together. When theophylline is micronised alone, the deposition profiles of the two actives differ. Conclusion

Inhalation capsules filled with powder blends manufactured with co-micronised APIs showed significantly higher product performance compared to powder blends manufactured with APIs micronised using standard techniques. Moreover, aerodynamic particle size (measured by NGI) was similar for the two APIs when these were co-micronised, which would result in co- deposition of the two APIs in the lungs.

Example 2: Preparation of formulations containing 150µ fluticasone propionate and ΙΟΟΟµε 2000u.g or 4000ug theophylline

Three formulations of different strengths were prepared, comprising theophylline anhydrous, fluticasone propionate, magnesium stearate and lactose monohydrate, with the target dose of the active agents being in the following amounts.

KXX g TP and 15(^g FP

200(^g TP and 150µg FP

4000 g T and 15(^g FP

Lactose monohydrate and 1% by weight magnesium stearate were also present in all formulations.

The formulations were prepared in accordance with the invention and as described above in Example 1 by co-micronising TP, FP and MgS and subsequently blending the co-micronised components with lactose monohydrate. However, a MC 100 spiral jet mill using nitrogen at 10 bar as micronisation gas was used instead of the Alpine Hosokawa 50 AS spiral air jet mill.

The APSD results were measured using a NGI, as described above for Example 1, and are shown in Figures 17, 18 and 1 . It can be seen from these figures that the APSD of theophylline and fluticasone propionate relative to their delivered doses is substantially the same and that the results for each active agent are almost superimposed on each other. These results demonstrate that in-vitro co-deposition is achieved regardless of the dose level of the active agents. Example 3: Stability of formulations of Example 2

The batches of formulations prepared in accordance with the invention in Example 2 were stored at 40°C and 75% rh and were analysed at TO, after 1 month and after 3 months to determine the APSD, using a NGI as described in Example 1.

The results are shown in Figures 20 and 1 and demonstrate that the in-vitro co-deposition profile is maintained for all three formulations after 3 months storage and therefore provides evidence of the stability of the formulations.

Example 4: particle size distribution of the blends

A 600 g batch 076ABO1 of theophylline, fluticasone and magnesium stearate as provided by the different manufacturers was prepared for co-micronisation in the ratio 1000 : 150 : 250 using a tumble blending process. The mixture was tested for drug content and homogeneity and found conform to the requirements given by Ph. Eur. 2.9.40. Uniformity of Dosage Units). The particle size distribution of a sample before co-micronisation was analysed by laser diffraction using a Sympatec Helos particle analyser with Rodos/Vibri dry dispersion unit at 3 bar feeding pressure. The particle size distribution curve confirmed the presence of the different particle entities (Figure 23). Micronisation of the batch was performed on a MC 100 spiral jet mill using nitrogen at 10 bar as micronisation gas. The laser diffraction particle analysis of the co-micronised batch showed a mono-modal Gaussian particle size distribution which confirmed that both drug substances and magnesium stearate were micronised to similar size below 10 microns (Figure 24). The 10th, 50th (median) and 90th percentile of the measured volume distribution curves are given in Table 11 below.

Table 11: 10th, 50th and 90th percentile of particle size distribution curve of theophylline- fluticasone-magnesium stearate batch 076AB01 before and after micronisation Conclusion

The particle size measurement of micronised the theophylline-fluticasone-magnesium stearate mixture confirmed that all components were micronised to a similar size whereas the particle size measurement of the non-micronised mixture showed the presence of different particle entities. Claims

1. A pharmaceutical composition for inhalation comprising a first active agent and a second active agent, wherein the aerodynamic particle size distribution of the first and second active agents relative to their delivered doses is substantially the same.

2. The pharmaceutical composition of claim 1, wherein the aerodynamic particle size distribution of the first and second active agents relative to their delivered doses is substantially the same within ± 25% on each impactor stage, preferably within ± 20% on each, more preferably within ±15% on each impactor stage.

3. The pharmaceutical composition of claim 1 or claim 2, wherein the first and second active agent belong to different classes of pharmacological active agents.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the first active and second active agents comprise a long acting beta 2 agonist and a long acting muscarinic antagonist; a long acting beta 2 agonist and a corticosteroid; or a long acting muscarinic antagonist and a corticosteroid.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the first and second active agents comprise a methylxanthine and a corticosteroid.

6. The pharmaceutical composition according to any one of claims 1 to 4, wherein the first and second active agents comprise a phosphodiesterase IV inhibitor and a corticosteroid; or a phosphodiesterase V inhibitor and a corticosteroid.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the first and second active agents have a synergistic pharmacological effect. 8. The pharmaceutical composition according to claim 5, wherein the methylxanthine is selected from the group consisting of theophylline, aminophylline, oxtriphylline, IBMX (3- isobutyl-1-methylxanthine), paraxanthine, pentoxifylline and theobromine or a pharmaceutically acceptable salt or derivative thereof.

9. The pharmaceutical composition according to any one of claims 4, 5 or 6, wherein the inhaled corticosteroid is selected from the group consisting of beclometasone, budesonide, fluticasone, flunisolide, mometasone, triamcinolone and ciclesonide or a pharmaceutically acceptable salt or derivative thereof.

10. The pharmaceutical composition according to claim 4, wherein the long acting beta2 agonist is selected from the group consisting of arformoterol, formoterol, salmeterol, bambuterol, carmoteroli indacaterol, olodaterol, vilanterol, or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition according to claim 4, wherein the long acting muscarinic antagonist is selected from the group consisting of glycopyrronium, tiotropium, aclidinium, umeclidinium, oxitropium, ipratropium, or a pharmaceutically acceptable salts or derivatives thereof.

12. The pharmaceutical composition according to claim 4, wherein the muscarinic antagonist- beta 2 agonist is selected from the group consisting of THRX-198321 or GSK96 1081 or pharmaceutically acceptable salts or derivatives thereof.

13. The pharmaceutical composition according to claim 6, wherein the phosphodiesterase IV inhibitor is selected from the group consisting of apremilast, ciclamilast, cilomilast, ibudilast, piclamilast, roflumilast, BAY 19-8004, CI-1044, SCH 351591 or a pharmaceutically acceptable salt or derivative thereof; or the phosphodiesterase V inhibitor is selected from the group consisting of avanafil, benzamidenafil, lodenafil, mirodenafil, sildenafil, tadalafil, udenafil, vardenafil, zaprinast, T-1032, icariin or a pharmaceutically acceptable salt or derivative thereof. 14. The pharmaceutical composition according to any one of claims 1 to 12, further comprising a third active agent, wherein the third active agent is preferably selected from the group consisting of a long acting beta 2 agonist, a long acting muscarinic antagonist or a muscarinic antagonist- beta 2 agonist.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the composition is a dry powder for inhalation or a suspension or solution formulation for inhalation.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the composition further comprises a carrier or HFA propellant.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the composition further comprises magnesium stearate.

18. The pharmaceutical composition according to any of claims 1 to 17, wherein the composition is formulated for administration by a dry powder inhaler, nebuliser or pressurised metered dose inhaler.

19. A pharmaceutical composition for inhalation comprising a first active agent and a second active agent, wherein the composition is obtainable by co-micronising the two active agents.

20. The pharmaceutical composition of claim 19, wherein the first and second active agents are mixed prior to co-micronisation, or are mixed and co-micronised in a one step process.

21. The pharmaceutical composition of claim 17, wherein the composition is obtainable by co-micronising the first active agent, the second active agent and magnesium stearate.

22. The pharmaceutical composition of any one of claims 1 to 18, further comprising a step of mixing the co-micronised first and second active agents, or the co-micronised first and second active agents and magnesium stearate with a carrier. 23. The pharmaceutical composition according to any one of claims 11 to 17, wherein the composition is obtainable by co-micronising the first active agent, second active agent and third active agent, optionally with magnesium stearate.

24. The pharmaceutical composition according to any one of claims 11 to 17, wherein the composition is obtainable by co-micronising the first and second active agents, optionally with magnesium stearate, and subsequently adding a third active agent.

25. The pharmaceutical composition according to any one of claims 1 to 24 for use in the treatment of a respiratory disease, preferably a respiratory disease selected from the group consisting of asthma, severe asthma, paediatric asthma, COPD, cystic fibrosis, pulmonary hypertension, pulmonary arterial hypertension, interstitial lung disease, alveolar hypoventilation disorders, respiratory distress syndrome, asthma- COPD overlap syndrome (ACOS) or idiopathic pulmonary fibrosis.

26. A method of treating a respiratory disease comprising administering an effective amount of a pharmaceutical composition according to any one of claims 1 to 24 to a patient in need of treatment, preferably wherein the respiratory disease is selected from the group consisting of asthma, severe asthma, paediatric asthma, COPD, cystic fibrosis, pulmonary hypertension, pulmonary arterial hypertension, interstitial lung disease, alveolar hypoventilation disorders, respiratory distress syndrome, asthma- COPD overlap syndrome (ACOS) or idiopathic pulmonary fibrosis.

27. A method of making a pharmaceutical composition for inhalation, comprising co- micronising at a first active agent, a second active agent and optionally magnesium stearate.

28. The method of claim 27, wherein the co-micronised first and second active agents and optional magnesium stearate are mixed with a carrier.

29. The method of claim 27 or 28, wherein the co-micronised first and second active agents and optional magnesium stearate are co-micronised with a third active agent.

A . CLASSIFICATION O F SUBJECT MATTER INV. A61K9/14 ADD.

According to International Patent Classification (IPC) o r t o both national classification and IPC

B . FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

EPO-Internal , WPI Data, BIOSIS, EMBASE

C . DOCUMENTS CONSIDERED T O B E RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

WO 2008/000482 Al (N0VARTIS AG [CH] ; 1-29 N0VARTIS PHARMA GMBH [AT] ; HAEBERLIN BARBARA [CH] ; S) 3 January 2008 (2008-01-03) page 6, l i ne 3 - l i ne 11 page 7, l i ne 12 - l i ne 18 page 9 , l i ne 16 - page 11 , l i ne 26 page 13 - page 14; exampl es cl aims

W0 2013/109220 Al (BI LGIC MAHMUT [TR] ) 1-29 25 July 2013 (2013-07-25) page 6, l i ne 12 - l i ne 22 page 10 - page 11 ; exampl e 1 cl aims -/-

X| Further documents are listed in the continuation of Box C . See patent family annex.

* Special categories of cited documents : "T" later document published after the international filing date o r priority date and not in conflict with the application but cited to understand "A" document defining the general state of the art which is not considered the principle o r theory underlying the invention to be of particular relevance "E" earlier application o r patent but published o n o r after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel o r cannot b e considered to involve a n inventive "L" documentwhich may throw doubts o n priority claim(s) orwhich is step when the document is taken alone cited to establish the publication date of another citation o r other "Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve a n inventive step when the document is "O" document referring to a n oral disclosure, use, exhibition o r other combined with one o r more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

8 December 2016 15/12/2016

Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 N L - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Mul l er, Sophi e C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

X WO 2013/109219 Al (BI LGIC MAHMUT [TR] ) 1-29 25 July 2013 (2013-07-25) page 5 , l i ne 22 - l i ne 32 page 9 - page 10; exampl e 1 c l aims

X W0 2013/109218 Al (BI LGIC MAHMUT [TR] ) 1-29 25 July 2013 (2013-07-25) page 5 , l i ne 18 - l i ne 2 page 10; exampl e 1 c l aims

X US 2006/257324 Al ( LEWIS DAVID A [IT] ET 1-29 AL) 16 November 2006 (2006-11-16) page 2 , paragraph 0030 - paragraph 0036 page 5 , paragraph 0084 - paragraph 0086 c l aims

X EP 2 881 108 Al (JAG0TEC AG [CH] ) 1-29 10 June 2015 (2015-06-10) paragraph [0052] - paragraph [0056] paragraph [0085] c l aims f i gure 1

X W0 2007/068443 Al (JAG0TEC AG [CH] ; 1-29 MUELLER-WALZ RUDI [DE] ) 2 1 June 2007 (2007-06-21) page 4 , l i ne 3 - l i ne 7 page 10, l i ne 3 - l i ne 11 page 11 , l i ne 7 - l i ne 14 page 17 - page 18; exampl e 1 c l aims Patent document Publication Patent family Publication cited in search report date member(s) date

WO 2008000482 Al 03-01-2008 AU 2007264000 Al 03-01 2008 CA 2655381 Al 03-01 2008 CN 101484134 A 15-07 2009 EP 2037879 Al 25- 03 2009 ES 2424754 T3 08-10 2013 P 5266213 B2 21-08 2013 P 2009541393 A 26- 11 2009 KR 20090023650 A 05-03 2009 PT 2037879 E 27- 08 2013 RU 2009102934 A 10-08 2010 US 2009209502 Al 20-08 2009 US 2012065174 Al 15-03 2012 US 2015224194 Al 13-08 2015 US 2016081934 Al 24-03 2016 O 2008000482 Al 03-01 2008

WO 2013109220 Al 25 -07 -2013 EP 2804585 Al 26 -11 -2014 WO 2013109220 Al 25 -07 -2013

wo 2013109219 Al 25 -07 -2013 EP 2804590 Al 26 -11 -2014 WO 2013109219 Al 25 -07 -2013

wo 2013109218 Al 25 -07 -2013 EP 2804584 Al 26 -11 -2014 WO 2013109218 Al 25 -07 -2013

US 2006257324 Al 16-11-2006 AU 2007241336 Al 0 1-11 -2007 B R PI0709510 A2 19 -07 -2011 CA 2649556 Al 0 1-11 -2007 CN 101389341 A 18 -03 -2009 CN 102908308 A 06 -02 -2013 CN 105963249 A 28 -09 -2016 CN 106074359 A 09 -11 -2016 DK 2010190 T3 26 -08 -2013 EA 200802012 Al 28 -04 -2009 EP 2010190 A2 07 -01 -2009 ES 2424753 T3 08 -10 -2013 HR P20130835 Tl 25 -10 -2013 P 5289306 B2 11 -09 -2013 P 2009534333 A 24 -09 -2009 KR 20080110985 A 22 -12 -2008 PT 2010190 E 26 -08 -2013 RS 52940 B 28 -02 -2014 SI 2010190 Tl 3 -10 -2013 US 2006257324 Al 16 -11 -2006 US 2009130026 Al 2 1-05 -2009 WO 2007121913 A2 0 1-11 -2007 ZA 200808965 B 27 -01 -2010

EP 2881108 Al 10-06-2015 AU 2010305698 Al 26 -04 -2012 B R 112012008983 A2 05 -04 -2016 CA 2776359 Al 2 1-04 -2011 CN 102665675 A 12 -09 -2012 DK 2488158 T3 23 -03 -2015 EP 2488158 Al 22 -08 -2012 EP 2881108 Al 1 -06 -2015 ES 2533372 T3 09 -04 -2015 HK 1173077 Al 1 -07 -2015 HK 1211207 Al 2 -05 -2016

page 1 o f 2 Patent document Publication Patent family Publication cited in search report date member(s) date

HR P20150174 Tl 22- 05 2015 P 2013507430 A 04- 03 2013 P 2015129162 A 16-07 2015 NZ 599901 A 30-08 2013 PT 2488158 E 16-03 2015 SI 2488158 Tl 30-04 2015 SM T201500052 B 05- 05 2015 US 2012282189 Al 08-11 2012 US 2014314684 Al 23- 10 2014 O 2011045432 Al 21-04 2011 ZA 201202452 B 25-09- 2013

W0 2007068443 Al 21-06-2007 AU 2006326315 Al 21-06 2007 CA 2632831 Al 21-06 2007 CN 101325945 A 17-12 2008 EA 200870002 Al 30-12 2009 EP 1962797 Al 03-09 2008 HK 1126431 Al 24-07 2015 I L 191809 A 30- 04 2014 P 5207976 B2 12-06 2013 P 2009518449 A 07-05 2009 NZ 569012 A 31- 08 2012 US 2010015238 Al 21-01 2010 US 2012328704 Al 27-12 2012 US 2015037425 Al 05-02 2015 WO 2007068443 Al 21-06 2007 ZA 200804654 B 30-07- 2014

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