Improved pharmaceutical aerosol formulation

Abstract

To provide a pharmaceutical aerosol formulation for use in a pressurized metered dose inhaler (abbreviated as pMDI or MDI), particularly an improved pharmaceutical aerosol formulation for aerosol administration.SOLUTION: The present invention provides a pharmaceutical aerosol suspension formulation for MDI administration, comprising: (a) an atomization β2-stimulant, (b) micronized corticosteroid, (c) a quasi-therapeutic amount of a moisture scavenging excipient, and (d) an HFA propellant. The (a), (b) and (c) and their respective relevant amounts are selected such that they associate to form fluorocarbon having substantially the same density as that of the HFA (hydrofluoroalkane) propellant.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical aerosol formulations for use in pressurized metered dose inhalers (pMDIs or MDIs for short), and in particular to improved pharmaceutical aerosol formulations for aerosol administration. [Background technology]

[0002] Drugs for treating respiratory diseases and disorders, such as β2-agonists, anticholinergics, corticosteroids, and antiallergic drugs, are often administered directly to the lungs by inhalation. Administration by inhalation can increase the therapeutic index of the drug and reduce side effects compared to administration by other routes, such as oral or intravenous administration. Administration by inhalation can be in the form of either a dry powder or an aerosol formulation, which is inhaled by the patient using either an inhaler or a spray.

[0003] MDIs are known devices for the administration of aerosol pharmaceutical formulations to a patient's respiratory tract by inhalation. The term "MDI" is used to describe a metered dose inhaler, a standard unit of which comprises a canister filled with a pharmaceutical formulation, a medication metering valve, and a mouthpiece. MDIs can be selectively actuated by the user to deliver successive individual doses of medication by actuation of the metering valve, such that precisely metered doses of the formulation are expelled via the actuator mouthpiece for delivery into the patient's respiratory tract.

[0004] MDI formulations are advantageous delivery methods for a variety of reasons, including the fact that they deliver medication immediately and are not dependent on the user's ability to inhale. This is particularly important given the types of illnesses that medications are used to treat, such as asthma attacks. Because MDI devices typically contain sufficient quantities of pharmaceutical formulation for multiple unit administration, it is important that the formulation be successfully used repeatedly in the MDI device. The formulation must be delivered reliably and at precisely calculated doses. The formulation must also meet pharmaceutical quality, stability, and soundness requirements set by regulatory agencies.

[0005] MDIs generally use a propellant to expel droplets or particles of a drug-containing formulation into the respiratory tract as an aerosol.

[0006] The propellant gases that have long been used are fluorochlorohydrocarbons, commonly referred to as Freons® or CFCs, such as CC13F (Freon 11 or CFC-11), CC12F2 (Freon 12 or CFC-12), and CCClF2-CClF2 (Freon 114 or CFC-114). However, these CFC propellants have proven particularly harmful to the environment, and their production and use in pharmaceutical formulations at the time of writing is being phased out. Therefore, there is a need for alternative propellants that are safe for use in inhaled medications.

[0007] Hydrofluoroalkanes (HFAs), also known as hydrofluorocarbons (HFCs), have been proposed as alternative propellant gases because they do not contain chlorine and are thought to have less of an impact on the atmosphere. In particular, 1,1,1,2-tetrafluoroethane (HFA143a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA227) have been found to be good alternatives to CFC propellants, and many pharmaceutical aerosol formulations have been proposed using these propellants.

[0008] Formulations administered via MDIs can be in the form of solutions or suspensions. In suspension formulations, the drug is prepared as a finely divided powder and then suspended in a liquefied propellant or propellant mixture. Suspension formulations can be stored in sealed canisters at pressures sufficient to maintain the propellant in a liquid state. For example, the vapor pressure of HFA227 formulations is typically about 1.96 bar at 0°C, about 3.90 bar at 20°C, and about 7.03 bar at 40°C. In solution formulations, the drug is dissolved in the liquefied propellant phase. Upon actuation of the metering valve, the dose is delivered in rapidly dispersing fine droplets.

[0009] In general, suspension formulations are usually preferred due to the superior chemical stability of suspended particles compared to solubilized drugs. Stability problems associated with chemical degradation of solubilized drug compounds are well known in the art.

[0010] For a pharmaceutical formulation to be suitable for use in an MDI device, the particle size of the dispersed aerosol must be small enough to be inhaled into the lungs of the user, whether adult, child, or elderly / infirm. Thus, the particles of a suspension formulation must be ultrafine, having a mean aerodynamic diameter (measured as mass median aerodynamic diameter (MMDA)) of approximately 1-10 μm, preferably 1-6 μm. Micronized particles of this size can be obtained by various methods known in the art, such as mechanical grinding or spray drying.

[0011] The amount of active agent dispersed into fine, respirable 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 emitted. Both are determined by measuring the aerodynamic particle size distribution using a cascade impactor or a liquid impinger. These are routine tests, and the methods and equipment are disclosed in pharmacopoeias. For example, the formulations of the present invention comply with the requirements set out in Chapter 32 <601> of the United States Pharmacopoeia (USP) or Monograph 2.9.18 of the European Pharmacopoeia (Ph.Eur.), 6th Edition (2009) for inhalants.

[0012] However, extremely small particles for suspension formulations naturally have several associated drawbacks. They have a large surface area and therefore an unfavorable surface area to volume or mass ratio. This ratio results in strong interparticle interaction forces and an unfavorable tendency for the powder to clump and adhere. This can result in difficult handling due to poor flow rates of the powdered drug during manufacturing and poor suspension properties in MDI formulations. Therefore, such powders are difficult to formulate and handle for use in MDI devices and are also strongly affected by electrostatic charging, processing methods, moisture, etc.

[0013] Formoterol fumarate dihydrate (hereafter referred to as formoterol) is a long-acting beta-agonist bronchodilator (beta-sympathomimetic) commonly used to relieve asthma symptoms. Fluticasone propionate (hereafter referred to as fluticasone) is a potent synthetic corticosteroid that is also often prescribed to treat asthma, chronic obstructive pulmonary disease, and allergic rhinitis. Both are examples of medications that are individually delivered by MDI products.

[0014] Formoterol and fluticasone (particularly formoterol) are notoriously difficult compounds to formulate for MDIs. One reason for this is that the potency of these drugs means that only very small doses must be delivered in any given case, resulting in very low drug concentrations within the HFA formulation. This exacerbates the problems highlighted above regarding the manufacture of aerosol formulations and may therefore compromise the pharmaceutical quality, stability, and integrity of aerosol formulations as required by regulatory authorities. Formulation integrity can be determined by prolonged storage or storage under stress conditions (e.g., freeze-thaw cycles) and handling by patients under different use conditions. Due to the low drug concentration present within the formulation, variations in the local homogeneity of the drug suspended in the propellant (i.e., within a volume range of approximately 50 μL) can result in deviations in the delivered dose.

[0015] Formulating MDI formulations containing hydrofluoroalkanes (HFAs) as propellants has also proven difficult due to the limited number of currently known suspension adjuvants that are considered safe for inhalation that can be used to reduce undesirable particle aggregation and adhesion tendencies and to improve the physical stability of suspension formulations that use HFA propellants.

[0016] Furthermore, the chemical stability of HFA formulations is particularly problematic when using bronchodilator β2-agonists such as formoterol due to their susceptibility to oxidative and hydrolytic conditions. Hydrolysis is one of the major identified factors affecting the degradation of formoterol under stress conditions (e.g., 40°C / 75% relative humidity), as such formulations are typically moisture-sensitive and susceptible to moisture ingress from the ambient air.

[0017] Small changes in concentration or physical stability of MDI suspensions that may occur during storage due to temperature changes and / or moisture ingress can lead to significant differences between the metered dose and the delivered dose (e.g., dose uniformity defects). These differences can also be seen as a reduction in the respirable fraction of the emitted dose determined in vitro as the FDP or FPF.

[0018] This loss can occur due to strong adsorption of drug particles to the internal surfaces of the container closure system (canister and metering valve) and due to aggregation of ultrafine particles as a result of poor suspension stability. Water molecules, which can accumulate within MDI formulations over extended periods of storage and use, have been shown to be particularly detrimental to suspensions as they interact with polar drug particles, resulting in strong interparticle bonding.

[0019] In view of the above problems, it is generally considered important to prevent water ingress to reduce hydrolysis of formoterol formulations.

[0020] Cromolyn sodium (DSCG) is an excellent internal water scavenger and suspension enabler. It has been used for administration by the inhalation route and has been shown to be clinically safe. However, because cromolyn sodium itself has biological pharmacological activity, its use in the above-mentioned HFA formulations has been avoided to date, and its effect in addition to those of fluticasone and formoterol has not been investigated.

[0021] The type of propellant used also affects the operation of metered-dose inhalers. The use of HFA propellants instead of CFC propellants has led to additional problems with particulates in suspended medications. This is because HFA propellants have a higher polarity than the CFC propellants previously used, making HFA suspension formulations more susceptible to physical stability issues. When an active agent is used that has a lower density than the liquid in which it is placed, this tends to result in suspensions or creams that can become inhomogeneous in the delivered medication. The medication also often adheres to the interior walls of the device and dispensing mechanism.

[0022] Deposition on the walls of the throttle valve has been found to be significantly increased compared to CFC propellants. This deposition can result in a reduction in the actual dispensed volume. This buildup can also result in device failure due to clogging of the internal mechanisms of the canister or obstruction of the throttle valve.

[0023] Previously proposed devices employ containers whose interior walls are coated with a fluorocarbon polymer resin, see U.S. Patent Nos. 5,629,997 and 5,629,997. However, problems with such systems include the solubility of fluorocarbon polymers and their constituents in the propellants used in aerosol formulations. Additionally, such coatings themselves require safety testing and product formulation development to provide a safe and stable product. These tests further add to production costs and are factored into the overall cost of the product.

[0024] Coating the interior walls of the container to prevent adsorption also poses problems for the use of certain metals in canisters. The most commonly used metal for canisters is aluminum alloy. Resin coatings must be heat-treated to harden, which reduces the strength of the canister because the metal canister layer softens and becomes malleable due to the heat.

[0025] The resin coating material itself may also lead to contamination of the pharmaceutical formulation, as leachable compounds may find their way into the formulation contained within the canister. Such leachable compounds may result in degradation of the drug compound in the pharmaceutical formulation, resulting in a less effective and less wholesome product. The shelf life of the product may also be compromised by degradation of the active ingredient during storage.

[0026] Therefore, there are many important parameters to consider when manufacturing a pharmaceutical aerosol formulation for use in an MDI.

[0027] Some of the difficulties in formulating fluticasone propionate and formoterol fumarate in a single formulation have been addressed in U.S. Patent No. 5,623,599 by introducing a drying step to dry the formoterol fumarate before mixing it with the other ingredients. However, the challenges associated with long-term storage of such formulations have not been addressed. [Prior art documents] [Patent documents]

[0028] [Patent Document 1] International Publication No. 1996-32150 [Patent Document 2] U.S. Patent No. 6,596,260 [Patent Document 3] International Publication No. 2005-034911 Summary of the Invention

[0029] The present application aims to alleviate at least some of the problems of the prior art discussed above.

[0030] Accordingly, a first aspect of the present invention relates to a pharmaceutical aerosol suspension formulation for MDI administration comprising (a) a micronized β2-agonist, (b) a micronized corticosteroid, (c) a subtherapeutic amount of a moisture-scavenging excipient, and (d) an HFA propellant, wherein (a), (b), and (c) and the relative amounts of each are selected so that they associate to form floccules having a density substantially the same as that of the HFA propellant.

[0031] The components of the present formulation have been found to tend to associate to form floccules (also known as aggregates, plaques, or floccules). Floccules consist of loosely held clumps or aggregates of individual particles held together in a network-like, fragile structure suspended in solution. The aggregates formed by floccules tend to readily break down under the application of small amounts of shear stress, such as gentle agitation of a canister, and reform the elongated network of particles after the force is removed. Thus, floccules provide structure to the suspension without substantial viscosity increase. In contrast to deflocculating systems, floccules settle rapidly, usually to a high sediment volume, and can be easily resuspended even after extended storage periods, e.g., 3, 6, 9, 12, 18 months, or longer.

[0032] Once assembled, the floccule of the present formulation has been found to have a density that matches that of the propellant in which it is placed. This gives the floccule the ability to remain in suspension without the tendency to cream, float, or sink. Thus, the suspension formulation of the present invention remains a long-lasting formulation, resulting in an extended shelf life and a robust product with excellent reliability for the final product.

[0033] Furthermore, these floccule formation tendencies increase the homogeneity of the suspension and reduce local homogeneity variations, resulting in a product that may reduce errors in the delivered dose.

[0034] In addition, flocculants provide improved stability to suspension formulations. This improved stability of the suspension means that the components preferentially associate with each other rather than with the inner wall of the canister or metering valve of the inhaler. Therefore, the suspension formulation is less likely to adhere to the inside of the metering valve of the container or canister through which it must pass. This can lead to more reliable delivery of the dose. Furthermore, the reduced tendency to clog the actuation mechanism or metering valve provides a formulation that can be reliably and repeatedly dispensed in accurate amounts.

[0035] Generally, suspension formulations, especially MDI suspension formulations using HFA propellants, are inherently physically unstable. They form two phases that separate due to gravity: a liquid propellant phase and a suspended particulate phase. Within the canister, regions with different concentrations of suspended particles may also exist as a result of small temperature fluctuations within the canister, which lead to thermal movement of the particles. However, formulations according to the present invention that associate to form floccules tend to ensure that all of the active ingredients remain in a tightly associated state until the moment they are dispensed from the MDI and enter the patient's respiratory system. This provides formulations with superior quality and improved fidelity to the calculated dose.

[0036] The preferred HFA propellant is HFA227. HFA227 is a low-toxicity, inert propellant suitable for use in metered-dose inhalers. When mixed with a small amount of ethanol to form a liquid propellant phase, HFA227 propellant has a calculated density over the following temperature range:

[0037] [Table 1]

[0038] The above values ​​were calculated using the laws of thermodynamics for ideal mixtures. However, in reality, liquid mixtures behave as non-ideal mixtures, and the "true" density may differ slightly from the calculated value.

[0039] Therefore, the average density of the floccule (containing the micronized β2-agonist, micronized corticosteroid, and moisture-trapping excipients) is ±0.2 g / cm of the density of the propellant. 3 , preferably ±0.1 g / cm 3 , more preferably ±0.05 g / cm 3 It would be advantageous to have a formulation that is substantially the same as

[0040] The average density of the floccule can be calculated using any standard technique, for example, by determining the true particle density of each solid component by helium pycnometry. Thus, the density of the floccule may substantially match the density of the propellant over the temperature range of 10°C to 30°C over which users typically operate MDIs.

[0041] Preferably, the corticosteroid is fluticasone propionate or a pharmaceutically acceptable salt thereof. Advantageously, the corticosteroid is present in an amount of 0.01 to 0.6% by weight, preferably 0.02 to 0.5% by weight, and more preferably 0.03 to 0.4% by weight, based on the total weight of the formulation. This is an amount that is effective in use and advantageous for forming the correct density of the suspension in the propellant.

[0042] Preferably, the corticosteroid has a defined particle size of less than 10 μm for 100% of the particles, less than 6 μm for 90% of the particles, less than 3 μm for 50% of the particles, and less than 2 μm for 10% of the particles.

[0043] The β2-agonist is preferably formoterol fumarate dihydrate or a pharmaceutically acceptable salt or derivative thereof. The β2-agonist is preferably present in an amount of 0.003 to 0.04 wt.%, preferably 0.004 to 0.03 wt.%, and more preferably 0.005 to 0.02 wt.%, based on the total weight of the formulation. In a preferred embodiment, formoterol fumarate dihydrate is used in an amount of 0.003 to 0.008 wt.%, based on the total weight of the formulation. In another preferred embodiment, formoterol fumarate dihydrate is used in an amount of 0.001 to 0.04 wt.%, based on the total weight of the formulation. Like corticosteroids, this is an advantageous amount of β2-agonist to provide efficacy during use and to form the correct density of the suspension in the propellant.

[0044] Preferably, the β2-agonist has a defined particle size of less than 10 μm for 100% of the particles, less than 6 μm for 90% of the particles, less than 3 μm for 50% of the particles, and less than 2 μm for 10% of the particles.

[0045] The moisture-sequestering excipient is preferably cromolyn sodium (DSCG), and is advantageously present at sub-therapeutic levels such that it has no biological activity and is pharmacologically inactive. The moisture-sequestering excipient is therefore suitably present in an amount of 0.01 to 0.1% by weight, preferably 0.016 to 0.09% by weight, more preferably 0.02 to 0.08% by weight, even more preferably 0.025 to 0.07% by weight, even more preferably 0.03 to 0.05% by weight, and even more preferably 0.03 to 0.04% by weight, based on the total weight of the formulation.

[0046] Preferably, the moisture-scavenging excipient has a defined particle size of less than 10 μm for 100% of the particles, less than 6 μm for 90% of the particles, less than 3 μm for 50% of the particles, and less than 2 μm for 10% of the particles.

[0047] DSCG has been found to be an excellent suspension enhancer when used in formulations containing HFA propellants. DSCG itself consists of particles that promote and enable the formation of a heterogeneous floccule with the active agent.

[0048] DSCG acts to help stabilize formulations, particularly against hydrolysis due to competitive water absorption. DSCG is nonstoichiometric with respect to water content and exists as a single crystalline form that rapidly absorbs or releases water in response to changes in relative humidity. DSCG crystals can reversibly absorb up to nine molecules of water per mole, or approximately 24% w / w, without collapse of the crystal lattice. Analysis of the crystal structure by X-ray diffraction revealed channels within the lattice that can reversibly accommodate a variable number of water molecules (depending on the atmospheric relative humidity) with only minor dimensional changes. Despite its large water absorption capacity, DSCG is not deliquescent (e.g., like sodium sulfate) and remains solid in the range of 10–90% relative humidity.

[0049] In the present invention, DSCG acts to stabilize the fine particle fraction (FPF) in the formulation by competitively binding free (i.e., dissolved molecules) water present in the propellant phase. This helps stabilize the fine particle fraction by preventing agglomeration of suspended particles (i.e., formation of liquid and / or crystalline bridges) and particle growth (i.e., Oswald ripening) leading to stability. This allows for a more robust product during storage and use, as the formulation has improved tolerance to the presence of internal water. For example, it can tolerate up to 600 ppm total internal water. This further allows for a longer "use life" once the product is delivered to the patient. Furthermore, the tendency to adhere to surfaces is reduced, thereby allowing the pharmaceutical formulation to be used in uncoated canisters instead of canisters with polymer-coated interior walls.

[0050] Preferably, the pharmaceutical aerosol suspension formulation further comprises a wetting agent, more preferably the wetting agent is absolute alcohol, and most preferably the wetting agent is ethanol, which may be present in an amount of 0.01 to 3% by weight, preferably 0.05 to 2.5% by weight, and even more preferably 1.0 to 2.0% by weight, based on the total weight of the formulation.

[0051] Wetting agents facilitate wetting of the active agent in the liquefied propellant, thus facilitating suspension formation without partial solubilization of the active agent. The addition of such agents requires a delicate balance between wetting the active agent without partial solubilization and partial solubilization, which can lead to Ostwald ripening, particle growth, and ultimately stability problems.

[0052] Ethanol can be added in small amounts as it helps prevent deposition of the activator on the walls of the canister and mechanical parts.

[0053] Thus, in a preferred form, the formulation of the present invention comprises formoterol and fluticasone as the pharmaceutically active ingredients, and cromolyn sodium, HFA227 and ethanol as the pharmaceutically inactive ingredients.

[0054] A further aspect of the invention relates to a pharmaceutical composition comprising 0.01 to 0.6% by weight of a micronized corticosteroid, 0.003 to 0.04% by weight of a micronized β2-agonist and 0.01 to 0.1% by weight of cromolyn sodium.

[0055] Preferably, the corticosteroid is micronized fluticasone propionate.

[0056] Advantageously, the beta2-agonist is micronised formoterol fumarate dihydrate.

[0057] Preferably, the pharmaceutical composition further comprises a humectant, more preferably anhydrous alcohol, most preferably ethanol, and the humectant is present in an amount of 0.01 to 3% by weight, preferably 0.05 to 2.5% by weight, and even more preferably 1.0 to 2.0% by weight, based on the total weight of the formulation.

[0058] A further aspect of the present invention relates to a pharmaceutical suspension formulation comprising about 0.003-0.04% by weight of formoterol fumarate dihydrate, about 0.01-0.6% by weight of fluticasone propionate, about 0.01-0.1% by weight of a suspending agent, and about 0.01-3% by weight of absolute alcohol.

[0059] The suspending agent is preferably cromolyn sodium (DSCG), which allows the active agent to remain in suspension for an extended period of time, improving the shelf life of the product by allowing it to remain effective for an extended period of time after manufacture.

[0060] Furthermore, DSCG acts as a "bulking agent" and its use increases the concentration of suspended particles in the formulation, thereby minimizing inherent concentration variations in the suspension without the need for the addition of other excipients. DSCG also provides the usual benefits of a bulking agent, namely, allowing for the preparation of a more homogeneous suspension, leading to improved dosing accuracy.

[0061] A further aspect of the invention relates to a product comprising formoterol fumarate dihydrate, fluticasone propionate and cromolyn sodium as a combined preparation for separate, simultaneous or sequential use for the treatment of inflammation, preferably asthma and allergic rhinitis.

[0062] A further aspect of the present invention relates to the use of cromolyn sodium in the preparation of a pharmaceutical suspension formulation in an HFA propellant comprising fluticasone propionate microparticles and formoterol fumarate dihydrate microparticles to form a floccule of fluticasone propionate, formoterol fumarate dihydrate and cromolyn sodium having substantially the same density as that of the HFA propellant.

[0063] According to a further aspect of the present invention there is provided the use of 0.01 to 0.1% cromolyn sodium in the preparation of a pharmaceutical suspension formulation in an HFA propellant comprising 0.01 to 0.6% fluticasone propionate microparticles and 0.003 to 0.04% formoterol fumarate dihydrate microparticles to form a flocculate of fluticasone propionate, formoterol fumarate dihydrate and cromolyn sodium having substantially the same density as that of the HFA propellant.

[0064] The average density of the flocculant is ±0.2 g / cm of the density of the HFA propellant. 3 , preferably ±0.1 g / cm 3 , more preferably ±0.05 g / cm 3 It is preferable that it is substantially the same as

[0065] Preferably, the pharmaceutical suspension formulation further comprises a wetting agent, preferably absolute alcohol, more preferably ethanol.

[0066] According to yet another aspect of the present invention, there is provided a method for increasing the stability of a pharmaceutical aerosol suspension formulation of a micronized beta-agonist and a micronized corticosteroid in an HFA propellant over extended periods of storage, the method comprising adding a subtherapeutic amount of cromolyn sodium, wherein the relative amounts of each of the micronized beta-agonist, micronized corticosteroid, and cromolyn sodium are selected so that they associate to form a floccule having substantially the same density as that of the HFA propellant.

[0067] Preferably, the long-term storage is 3, 9, 12 or 18 months. Preferably, the water content of the suspension formulation after long-term storage is in the range of 500 ppm to 800 ppm, preferably 600 ppm to 700 ppm.

[0068] Examples of suitable dosage strengths of pharmaceutical compositions according to the present invention are disclosed in the table below.

[0069] Table 2: Composition of example dosage strengths of formulations (% w / w) [Table 2]

[0070] [The present invention 1001] a) micronized formoterol fumarate or a pharmaceutically acceptable salt or derivative thereof; b) micronized fluticasone propionate or a pharmaceutically acceptable salt or derivative thereof; c) a moisture-sequestering vehicle containing a subtherapeutic amount of cromolyn sodium; d) an HFA propellant; 1. A pharmaceutical aerosol suspension formulation for MDI administration, wherein (a), (b) and (c) and the relative amounts of each thereof are selected so that they associate to form a floccule having substantially the same density as that of the HFA propellant. [The present invention 1002] The average density of the flocculant is ±0.2 g / cm of the density of the propellant. 3 , preferably ±0.1 g / cm 3, more preferably ±0.05 g / cm 3 The pharmaceutical aerosol suspension formulation of the present invention is substantially the same as the above. [The present invention 1003] 1001 or 1002. The pharmaceutical aerosol suspension formulation of invention 1001 or 1002, wherein said HFA propellant is HFA227. [The present invention 1004] The pharmaceutical aerosol suspension formulation of any of the present inventions 1001 to 1003, wherein the formoterol fumarate or a pharmaceutically acceptable salt or derivative thereof is present in an amount of 0.003 to 0.04% by weight, preferably 0.004 to 0.03% by weight, and more preferably 0.005 to 0.02% by weight, relative to the total weight of the formulation. [The present invention 1005] The pharmaceutical aerosol suspension formulation of any of the present inventions 1001 to 1004, wherein the fluticasone propionate or a pharmaceutically acceptable salt or derivative thereof is present in an amount of 0.01 to 0.6% by weight, preferably 0.02 to 0.5% by weight, and more preferably 0.03 to 0.4% by weight, relative to the total weight of the formulation. [The present invention 1006] The pharmaceutical aerosol suspension formulation of any of the present inventions 1001 to 1005, wherein the cromolyn sodium is present in an amount of 0.01 to 0.1 wt %, preferably 0.016 to 0.09 wt %, more preferably 0.02 to 0.08 wt %, even more preferably 0.025 to 0.07 wt %, even more preferably 0.03 to 0.05 wt %, and even more preferably 0.03 to 0.04 wt %, relative to the total weight of the formulation. [The present invention 1007] 1007. The pharmaceutical aerosol suspension formulation of any one of claims 1001 to 1006, further comprising a wetting agent. [The present invention 1008] The pharmaceutical aerosol suspension formulation of the present invention 1007, wherein said wetting agent is absolute alcohol. [The present invention 1009] The pharmaceutical aerosol suspension formulation of the present invention 1008, wherein said wetting agent is ethanol. [The present invention 1010] The pharmaceutical aerosol suspension formulation of the present invention 1008 or 1009, wherein said alcohol is present in an amount of 0.01 to 3 wt %, preferably 0.05 to 2.5 wt %, more preferably 1.0 to 2.0 wt %, based on the total weight of the formulation. [The present invention 1011] a) 0.01 to 0.6% by weight of micronized fluticasone propionate or a pharmaceutically acceptable salt or derivative thereof; b) 0.003 to 0.04% by weight of micronized formoterol fumarate dihydrate or a pharmaceutically acceptable salt or derivative thereof; c) 0.01 to 0.1% by weight of cromolyn sodium. [The present invention 1012] The pharmaceutical composition of the present invention further comprising a wetting agent. [The present invention 1013] The pharmaceutical composition of the present invention 1011 or 1012, wherein the wetting agent is an absolute alcohol, preferably ethanol, and is present in an amount of 0.01 to 3% by weight, preferably 0.05 to 2.5% by weight, more preferably 1.0 to 2.0% by weight, based on the total weight of the formulation. [The present invention 1014] a) about 0.003 to 0.04 wt. % formoterol fumarate dihydrate; b) about 0.01 to 0.6% by weight of fluticasone propionate; c) about 0.01 to 0.1% by weight of cromolyn sodium; d) about 0.01 to 3% by weight of absolute alcohol. [The present invention 1015] A product containing formoterol fumarate dihydrate, fluticasone propionate and cromolyn sodium as a combination preparation for simultaneous, separate or sequential use in the treatment of inflammation, particularly asthma and allergic rhinitis. [The present invention 1016] Use of cromolyn sodium in the preparation of a pharmaceutical suspension formulation in an HFA propellant comprising formoterol fumarate dihydrate and fluticasone propionate microparticles to form a floccule of formoterol fumarate dihydrate, fluticasone propionate and cromolyn sodium having substantially the same density as that of the HFA propellant. [The present invention 1017] Use of 0.01 to 0.1% cromolyn sodium in the preparation of a pharmaceutical suspension formulation in an HFA propellant comprising 0.003 to 0.004% formoterol fumarate dihydrate and 0.01 to 0.6% fluticasone propionate fine particles to form a floccule of formoterol fumarate dihydrate, fluticasone propionate, and cromolyn sodium having substantially the same density as that of the HFA propellant. [The present invention 1018] The average density of the flocculant is ±0.2 g / cm of the density of the propellant. 3 , preferably ±0.1 g / cm 3 , more preferably ±0.05 g / cm 3 The use of the present invention 1016 or 1017 is almost the same. [The present invention 1019] The use of any of claims 1016 to 1018, wherein said pharmaceutical suspension formulation further comprises a wetting agent, preferably absolute alcohol, more preferably ethanol. [The present invention 1020] a) 0.0071 w / w of formoterol fumarate dihydrate, b) 0.0357 w / w, 0.0714 w / w, 0.1784 w / w or 0.3570 w / w of fluticasone propionate; c) 0.0343 w / w of cromolyn sodium; d) the remainder being HFA227 propellant. [The present invention 1021] a) 0.0142 w / w of formoterol fumarate dihydrate, b) 0.0357 w / w of fluticasone propionate; c) 0.0343 w / w or 0.0686 w / w of cromolyn sodium; d) the remainder being HFA227 propellant. [The present invention 1022] The pharmaceutical composition of invention 1020 or 1021, further comprising 1.43 w / w of ethanol. [The present invention 1023] 1. A method of increasing the stability of a pharmaceutical aerosol suspension formulation of micronized formoterol fumarate dihydrate and micronized fluticasone propionate in an HFA propellant over extended periods of storage, comprising adding a subtherapeutic amount of cromolyn sodium, wherein the relative amounts of each of the micronized formoterol fumarate dihydrate, micronized fluticasone propionate, and cromolyn sodium are selected so that they associate to form floccules having substantially the same density as that of the HFA propellant. [The present invention 1024] 1023. The method of claim 1023, wherein said long-term storage is 3, 6, 9, 12, or 18 months. [The present invention 1025] The method of invention 1023 or 1024, wherein the water content of the suspension formulation after long-term storage is within the range of 500 ppm to 800 ppm, preferably 600 ppm to 700 ppm. Embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0071] [Figure 1] Aerodynamic particle size distribution of fluticasone and formoterol. [Figure 2] Photographs of the suspension in a glass vial at different times after shaking [Example]

[0072] Example 1 The compositions shown in Table 3 below were prepared and the densities of fluticasone, formoterol and cromolyn sodium floccules were calculated over various temperature ranges and compared with the calculated density of the liquid phase (consisting of 1.43% w / w absolute ethanol and HFA227).

[0073] Table 3: Composition of pharmaceutical formulations [Table 3]

[0074] The density of the liquid phase was determined based on thermodynamic laws for ideal mixtures. However, in reality, liquid mixtures behave as non-ideal mixtures, and the "true" density may differ slightly from the calculated density.

[0075] The average density of the floccule was determined by measuring the true particle density of each solid component by helium pycnometer.

[0076] The results of the density calculations are shown in Tables 4 and 5.

[0077] Table 4: Calculated density of the liquid phase [Table 4]

[0078] Table 5: Calculated densities of floccules [Table 5]

[0079] The results in Tables 4 and 5 above show that the average density of the floccule closely matches the calculated density of the liquid phase within ±0.2 g / ml.

[0080] Example 2 The batches shown in Table 6 were made and tested (with a "use temperature" range of 10-30°C).

[0081] Table 6: Composition of Batch 1 and Batch 2 [Table 6]

[0082] Each batch size was 3.3 kg (approximately 300 units). 96.5% w / w ethanol (97.75% v / v) was used to bring the formulations to a moisture level approximately equal to that which will be present in the formulation at the end of its expected shelf life. The moisture content of all ingredients except HFA227 was determined by Karl Fischer analysis prior to preparation of the suspensions.

[0083] The appropriate amount of micronized active agent was weighed and transferred to a batch container. The appropriate amount of cromolyn sodium (DSCG) was added and the container was sealed. A propellant mixture of HFA227 (apaflurane) and 1.45% alcohol was prepared in a separate container and transferred to the batch container. The solids were dispersed in the liquefied propellant using a rotor-stator homogenizer at 2900 rpm for 30 minutes. The homogenous bulk suspension was cooled to 4°C and recirculated between the container and a Pamasol aerosol filling machine P2001.

[0084] Pharmaceutical aerosol canisters with a maximum full volume of 14 ml were crimped with a 50 mcl restrictor valve using a Pamasol P2005 crimping machine. Aliquots of 11±0.5 g suspension were filled into the crimped canisters using a P2001 filling machine. The weight of each filled canister was checked, and all filled canisters were subjected to a heat stress test at 56°C and stored for one month before assembly with the test actuator.

[0085] In addition to the canisters described above, glass vials were filled with the fluticasone / formoterol formulations of Batch 1 and Batch 2 of HFA-MDI to visually and photographically assess the stability of the suspension over time, see Figure 2. The glass vials were shaken and photographs were taken at 15 seconds, 30 seconds, 45 seconds, 1 minute, 1 minute 30 seconds, 2 minutes, 3 minutes, 5 minutes, and 2 hours after shaking.

[0086] The following analytical tests were performed on Batch 1 and Batch 2.

[0087] Table 7: Tests performed [Table 7]

[0088] Table 8: Drug, DSCG, and water content in release from MDIs of batch 1 (fluticasone / formoterol 100 / 10 formulation containing DSCG) and batch 2 (fluticasone / formoterol 100 / 10 formulation without DSCG) [Table 8]

[0089] Table 8 shows the moisture content of batches when 96.5% w / w ethanol was included in the formulation, thereby adding 500 ppm to the formulation in addition to the moisture normally present due to the manufacturing process itself. The slightly higher value for Batch 1 is due to the presence of DSCG. The moisture levels detected in the two batches are what would normally be expected after long-term product storage or short-term storage in humid conditions (e.g., 75% RH or higher). The results thus demonstrated that the formulations of Batch 1 and Batch 2 (or other equivalent batches manufactured in the same manner using 96.5% w / w ethanol) can be used to demonstrate the effect of including DSCG in fluticasone / formoterol formulations, for example, on the parameters listed in Table 7 above after long-term storage of the formulations.

[0090] It can be seen that the drug concentrations for the DSCG-containing formulations were higher than those for Batch 2, with 95.1% of the target fluticasone content and 95.5% of the target formoterol content being achieved with DSCG compared to 92.2% and 90.6%, respectively, without DSCG, which may be related to drug losses during manufacturing due to drug absorption on the manufacturing equipment.

[0091] Table 9: Uniformity of drug content (inside the inhaler) in the release from the MDI of batch 1 (fluticasone / formoterol 100 / 10 formulation containing DSCG) and batch 2 (fluticasone / formoterol 100 / 10 formulation without DSCG) of fluticasone / formoterol 100 / 10 [Table 9]

[0092] Table 9 shows the results of testing the dose delivered from 10 inhalers for each batch, showing that including DSCG in the formulation delivers higher doses of both drugs (e.g., 92% for fluticasone with DSCG compared to 79% without).

[0093] Table 10: Uniformity of drug content over canister life in release from MDIs of batch 1 (fluticasone / formoterol 100 / 10 containing DSCG) and batch 2 (fluticasone / formoterol 100 / 10 without DSCG) of fluticasone / formoterol formulation [Table 10]

[0094] As shown in Table 10, the results of a study of drug content uniformity over the canister life showed that a higher dose of both drugs was delivered by Batch 1 (containing DSCG) (89.6% for fluticasone with DSCG vs. 79.9% without).

[0095] Table 11: Residues of drug and DSCG in the canister and on the valve after depletion of batch 1 (fluticasone / formoterol 100 / 10 containing DSCG) and batch 2 (no DSCG) of fluticasone / formoterol 100 / 10 formulations released from MDIs. [Table 11]

[0096] The table above shows that almost twice as much of both drugs was recovered from the canister and valve in Batch 2 compared to Batch 1 (containing DSCG) (e.g., 608 μg of fluticasone was recovered in Batch 1 compared to 1100 μg in Batch 2).

[0097] Figure 1 shows the aerodynamic size distribution results for tests conducted on five inhalers for each batch. Similar to the delivered dose results in Tables 5 and 6, lower amounts of fluticasone and formoterol were delivered from the actuator in Batch 2 compared to Batch 1.

[0098] Figure 2 shows the results of time-lapse photography of glass vials containing the two batches of formulation. Visual inspection of the glass vials also revealed the following differences in suspension stability:

[0099] Batch 1 (containing DSCG) shows a large loose flocculate immediately after stirring is stopped (a result different from that observed when the formulation is not administered with water), whereas batch 2 (without DSCG) becomes more dispersed and homogeneous.

[0100] However, after an extended period of time, Batch 1 remained in the form of a loose flocculent precipitate, forming a bulky but easily redispersible precipitate, while Batch 2 appeared to form aggregates of varying densities, some of which settled and others which were floating. At least a portion of the precipitated material present in the glass vial of Batch 2 formed a creamy material which accumulated on the surface of the glass vial at the air-liquid interface and was difficult to redisperse into a homogenous suspension.

[0101] Thus, visual examination showed that the DSCG-containing fluticasone / formoterol formulation (Batch 1) flocculated more quickly than the same formulation without the administration of additional water, yet remained homogeneous long enough to provide good and consistent dose uniformity. In contrast, the DSCG-free formulation prepared for comparison (Batch 2) creamed quickly, resulting in drug deposition on the surface of the glass vial at the air-liquid interface. Thus, these visual observations provide evidence that the formulations of the present invention can tolerate high amounts of internal water.

[0102] Therefore, in conclusion, the use of DSCG as a permitted excipient in fluticasone / formoterol HFA-MDI formulations provides a more robust final drug product, particularly against moisture ingress, which inevitably occurs during storage and use.

[0103] Example 3 The following batches were made using the method described in Example 1:

[0104] Table 12: Composition of batch 3 [Table 12]

[0105] The filled non-bag inhalers were subjected to a 6-month stability study program at 40°C / 75% RH and demonstrated good product quality and integrity in product performance testing, as shown in the results in Tables 13 and 14 below.

[0106] Table 13: Andensen Cascade Impactor Results for Fluticasone / Formoterol Formulation (250 μg Fluticasone / 12 μg Formoterol) at Release and After 1-6 Months of Storage at 40°C / 75% RH [Table 13]

[0107] Table 14: Test results for uniformity of delivered dose over inhaler life at release and after 1-6 months storage at 40°C / 75% RH for a fluticasone / formoterol formulation (250 μg fluticasone / 12 μg formoterol). [Table 14]

[0108] Example 4 The following batches were made using the method described in Example 1:

[0109] Table 15: Composition of Batch 4 and Batch 5 [Table 15]

[0110] As shown in the results in Tables 16 and 17 below, the results of the stability studies up to 12 months demonstrated good product quality and integrity for both formulations.

[0111] Table 16: Summary of ACI results for fluticasone / formoterol formulation Flutiform 250 / 10 (batch 4) at 25 °C / 60 %RH and 40 °C / 75 %RH up to 12 months. Each result is the average of six measurements (start and end of three canisters). [Table 16]

[0112] Table 17: Summary of ACI results for fluticasone / formoterol formulation Flutiform 250 / 5 (batch 5) at 25°C / 60%RH and 40°C / 75%RH up to 12 months. Each result is the average of six measurements (start and end of three canisters). [Table 17]

Claims

1. a) 0.01 to 0.6% by weight of micronized fluticasone propionate; b) 0.003 to 0.04 wt. % micronized formoterol fumarate dihydrate; and c) 0.02 to 0.08% by weight of cromolyn sodium; d) HFA propellant; 1. A pharmaceutical composition comprising: The pharmaceutical composition further comprises anhydrous alcohol.

2. 2. The pharmaceutical composition of claim 1, wherein the absolute alcohol is ethanol.

3. a) 0.003 to 0.04 wt. % of formoterol fumarate dihydrate; b) 0.01 to 0.6% by weight of fluticasone propionate; c) 0.02 to 0.08% by weight of cromolyn sodium; d) 0.01 to 3% by weight of absolute alcohol; e) HFA propellant; 1. A pharmaceutical suspension formulation comprising: A pharmaceutical suspension formulation wherein the absolute alcohol is ethanol.

4. a) 0.0071 w / w of formoterol fumarate dihydrate; b) 0.0357 w / w, 0.0714 w / w, 0.1784 w / w or 0.3570 w / w of fluticasone propionate; c) 0.0343 w / w of cromolyn sodium; d) 1.43 w / w of absolute alcohol; e) the remaining HFA227 propellant; A pharmaceutical composition comprising:

5. 1. A method for extending the shelf life of a pharmaceutical aerosol suspension formulation for MDI administration, comprising: a) 0.003 to 0.04 wt. % micronized formoterol fumarate; b) 0.01 to 0.6% by weight of micronized fluticasone propionate; c) 0.02 to 0.08% by weight of cromolyn sodium; d) HFA227 propellant; A method comprising:

6. 1. A method for reducing deviations in delivered doses of fluticasone propionate and formoterol fumarate for a pharmaceutical aerosol suspension formulation for MDI administration, said formulation comprising the following components: a) 0.003 to 0.04 wt. % micronized formoterol fumarate; b) 0.01 to 0.6% by weight of micronized fluticasone propionate; c) 0.02 to 0.08% by weight of cromolyn sodium; d) HFA227 propellant; A method comprising:

7. 1. A method for increasing uniformity in a pharmaceutical aerosol suspension formulation for MDI administration, comprising: a) 0.003 to 0.04 wt. % micronized formoterol fumarate; b) 0.01 to 0.6% by weight of micronized fluticasone propionate; c) 0.02 to 0.08% by weight of cromolyn sodium; d) HFA227 propellant; A method comprising:

8. 1. A method for reducing the adhesion of components of a pharmaceutical aerosol suspension formulation for administration by MDI to the interior walls of the canister or metering valve of the MDI, said formulation comprising: a) 0.003 to 0.04 wt. % micronized formoterol fumarate; b) 0.01 to 0.6% by weight of micronized fluticasone propionate; c) 0.02 to 0.08% by weight of cromolyn sodium; d) HFA227 propellant; A method comprising:

9. 1. Use of 0.02 to 0.08% by weight of cromolyn sodium to stabilize the fine particle fraction of a pharmaceutical suspension formulation in an HFA propellant comprising 0.003 to 0.04% by weight of formoterol fumarate, 0.01 to 0.6% by weight of fluticasone propionate fine particles, and absolute alcohol.

10. 1. Use of 0.02 to 0.08% by weight of cromolyn sodium in the preparation of a pharmaceutical suspension formulation in an HFA propellant comprising 0.003 to 0.04% by weight of formoterol fumarate, 0.01 to 0.6% by weight of fluticasone propionate microparticles, and absolute alcohol to improve the shelf life of the formulation.

11. 11. The use according to claim 9 or 10, wherein the absolute alcohol is ethanol.

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