Method to increase the stability of a medicinal formulation in aerosol suspension, e, using cromoline sodium

Abstract

"medicinal suspension formulation, pharmaceutical composition, product, use of cromolyn sodium, and method for increasing the stability of a medicinal aerosol suspension formulation." The present invention relates to a medical aerosol suspension formulation for administration with mdi, comprising: a) micronized b2 agonist; b) micronized corticosteroid; c) a subtherapeutic amount of a unit removing excipient; and d) an hfa propellant; wherein (a), (b) and (c) and their respective relative amounts are selected such that it associates to form flocs with a density substantially equal to that of the hfa propellant.

Description

/ 27 METHOD FOR INCREASING THE STABILITY OF A MEDICINAL FORMULATION IN AEROSOL SUSPENSION

[001] The present invention relates to aerosol medicinal formulations for use with pressurized metered-dose inhalers (abbreviated pMDI or MDI), and especially improved aerosol medicinal formulations suitable for aerosol administration.

[002] Medications for the treatment of respiratory diseases and disorders, such as β2 agonists and anticholinergics, corticosteroids, antihistamines, and others, are frequently administered directly into the lungs via inhalation. Administration via inhalation can increase the therapeutic index and reduce side effects of medications compared to administration by other routes, such as orally or intravenously. Inhalation administration can be in the form of either dry powders or aerosol formulations that are inhaled by the patient either through the use of an inhalation device or as a spray.

[003] MDIs are devices known for administering aerosolized medicinal formulations to the respiratory tract via inhalation by the patient. The term MDI is used to describe a metered-dose inhaler, of which a standard unit comprises a cartridge filled with the medicinal formulation, a drug dispensing valve, and a mouthpiece. The MDI can be selectively activated by the user to dispense successive individual doses of medication by actuation of the dispensing valve, such that a precisely measured dose of the formulation is expelled through the actuator mouthpiece for dispensing into the patient's respiratory tract.

[004] MDI formulations are an advantageous dispensing method for many reasons, including the fact that it dispenses the medication instantly and does not rely on the user's inhalation ability. This is particularly important when considering the type of condition to be treated. Petition 870260057651, dated 12 / 06 / 2026, page 89 / 152 / 27 treated with the medication, such as an asthma attack. Since MDI devices typically contain a sufficient quantity of the medicinal formulation for multiple unit doses, it is important that the formulation be such that it can be successively and repeatedly used with an MDI device. The formulation must be dispensed reliably and at the correctly calculated dose. The formulation must also comply with the pharmaceutical quality, stability, and robustness requirements set by regulatory bodies.

[005] MDIs typically use a propellant to expel droplets or particles of the formulation as an aerosol, containing the medication, from the respiratory tract.

[006] For a long time, the propellant gases used were fluorochlorohydrocarbons, commonly referred to as Freons or CFCs, such as CCUF (Freon 11 or CFC-11), CO2F2 (Freon 12 or CFC-12), and CCClF CClF2 (Freon 114 or CFC-114). However, these CFC propellants have been found to be particularly harmful to the environment, and their production and, at the time of writing, their use in medicinal formulations is becoming obsolete. Therefore, an alternative propellant that is safe for use with inhalation medications has been sought.

[007] Hydrofluoroalkanes (HFAs), also known as hydrofluorocarbons (HFCs), have been proposed as alternative propellant gases because they do not contain chlorine and are considered less destructive to the atmosphere. In particular, 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been observed to be good replacement propellants for CFC propellants, and numerous medicinal aerosol formulations using these propellants have been proposed.

[008] Formulations administered via MDIs can be in the form of solutions or suspensions. In suspension formulations, the drug is manufactured in the form of a fine-particle powder that is then Petition 870260057651, dated 12 / 06 / 2026, page 90 / 152 / 27 suspended in a liquefied propellant or propellant mixture. The suspension formulation can be stored in a sealed cartridge with sufficient pressure to maintain the propellant in liquid form. For example, the vapor pressure for an HFA227 formulation can typically be around 1.96 bar at 0 °C, 3.90 bar at 20 °C, and 7.33 bar at 40 °C. In solution formulations, the drug is solubilized in the liquefied propellant phase. When the dispensing valve is activated, a dose is dispensed in rapidly unfolding fine droplets.

[009] Suspension formulations are generally preferred due to the improved chemical stability of the suspended particles compared with solubilized drugs. Stability problems associated with the chemical degradation of solubilized drug compounds are known in the art.

[0010] In order for a medicinal formulation to be suitable for use with an MDI device, the particle size of the deployed aerosol must be small enough to be inhaled into the lungs of users, whether they are adults, children, or elderly / sick individuals. Therefore, the particles of the suspended formulation need to be microfine with an average aerodynamic particle diameter (measured as Mass Average Aerodynamic Diameter (MAAD)) of about 1 to 10 μm, and preferably 1 to 6 μm. Micronized particles of this size can be obtained by various methods known in the art, for example, mechanical milling or spray drying.

[0011] The amount of active drug broken down into fine inhalable particles is called the fine particle dose (FPD) or the fine particle fraction (FPF), which is defined as the percentage of the fine particle dose relative to the total amount of active compound released. Both are determined by measuring the aerodynamic dispensing of particle size with a cascade impactor or liquid collision devices. Petition 870260057651, dated 12 / 06 / 2026, page 91 / 152 / 27 These are routine tests for which the methods and apparatus are described in pharmacopoeias. For example, formulations of the present invention satisfy the requirements set forth in Chapter <601> of the United States Pharmacopeia (USP) 32 or in the inhalant monographs 2.9.18 of the European Pharmacopeia (PfcuEur.), 6th edition 2009.

[0012] Fine microparticles for use in suspension formulations, however, have some associated drawbacks. They have a large surface area and therefore an unfavorable surface area to volume or mass ratio. This ratio results in strong interaction forces between the particles and undesirable powder cohesion and adhesion tendencies. This, in turn, can lead to difficult handling due to poor flow rate of the sprayed drug during manufacturing and poor suspension properties of the MDI formulation. Such powders are therefore difficult to formulate for use with an MDI device, difficult to handle, and are strongly influenced by electrostatic charge, processing methods, humidity, etc.

[0013] Formoterol fumarate dihydrate (hereinafter referred to as formoterol) is a long-acting β2 agonist bronchodilator (β-sympathomimetic) commonly used for the relief of asthma symptoms. Fluticasone propionate (hereinafter referred to as fluticasone) is a potent synthetic corticosteroid that is also frequently prescribed as a treatment for asthma, chronic obstructive pulmonary disease, and allergic rhinitis. Both are examples of medications that can be individually dispensed via an MDI product.

[0014] Formoterol and fluticasone (but in particular formoterol) are each notoriously difficult compounds to formulate for use with MDIs. One reason for this is that the potency of these drugs means that only a very small dose needs to be dispensed in each case and the drug concentration in the HFA formulation must be, Petition 870260057651, dated 12 / 06 / 2026, page 92 / 152 / 27 therefore, very low. This exacerbates the problems highlighted earlier regarding the manufacture of the aerosol formulation and the pharmaceutical quality, stability and robustness of the aerosol formulation, as required by regulatory authorities, may therefore be compromised. Robustness of the formulation can be determined when handled by the patient, under different conditions of use, through prolonged storage or through storage under stress conditions (e.g., freeze-thaw cycles). Due to the low concentration of drug present in the formulation, fluctuations in the local homogeneity of the drug suspended in the propellant (i.e., in a volume range of approximately 50 pL) may result in deviation in the dispensed dose.

[0015] It has also been shown that MDI formulations comprising hydrofluoroalkanes (HFAs) as propellants are difficult to formulate due to the limited number of suspension aids currently known that are considered safe for inhalation, which can be employed to reduce undesirable particle cohesion and adhesion tendencies and increase the physical stability of the suspension formulation using such HFA propellants.

[0016] Furthermore, the chemical stability of HFA formulations is particularly problematic when β2 bronchodilator agonists, such as formoterol, are used due to their susceptibility to oxidizing and hydrolytic conditions. Hydrolysis is one of the main factors identified that affect the degradation of formoterol under stress conditions (e.g., 40 °C 75% relative humidity) because such formulations are normally sensitive to moisture and susceptible to moisture ingress from the surrounding air.

[0017] Slight changes in concentration or changes in the physical stability of the MDI suspension that may occur during storage in Petition 870260057651, dated 12 / 06 / 2026, page 93 / 152 / 27 due to changes in temperature and / or humidity input can lead to significant differences in measured and dispensed doses (e.g., lack of dose uniformity). These differences can also be seen as a reduction in the inhalable proportion of the delivered dose, which is determined in vitro as the FDP or FPF.

[0018] This reduction may be caused by strong adsorption of drug particles onto the internal surfaces of the cartridge closure system (cartridge and dispensing valve) and by agglomeration of fine microparticles due to imperfect suspension stability. It has been observed that water molecules, which can accumulate in the MDI formulation during long-term storage and use, are particularly detrimental to the suspension since they interact with the polar drug particles and result in a stronger bond between the particles.

[0019] In view of the problems described above, it is generally considered that the key point is to prevent water ingress in order to reduce hydrolysis of formoterol formulations.

[0020] Cromoline sodium (DSCG) is an excellent internal moisture remover and suspension activator. It has been used for administration via inhalation and has been shown to be clinically safe. However, cromoline sodium itself has been shown to have a biological pharmacological effect, and thus its use in the previously described HFA formulations has been avoided, so that an effect greater than or equal to that of fluticasone and formoterol is not seen.

[0021] The type of propellant used also has an effect on the performance of the metered-dose inhaler. The use of HFA propellants instead of CFC propellants has led to an additional problem with fine particles of suspended medication. This is because HFA propellants have a higher polarity than the previously used CFC propellants, which makes HFA suspension formulations relatively more susceptible to Petition 870260057651, dated 12 / 06 / 2026, page 94 / 152 / 27 problems of physical stability. When active agents are used that have a lower density than the liquid in which they are placed, they tend to float and become creamy, which can lead to irregularities in the dispensed dosage. Medications also frequently adhere to the inner surface of the device and the dosing mechanism.

[0022] It was observed that this deposition on the walls of the dosing valve increased significantly compared with the CFC propellant. This deposition can lead to a reduction in the actual dose dispensed. This adhesion can also lead to device failure due to clogging of the internal cartridge mechanisms or blockage of the dosing valve.

[0023] Previously proposed devices used a cartridge in which the internal surfaces are coated with fluorocarbon polymer plastics; see WO-A-96 / 321 SO and US-A-6,596,260. However, problems with such systems include those of fluorocarbon polymers, and their constituents may be soluble in the propellants used in aerosol formulations. Also, such coatings themselves need to undergo safety testing and product formulation development in order to provide a safe and stable product. These tests additionally increase the cost of production, which increases the total cost of the product.

[0024] Coating the internal surfaces of cartridges to prevent adsorption also causes problems with regard to the use of certain metals for the cartridge. Most metals commonly used for cartridges are aluminum alloys. The plastic coating must undergo heat treatment in order to be cured, which causes the cartridge's resistance to be compromised because the metallic cartridge layer becomes softer and more malleable from the heat.

[0025] The plastic coating material itself can also lead to contamination of the medicinal formulation due to the presence of Petition 870260057651, dated 12 / 06 / 2026, page 95 / 152 / 27 potential for leachable compounds to find their way into the formulation contained in the cartridge. Such leachable compounds can lead to degradation of the drug compound in the medicinal formulation and a less effective and less robust product. The shelf life of the dye product may also be compromised by degradation of the active ingredients during storage.

[0026] There are therefore numerous important parameters that need to be considered during the production of an aerosol medicinal formulation for use with an MDI.

[0027] Some of the difficulties in formulating fluticasone propionate and formoterol fumarate into a single formulation were addressed in WO 2005 / 034911 by introducing a drying step to dry the formoterol fumarate before mixing it with the other ingredients. However, the problems associated with long-term storage of such formulations were not addressed.

[0028] This application seeks to alleviate at least some of the aforementioned problems with the previous technology.

[0029] In this way, a first aspect of the present invention relates to a medicinal aerosol suspension formulation for administration with MDI, comprising (a) a micronized β2 agonist, (b) a micronized corticosteroid, (c) a subtherapeutic amount of a moisture-wicking excipient, and (d) an HFA propellant wherein (a), (b) and (c) and their respective relative amounts are selected in such a way that they associate to form flocs with a density substantially equal to that of the HFA propellant.

[0030] It has been observed that the constituents of the present formulation tend to associate in such a way as to form flocs (also known as flakes, tufts or flocculated particles). Flocs comprise a loose mass or aggregation of discrete fine particles grouped in a fragile structure. Petition 870260057651, dated 12 / 06 / 2026, page 96 / 152 / 27 network type, suspended in solution. The aggregates formed by the flocs tend to break easily upon application of small amounts of shear stress, such as gentle agitation of the cartridge, and reform an extended network of particles after the force is removed. Flocculation, therefore, imparts a structure to the suspension with virtually no increase in viscosity. Unlike deflocculated systems, the flocs will settle rapidly, typically in a high volume of sediment, and can be easily resuspended even after prolonged storage periods, for example, after 3, 6, 9, or 12, 18 months or more.

[0031] It has been observed that, once associated, the flakes of the present formulation have a density to match the density of the propellant in which they are placed. This gives the flakes the ability to remain in suspension without the tendency to become creamy, float or sink. The suspension formulation of the present invention can therefore remain in a viable formulation for an extended period of time and result in a robust product with an extended shelf life and greater reliability of the final product.

[0032] In addition, the tendency to form these flocs can provide greater uniformity in the suspension and less fluctuation in local homogeneity, which then results in a product that may have less deviation in the dispensed dose.

[0033] In addition to the above, the flakes provide greater stability to the suspension formulation. This greater stability of the suspension means that the ingredients preferentially bind to each other rather than to the internal surfaces of the cartridge or dosing valve of the inhaler. Therefore, there is less tendency to adhere to the inside of the cartridge or the cartridge's dosing valve through which the suspension formulation must pass. This can lead to an increase in Petition 870260057651, dated 12 / 06 / 2026, page 97 / 152 / 27 reliability of the dispensed dose. Furthermore, there is a lower tendency to block the actuation mechanism and the dosing valve, which in turn provides a formulation that can be reliably and repeatedly dispensed in the correct quantity.

[0034] Typically, suspension formulations, especially MDI suspension formulations using HFA propellants, are inherently physically unstable. The formulations form two phases, a liquid propellant phase and a suspended particulate phase, which segregate due to gravitational force. In the cartridge, areas with different concentrations of suspended particles may also exist due to small temperature fluctuations within the cartridge leading to thermal movement of the particles. However, the tendency of formulations according to the present invention to associate to form flocs causes all active ingredients to remain associated until they are dispensed from the MDI and enter the patient's respiratory system. This provides a formulation with higher quality and greater ability to adhere to a calculated dose.

[0035] Preferably, the HFA propellant is HFA 227. HFA 227 is an inert propellant with low toxicity and is suitable for use in metered-dose inhalers. HFA 227 propellant, when combined with a small amount of ethanol to form the liquid propellant phase, has a calculated density, over a range of temperatures, as follows:

[0036] Temperature

[0037] Calculated density [g / mL]

[0038] 10 °C

[0039] 1.45

[0040] 15 °C

[0041] 1.43

[0042] 20 °C

[0043] 1.41

[0044] 22 °C

[0045] 1.40

[0046] 25 °C

[0047] 1.39

[0048] 30 °C

[0049] 1.36

[0050] The previous figures were calculated using thermodynamic laws for ideal mixtures. However, in practice, liquid mixtures likely behave as non-ideal mixtures, and the true densities may be slightly different from the calculated values.

[0051] It is therefore advantageous to have a formulation in which the density Petition 870260057651, dated 12 / 06 / 2026, page 98 / 152 / 27 average of the flocs (comprising the micronized β2 agonist, micronized corticosteroid and moisture-removing excipient) is substantially equal to the propellant density ±0.2 g / cm3, preferably ±0.1 g / cm3, more preferably ±0.05 g / cm3 of the propellant.

[0052] The average density of the flocs can be calculated using any standard technique, for example, by determining the true particle density of each solid component by helium pycnometry. The density of the flocs can therefore match substantially with the density of the propellant in a temperature range of 10 °C to 30 °C in which an MDI would normally be operated by a user.

[0053] Preferably, the corticosteroid is fluticasone propionate or a pharmaceutically acceptable salt thereof. The corticosteroid is advantageously present in an amount of 0.01-0.6% by weight, preferably between 0.02-0.5% by weight, and most preferably 0.03-0.4% by weight, based on the total weight of the formulation. This is the advantageous amount in order to be effective in use and also to form the correct density of flocs for suspension in the propellant.

[0054] The corticosteroid preferably has a defined particle size of less than 10 μm for 100%, less than 6 μm for 90%, less than 3 μm for 50%, and less than 2 μm for 10% of the particles.

[0055] Preferably, the β2 agonist is formoterol fumarate dihydrate or a pharmaceutically acceptable salt or derivative thereof. The β2 agonist is preferably present in an amount of 0.003-0.04% by weight; preferably 0.004-0.03% by weight; and more preferably 0.005-0.02% by weight, based on the total weight of the formulation. In a preferred embodiment, formoterol fumarate dihydrate may be employed in an amount of 0.003-0.008% by weight, based on the total weight of the formulation. In an alternative preferred embodiment, formoterol fumarate dihydrate may be employed in an amount of 0.01-0.04 Petition 870260057651, dated 12 / 06 / 2026, page 99 / 152 / 27% by weight, based on the total weight of the formulation. As with the corticosteroid, this is the advantageous amount of β2a agonist in order to be effective in use and also to form the correct density of flocs for suspension in the propellant.

[0056] The β2 agonist preferably has a defined particle size of less than 10 μm for 100%, less than 6 μm for 90%, less than 3 μm for 50%, and less than 2 μm for 10% of the particles.

[0057] Preferably, the moisture-wicking excipient is sodium cromolyn (DSCG) and is advantageously present at subtherapeutic levels in such a way that it does not exert a biological effect by itself and is pharmaceutically inactive. The moisture wick is therefore suitably present in an amount of 0.01-0.1% by weight; preferably 0.01-0.09% by weight; more preferably 0.02-0.08% by weight; more preferably 0.02-0.07% by weight; more preferably 0.03-0.05% by weight; more preferably 0.03-0.04% by weight, based on the total weight of the formulation.

[0058] The moisture remover preferably has a defined particle size of less than 10 μm for 100%, less than 6 μm for 90%, less than 3 μm for 50%, and less than 2 μm for 10% of the particles.

[0059] DSCG has been observed to be an excellent suspension activator when used in formulations including an HFA propellant. DSCG itself consists of particles that encourage and enable the formation of heterogeneous flocs with the active agents.

[0060] DSCG acts to help stabilize the formulation, particularly against hydrolysis by competitive water absorption. DSCG exists as a unique crystalline form that is non-stoichiometric with respect to water content and adsorbs or desorbs water rapidly in response to changes in relative humidity. DSCG crystals are universal in the extent of reversible water absorption without collapse of the crystal lattice and can Petition 870260057651, dated 12 / 06 / 2026, page 100 / 152 / 27 absorbs up to 9 water molecules per mole, which is about 24% w / w. Analysis of the crystal structure by X-ray diffraction reveals the existence of channels that are capable of reversibly accommodating a variable number of water molecules (depending on the relative humidity of the environment) with only small dimensional changes in the lattice. Despite its high moisture adsorption capacity, DSCG is not deliquescent (like, for example, sodium sulfate) but is solid in the range of 10 to 90% RH.

[0061] In the present invention, DSCG acts to stabilize the fine particle fraction (FPF) in the formulation by competitively binding to (i.e., molecularly dissolved) water present in the propellant phase. This helps stabilize the fine particle fraction by preventing agglomeration of suspended particles (i.e., formation of liquid bonds and / or crystals) and particle growth (i.e., Ostwald ripening) at stability. This allows for a more robust product during storage and use since the formulation has greater tolerance to the presence of internal water. For example, up to 600 ppm of total internal water can be tolerated. Furthermore, this allows for a much longer shelf life once the product is in the hands of patients. Additionally, there is less tendency to adhere to surfaces, which allows the medicinal formulation to be used with an uncoated cartridge instead of a cartridge that has its internal surfaces coated with a polymer.

[0062] Preferably, the medicinal aerosol suspension formulation further comprises a wetting agent, most preferably the wetting agent is a dehydrated alcohol; and above all preferably the wetting agent is ethanol which may be present in an amount of 0.01-3% by weight; preferably 0.05-2.5% by weight; and most preferably 1.0-2.0% by weight, based on the total weight of the formulation.

[0063] A wetting agent facilitates the wetting of the active agents in the liquefied propellant and thus the manufacture of the suspension in such a way that the Petition 870260057651, dated 12 / 06 / 2026, page 101 / 152 / 27 active agents do not become partially solubilized. The addition of such agents requires a delicate balance between allowing the active agents to become wet without being partially solubilized and causing them to be partially solubilized in such a way that Ostwald ripening, particle growth and, eventually, instability occur.

[0064] Ethanol can be added in small quantities as it also helps to prevent the deposition of active agents on the walls of cartridges and mechanical parts.

[0065] In a preferred form, the formulation of the present invention therefore comprises formoterol and fluticasone as pharmaceutically active ingredients and cromolyn sodium, HFA 227 and ethanol as pharmaceutically inactive ingredients.

[0066] A further aspect of the present invention relates to a pharmaceutical composition comprising 0.01-0.6% by weight of micronized corticosteroid; 0.003-0.04% by weight of micronized β2 agonist; and 0.01-0.1% by weight of sodium cromolyn.

[0067] Preferably, the corticosteroid is micronized fluticasone propionate.

[0068] Advantageously, the β2 agonist is micronized formoterol fumarate dihydrate.

[0069] Preferably, the pharmaceutical composition further comprises a humectant, most preferably the humectant is a dehydrated alcohol, above all preferably ethanol. Preferably, the humectant is present in an amount of 0.01-3% by weight; preferably 0.05-2.5% by weight; and most preferably 1.0-2.0% by weight, based on the total weight of the formulation.

[0070] A further aspect of the present invention relates to a pharmaceutical suspension formulation comprising about 0.003-0.04 Petition 870260057651, dated 12 / 06 / 2026, p. 102 / 152 / 27% of formoterol fumarate dihydrate, approximately 0.01-0.06% of fluticasone propionate, approximately 0.01-0.1% of suspending agent and approximately 0.01-3% of dehydrated alcohol.

[0071] Preferably, the suspending agent is sodium cromolyn (DCSG), which also allows the active agents to remain in suspension for an extended period of time. This increases the shelf life of the product since it can be effective for a longer time after production.

[0072] In addition, DSCG acts as a bulking agent, since its use increases the concentration of suspended particles in the formulation, thus minimizing inherent concentration changes in the suspension without the need to add other excipients. DSCG also provides the usual benefits of bulking agents, namely, providing the preparation of a more homogeneous suspension, which leads to greater dose accuracy.

[0073] A further aspect of the present invention relates to a product containing formoterol fumarate dihydrate, fluticasone propionate and cromolyn sodium as a combined preparation for separate, sequential or simultaneous use in the treatment of inflammation and preferably for the treatment of asthma and allergic rhinitis.

[0074] A further aspect of the present invention relates to the use of sodium cromolyn in the preparation of a pharmaceutical formulation in suspension in an HFA propellant comprising fluticasone propionate and formoterol fumarate dihydrate microparticles to form flakes of fluticasone propionate, formoterol fumarate dihydrate and sodium cromolyn with a density substantially equal to that of the HFA propellant.

[0075] According to a further aspect of the present invention, the use of 0.01 to 0.1% of sodium cromolyn is provided in the preparation of a Petition 870260057651, dated 12 / 06 / 2026, page 103 / 152 / 27 pharmaceutical formulation in suspension in HFA propellant comprising 0.01 to 0.6% fluticasone propionate and 0.003 to 0.04% formoterol fumarate dihydrate microparticles to form fluticasone propionate, formoterol fumarate dihydrate and sodium cromolyn flocs with a density substantially equal to that of the HFA propellant.

[0076] Preferably, the average density of the flakes is substantially equal to the density of the HFA propellant ±0.2 g / cm3, preferably ±0.1 g / cm3, more preferably ±0.05 g / cm3 of the propellant.

[0077] Preferably, the pharmaceutical suspension formulation further comprises a wetting agent, preferably a dehydrated alcohol, preferably ethanol.

[0078] According to a further aspect of the present invention, a method is provided for increasing the stability of a medicinal aerosol suspension formulation of a micronized β2 agonist and a micronized corticosteroid in an HFA propellant for a prolonged storage period, comprising adding a subtherapeutic amount of sodium cromoglycate, wherein the respective relative amounts of the micronized β2 agonist, micronized corticosteroid and sodium cromoglycate are selected in such a way that they associate to form flocs with a density substantially equal to that of the HFA propellant.

[0079] Preferably, prolonged storage is for 3, 6, 9, 12 or 18 months. Preferably, the water content of the suspension formulation after prolonged storage is in the range of 500 ppm to 800 ppm, preferably 600 ppm to 700 ppm.

[0080] Examples of suitable dosage concentrations of a pharmaceutical composition according to the present invention can be seen in the following table. Table 1: Composition of examples of dosage concentrations of Petition 870260057651, dated 12 / 06 / 2026, page 104 / 152 / 27 formulation % p / p Flutiform 25 / 5 Flutiform 50 / 5 Flutiform 125 / 5 Flutiform 250 / 5 Nominal dose 50 mcg FP and 10 mcg FF 100 mcg FP and 10 mcg FF 250 mcg FP and 10 mcg FF 500 mcg FP and 10 mcg FF Fluticasone 0.0357 0.0714 0.1785 0.3570 Formoterol 0.0071 0.0071 0.0071 0.0071 Cromolin sodium 0.0343 0.0343 0.0343 0.0343 Ethanol 1.43 1.43 1.43 1.43 HFA 227 qs to 100.0 qs to 100.0 qs a 100.0 qs a 100.0 Flutiform 250 / 5 Flutiform 250 / 5 Nominal dose 500 mcg FP and 20 mcg FF 500 mcg FP and 20 mcg FF Fluticasone 0.3570 0.3570 Formoterol 0.0142 0.0142 Cromoline sodium 0.0343 0.0686 Ethanol 1.43 1.43 HFA 227 qs to 100.0 qs to 100.0

[0081] The following is an example description, with reference to the accompanying drawings, of embodiments of the present invention. In the drawings:

[0082] Figure 1 - Aerodynamic dispensing of particle size for fluticasone and formoterol.

[0083] Figure 2 - Photographs of suspension in glass vials at different time points after shaking. Examples Example 1

[0084] The following compositions shown in Table 2 were made and the density of the fluticasone, formoterol and cromolyn sodium flocs was calculated and compared with the calculated density of the liquid phase (comprising 1.43% w / w anhydrous ethanol and HFA 227) over a range of temperatures. Table 2: Composition of pharmaceutical formulations Flutiform 25 / 5 Flutiform 50 / 5 Flutiform 125 / 5 Flutiform 250 / 5 Flutiform 250 / 10 Nominal dose 50 mcg FP and 10 mcg FF 100 mcg FP and 10 mcg FF 250 mcg FP and 10 mcg FF 500 mcg FP and 10 mcg FF 500 mcg FP and 20 mcg FF Fluticasone 0.0357 0.0714 0.1785 0.3570 0.3570 Formoterol 0.0071 0.0071 0.0071 0.0071 0.0142 Cromolin sodium 0.0343 0.0343 0.0343 0.0343 0.0343 Ethanol 1.43 1.43 1.43 1.43 1.43 HFA 227 qs at 100.0 qs at 100.0 qs at 100.0 qs at 100.0 qs at 100.0

[0085] The density of the liquid phase was determined based on the thermodynamic laws for ideal mixtures. However, in practice, liquid mixtures likely behave as non-ideal mixtures, and the true densities may be slightly different from the calculated values. Petition 870260057651, dated 12 / 06 / 2026, page 105 / 152 / 27

[0086] The average density of the flocs was determined by measuring the true particle density of each solid component by helium picometry.

[0087] The results of the density calculations are shown in tables 3 and 4. Table 3: Calculated density of the liquid phase Temperature | Calculated density of the liquid phase [g / mL] | 10 °C | 1.45 | 15 °C | 1.43 | 20 °C | 1.41 | 22 °C | 1.40 | 25 °C | 1.39 | 30 °C | 1.36 Table 4: Calculated floc density Composition: Fluticasone / formoterol 25 / 5 (25 mg of fluticasone and 5 mg of formoterol per action) 1.47 mg; Fluticasone / formoterol 50 / 5 1.43 mg; Fluticasone / formoterol 125 / 5 1.40 mg; Fluticasone / formoterol 250 / 5 1.38 mg; Fluticasone / formoterol 250 / 10 1.38 mg

[0088] It can be observed from the previous results in tables 3 and 4 that the average density of the flocs substantially matches the calculated density of the liquid phase within ±0.2 g / mL. Example 2

[0089] The batches shown in Table 5 were made and tested (in a range of operating temperatures from 10 to 30 degrees Celsius): Table 5: Compositions of batch 1 and batch 2 Lot 1 Description Fluticasone / formoterol formulation (nominal dose 100 pg fluticasone / 10 pg formoterol) Lot 2 Fluticasone / formoterol formulation without DSCG (for comparison, not part of the present invention) Composition % w / pg % w / pg Propionate 0.0714 2.340 0.0714 2.340 Fluticasone Dihydrate 0.0071 0.234 0.0071 0.234 Formoterol Fumarate Cromoline Sodium 0.0343 1.123 0.0000 0.000 (SDCG) Ethanol 1.43 46.8 1.43 46.8 HFA 227 qs at 1000.0 3225.5 qs at 1000.0 3226.6

[0090] The size of each batch was 3.3 kg (approximately 300 (units). Ethanol 96.5% w / w (97.75% v / v) was used to challenge the formulation with a water level approximately similar to the amount contained in the formulation at the end of the intended shelf life. The water content of all raw materials except HFA 227 was determined by analysis. Petition 870260057651, dated 12 / 06 / 2026, page 106 / 152 / 27 Karl-Fischer before preparing the suspension.

[0091] The appropriate amounts of micronized active substances were weighed and transferred to the batch vessel. The appropriate amount of sodium cromolyn (DSCG) was added and the vessel closed. The mixture of HFA 227 (apaflurane) propellant with 1.45% alcohol was made in a separate vessel and transferred to the batch vessel. The solid materials were dispersed in the liquefied propellant using a rotor-stator homogenizer at 2,900 rpm for 30 minutes. The volume of the homogeneous suspension was cooled to 4 °C and recirculated between the vessel and the Pamasol P2001 aerosol filling machine.

[0092] Pharmaceutical aerosol cartridges with a volume of 14 mL completely filled were stapled with 50 mcl measuring valves using a Pamasol P2005 stapling machine. Aliquots of 11 ±0.5 g of suspension were filled into the stapled cartridges by the P2001 filling machine. The weight of each filled cartridge was checked; all filled cartridges were subjected to a thermal stress test at 56 °C and stored for one month before assembly with the actuator for testing.

[0093] Glass vials were filled beyond the exposed cartridges with Lot 1 and Lot 2 HFA-MDI fluticasone / formoterol formulations to assess suspension stability visually and by time interval photography, see Figure 2. The glass vials were shaken and photographs were taken 15 seconds, 30 seconds, 45 seconds, 1 minute, 1 minute and 30 seconds, 2 minutes, 3 minutes, 5 minutes and 2 hours after this shaking.

[0094] The following analytical tests were performed on Lots 1 and 2: Table 6: Tests performed Description Method Table in which the results are displayed ____________________________________________________________________________________________________ Drug content (assay) HPLC Table 7 Uniformity of dose content (inter-inhaler) HPLC Table 8 Uniformity of dose content during cartridge life (intra-HPLC Table 9) Particle size dispensing (by HPLC cascade impactor Figure 1 Andersen) Water content Karl Fischer Table 7 Petition 870260057651, dated 12 / 06 / 2026, page 107 / 152 / 27 Interaction between content and container (cartridge and valve) HPLC Table 10 Suspension stability (in filled glass vials) Time interval of Figure 2 ____________________________________________________________________________photograph_____________________________________________________ Table 7: Drug content, DSCG and water content of the fluticasone / formoterol 100 / 10 formulation from batch 1 (fluticasone / formoterol 100 / 10 formulation with DSCG) and batch 2 (without DSCG) Lot No. 1 2 Average fluticasone content [pg per g of suspension / % of target] 679.0 / 95.1% (0.4%) 658.0 / 92.2% (4.6%) (RSD %, n=30) Average formoterol content [pg per g of suspension / % of target] 68.2 / 95.5% (0.4%) 64.7 / 90.6% (5.3%) (RSD %, n=30) Average DSCG content [pg per g of suspension / % of target] 321.0 / 93.7% (0.3%) NA (RSD %, n=30) Average water content [pg per g of suspension / % of target] 672 (12.6%) 624 (5.1%) (RSD %, n=30)

[0095] Table 7 shows the water content of the batches when 96.5% w / w ethanol was included in the formulation, thereby adding 500 ppm to the formulation, in addition to the moisture typically present due to the manufacturing process itself. The slightly higher value for Batch 1 may have been due to the presence of DCSG. The water level observed in both batches is that which would typically be expected after long-term storage of the product or after shorter-term storage under humid conditions (e.g., 75% RH or more). The values ​​obtained therefore demonstrate that the formulations of Batch 1 and Batch 2 (or other equivalent batches produced in the same way using 96.5% w / w ethanol) can be used to demonstrate the effect of DCSG inclusion in a fluticasone / formoterol formulation on the parameters listed previously in Table 6, as can be observed, for example, after long-term storage of the formulation.

[0096] It can be observed that the drug concentration for the DCSG formulation was higher than that of Lot 2, with 95.1% target fluticasone content and 95.5% target formoterol content obtained with DCSG compared to 92.2% and 90.6% respectively without DCSG. This may Petition 870260057651, dated 12 / 06 / 2026, page 108 / 152 / 27 to be associated with drug losses during manufacturing due to absorption of the drug in the manufacturing equipment. Table 8: Dose content uniformity (inter-inhaler) of the fluticasone / formoterol 100 / 10 formulation from batch 1 (fluticasone / formoterol 100 / 10 formulation with DSCG) and batch 2 (without DSCG) based on MDI release. Lot No. 1 2 Average fluticasone dispensed dose [gg] (RSD %, n=10) 92.0 (5.2%) 79.0 (4.7%) Average dispensed dose of formoterol [gg] (RSD %, n=10) 8.9 (6.0%) 7.4 (4.8%)

[0097] Table 8 shows the results of the test dose dispensing of the 10 inhalers for each Lot. The inclusion of DCSG in the formulation is shown to dispense a higher dose of good medicines (e.g., 92% with DCSG compared to 79% without for fluticasone). Table 9: Uniformity of dose content during the cartridge life of the fluticasone / formoterol 100 / 10 formulation from batch 1 (fluticasone / formoterol 100 / 10 formulation with DSCG) and batch 2 (without DSCG) as determined by MDI release. Lot No. 1 2 Average fluticasone dispensed dose [gg] (RSD %, n=9) 89.6 (8.0%) 79.9 (3.8%) Average dispensed dose of formoterol [gg] (RSD %, n=9) 8.8 (7.7%)______7.5 (5.5%)

[0098] The results of the dose content uniformity study during cartridge life, as shown in Table 9, also show that a higher dose of good medicines is dispensed by Lot 1 (with DCSG) (89.6% with DCSG compared to 79.9% without for fluticasone). Table 10: Drug residue and DSCG in the cartridge and valve after exhaustion of the fluticasone / formoterol 100 / 10 formulation from lot 1 (fluticasone / formoterol 100 / 10 formulation with DSCG) and lot 2 (without DSCG) upon MDI release. Lot 1 Formoterol assay [gg] (RSD %, n=3) Fluticasone assay [gg] (RSD %, n=3) DCSG assay [gg] (RSD %, n=3) Cartridge 31.2 (13.4%) 330 (14.7%) 74.8 (16.9%) Valve 31.9 (21.3%) 278 (22.3%) 69.4 (23.0%) Total (%) 608 (13.5%) 144 (15.1%) Lot 2 Cartridge Valve Total Formoterol assay [gg] (RSD %, n=3) 51.4 (17.2%) 62.7 (14.0%) 114.1 (15.1%) Fluticasone assay [gg] (RSD %, n=3) 539 (16.5 %) 561 (16.7 %) 1,100 (15.8 %) DCSG [gg] test (RSD %, n=3) NA NA NA Petition 870260057651, dated 12 / 06 / 2026, page 109 / 152 / 27

[0099] The table above shows that up to twice as much of both drugs was recovered from the cartridges and valve of Lot 2 compared with Lot 1 (with DCSG) (e.g., 608 μg of fluticasone recovered for Lot 1, compared with 1,100 pg for Lot 2).

[00100] Figure 1 shows the aerodynamic particle size dispensing results from tests performed on five inhalers for each batch. Similar to the dose dispensing results in Tables 4 and 5, less fluticasone and formoterol were dispensed from the actuator for Batch 2 compared to Batch 1.

[00101] Figure 2 shows the time-interval photography results for glass vials containing formulations from the two batches. The glass vials were also visually examined and the following differences in suspension stability were observed.

[00102] Lot 1 (with DSCG) showed large loose flocs long after agitation ended (this result was different from that observed when the formulation is not challenged with water) while Lot 2 (without DSCG) remained more dispersed and more homogeneous.

[00103] After a longer period of time, however, Lot 1 remained in loose flocculated form, resulting in a voluminous but easily redispersible sediment, while Lot 2 appeared to form clumps of different densities, some of which sedimented and others of which floated. At least some of the sedimented material present in the glass flask from Lot 2, which formed a creamy material deposited on the surface of the glass flask at the liquid-gas interface, was difficult to redisperse into a homogeneous suspension.

[00104] Visual examination revealed, therefore, that the fluticasone / formoterol formulation with DSCG (Lot 1) flocculates more rapidly than the same formulation when not challenged by additional water, but remains homogeneous for a sufficient time to provide dose uniformity. Petition 870260057651, dated 12 / 06 / 2026, page 110 / 152 / 27 satisfactory and consistent. In contrast, the DSCG-free formulation prepared for comparison (Lot 2) quickly became creamy and resulted in drug deposition on the surface of the glass vial at the liquid-gas interface. These visual observations, therefore, provide evidence that the formulation of the present invention is capable of tolerating large amounts of internal water.

[00105] In conclusion, the use of DSCG as an enabling excipient in the fluticasone / formoterol HFA-MDI formulation thus provided a more robust finished drug product, particularly against moisture ingress, which inevitably occurs during storage and use. Example 3:

[00106] The following batch was made using the process described in Example 1: Table 11: Composition of Lot 3 Description of batch 3 Fluticasone / formoterol formulation (nominal dose ______________________________________250 mg fluticasone / 12 mg formoterol)___________ Composition % w / g Fluticasone propionate 0.1785 3.900 Formoterol fumarate dihydrate 0.0086 0.187 Cromolin sodium 0.0343 0.749 Ethanol 1.43 31.2 HFA 227 qs a 100.0 2,148.0

[00107] The bagless inhalers that were filled were placed in an investigational stability program for 6 months at 40 °C / 75% RH and showed good product qualities and robustness in product performance tests, as shown by the results in Tables 12 and 13 below. Table 12: Results of Andersen cascade impactor of the fluticasone / formoterol formulation (250 µg fluticasone / 12 µg formoterol) at release and after 1 to 6 months of storage at 40°C / 75% RH. Lot 3 Fluticasone Medium Release (RSD%, n=4) 1 month (40 UR) Cartridge 1 oC / 75% of Cartridge 2 3 months (40 UR) Cartridge 1 oC / 75% of Cartridge 2 6 months (40 UR) Cartridge 1 oC / 75% of Cartridge 2 Dose dispensed [pg, 2 actuations] 197 (7.2%) 173.1 191.5 184.5 203.7 189.0 173.8 Petition 870260057651, dated 12 / 06 / 2026, page 111 / 152 / 27 Measured dose [pg, 2 actuations] 211 (8.4%) 198.5 207.2 204.7 216.6 229.5 nd Fine particle dose [pg, 2 actuations] 102 (8.5%) 79.7 83.7 80.0 86.0 102.7 73.4 Fine particle fraction [pg, % based on dispensed dose] 52.0 46.1 43.7 43.3 42.2 54.3 42.2 Fine particle fraction [pg, % based on measured dose] 48.5 40.2 40.4 39.1 39.7 44.7 nd Formoterol Dispensed dose [pg, 2 actuations] 9.5 (5.1%) 8.6 9.5 9.8 10.5 8.4 7.9 Measured dose [pg, 2 actuations] 10.9 (5.3%) 11.5 11.3 12.7 12.5 10.5 nd Fine particle dose [pg, 2 actuations] 5.6 (8.3%) 5.3 5.7 5.6 6.0 5.4 3.8 Fine particle fraction [pg, % based on dispensed dose] 58.4 61.6 60.0 56.4 57.2 63.6 48.6 Fine particle fraction [pg, % based on measured dose] 51.1 46.0 50.6 43.6 47.8 51.3 nd Table 13

[00108] Dosage uniformity test results throughout the life of the inhaler of the fluticasone / formoterol formulation (250 pg fluticasone / 12 pg formoterol) at release and after 1 to 6 months of storage at 40°C / 75% RH Lot 3 Release N=10 1 month (40°C / 75% RH) N=12 3 months (40°C / 75% RH) N=10 6 months (40°C / 75% RH) N=12 Fluticasone dose dispensed average [gg, 2 actuations] (RSD %) 197 (3.7%) 208 (4.0%) 109 (11.7%) 191 (5.9%) Formoterol dose dispensed average [gg, 2 actuations] (RSD %) 10.2 (7.0%) 10.4 (4.3%) 9.3 (12.3%) 9.2 (5.8%) Example 4

[00109] The following batches were made using the process described in Example 1: Table 14: Composition of Lot 4 and Lot 5 Lot 4 Lot 5 Description Formulation of fluticasone / formoterol (nominal dose 500 mg of fluticasone / 20 mg of fluticasone / 10 mg of formoterol) Composition % w / w % w / w Fluticasone propionate 0.3571 0.3571 Formoterol fumarate dihydrate 0.0143 0.0143 Ethanol 1.43 1.43 HFA 227 qs to 100.0 qs to 100.0

[00110] Results of the stability investigation up to 12 months Petition 870260057651, dated 12 / 06 / 2026, page 112 / 152 / 27 demonstrated good product qualities and robustness of both formulations, as shown by the results presented in tables 15 and 16 below. Figure Captions Figure 1: Aerodynamic particle size distribution of fluticasone / formoterol formulation batches 2028 / 10AI01 (solid symbols) and 7 (clear symbols) as determined by ACI at a flow rate of 28.3 L / minute, volume 4 L, n=5. Top graph: fluticasone results, bottom graph: formoterol results. Figure 2: Time interval of the photograph of the glass vials filled with the fluticasone / formoterol formulation from batch 1 (with DCSG on the left) and batch 2 (without DCSG on the right) taken at 15 seconds, 30 seconds, 45 seconds, 1 minute, 1 minute and 30 seconds, 2 minutes, 3 minutes, 5 minutes and 2 hours after this shaking. Petition 870260057651, dated 12 / 06 / 2026, page 113 / 152 / 27 Table 15: Summary of ACI results for the fluticasone / formoterol formulation Flutiform 250 / 10 (Lot 5) up to 12 months at 25°C / 60% RH and 40°C / 75% RH. Each result is the average of 6 determinations (beginning and end of 3 cartridges). Fluticasone Initial 3 months 25°C / 60%RH 6 months 12 months 1 month 3 months 40°C / 75%RH 6 months 12 months Measured dose [pg] 428.9 419.8 426.8 427.7 425.9 454.8 429.3 437.1 412.6 442.3 449.8 430.0 431.2 447.9 Dispensed dose [pg] 407.5 400.9 407.3 413.9 408.5 434.2 413.5 417.0 392.2 423.2 417.3 415.6 414.1 429.8 FPD (stage 3- (filter) 173.6 184.0 179.1 181.8 184.0 186.1 177.0 180.1 177.0 193.2 183.1 174.7 181.0 172.1 Group 1 (USP inlet nozzle) [pg] 186.2 172.6 185.2 179.5 180.3 195.9 182.6 185.6 164.9 179.9 206.5 182.6 179.6 196.6 Group 2 (stage 0-stage 2) [pg] 60.2 52.3 52.6 56.7 53.5 65.0 60.8 60.7 61.3 59.7 52.5 63.3 61.5 69.9 Group 3 (stage 3-stage 5) [pg] 168.8 178.5 174.2 177.1 179.2 181.1 172.1 175.1 172.4 188.6 178.1 170.7 176.6 168.5 Group 4 (stage 6-filter) [pg] 4.9 5.5 5.0 4.7 4.8 5.0 4.8 5.0 4.6 4.7 5.0 3.9 4.4 3.7 Formoterol Measured dose [pg] 18.50 18.27 18.12 18.22 18.00 19.25 17.60 18.15 17.51 ​​18.59 19.05 18.42 18.21 18.43 Dispensed dose [pg] 16.89 16.71 16,47 16.89 16.57 17.54 16.34 16.76 16.05 17.13 16.56 17.04 16.76 16.81 FPD (stage 3 - filter) [pg] 8.40 8.87 8.66 8.90 9.04 9.01 8.29 8.61 8.48 9.23 8.92 8.64 9.00 8.23 ​​Group 1 (nozzle - USP (nozzle) [pg] 8.06 7.61 7.67 7.42 7.21 8.16 7.30 7.49 7.01 7.42 8.44 7.72 7.23 8.03 Group 2 (Stage 0-Stage 2) [pg] 1.75 1.41 1.45 1.57 1.45 1.81 1.68 1.68 1.70 1.61 1.42 1.74 1.67 1.85 Group 3 (Stage 3-Stage 5) [pg] 8.18 8.60 8.43 8.68 8.81 8.77 8.08 8.36 8.27 9.00 8.69 8.44 8.79 8.05 Group 4 (Stage 6-Filter) [pg] 0.22 0.27 0.23 0.23 0.23 0.23 0.21 0.25 0.21 0.23 0.23 0.20 0.21 0.18 Petition 870260057651, dated 12 / 06 / 2026, page 114 / 152 / 27 Table 16: Summary of ACI results for the fluticasone / formoterol formulation Flutiform 250 / 10 (Lot 5) up to 12 months at 25°C / 60% RH and 40°C / 75% RH. Each result is the average of 6 Determinations (beginning and end of 3 cartridges) Fluticasone 25 °C / 60 %RH 40 °C / 75 %RH Initial 6 months 12 months 1 month 6 months 12 months Measured dose [pg] 402.2 432.1 426.9 433.0 420.3 419.0 417.1 431.4 428.9 417.9 Dispensed dose [pg] 378.4 413.9 411.6 416.2 405.5 404.5 401.0 412.1 417.3 402.7 FPD (Stage 3 - F) [pg] 181.0 203.2 195.1 193.6 185.6 185.0 181.2 194.1 193.9 178.9 Group 1 (MP - Nozzle-entry USP) [pg] 171.5 175.9 180.1 175.6 178.9 181.4 183.7 179.9 175.5 171.2 Group 2 (Stage 0 - Stage 2) [pg] 42.1 46.3 46.2 54.2 47.8 43.6 45.0 50.8 52.3 58.1 Group 3 (Stage 3 - Stage 5) [pg] 177.1 199.1 190.8 189.9 182.0 181.0 177.2 190.7 190.3 175.7 Group 4 (Stage 6 - F) [pg] 3.8 4.0 4.4 3.7 3.6 4.0 4.0 3.4 3.5 3.2 Formoterol Measured dose [pg] 8.47 9.28 9.22 9.22 8.78 9.09 9.10 9.13 9.07 8.49 Dispensed dose [pg] 7.62 8.38 8.40 8.45 8.03 8.36 8.26 8.23 ​​8.37 7.76 FPD (Stage 3 - F) [pg] 3.81 4.42 4.28 4.27 4.04 4.08 4.00 4.19 4.20 3.82 Group 1 (MP - USP throat) [pg] 3.78 3.91 4,Group 1 (Stage 0 - Stage 2) [pg] 0.75 0.82 0.81 0.92 0.81 0.79 0.81 0.86 0.89 0.92 Group 3 (Stage 3 - Stage 5) [pg] 3.75 4.34 4.19 4.17 3.97 3.96 3.89 4.11 4.11 3.75 Group 4 (Stage 6 - F) [pg] 0.06 0.08 0.10 0.10 0.08 0.11 0.11 0.08 0.09 0.07 Petition 870260057651, dated 12 / 06 / 2026, pages 115 / 152

Claims

1 / 6 CLAIMS 1. A method for increasing the stability of a medicinal aerosol suspension formulation of formoterol fumarate dihydrate and fluticasone propionate in HFA 227 propellant for an extended storage period, characterized in that it comprises adding a selected amount of (a) 0.01-0.1% by weight of sodium cromolyn, to (b) 0.003 to 0.008% or 0.01 to 0.04% by weight of formoterol fumarate having an MMAD of 1 to 10 μm and (c) 0.01-0.6% by weight of fluticasone propionate having an MMAD of 1 to 10 pm and then dispersing (a), (b) and (c) in HFA 227 propellant, such that (a), (b) and (c) combine to form Flocculents with an average density within 0.2 g / cm3 of the HFA propellant density, where the weights are based on the total weight of the formulation.

2. Method according to claim 1, characterized in that the method comprises the steps of: selecting the required amount of (a) formoterol fumarate dihydrate from 0.003 to 0.008% by weight and the required amount of (b) fluticasone propionate from 0.01-0.6% by weight; determining the density of the HFA 227 propellant; calculating the required amount of (c) sodium cromolyn in the range of 0.01 to 0.1% by weight required to form the flocs of (a), (b) and (c) having an average density within 0.2 g / cm3 of the density of the HFA 227 propellant; and incorporating the selected amounts of (a) and (b) and the calculated amount of (c) into the HFA propellant.

3. Method according to claim 2, characterized in that the density of the flakes is determined by measuring the true particle density of (a), (b) and (c).

4. Method according to any of claims 1 to Petition 870260057651, dated 12 / 06 / 2026, page 116 / 152 2 / 6 3, characterized in that the prolonged storage is for 3, 6, 9, 12 or 18 months.

5. A method according to any one of claims 1 to 4, characterized in that the water content of the suspension formulation after prolonged storage is in the range of 0.05% to 0.08% by weight, preferably 0.06% to 0.07% by weight, based on the total weight of the formulation.

6. Method according to claim 1, characterized in that the average density of the flakes is within 0.1 g / cm3; preferably ± 0.05 g / cm3 of the propellant density.

7. Method according to any one of claims 1 to 6, characterized in that fluticasone propionate is present in an amount of 0.02–0.5% by weight; preferably 0.03–0.4% by weight, based on the total weight of the formulation.

8. Method according to any one of claims 1 to 7, characterized in that sodium cromolyn is present in an amount of 0.016-0.09% by weight; preferably 0.02-0.08% by weight, more preferably 0.025-0.07% by weight, more preferably 0.03-0.05% by weight, most preferably 0.03-0.04% by weight, based on the total weight of the formulation.

9. A method according to any one of claims 1 to 8, characterized in that it further comprises a wetting agent comprising a dehydrated alcohol.

10. Method according to claim 9, characterized in that the wetting agent is ethanol.

11. Method according to claim 9 or claim 10, characterized in that the alcohol is present in an amount of 0.01-3% by weight; preferably 0.05-2.5% by weight, and more preferably 1.0-2.0% by weight, based on the total weight of the formulation. Petition 870260057651, dated 12 / 06 / 2026, pp. 117 / 152

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