(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 agonists, corticosteroids, muscarinic antagonists and phosphodiesterase 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 asthma 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 inflammation 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).