DRY POWDER FORMULATION FOR INHALATION, ITS USE, AND RELEASE SYSTEM

专利摘要:
DRY POWDER PARTICLE FORMULATIONS CONTAINING TWO OR MORE ACTIVE INGREDIENTS FOR THE TREATMENT OF OBSTRUCTIVE OR INFLAMMATORY AIRWAYS DISEASES. The invention relates to dry powder inhalation formulations comprising spray dried particles and their use in the treatment of an obstructive or inflammatory airway disease. Each particle has a core of a first active ingredient in substantially crystalline form which is coated with a layer of a second active ingredient in substantially amorphous form which is dispersed in a pharmaceutically acceptable hydrophobic excipient. The invention also relates to a process for preparing such formulations.
公开号:BR112013019540B1
申请号:R112013019540-1
申请日:2012-02-03
公开日:2021-08-17
发明作者:Jeffry Weers；Nagaraja Rao；Daniel Huang；Danforth Miller；Thomas E. Tarara
申请人:Novartis Ag；
IPC主号:

专利说明:

FIELD OF THE INVENTION
[1] The invention relates to organic compounds and their uses as pharmaceuticals, more specifically to dry powder formulations comprising spray dried particles that contain fixed dose combinations of two or more active ingredients that are useful for the treatment of diseases obstructive or inflammatory diseases of the airways, especially asthma and chronic obstructive pulmonary disease (COPD). BACKGROUND OF THE INVENTION
[2] Active pharmaceutical ingredients (APIs) that are useful for the treatment of respiratory diseases are usually formulated for administration by inhalation with portable inhalers. The two most popular classes of portable inhalers are pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs).
[3] The vast majority of dry powder inhalers rely on the patient's respiratory effort to fluidize and disperse drug particles. In order for the drug to be effectively deposited in the lungs, it is generally accepted that the aerodynamic diameter of the particles must be between 1 µm and 5 µm. As a result, APIs are typically micronized to obtain fine particles with a mass average diameter (as determined by laser diffraction) in this size range. Unfortunately, micronized fine drug particles generally exhibit poor powder flow, fluidization and dispersion properties. Powder flow or "powder fluidity" is the ability of a powder to flow. It is important with respect to measuring powder particles in a unit dose, from a reservoir or in pre-packaged unit dose containers (eg capsules or blisters). Powder fluidization, which is the mobilization of powder in the airway during patient inspiration, impacts the dose delivered by the inhaler. Finally, powder dispersion is the dissolution of powder agglomerates into primary drug particles. Poor dispersion of the powder negatively impacts the aerodynamic particle size distribution, and ultimately the release of APIs into the lungs.
[4] Two approaches have been employed in currently marketed products to improve the flow, fluidization and dispersion of drug particles.
[5] The first approach involves controlled aggregation of the undiluted drug to form loosely adherent pellets. The aggregates are formed in gyratory mixers with the resulting large particle size distribution providing the required flow properties necessary for accurate measurement and improved fluidization of the powder. In the TURBUHALER™ device (AstraZeneca), the dispersion of aggregates takes place by turbulent mixing. Dispersion energy is sufficient at optimal inspiratory flow rates to overcome the interparticle cohesive forces that hold micronized particles together. As powder dispersion critically depends on the energy used to break down the aggregates, the aerosol performance of pellet formulations generally exhibits a marked dependence on the patient's inspiratory flow rate. In one study, total pulmonary deposition of pelleted budesonide was 28% when patients were asked to breathe rapidly through the TURBUHALER™ device and 15% when patients were asked to breathe more slowly through the TURBUHALER™ device (Borgstrom L, Bondesson E, Moren F et al: Lung deposition of budesonide inhaled via TURBUHALER: a comparison with terbutaline sulphate in normal subjects, European Respiratory Journal, 1994, 7, 69-73).
[6] The second approach uses an ordered binary mixture that comprises fine drug particles mixed with coarse carrier particles. α-lactose monohydrate has most often been employed as a vehicle and typically has a particle size between 30 and 90 µm. In most dry powder formulations, dry particles are present in low concentrations, with a drug to vehicle ratio of 1:67.5 (weight/weight) being typical. Micro-sized crystals exhibit attractive forces, dictated primarily by van der Waals, electrostatic, and capillary forces, which are affected by the size, shape, and chemical properties (eg, surface energy) of the crystal. Unfortunately, adhesive strengths between the drug crystals and the vehicle are difficult to predict and may differ for different drugs in a fixed dose combination. During inhalation, drug particles are dispersed from the surface of the carrier particles by the energy of the inspired air flow. Large carrier particles primarily impact the oropharynx (ie, the area of the throat that is behind the mouth), while small drug particles penetrate the lungs.
[7] A key requirement for combining uniformity in an ordered mixture is that the drug and vehicle particles interact sufficiently to prevent segregation. Unfortunately, this can reduce pulmonary drug deposition due to poor drug dispersion from the vehicle. The mean pulmonary deposition of drugs in ordered mixtures is typically 10 to 30% of the administered dose. The poor lung targeting seen in ordered mixtures results in high deposition in the oropharynx and the potential for local side effects and increased variability. The increased variability in pulmonary delivery observed is the result of variability in inertial impaction within the oropharynx, which is a consequence of powder properties and anatomical differences between individuals. The mean variability in pulmonary dose for micronized particle mixture formulations is typically between about 30% and 50% (see Olsson B, Borgstrom L: Oropharyngeal deposition of drug aerosols from inhalation products. Respiratory Drug Delivery, 2006, pages 175-182 ). This is further exacerbated when aerosol delivery is dependent on the patient's peak inspiratory flow rate.
[8] The problems mentioned above become especially acute when formulated pharmaceutical products contain two or more active ingredients in a fixed-dose combination.
[9] This was illustrated in a study recently published by Taki et al, Respiratory Drug Delivery 2006, pages 655-657. The study measured the particle size distributions of the two active ingredients of SERETIDE™, namely salmeterol xinafoate (SX) and fluticasone propionate (FP), as a function of flow rate in an ANDERSEN™ cascade impactor (ACI ). The two SERETIDE™ formulations tested, S100 and S500, refer to differences in inhaled corticosteroid potency (ICS) fluticasone propionate, ie 100 μg and 500 μg. The long-acting β2 agonist (LABA) dose of salmeterol xinafoate was kept constant at 72.5 μg. The aerodynamic particle size distribution (aPSD) differed significantly for the two active ingredients in the blend formulation (see Table 1). Also, aPSD was dramatically different for the two formulations. Mass mean aerodynamic diameters (MMAD) ranged from 1.8 μm to 3.6 μm, geometric standard deviations from 1.7 to 3.9. The proportion of the two active ingredients in the fine particle fraction (FPF<3μm and FPF<5μm) also differed significantly at the two flow rates tested. Therefore, the adhesive properties between drugs and vehicle differed significantly for each active ingredient and between formulations as well. The nominal SX/FP (weight/weight) ratio in S100 is 0.725 and 0.145 in S500. The SX/FP ratio in the fine particle dose differs significantly from the nominal ratio, usually enriched in the FP component. The SX/FP ratio ranges from +3.5% to -28% of the nominal dose ratios with flow rate and combination ratio. The observed differences are likely the result of differences in API particle size distribution and differences in dose ratios that can result from improper mixing. Additionally, an API may have lower affinity for the carrier and may segregate in the formulation at any stage in the manufacturing process. Moisture absorption may also differ for the two APIs, leading to differences in storage agglomeration. All of these factors taken together dramatically increase the complexity of the development process and the global variability in drug release.
[10] Aerodynamic particle size distributions of fixed dose combinations of salmeterol xinafoate and fluticasone propionate formulated as ordered mixtures with coarse lactose monohydrate (Taki et al. Respiratory Drug Delivery 2006, pp. 655-657 )


[11] In order to get around the problem of formulating multiple active ingredients in a single combination, devices (eg the GEMINI device from WO 05/14089) that are known incorporate two separate blister packs containing each independent drug mixture, which is then triggered concurrently. While such device options for combination therapy can minimize the potential interactions between active ingredients and device components, they do nothing to address other problems inherent in drug targeting and variability associated with lactose blends. Therefore, there is a need for improved formulations that overcome the dosing problems associated with mixtures of multiple active ingredients and that provide improvement in dose consistency and lung targeting. The need is especially acute for APIs with widely different physicochemical properties (eg solubility), where finding a common solvent for particle manipulation is problematic.
[12] It has now been found that inhalable dry powder formulations that contain two or more active ingredients and still possess fluidizing and dispersing properties of the drug particles can be prepared by manipulating the active ingredients within inhalable spray dried particles. SUMMARY OF THE INVENTION
[13] In a first aspect, the present invention relates to a dry powder formulation for inhalation comprising spray dried particles comprising a core of a first active ingredient in substantially crystalline form which is coated with a layer of a second active ingredient in substantially amorphous form which is dispersed in a pharmaceutically acceptable hydrophobic excipient.
[14] The first active ingredient, the second active ingredient and the hydrophobic excipient have a substantially separate phase in the spray dried particles.
[15] Such a formulation having particles that are structured or "manipulated" in this way eliminates the significant differences in aerodynamic particle size distribution and fine particle dose that occur when the same active ingredients are formulated as ordered mixtures. The particles also exhibit improved pulmonary targeting (eg, increased pulmonary delivery efficiency, reduced oropharyngeal and systemic deposition) and improved dose consistency (through reduced interpatient variability and systemic deposition) relative to lactose blends and standardized pellet formulations.
[16] Active ingredients can be any active pharmaceutical ingredients that are useful to treat obstructive or inflammatory airway diseases, particularly asthma and COPD. Suitable active ingredients include long-acting β2 agonists such as salmeterol, formoterol, indacaterol and their salts, muscarinic antagonists such as tiotropium and glycopyrronium and their salts, and corticosteroids including budesonide, ciclesonide, fluticasone and mometasone and their salts. Suitable combinations include (formoterol and budesonide fumarate), (salmeterol xinafoate and fluticasone propionate), (salmeterol xinafoate and tiotropium bromide) and (indacaterol maleate and glycopyrronium bromide).
[17] The presence of amorphous drug domains in micronized crystalline drugs for inhalation is considered to be generally undesirable. Amorphous domains are thermodynamically unstable and can convert to a stable crystalline polymorph over time. The recrystallization process generally results in thickening of the micronized drug particles and decreased aerosol performance. High energy amorphous domains also exhibit greater solubility, faster dissolution and decreased chemical stability when compared to the crystalline drug. As a result, it is common practice to try to reduce the amorphous content in micronized drug particles and companies go to great lengths to "condition" powders to reduce the amorphous content.
[18] Spray drying is a method of producing a dry powder from a liquid or a dispersion in a liquid by rapid drying with a hot gas. Its main advantages in producing manipulated particles for inhalation include the ability to quickly produce a dry powder and to control particle attributes including size, morphology, density and surface composition. The spray drying process is very fast (on the order of milliseconds). As a result, the most active pharmaceutical ingredients that are dissolved in the liquid phase precipitate out as amorphous solids as they do not have time to crystallize.
[19] For fixed-dose combinations, it is common practice to find a common solvent where both drugs are soluble. Formulating two drugs in a single amorphous phase poses potential incompatibility problems. One of the drugs is likely to have improved physical and chemical stability, while the other will have reduced stability.
[20] When planning aerosol formulations, which comprise fixed-dose combinations of two or more drugs, it is not always possible to identify a solvent in which each drug is miscible or immiscible. Therefore, to formulate fixed dose combinations of these drugs, it may be necessary to spray dry a complex dispersion of one drug in solution and another in suspension. This results in crystalline and amorphous domains in the spray dried drug product. Surprisingly, it has been found that stable formulations comprising such crystalline and amorphous drug domains can be obtained. By incorporating a hydrophobic excipient that is effectively concentrated at the particle interface, it becomes possible to also control the surface energy and morphology of the spray dried particles resulting in reduced interparticle cohesive forces and enhanced aerosol performance.
[21] A third active ingredient can be introduced into the particle, either as an additional insoluble crystalline active ingredient or as an additional amorphous active ingredient. The third active ingredient can be selected, for example, from bronchodilators, anti-inflammatory drugs and their mixtures, especially β2 agonists, muscarinic antagonists, steroids, β2-agonists double muscarinic antagonists, PDE4 inhibitors, A2A agonists, calcium blockers and their mixtures . Suitable triple combinations include (salmeterol xinafoate, fluticasone propionate and tiotropium bromide), (indacaterol maleate, mometasone furoate and glycopyrronium bromide) and (indacaterol acetate, mometasone furoate and glycopyrronium bromide).
[22] In a second aspect, the present invention relates to a process for preparing a dry powder formulation of spray dried particles containing a first active ingredient and a second active ingredient, the process comprising the steps of:
[23] (a) preparing a raw material comprising the second active ingredient dissolved in a solvent phase, a hydrophobic excipient and crystalline particles of the first active ingredient, said crystalline particles being substantially insoluble in said solvent phase; and
[24] (b) spray drying said raw material to provide the formulation, wherein said particles comprise a core of the first active ingredient in substantially crystalline form which is coated with a layer of the second active ingredient in substantially amorphous form which is dispersed in a pharmaceutically acceptable hydrophobic excipient.
[25] In a preferred embodiment, the solvent phase is water or a mixture of ethanol and water.
[26] In a third aspect, the present invention relates to a method for the treatment of an obstructive or inflammatory airway disease, which comprises administering to an individual in need thereof, an effective amount of the aforementioned dry powder formulation. Obstructive or inflammatory airway disease is suitably asthma or COPD.
[27] In a fourth aspect, the present invention relates to the use of the aforementioned dry powder formulation in the manufacture of a medicament for the treatment of an obstructive or inflammatory airway disease. Obstructive or inflammatory airway disease is suitably asthma or COPD.
[28] In a fifth aspect, the present invention relates to the aforementioned dry powder formulation for use in the treatment of an obstructive or inflammatory airway disease. Obstructive or inflammatory airway disease is suitably asthma or COPD.
[29] In a sixth aspect, the present invention relates to a delivery system comprising an inhaler containing the aforementioned dry powder formulation.
[30] A seventh aspect of the present invention comprises any two or more of the foregoing aspects, embodiments, or features.
[31] The expressions used in the order have the following meanings:
[32] "Active ingredient" or "drug", as used herein, means an active ingredient of a pharmacist, also known as an active pharmaceutical ingredient (API).
[33] "Amorphous", as used here, refers to a state in which a material lacks long-range order at the molecular level and, depending on temperature, can exhibit the physical properties of a solid or a liquid. Typically, such materials do not provide distinct X-ray diffraction patterns and, although they exhibit the properties of a solid, they are more formally described as a liquid. Upon heating, a change in properties from solid to liquid occurs which is characterized by a change of state, typically a second order ("glass transition").
[34] "Crystalline", as used here, refers to a solid phase in which the material has a regular internal structure organized at the molecular level and provides a distinct X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order ("melting point"). In the context of the present invention, a crystalline active ingredient means an active ingredient with a crystallinity greater than 85%. In certain embodiments, the crystallinity is suitably greater than 90%. In other modalities, the crystallinity is adequately above 95%.
[35] "Released dose" or "DD", as used herein, refers to an indication of the release of dry powder from an inhaler device after an event of activation or dispersion of a powder unit. DD is defined as the proportion of the dose delivered by an inhaler device to the nominal dose or metered dose. DD is an experimentally determined parameter and can be determined using an in vitro configured device that mimics patient dosing. This is sometimes also referred to as the emitted dose (ED).
[36] "Fine particle fraction" or "FPF", as used herein, refers to the mass of an active ingredient below the specified minimum aerodynamic size in relation to the nominal dose. For example, FPF<3.3 µm refers to the percent of the nominal dose that has an aerodynamic particle size less than 3.3 µm. FPF values are determined using cascade impaction, either on an ANDERSEN™ cascade impactor or on a NEXT GENERATION IMPACTOR™ cascade impactor. In order to minimize inter-patient variability and improve lung targeting, it is preferred that a fine particle fraction less than 3.3 µm (FPF<3.3 µm) greater than 40% wt/wt of the nominal dose is achieved.
[37] "Fixed dose combination" as used herein refers to a pharmaceutical product that contains two or more active ingredients that are formulated together in a single dosage form available in certain fixed doses.
[38] "Mass average diameter" or "MMD" or "x50" as used herein, refers to the average diameter of a plurality of particles, typically in a population of polydisperse particles, ie, consisting of a range of sizes of particle. MMD values as reported here are determined by laser diffraction (Sympatec Helos, Clausthal-Zellerfeld, Germany) unless the context otherwise indicates. In certain embodiments of the present invention, the inhalable drug particles have an MMD between 1 and 10 microns.
[39] "Mass average aerodynamic diameter" or "MMAD", as used herein, refers to an average aerodynamic size of a plurality of particles, typically in a polydisperse population. "Aerodynamic diameter" is the diameter of a unit density sphere that has the same deposition rate, generally in air, as a powder and is therefore a useful way to characterize an aerosolized powder or other dispersed particle or particle formulation. in terms of their deposition behavior. MMAD is determined here by cascade impaction. In one or more embodiments, a powder of the present invention comprises a mass median aerodynamic diameter between about 1 µm to 5 µm, such as about 1.5 µm to about 4.0 µm, or about 2.0 µm at 4.0 µm. In general, if the particles are very large, few particles will reach the depth of the lung. If the particles are too small, a large percentage of the particles can be exhaled. In certain embodiments of the present invention, the inhalable drug particles have an MMAD of between 1 to 5 microns.
[40] "Rough", as used herein, means having numerous wrinkles or creases, that is, being striated or wrinkled.
[41] "Roughness" as used here. is a measure of the surface irregularity of a manipulated particle. For the purposes of this invention, roughness is calculated from a specific surface area obtained from BET measurements, actual density obtained from helium pycnometry and the surface to volume ratio obtained by laser diffraction (Sympatec), ie: Roughness = (SSA-preai) / Sv
[42] where Sv = 6/D32, where D32 is the mean diameter based on the surface area unit.
[43] Increases in surface irregularity are expected to reduce interparticle cohesive forces and improve aerosol delivery to the lungs. Improved pulmonary targeting is expected to reduce interpatient variability and drug levels in the oropharynx and systemic circulation. In one or more modalities, the roughness Sv is between 3 to 20, for example, between 5 to 10.
[44] "Insoluble" as used herein means having a solubility in the solvent of less than 1 mg/mL. In certain embodiments of the present invention, the solubility or example of the active ingredient is suitably less than 0.1 mg/ml or, preferably, less than 0.01 mg/ml.
[45] "Soluble" as used herein, means having a solubility in the solvent of 1 mg/mL or more. In certain embodiments of the present invention, the solubility of, for example, the active ingredient is suitably greater than 10 mg/ml, or preferably greater than 20 mg/ml.
[46] Throughout this application and the appended claims, unless the context otherwise requires, the word "comprise" or variations such as "comprises" or "comprising" shall be understood to imply the inclusion of an integer or step or group of integers or established steps, but not the exclusion of any integer or step group of integers or steps.
[47] The complete description of each United States patent and international patent application referenced in that patent application is fully incorporated by reference for all purposes. DETAILED DESCRIPTION OF THE DRAWINGS
[48] The dry powder formulation of the present invention can be described with reference to the accompanying figures. In these figures:
[49] Figure 1 is a graph of drug solubility required for "insoluble" API to obtain a total dissolved fraction of less than 5% weight/volume in the raw material as a function of drug loading and solids content. The soluble drug is expected to be converted to an amorphous solid in the spray dried particles.
[50] Figure 2 is a graph of the drug solubility required for "soluble" API to be completely miscible in the raw material as a function of variations in drug loading and solids content.
[51] Figure 3 shows high angle powder diffraction patterns of: (a) a spray-dried vehicle formulation comprising a 2:1 mol ratio of DSPC:CaCl2; (b) micronized crystalline indacaterol API (QAB149); (c) spray dried formulation comprising indacaterol (QAB149) 6% wt/wt and glycopyrrolate (NVA237) 2% wt/wt; (d) spray dried formulation comprising indacaterol (QAB149) 45% and glycopyrrolate (NVA237) 15%. The powder patterns of the spray-dried fixed-dose combination products illustrate that the two drugs and the hydrophobic excipient are phase-separated into distinct domains: indacaterol is present in crystalline form, glycopyrrolate is present as an amorphous solid, and DSPC is present in a phospholipid gel phase. DETAILED DESCRIPTION OF THE INVENTION
[52] The present invention relates to dry powder formulations for inhalation comprising spray dried particles. Such spray dried particles comprise fixed dose combinations of two or more active ingredients that are suitable for treating an obstructive or inflammatory airway disease, particularly asthma and COPD.
[53] In one aspect or embodiment, the dry poratomization particles comprise a first active ingredient that is in substantially crystalline form, a second active ingredient in substantially amorphous form, and a pharmaceutically acceptable hydrophobic excipient, wherein the three materials are in phases. substantially separated into the spray dried particles. Therefore, particles can be described as being "structured" or "manipulated".
[54] Active ingredients can be any active pharmaceutical ingredients that are useful for treating obstructive or inflammatory airway diseases, particularly asthma and COPD. They can be selected, for example, among bronchodilators, anti-inflammatory drugs and their mixtures, especially β2 agonists, muscarinic antagonists, steroids, dual muscarinic β2-antagonists, PDE4 inhibitors, A2A agonists, calcium blockers and their mixtures.
[55] Suitable active ingredients include β2 agonists. Suitable β2 agonists include formoterol (e.g. tartrate), albuterol/salbutamol (e.g. racemate or the isolated enantiomer such as the R-enantiomer, or a salt thereof especially sulfate), AZD3199, bambooterol, BI-171800, bitolterol (eg mesylate), carmoterol, clenbuterol, ethanterol, fenoterol (eg racemate or the isolated enantiomer such as the R-enantiomer, or a salt thereof especially hydrobromide), flerbuterol, formoterol (eg racemate or the isolated diastereoisomer such as the R,R diastereoisomer, or a salt of such especially fumarate or fumarate dihydrate), GSK-159802, GSK-597901, GSK-678007, indacaterol (e.g. racemate or the isolated enantiomer such as the R enantiomer, or a salt of this especially maleate, acetate or xinafoate), LAS100977, metaproterenol, milveterol (eg hydrochloride), naminterol, olodaterol (eg racemate or the isolated enantiomer such as the R-enantiomer, or a salt of such especially hydrochloride to), PF-610355, pirbuterol (eg acetate), procaterol, reproterol, salmephamol, salmeterol (eg racemate or the isolated enantiomer such as the R-enantiomer, or a salt of such especially xinafoate), terbutaline (eg sulphate) and vilanterol (or a salt of this especially trifenatate). In certain preferred embodiments, the β2 agonist is an ultra-long-acting β2 agonist such as indacaterol, or potentially carmoterol, LAS-100977, milveterol, olodaterol, PF-610355 or vilanterol.
[56] In a preferred embodiment, one of the active ingredients is indacaterol (ie, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H -quinolin-2-one) or a salt thereof. This is a β2 adrenoreceptor agonist that has an especially long duration of action (ie, beyond 24 hours) and a short onset of action (ie, about 10 minutes). This compound is prepared by the process described in international patent applications WO 2000/75114 and WO 2005/123684. It is capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable acid addition salts of the compound of Formula I include those of inorganic acids, for example, hydrolic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, p-chlorobenzoic acid, diphenylacetic acid, triphenylacetic acid, 1-hydroxynaphthalene-2-carboxylic acid, acid 3-hydroxynaphthalene-2-carboxylic acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as fumaric acid, maleic acid or succinic acid and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid. Such salts can be prepared from the compounds by known salt formation procedures. A preferred salt of (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one is the maleate salt. Another preferred salt is (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one acetate. Another preferred salt is (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one xinafoate. Other useful salts include succinate, fumarate, hippurate, hydrogen mesylate, hydrogen sulfate, hydrogen tartrate, hydrogen chloride, hydrogen bromide, formate, esylate, tosylate, glycolate, and hydrogen malonate salts that such as acetate and xinafoate salts are described in international patent application WO 2008/000839 together with methods for their respective preparation.
[57] Suitable active ingredients include muscarinic or antimuscarinic antagonists. Suitable muscarinic antagonists include aclidinium (eg bromide), BEA-2108 (eg bromide), BEA-2180 (eg bromide), CHF-5407, darifenacin (eg bromide), darotropium (eg bromide ), glycopyrrolate (for example racemate or the isolated enantiomer or a salt thereof, especially bromide), dexpyrronium (for example bromide), iGSK-202405, GSK-203423, GSK-573719, GSK-656398, ipratropium (for example , bromide), LAS35201, LAS186368, otilonium (eg bromide), oxitropium (eg bromide), oxybutynin, PF-3715455, PF-3635659, pirenzepine, revatropate (eg hydrobromide), solphenacin (eg , succinate), SVT-40776, TD-4208, terodiline, tiotropium (eg bromide), tolterodine (eg tartrate) and trospium (eg chloride). In certain preferred embodiments, muscarinic antagonists are long-acting muscarinic antagonists such as darotropium bromide, glycopyrrolate or tiotropium bromide.
[58] In a preferred embodiment, one of the active ingredients is a glycopyrronium salt. Glycopyrronium salts include glycopyrronium bromide, also known as glycopyrrolate, which is known to be an effective antimuscarinic agent. More specifically, it inhibits acetylcholine from binding to muscarinic M3 receptors, thereby inhibiting bronchoconstriction. Glycopyrrolate is a quaternary ammonium salt. Suitable counterions are pharmaceutically acceptable counterions including, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate , p-chlorobenzoate, diphenyl-acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate and benzenesulfonate. Glycopyrrolate can be prepared using the procedures described in US patent US 2956062. It has two stereogenic centers and therefore exists in four isomeric forms, namely (3R,2'R)-, (3S,2'R) bromide )-, (3R,2'S)- and (3S,2'S)-3-[(cyclopentylhydroxyphenyl-acetyl)oxy]-1,1-dimethylpyrrolidinium, as described in US patent applications US 6307060 and US 6,613. 795. When the drug substance of the dry powder formulation is glycopyrrolate, it may have one or more of these isomeric forms, especially the 3S,2'R isomer, the 3R,2'R isomer or the 2S,3'R isomer, including hence the isolated enantiomers, mixtures of diastereoisomers or racemates, especially (3S,2'R/3R,2'S)-3-[(cyclopentylhydroxy-phenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide. R,R-glycopyrrolate is also known as dexpyrronium.
[59] Suitable active ingredients include bifunctional active ingredients such as dual muscarinic β2-agonists. Dual muscarinic β2-antagonist agonists include GSK-961081 (eg, succinate).
[60] Suitable active ingredients include steroids, eg corticosteroids. Suitable steroids include budesonide, beclamethasone (eg, dipropionate), butixocort (eg, propionate), CHF5188, ciclesonide, dexamethasone, flunisolide, fluticasone (eg, propionate or furoate), GSK-685698, GSK-870086, LAS40369 , methyl prednisolone, mometasone (eg, furoate), prednisolone, rofleponide, and triamcinolone (eg, acetonide). In certain preferred embodiments, the steroid is a long-acting corticosteroid such as budesonide, ciclesonide, fluticasone or mometasone.
[61] In a preferred embodiment, one of the active ingredients is mometasone (ie, 17-(2'-furoate) (11 β, 16α)-9,21-dichloro-17-[(2-furanylcarbonyl)oxy] -11-hydroxy-16-methylpregna-1,4-diene-3,20-dione, alternatively designated as 9α,21-dichloro-16α-methyl-1,4-pregnadiene-11β,17a-diol-3,20- dione) or a salt thereof, for example mometasone furoate and mometasone furoate monohydrate. Mometasone furoate and its preparation are described in US 4472393. Its use in the treatment of asthma is described in US 5889015. Its use in the treatment of other respiratory diseases is described in US 5889015, US 6057307, US 6057581, US 6677322, US 6677323 and US 6365581.
[62] Esters, acetals, and pharmaceutically acceptable salts of the above therapeutics are contemplated. Determination of the appropriate esters, acetals or salt forms is guided by the duration of action and safety/tolerability data. API selection may also be important from the standpoint of selecting therapeutics with the appropriate physical properties (eg, solubility) to obtain the embodiments of the present invention.
[63] Suitable combinations include those containing a β2 agonist and a corticosteroid, eg (carmoterol and budesonide), (formoterol and beclomethasone), (formoterol fumarate and budesonide), (formoterol fumarate dihydrate). and mometasone furoate), (formoterol and ciclesonide fumarate), (indacaterol maleate and mometasone furoate), (indacaterol acetate and mometasone furoate), (indacaterol xinafoate and mometasone furoate), (hydrochloride - milveterol and fluticasone tote), (olodaterol hydrochloride and fluticasone furoate), (olodaterol hydrochloride and mometasone furoate), (salmeterol xinafoate and fluticasone propionate), (vilanterol trifenate and fluticasone furoate ), and (vilanterol trifenate and mometasone furoate); a β2 agonist and a muscarinic antagonist, for example, (formoterol and aclidinium bromide), (indacaterol and darotropium), (indacaterol maleate and glycopyrrolate); (indacaterol maleate and GSK573719), (milveterol hydrochloride and glycopyrrolate), (milveterol hydrochloride and tiotropium bromide), olodaterol hydrochloride and glycopyrrolate), (olodaterol hydrochloride and tiotropium bromide), (xine and salt tiotropium bromide), (vilanterol trifenatate and darotropium), (vilanterol tripenatate and glycopyrrolate), (vilanterol tripenatate and GSK573719), and (vilanterol tripenatate and tiotropium bromide); and a muscarinic antagonist and a corticosteroid, for example, (glycopyrrolate and mometasone furoate), and (glycopyrrolate and ciclesonide); or a dual muscarinic β2-antagonist and a corticosteroid, for example, (GSK-961081 succinate and mometasone furoate), (GSK-961081 succinate and mometasone furoate monohydrate) and (GSK-961081 succinate and ciclesonide).
[64] The spray dried particles of the powder formulation of the present invention may contain three active ingredients. In a suitable embodiment, the third active ingredient in these particles is substantially crystalline. In other suitable embodiments, the third active ingredient in these particles is substantially amorphous and is mixed with the amorphous phase of the second active ingredient.
[65] Suitable triple combinations include those containing a β2 agonist, a muscarinic antagonist and a corticosteroid, eg salmeterol xinafoate, fluticasone propionate and tiotropium bromide), indacaterol maleate, mometasone furoate and glycopyrrolate) and (acetate) of indacaterol, mometasone furoate and glycopyrrolate).
[66] Active ingredients can exist in a continuum of solid states ranging from completely amorphous to completely crystalline. For the purposes of the present invention, an active ingredient is in a substantially crystalline form when it has a crystallinity greater than 85%. In certain modalities, the crystallinity is adequately above 90%. In other embodiments, the crystallinity is suitably greater than 95%, for example greater than 99%.
[67] The first active ingredient is substantially crystalline. The first active ingredient must also be substantially insoluble in the solvent that is used to prepare the raw material which is spray dried to form the particles. For purposes of the present invention, the first active ingredient has a solubility of less than about 1 mg/ml, for example, less than 0.05 mg/ml. In certain embodiments, the first active ingredient has a solubility of less than 0.01 mg/ml, for example less than 0.005 mg/ml. The proposed limits of solubility are driven by the desire to minimize the percentage of drug that dissolves in the solvent phase and subsequently ends up as an amorphous solid in the spray dried powder.
[68] The second active ingredient, which is soluble in the solvent to be spray dried, is present in substantially amorphous form in the spray dried particles. It should be noted that the second active ingredient is in this form when the particles have already formed. The second active ingredient can be in a substantially amorphous or substantially crystalline form when the active ingredient is received. The physical form of the second active ingredient and the particle size of that ingredient are irrelevant when preparing the raw material, as long as the second active ingredient is dissolved in the solvent. The rapid drying provided by the dryer causes the second active ingredient to have a substantially amorphous form. The first active ingredient retains its crystalline form during the drying process, since it is substantially insoluble in the solvent that is used in the raw material.
[69] For the purposes of the present invention, an active ingredient is in a substantially amorphous form when it has a crystallinity of less than 15%. In certain modalities, the crystallinity is suitably less than 10%. In other modalities, the crystallinity is suitably less than 5%, for example, less than 2% or less than 1%.
[70] For the purposes of the present invention, a hydrophobic excipient is included in the formulation. By careful control of the formulation and process, it is possible that the surface of the spray dried particles will be comprised primarily of hydrophobic excipient. Surface concentrations in excess of 70% are contemplated. In certain embodiments, the surface is comprised of greater than 90% hydrophobic excipient or greater than 95% hydrophobic excipient, for example greater than 98% hydrophobic excipient or greater than 99% hydrophobic excipient.
[71] In certain preferred embodiments, the hydrophobic excipient facilitates the development of a rough particle morphology. This means that the particle's morphology is wrinkled and wrinkled rather than smooth. This means that the inner and/or outer surface of the inhalable drug particles are at least partly rough. This roughness is useful in providing dose consistency and directing the drug by improving powder fluidization and dispersibility. While not wishing to be bound by theory, increases in particle roughness result in decreases in interparticle coercive forces as a result of an inability of the particles to approach within van der Waals contact. The decrease in cohesive forces is sufficient to dramatically improve powder fluidization and dispersion into coarse particle clusters.
[72] Particle roughness can be increased by using a pore-forming agent, such as perflubron, during its manufacture or by controlling the formulation and/or process to produce the roughened particles.
[73] The hydrophobic excipient can take various forms that will depend at least to some extent on the composition and intended use of the dry powder formulation. Suitable pharmaceutically acceptable hydrophobic excipients can, in general, be selected from the group consisting of long-chain phospholipids, hydrophobic amino acids and peptides, and long-chain fatty acid soaps.
[74] Phospholipids are natural and synthetic sources that can be used in varying amounts. When phospholipids are present, the amount is typically sufficient to provide a porous phospholipid coating matrix. If present, the phospholipid content generally ranges from about 40 to 99% weight/weight of the drug, for example 70 to 90% weight/weight of the drug. The high percentage of excipient is also driven by the high potency and therefore typically small doses of the active ingredients. Since no carrier particles are present in the spray dried particles, the excipients also serve as bulking agents in the formulation, enabling the effective delivery of low therapeutic doses. In some embodiments, it is also desirable to keep drug loading low to ensure that particle properties are controlled by surface composition and particle morphology. This enables comparable physical stability and aerosol performance between mono and combined particles to be achieved.
[75] The minimum fill mass of fine powder that can be reasonably filled commercially with a relative standard deviation of less than 3% is about 0.5 mg. In contrast, the required pulmonary dose of the active ingredients can be as low as 0.01 mg and is routinely about 0.2 mg or less. Therefore, significant amounts of excipient are required. In some instances, where the drugs are less potent, it may be possible to reduce the required excipient content, although maintaining the high excipient concentration allows for control of surface composition and particle morphology, attributes considered critical in achieving equivalent performance between single-component and fixed-dose combination formulations. It should be kept in mind, however, that low drug loadings increase the potential of the crystalline active ingredient to dissolve in the solvent to be spray dried. Care must be taken to minimize dissolution of the crystalline active ingredient as far as possible.
[76] Generally, compatible phospholipids comprise those having a gel-to-liquid crystal transition phase greater than about 40°C, such as greater than about 60°C or greater than about 80°C. Incorporated phospholipids can be relatively long chain saturated phospholipids (eg, C16-C22). Exemplary phospholipids useful in the stabilized preparations described include, but are not limited to, phosphatidylcholines such as dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC) and hydrogenated egg or soy phosphatidylcholines (e.g., E-100-3, S-100-3, available from Lipoid KG, Ludwigshafen, Germany). Natural phospholipids are preferably hydrogenated with a low iodine value (<10).
[77] Phospholipids can optionally be combined with cholesterol to modify the fluidity of the phospholipid's acyl chains.
[78] Long-chain phospholipids can optionally be combined with a divalent metal ion (eg, calcium, magnesium). Such a divalent metal ion acts to decrease headgroup hydration, thereby increasing the transition from the phospholipid gel to the liquid crystal phase and the wetting of the powders in the lung lining fluid. The molar ratio of polyvalent cation to phospholipid can be at least about 0.05:1, such as about 0.05:1 to 0.5:1. In one or more embodiments, the polyvalent cation:phospholipid molar ratio is 0.5:1. While not wishing to be bound by theory, it is considered that the divalent metal ion binds to the phosphate groups on the zwitterionic phosphatidylcholine head group, displacing water molecules in the process. Molar ratios of metal ion to phospholipid in excess of 0.5 can result in free metal ion not bound to phosphate groups. This can significantly increase the hygroscopicity of the resulting dry powder and is not preferred. When the divalent metal ion is calcium, it can be in the form of calcium chloride. Although metal ions, such as calcium, are generally included with phospholipids, none are necessary and their use can be problematic when other ions are present in the formulation (eg, phosphate, which can precipitate calcium ions as phosphate of calcium). When compatibility issues occur. there may be benefit in using Mg++ salts, as they have Ksp values that are three to four orders of magnitude higher than Ca++ salts.
[79] The hydrophobic excipient may also comprise long-chain fatty acid soaps. The length of the alkyl chain is generally 14 to 22 carbons in length with saturated alkyl chains preferred. Fatty acid soaps can use monovalent (eg Na+, K+) or divalent (eg Ca++, Mg++) counterions. Particularly preferred fatty acid soaps are sodium stearate and magnesium stearate. The solubility of fatty acid soaps can be increased above the Krafft point. Fatty acid potassium salts generally have the lowest Krafft point temperature and the highest aqueous solubility at a given temperature. Calcium salts are expected to have the lowest solubility. Hydrophobic fatty acid soaps provide a similar waxy coating on the particles. The proposed loadings on the spray dried particles are similar to the phospholipids previously detailed.
[80] The hydrophobic excipient may also comprise hydrophobic amino acids, peptides or proteins. Particularly preferred are the amino acid leucine and its oligomers dileucine and trileucine. Proteins such as human serum albumin are also contemplated. Trileucine is particularly preferred, as its solubility profile and other physicochemical properties (eg surface activity, log P) facilitate the creation of core-shell particles, where trileucine controls the surface properties and morphology of the resulting particles. .
[81] The dry powder formulation of the present invention may additionally comprise one or more excipients.
[82] The amorphous phase may optionally contain additional glass-forming excipients chosen to: increase the glass transition temperature, Tg, and the relaxation time of the amorphous phase. Preferred glass-forming materials are selected from sugars (eg sucrose, trehalose, lactose), sugar alcohols (eg mannitol), amino acids/peptides (eg leucine) and salts/buffers (eg sodium citrate , sodium maleate). Particularly preferred glass-forming excipients are those with a Tg >100°C (eg, sodium citrate, inulin and trehalose). Water-soluble glass forming excipients are chosen such that they will diffuse rapidly from the interface during the drying process, enabling the particle surface to be enriched with the hydrophobic excipient. In such a particle, the properties of the particle will be controlled to a significant extent by surface composition/surface morphology. The surface composition of the particles comprises more than 70% w/w of the hydrophobic excipient, more often more than 90% w/w or 95% w/w. The morphology of the particles (roughness or pores) and the ability to create core-coated particles is controlled by the composition of the raw material and its drying properties as characterized by the Peclet numbers of each component through the drying process.
[83] The amount of glass-forming excipient required will be determined by the glass transition temperatures of the drug substance to be stabilized and the glass stabilizing agent. The goal is to achieve the Tg for the drug product that is at least 80°C. Fox's equation can be used to assess the amount of excipient that forms glass required to achieve this goal, ie:

[84] Where w1 and w2 are the weight fractions of the drug and the glass-forming excipient, respectively. Care must be taken with sodium citrate to avoid precipitation with divalent ions that may be present with the hydrophobic excipients that form the coating. In such cases, the use of trehalose or inulin may be preferred. Table 2 provides a list of common glass-forming materials and their representative dry values of Tg.
[85] Dry Tg values of some common glass-forming excipients and related materials

[86] In one or more embodiments of the dry powder formulation of the present invention, the excipient may additionally or alternatively include additives to enhance the stability or biocompatibility of the formulation. For example, various salts, buffers, chelators and taste-masking agents are contemplated. The use of these additives will be understood by those skilled in the art and specific amounts, proportions and types of agents can be determined empirically without exhaustive experimentation.
[87] In one or more embodiments, the dry powder formulation of the present invention is by a two-step process.
[88] In the first step of the process for preparing a dry powder formulation of spray dried particles that contain a first active ingredient and a second active ingredient, a raw material is prepared comprising the second active ingredient dissolved in a solvent phase. , a hydrophobic excipient and crystalline particles of the first active ingredient. The crystalline particles of the first active ingredient are substantially insoluble in the solvent phase in order to minimize the presence of the first active ingredient in the amorphous phase.
[89] The choice of solvent depends on the physicochemical properties of the active ingredients. Useful solvents from which to select include water, ethanol, ethanol/water, acetone, dichloromethane, dimethylsulfoxide and other Class 3 solvents as defined in the ICH Q3C Guidelines, eg ICH Topic Q3C (R4) Impurities: Guideline for Residual Solvents (European Medicines Agency reference CPMP/ICH/283/95 of February 2009).
[90] In certain preferred embodiments, the first active ingredient is sparingly soluble in water, so suitable solvents are water to water mixed with ethanol. When the first active ingredient is indacaterol, the solvent is preferably water.
[91] According to Figure 1, the API solubility required to obtain a dissolved fraction of the first active ingredient of 5% w/w or less increases with increasing drug loading and raw material solids content to be spray dried. At preferred drug loadings (i.e. < 30%), drug solubility should be less than 1 mg/ml, preferably less than 0.01 mg/ml.
[92] The solubility of the first active ingredient in the raw material to be spray dried can be decreased by decreasing the raw material temperature. As a general rule, solubility decreases twice with every 10°C decrease in temperature. Therefore, from room temperature to refrigerated conditions, a decrease in solubility of about 4 times can be expected.
[93] In some examples, the addition of salts that "salt" the active ingredient can be used to further expand the range of insoluble active ingredients that can be prepared within the context of the invention. It may also be possible to modify the pH or add common ions for active ingredients with ionizable groups to limit solubility according to Le Chatelier's principle.
[94] The nature of the salt must be kept in mind, as it can be used to modify the physicochemical properties, in particular the solubility, of the active ingredient.
[95] The first active ingredient is preferably used in a micronized, size reduction process known in the art such as mechanical micronization, jet milling, wet milling, cryogenic milling, ultrasonic treatment, high pressure homogenization, processes of microfluidization and crystallization, in order to facilitate its dissolution in the aqueous liquid.
[96] The particle size distribution of the first active ingredient is useful in achieving uniformity within the atomized droplets during spray drying. When evaluated by laser diffraction (Sympatec), the x50 (average diameter) should be less than 3.0 μm, preferably less than 2.0 μm or up to 1.0 μm. In fact, the incorporation of insoluble nanoparticles (x50 < 1000 nm or 200 nm) is contemplated. The x90 should be less than 7 μm, preferably less than 5 μm, preferably less than 4 μm or even 3 μm. For nanoparticles, the x90 should be less than about 1000 nm.
[97] In preferred embodiments of the dry powder formulation, the drug loading for the first active ingredient is suitably less than 30% w/w, preferably less than 10% w/w. At drug contents less than about 30% wt/wt, the physical properties and aerosol performance of the powder are controlled by the hydrophobic excipient at the interface and the rough morphology of the particle, regardless of whether two or three drugs are incorporated into the particle.
[98] In embodiments, where two or more of the active ingredients are substantially insoluble in water, it may be preferred that they have a similar particle size distribution, such that the aerodynamic particle size distribution and lung deposition pattern are similar for the active ingredients in mono-formulations.
[99] In preferred embodiments, the water solubility of the second active ingredient is greater than 1 mg/ml, preferably greater than 10 mg/ml or 30 mg/ml (see Figure 2). It should be noted that the increase in solids content helps ensure that the first active ingredient (which is substantially insoluble in water) does not dissolve in the aqueous phase of the raw material, but also imposes additional restrictions as the solubility of the second active ingredient must be tall. Achieving the desired physical form for both active ingredients may require a compromise in terms of solids content and drug loading or even aerosol and blister fill mass performance. The presence of the amorphous active ingredient may also require the addition of an excipient to stabilize the amorphous phase.
[100] In preferred embodiments, the raw material is comprised of micronized crystals of the first active ingredient dispersed in the continuous phase of an oil-in-water emulsion and the second active ingredient is dissolved in the continuous phase.
[101] The dispersed oil phase serves as a pore-forming agent to increase particle roughness in the spray-dried drug product. Suitable pore forming agents include various fluorinated oils including perflubron, perfluorodecalin and perfluorooctyl ethane. The emulsion droplets are stabilized by a monolayer of a long-chain phospholipid, which serves as the hydrophobic excipient in the spray dried particles.
[102] The emulsion can be prepared by first dispersing the excipient in hot distilled water (eg 70°C) using a suitable high-shear mechanical mixer (eg ULTRA-TURRAX T-25 mixer) at 8000 rpm per 2 to 5 minutes. If the hydrophobic excipient is a phospholipid, a divalent metal, eg calcium chloride, can be added to decrease headgroup hydration as discussed previously. The fluorocarbon is then added dropwise with mixing. The resulting fluorocarbon-in-water emulsion can then be processed using a high pressure homogenizer to reduce particle size. Typically, the emulsion is processed in two to five different passes at 8000 to 20,000 psi to produce droplets with an average diameter of less than 600 nm. The second active ingredient and other water-soluble excipients are dissolved in the continuous phase of the emulsion. The first active ingredient, preferably in micronized form, is added into the continuous phase of the emulsion and mixed and/or homogenized until dispersed and a suspension has been formed. On drying, a film of hydrophobic phospholipid forms on the surface of the particles. The water-soluble drug and glass-forming excipients diffuse through the atomized droplets. Eventually, the oil phases evaporate leaving pores in the spray dried particles and a rough particle morphology. The crystalline drug, amorphous drug and phospholipid are in substantially separate phases in the spray dried particles, with the particle surface comprised primarily of the hydrophobic phospholipid excipient. The dispersed phase volume fraction is generally between 0.03 and 0.5 with values between 0.1 and 0.3 preferred.
[103] In preferred embodiments, the raw material is water-based, however, the inhalable drug powders of the present invention can also be prepared using organic solvents or bisolvent systems. Ethanol/water systems are especially useful as a means of controlling the solubility of one or more of the materials that comprise the particle.
[104] Additionally, it is possible to formulate two raw materials (ie to disperse the first active ingredient in water and dissolve a hydrophobic excipient and the second active ingredient in ethanol) and then combine the two raw materials using a fluid nozzle double, to produce a single raw material at the point of drying.
[105] It is important to minimize the solubility of the first API to avoid the formation of amorphous drug that can have a deleterious effect on long-term stability. The second API is formulated/processed to be amorphous. In that case, it may be advantageous to stabilize the amorphous phase. Excipients that elevate Tg (Table 2) are contemplated.
[106] As it is a dry powder formulation, it is important to control the moisture content of the drug product. For drugs that are not hydrates, the moisture content in the powder is preferably less than 5%, more typically less than 3% or up to 2% w/w. The low moisture content is important for maintaining a high glass transition temperature (Tg) for the amorphous phase comprising the second active ingredient. The moisture content must be high enough, however, to ensure that the powder does not exhibit significant electrostatic attraction forces. Moisture content in spray dried powders is determined by Karl Fischer titrimetry.
[107] Although preferred embodiments describe manufacturing processes using water-based raw materials, the amorphous coated crystals of the present invention can also be prepared using organic solvents or bi-solvent systems.
[108] In one embodiment, a micronized crystalline drug A is dispersed in an organic solvent in which the drug has poor solubility and in which drug B and the hydrophobic excipient are soluble. The resulting raw material is then spray dried to produce drug A crystals coated with an amorphous layer of drug B and the hydrophobic excipient. The preferred solvent mixture is ethanol/water. The ratio of ethanol to water can be varied to change the solubility of the excipient and drugs.
[109] Additionally, it is possible to formulate two raw materials (ie, disperse a water-insoluble drug in water and dissolve a hydrophobic excipient and a drug in ethanol) and then combine the two raw materials in the dual-fluid mouth. produce a single raw material at the drying point.
[110] In the second step of the process of the invention, the raw material prepared in the first step is spray dried to provide the dry powder formulation of the invention. The resulting spray dried particles comprise a core of the first active ingredient in substantially crystalline form, a second active ingredient in substantially amorphous form, and a pharmaceutically acceptable hydrophobic excipient, wherein the three materials are substantially phase-separated in the dry particles. by atomization.
[111] Spray drying can be performed using conventional equipment used to prepare spray dried particles for use in pharmaceuticals that are administered by inhalation. Commercially available spray dryers include those manufactured by Büchi Ltda and Niro Corp.
[112] The particle surface nature and morphology will be controlled by controlling the solubility and diffusibility of the components within the raw material. Surface-active hydrophobic excipients (eg, trileucine, phospholipids, fatty acid soaps) can be concentrated at the interface, improving fluidization and dispersibility of the powder, while also driving increased surface roughness of the particles.
[113] Typically, the raw material is sprayed into a stream of heated filtered air that evaporates the solvent and conveys the dry product to a collector. The used air is then eliminated with the solvent. The atomizing dryer operating conditions such as inlet and outlet temperature, feed rate, atomization pressure, drying air flow rate and nozzle configuration can be adjusted in order to produce the required particle size, the moisture content and the production yield of the resulting dry particles. The selection of the proper equipment and processing conditions are within the reach of an experienced technician in view of his teachings and can be obtained without exhaustive experimentation. Typical settings are as follows: an inlet air temperature between about 60°C and about 170°C, such as between 80°C and 120°C; an air outlet between about 40°C to about 120°C, such as about 50°C and 80°C; a feed rate between about 3 ml/min to about 15 ml/min; an air suction flow of about 300L/min; and an atomizing air flow rate between about 25 L/min and about 50 L/min. The solids content in the spray dried raw material will typically range from 0.5% w/w to 20% w/w, such as from 1.0% w/w to 10% w/w. Adjustments, however, will vary depending on the type of equipment used and the nature of the solvent systems employed. In any event, the use of these and similar methods allows the formation of particles with appropriate diameters for aerosol deposition in the lung.
[114] In certain embodiments no pore-forming agent is required to achieve the desired fluidization and dispersibility of the powder. In one such embodiment, crystals of the first active ingredient are dispersed in an aqueous phase that contains the dissolved hydrophobic excipient and the second active ingredient. In this modality, the surface roughness of the particle is controlled by the content of the very sparingly water-soluble hydrophobic excipient and the conditions of spray drying. For example, the hydrophobic excipient trileucine is surface active and has limited water solubility. As such, it tends to be present in high concentration at the air/water interface in the atomized droplets. During the drying process, the hydrophobic trileucine precipitates before other components in the solution, forming a film on the surface of the atomized droplets. The morphology/roughness of the coating is then controlled by the rheological properties of the trileucine film and the drying kinetics. The resulting coating can take on a raisin-like appearance. The rough layer of hydrophobic trileucine present at the particle interface improves powder fluidization and dispersibility of the resulting drug particles.
[115] In one embodiment, a phospholipid such as a long-chain phosphatidylcholine is introduced into the raw material in the form of liposomes (ie, there is no dispersion in the oil phase). The morphology of the resulting particles is controlled by phospholipid solubility and spray drying conditions, as discussed above for trileucine.
[116] A pore-forming agent can be added in the first or second steps in order to increase the surface roughness of the particles produced in the third step. This improves the fluidization and dispersibility characteristics of the particles.
[117] The present invention provides a dry powder formulation comprising the aforementioned spray dried particles.
[118] The dry powder formulation may comprise 0.1% to 30% w/w of a first active ingredient, 0.1% to 30% of a second active ingredient and optionally 0.1% to 30% of a third active ingredient.
[119] The particles of the dry powder formulation of the invention suitably have a mass median diameter (MMD) between 1 and 5 microns, for example between 1.5 and 4 microns.
[120] The particles of the dry powder formulation of the invention suitably have a mass median aerodynamic diameter (MMD) between 1 and 5 microns, for example between 1 and 3 microns.
[121] The dry powder formulation particles of the invention suitably have a roughness greater than 1.5, for example, from 1.5 to 20, 3 to 15 or 5 to 10.
[122] In order to minimize interpatient variability in lung deposition, the dry powder formulation particles of the invention suitably have a fine particle fraction, expressed as a percentage of the nominal dose < 3.3 μm (FPF < 3.3 μm ) greater than 40%, preferably greater than 50%, but especially greater than 60%. Pulmonary deposition as large as 50 to 60% of the nominal dose (60 to 80% of the delivered dose) is contemplated.
[123] The fine particle dose of the powdered formulation particles of the invention having a diameter of less than 4.7 μm (FPF<4.7μm) is suitably greater than 50%, for example between 40% and 90%, especially between 50% and 80%. This minimizes the interpatient variability associated with oropharyngeal filtration.
[124] Formulating both components of the active ingredients in the same drug particle is useful to ensure that the aerodynamic particle size distribution and, in particular, FPF<3.3 µm is consistent with both drugs in a given formulation. Aerodynamic particle size distributions are also consistent for mono-compounds and their combinations.
[125] Differences in FPF<3.3 µm for the two APIs in the manipulated particles should be less than 10%, preferably less than 5%, eg less than 1%.
[126] Differences in FPF<3.3 μm for the two APIs in the manipulated particles of the combination versus drugs in the corresponding monoformulations should be less than 15%, eg, less than 10% or less than that 5%.
[127] The variability in the particle fraction of the powdered formulation of the invention with a d2Q of less than 500 (expressed as the mean variability) is suitably less than 20%, eg less than 10%, especially less than 5% across a series of pressure drops in a dry powder inhaler from 2 kPa to 6 kPa. d2Q is a measure of inertial impaction.
[128] The mass ratio of the active ingredients in the fine particle dose (i.e. the mass ratio of the first active ingredient to the second active ingredient in the nominal dose) is suitably within 10%, preferably within 5% of the ratio of the nominal doses of drugs. In the spray dried particles of the dry powder formulation of the invention, the proportion of the two active ingredients is invariable in fine particle fractions as the active ingredients are co-formulated into a single particle.
[129] In one embodiment, the present invention provides a dry powder formulation comprising spray dried particles comprising 0.1% to 30% weight/weight of a first active ingredient that is substantially insoluble in water, 0, 1% to 30% of a second water-soluble active ingredient in substantially amorphous form and a pharmaceutically acceptable hydrophobic excipient, wherein the three materials are in substantially separate phases in the spray dried particles, wherein the particles have a mass average diameter (MMD) between 1 and 5 microns, a mass mean aerodynamic diameter (MMD) between 1 and 5 microns and a roughness greater than 1.5. Optionally, a third active ingredient in crystalline or amorphous form can be formulated into spray dried particles. In another embodiment, the present invention provides a dry powder formulation comprising spray dried particles comprising 0.1% to 30% weight/weight of indacaterol or a salt thereof, 0.1% to 30% of amorphous glycopyrrolate and a pharmaceutically acceptable hydrophobic excipient, wherein the particles have a mass median diameter (MMD) between 1 and 5 microns, a mass median aerodynamic diameter (MMD) between 1 and 5 microns, and a roughness greater than 1.5.
[130] Several excipients can be included when formulating drugs to enhance their stability, biocompatibility, and other characteristics. These can include, for example, salts, buffers, chelators and taste-masking agents. The use of these additives will be understood by those skilled in the art and specific amounts, proportions and types of agents can be determined empirically without exhaustive experimentation.
[131] The present invention also provides a unit dosage form comprising a container containing a dry powder formulation of the present invention.
[132] In one embodiment, the present invention is directed to a unit dosage form comprising a container containing a dry powder formulation comprising spray dried particles comprising 0.1% to 30% weight/weight of a first active ingredient which is in substantially crystalline form, 0.1% to 30% of a second active ingredient in substantially amorphous form, and a pharmaceutically acceptable hydrophobic excipient, wherein the three materials are in substantially separate phases in the spray dried particles , in which the particles have a mass median diameter (MMD) between 1 and 5 microns, a mass median aerodynamic diameter (MMD) between 1 and 5 microns, and a roughness greater than 1.5. Optionally, a third active ingredient in crystalline or amorphous form can be formulated into spray dried particles. In another embodiment, the present invention is directed to a unit dosage form comprising a container containing a dry powder formulation comprising spray dried particles comprising 0.1% to 30% weight/weight of crystalline indacaterol or a salt of that, 0.1% to 30% amorphous glycopyrrolate and a pharmaceutically acceptable hydrophobic excipient, wherein the particles have a mass median diameter (MMD) between 1 and 5 microns, a mass median aerodynamic diameter (MMD) between 1 and 5 microns and a roughness greater than 1.5.
[133] Examples of containers include, but are not limited to, caps, blisters, or container closure systems made of metal, polymer (eg, plastic, elastomer), glass, or the like.
[134] The container can be inserted into an aerosolization device. The container may be of a suitable shape, size and material to contain the dry powder formulation and to provide the dry powder formulation in a usable condition. For example, the capsule or blister may comprise a wall comprising a material that does not adversely react with the dry powder formulation. In addition, the wall may comprise a material that allows the capsule to be opened to allow the dry powder formulation to be aerosolized. In one or more versions, the wall comprises one or more of gelatin, hydroxypropylmethylcellulose (HPMC), HPMC compounded with polyethylene glycol, hydroxypropylcellulose, agar, aluminum foil and the like.
[135] The use of aluminum foil blisters is particularly preferred due to the fact that at least the second active ingredient of the dry powder formulation of the present invention is in substantially amorphous form. The selection of suitable aluminum foils for the blister is within the reach of the experienced technician in view of the blister's teachings. The nature of the sheets used will be driven by the moisture permeability of the seal and the ability of the material to be formed into a blister of the appropriate size and shape. In one embodiment, powders are loaded into aluminum foil blisters with a fill mass between 0.5 and 10 mg.
[136] The dry powder formulations of the present invention are useful to treat obstructive or inflammatory airway diseases, especially asthma and chronic obstructive pulmonary disease.
[137] Accordingly, the present invention provides a method for the treatment of an obstructive or inflammatory airway disease, especially asthma and chronic obstructive pulmonary disease, which comprises administering to an individual in need thereof an effective amount of the aforementioned dry powder formulation . For example, in one or more embodiments, a subject is treated with a dry powder formulation comprising 0.1% to 30% w/w of a first active ingredient in substantially crystalline form that is coated with a roughened layer comprising 0 .1% to 30% of a second active ingredient in substantially amorphous form that is dispersed in a hydrophobic excipient, wherein the three materials are in substantially separate phases in the spray dried particles, wherein the particles have a mass average diameter ( MMD) between 1 and 10 microns, a mass mean aerodynamic diameter (MMD) between 1 and 5 microns and a roughness Sv greater than 1.5.
[138] The present invention also relates to the use of the aforementioned dry powder formulation in the manufacture of a medicament for the treatment of an obstructive or inflammatory airway disease, especially asthma and chronic obstructive pulmonary disease.
[139] The present invention also provides the aforementioned powdery formulation for use in the treatment of an obstructive or inflammatory airway disease, especially asthma and chronic obstructive pulmonary disease.
[140] Treatment of a disease according to the invention may be symptomatic, prophylactic or both. Obstructive or inflammatory airway diseases to which the present invention is applicable include asthma of any type or origin, including both intrinsic (non-allergic) and extrinsic (allergic) asthma. The treatment of asthma should also be understood to encompass the treatment of individuals, for example, less than 4 to 5 years of age, who exhibit symptoms of difficult breathing and are diagnosed or diagnosable as "noisy breathing children", an established category of patients with great medical concern and now often identified as incipient or early-stage asthmatics. (For convenience, this particular asthmatic condition is referred to as "infant asthma syndrome").
[141] Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, eg, acute or bronchoconstrictor asthmatic attack, improved lung function, or improved airway hyperreactivity. It may be further evidenced by reduced need for other symptomatic therapy, ie therapy for or intended to restrict or abort a symptomatic attack when it occurs, eg anti-inflammatory (eg corticosteroid) or bronchodilator. The prophylactic benefit in asthma may, in particular, be apparent in individuals prone to 'morning dip'. "Morning dip" is a recognized asthma syndrome, common to a substantial percentage of asthmatics and characterized by an asthma attack, for example, between the hours of about 4 to 6 am, ie at a time substantially away from any therapy symptomatic for previously administered asthma.
[142] Other obstructive and inflammatory airway diseases and conditions to which the present invention is applicable include adult/acute respiratory distress syndrome (ARDS), chronic obstructive airway or pulmonary disease (COPD or COAD). ), including chronic bronchitis or dyspnea associated with it, emphysema as well as exacerbation of airway hyperreactivity consequent to other drug therapy, in particular inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of any type or origin including, for example, acute, arachidic, catarrhal, croup, chronic or "phthinoid" bronchitis. Other obstructive or inflammatory airway diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational disease of the lungs often accompanied by chronic or acute airway obstruction and caused by repeated inhalation of powders) of any type or origin including, for example, aluminosis, anthracosis, asbestosis, calicosis, ptilose, siderosis, silicosis, tobacco and byssinosis.
[143] The dry powder formulation of the present invention is especially useful for the treatment of asthma and COPD.
[144] The present invention also provides a delivery system, comprising an inhaler and a dry powder formulation of the invention.
[145] In one embodiment, the present invention is directed to a delivery system comprising an inhaler and a dry powder formulation for inhalation comprising spray dried particles comprising a core of a first active ingredient in substantially crystalline form, a second active ingredient in substantially amorphous form and a pharmaceutically acceptable hydrophobic excipient. The first active ingredient, second active ingredient and the hydrophobic excipient are in substantially separate phases in the spray dried particles.
[146] In a preferred embodiment, particles comprising 0.1% to 30% weight/weight of a first active ingredient that is in substantially crystalline form, 0.1% to 30% weight/weight of a second active ingredient that is in substantially amorphous form and a pharmaceutically acceptable hydrophobic excipient, wherein the particles have a mass median diameter (MMD) between 1 and 5 microns, a mass median aerodynamic diameter (MMD) between 1 and 5 microns, and a roughness greater than 1.5.
[147] In another embodiment, the present invention is directed to a delivery system comprising an inhaler and a dry powder formulation comprising spray dried particles comprising 0.1% to 30% weight/weight of a first active ingredient that is in substantially crystalline form, 0.1% to 30% weight/weight of a second active ingredient that is in substantially amorphous form, and a pharmaceutically acceptable hydrophobic excipient, wherein the particles have a mass median diameter (MMD) between 1 and 5 microns, a mass median aerodynamic diameter (MMD) between 1 and 5 microns and a roughness greater than 1.5.
[148] In yet another embodiment, the present invention is directed to a delivery system comprising an inhaler and a dry powder formulation comprising spray dried particles comprising 0.1% to 30% weight/weight of crystalline indacaterol , 0.1% to 30% wt/wt of amorphous glycopyrrolate and a pharmaceutically acceptable hydrophobic excipient, wherein the particles have a mass median diameter (MMD) between 1 and 5 microns, a mass median aerodynamic diameter (MMD) ) between 1 and 5 microns and a roughness greater than 1.5. [QVA149]
[149] Suitable inhalers include dry powder inhalers (DPIs). Some of such inhalers include those where the dry powder is stored in a capsule and the patient loads one or more of these capsules into the device before use. Other dry powder inhalers include those that are loaded with a capsule comb. Other dry powder inhalers include those that are loaded with a blister pack comprising multiple doses of powder. Given the amorphous nature of at least one of the active ingredients of the inhalable drug particles of the present invention, it is preferable that the drug containing such particles is prepackaged in aluminum foil blisters, for example, in a cartridge, strip or disk.
[150] Preferred dry powder inhalers include multi-dose dry powder inhalers such as DISKUS™ (GSK, described in US 6536427), DISKHALER™ (GSK, described in WO 97/25086), GEMINI™ (GSK, described in US) inhalers. WO 05/14089), GYROHALER™ (Vectura, described in WO 05/37353), PROHALER™ (Valois, described in WO 03/77979) and TWISTHALER™ (Merck, described in WO 93/00123, WO 94/14492 and WO 97/30743).
[151] Preferred single dose dry powder inhalers include AEROLIZER™ (Novartis, described in US 3991761) and BREEZHALER™ (Novartis, described in WO 05/113042) inhalers. These tend to be less complicated to operate than many multi-dose dry powder inhalers.
[152] Blister of preferred single-dose dry powder inhalers, which some patients find easier and more convenient to use to deliver medications that require once-daily administration include the inhaler described by Nektar Therapeutics in WO 08/51621 and WO 09/117112.
[153] Reservoir-based dry powder inhalers are generally not preferred for the powders of the invention, due to potential stability issues associated with the amorphous active ingredients.
[154] Single-dose capsule dry powder inhalers are generally not preferred for patients with asthma or when handling the capsule is difficult or the total masses of powder to be delivered (typically 1 to 2 mg) are less than what is typically required for such inhalers.
[155] Particularly preferred inhalers are multi-dose powder-dry inhalers, where the energy for fluidization and dispersion of the powder is supplied by the patient (ie, "passive" MD-DPIs). The powders of the present invention effectively fluidize and disperse at low peak inspiratory flow rates (PIF). As a result, the small changes in PIF powder dispersion observed effectively balance the increases in inertial impaction that occur with increases in PIF, leading to flow rate-independent pulmonary deposition. The absence of flow rate dependence observed for the powders of the present invention, directs the reduction in overall interpatient variability. Suitable blister-based multi-dose inhalers include DISKUS™ (GSK), GYROHALER™ (Vectura), DISKHALER™ (GSK), GEMINI™ (GSK), and PROHALER™ (Valois) devices.
[156] Some patients may prefer to use an "active" multi-dose post-dry inhaler, where the energy to fluidize and disperse the powder is provided by the inhaler. Suitable inhalers include pressurizable dry powder inhalers as described, for example, in WO 96/09085, WO00/021594 and WO 01/043530 and in ASPIRAIR™ (Vectura) inhalers. Other active devices may include those made available by MicroDose Technologies Inc., such as the device described in US patent publication no. 20050183724. Preferred devices may be those that not only disperse powders evenly with an active component of the device (eg, compressed air, propellant), but also standardize the respiratory profile so as to create a reverse flow rate dependence (this (ie, increases in lung deposition with decreases in PFIR), which is common with active ILDs.
[157] Additional modalities and features are described in part in the following description and in part will be clear to those skilled in the art upon examination of the application or may be learned by practice of the invention.
[158] This invention is further illustrated by the following examples which are not to be considered as limiting.EXAMPLESEXAMPLE 1 Preparation of a dry powder formulation comprising spray dried particles containing formoterol and budesonide
[159] A dry powder formulation comprising spray dried particles containing formoterol and budesonide was prepared by a two-step manufacturing process.
[160] In the first step, 1.38 g of distearoylphosphatidylcholine (DSPC) (Genzyme Pharmaceuticals, Cambridge, MA, USA), and 119.6 mg of calcium chloride (JT Baker) were dispersed in 164 g of deionized hot water ( T = 70°C) using an ULTRA-TURRAX™ high shear mixer (model T-25) at 10,000 rpm for about 1 minute. The resulting DSPC/CaCl2 dispersion was then cooled in an ice bath. 98 mg of micronized formoterol fumarate (Industrie Chimica s.r.i, Italia) was added with mixing. Formoterol has a solubility in water of about 1 mg/ml, and as such, dissolves in the aqueous phase. The resulting formoterol/DSPC/CaCl2 dispersion was then passed through a high pressure homogenizer (AVESTIN EMULSIFLEX-C5™ high pressure homogenizer, Ottawa, Canada) at 137,895 MPa (20,000 pounds per square inch (psi) ) for 2 passes. 1.45 g of crystalline micronized budesonide (Industriale Chimica s.r.i, Italia) was dispersed in the aqueous phase and the resulting dispersion was passed through the high pressure homogenizer at 137,895 MPa (20,000 psi) for 3 additional passes.
[161] In the second step, the resulting raw material was spray dried in a BÜCHI B-191™ mini spray dryer (Büchi, Flawil, Switzerland). The composition of the dry raw material components is listed in Table 3 below. The following spray conditions were employed: total flow rate = 28 SCFM, inlet temperature = 85°C, outlet temperature = 57°C, pump feed = ~2 mL min-1, atomizer pressure = 0.412 MPa mano - metric (60 psig), atomizer flow rate = 34 cm (rotameter). TABLE 3
[162] Composition of spray dried particles comprising formoterol fumarate and budesonide spray dried into a single particle

[163] A free-flowing white powder was collected using a centrifugal separator. The geometric diameter of the manipulated particles was measured using laser diffraction (SYMPATEC HELOS™ H1006, Clausthal-Zellerfeld, Germany), where a volume-weighted mean diameter (VMD) of 2.1 µm was found. Scanning electron microscopy (SEM) analysis showed the powders as small wrinkled particles with high surface irregularity. There was no evidence of any crystals of the drug budesonide not incorporated in the five SEM views provided by each collector. The composite particles contain micronized crystalline budesonide crystals coated with an amorphous layer of formoterol fumarate and DSPC/CaCl2. No powdering agent was used in the manufacture of this powder.EXAMPLE 2Preparation of dry powder formulations comprising spray dried particles containing fixed dose combinations of glycopyrrolate and phospholipid coated indacaterol maleate crystals
[164] In this Example, dry inhalable powders comprising indacaterol maleate, glycopyrrolate, and excipients (distearoylphophatidylcholine (DSPC), calcium chloride, and trehalose) were manufactured by spray drying an emulsion-based raw material.
[165] The raw material was prepared by mixing an individually prepared vehicle emulsion and an attached drug solution.
[166] The vehicle emulsion was prepared by emulsifying perfluooctyl bromide (PFOB, perflubron) in an aqueous dispersion of DSPC containing dissolved CaCl2. A two-step process was employed, in which a coarse emulsion was prepared with an ULTRA-TURRAX™ high shear mixer, followed by homogenization through an AVESTIN C-50™ homogenizer. The resulting vehicle emulsion was an oil-in-water emulsion with an average droplet size in the emulsion in the range of 0.20 to 0.40 µm.
[167] The drug attached solution was prepared by suspending micronized crystals of indacaterol maleate in water using an ULTRA-TURRAX™ high-shear mixer, then dissolving the glycopyrrolate in the aqueous medium. In those emulsions where trehalose was used as a glass forming agent, the ratio of trehalose to glycopyrrolate was 2:1 weight/weight.
[168] The raw material was prepared by mixing the appropriate proportions of the vehicle emulsion and the drug attached solution to obtain a solution with a solids content of 3% weight/volume and a PFOB volume fraction of about 0.2. Therefore, the final raw material consisted of an aqueous solution (continuous phase) of glycopyrrolate, trehalose and calcium chloride, with two distinct phases: micronized indacaterol maleate crystals and DSPC-stabilized emulsion droplets.
[169] The spray dryer configuration consisted of a single dual-fluid atomizer, a drying chamber, a centrifugal separator, an adapter, an isolation valve, and a 1 L manifold in a temperature-controlled housing. The spray drying parameters used for the manufacture of inhalable drug powders are shown in Table 4: TABLE 4
[170] Spray drying parameters used to prepare dry powder formulations comprising spray dried particles comprising fixed dose combinations of indacaterol maleate and glycopyrrolate

[171] During suction drying, a peristaltic pump fed the raw material fluid into the atomizer, generating a fine spray of liquid droplets. Preheated drying air was fed into the drying chamber and mixed with the droplets, resulting in the formation of solid particles comprising micronized indacaterol maleate crystals coated with a rough layer of amorphous glycopyrrolate and DSPC. Particles were collected with a yield of approximately 60% using a centrifugal separator. The nominal compositions of the spray dried powders are shown in Table 5. TABLE 5
[172] A spray-dried particle composition comprising fixed dose combinations of indacaterol maleate and glycopyrrolate
where1 Represents 6.0% wt/wt of indacaterol2 Represents 1.0% or 2.0% wt/wt of glycopyrrolate3 The ratio of DSPC:CaCl2 was 2:1 mol:mol4 The pH was adjusted to pH 5.0 with NaOHEXAMPLE 3Physicochemical properties of a dry powder formulation comprising spray dried particles containing fixed dose combinations of indacaterol maleate and glycopyrrolate
[173] In this Example, the physicochemical properties (eg, morphology, primary particle size) of powders prepared according to Example 2 were measured.
[174] Scanning electron microscopy (SEM) was used to qualitatively assess the morphology of spray dried particles. The samples were mounted on silicon wafers which were then mounted on top of a double-sided carbon tape on an SEM aluminum backing. The assembled powders were then spray coated with gold:palladium in a DENTON™ sprayer for 60 to 90 seconds at 75 mTorr and 42 mA, producing a coating thickness of approximately 150 Á. Images were taken with a PHILIPS™ XL30 ESEM™ scanning electron microscope, operated in high vacuum mode using an Everhart-Thornley detector to capture secondary electrons for image composition. Acceleration voltage was adjusted to 20 kV using a LaB6 source. The working distance was between 5 and 6 mm.
[175] SEM images of indacaterol/glycopyrrolate powders (lots A2, A3, A4, A5) showed evidence of significant porosity, a characteristic of the emulsion-based spray drying process. formulated with trehalose are higher under the drying conditions employed.
[176] Primary particle size distributions were determined using laser diffraction. Powder samples were measured using a SYMPATEC HELOS particle size analyzer equipped with an ASPIROS microdose feeder and a RODOS dry powder dispersion unit (SYMPATEC GmbH, Clausthal-Zellerfeld, Germany). The following adjustments were applied for the analysis of the samples: a sample mass of approximately 10 mg, an optical triggering concentration (Copt) of approximately 1% and a targeting pressure of 4 bar. Data were collected during a measurement duration of 10 seconds. Particle size distributions were calculated by the instrument program using a Fraunhofer model. Prior to sample measurement, the suitability of the system was evaluated by measuring the primary particle size distribution of a silicon carbide reference standard supplied by Sympatec GmbH.
[177] The MMD (x50) of trehalose-based powders (2.8 µm) was about 1 µm higher than those of powders prepared without trehalose (1.7 to 1.8 µm).EXAMPLE 4Aerosol performance of dry powder inhaler formulations comprising spray dried particles containing fixed dose combinations of indacaterol maleate and glycopyrrolate delivered by passive dry powder inhaler.
[178] The pulmonary delivery performance of representative dry powder formulations comprising spray dried particles containing fixed dose combinations of indacaterol maleate and glycopyrrolate prepared according to Example 2 was characterized by filling the powder in an aluminum foil blister and dispersing the powder with a dry powder inhaler described in international patent application WO 08/51621, i.e. a portable, unit dose blister-based dry powder inhaler developed by Novartis ( San Diego, CA, USA).
[179] The aerodynamic particle size distribution (aPSD) of the resulting aerosol dose was evaluated using a NEXT GENERATION IMPACTOR™, at flow rates of 35 LPM and 47 LPM, which correspond to inhaler pressure drops of 4 kPa and 6 kPa, respectively. Note that for present purposes, flow rate and pressure drop are related by the resistance to flow of the inhaler and are used alternatively. The mass distribution of each active ingredient in the cascade impactor stages was determined using an HPLC assay.
[180] Aerosol measurements determined for a representative powder formulation (Lot A2), which has a theoretical concentrated powder composition of 6% indacaterol (7.8%) maleate salt, 2% glycopyrrolate (2.5 %), 83% DSPC and 5.9% CaCl2 are shown in Table 6. TABLE 6
[181] Aerosol measurements for a dry powder formulation that contains spray dried particles comprising indacaterol maleate and glycopyrrolate delivered with a passive dry powder inhaler

[182] Table 6 presents the mass mean aerodynamic diameter (MMAD) and FPF<3.3μm for each drug component at two distinct flow rates, which roughly correspond to comfortable and forced inhalation maneuvers. At a given flow rate, the values of MMAD and FPF<3.3μm are broadly equivalent (less than 2% variation). This provides confirmation that the two drug substances were effectively formulated into a single particle.
[183] This is different from fixed dose combinations comprising micronized drug mixtures, where significant differences in fine particle dose are often observed for each active ingredient as a result of different adhesive properties with the coarse particles of lactose carrier.
[184] The formulations of the present invention are expected to lead to significant improvements in lung targeting and dose consistency over current marketed inhalers based on micronized drug mixtures or pellets.
[185] In terms of pulmonary targeting, the best correlation of total pulmonary deposition has been found to be the fraction of particles smaller than about 3 µm. Based on this measure, it is anticipated that total pulmonary deposition will be approximately 60% of the delivered dose. Improved pulmonary targeting lowers the nominal dose needed while significantly reducing oropharyngeal deposition. This is expected to reduce the potential for opportunistic infections (eg, candidiasis or pneumonia) in patients with asthma/COPD that result from the use of corticosteroids. Improved targeting can also lead to reduced systemic drug concentrations when therapy is orally bioavailable (eg, indacaterol).
[186] In terms of improved dose consistency, the spray-dried powders of the present invention are expected to improve dose consistency by one or more of: (a) reducing the variability associated with oropharyngeal filtration; (b) reduced variability associated with the patient's respiratory maneuvers, in particular peak inspiratory flow rate variations; reductions in variability in fixed-dose combinations associated with differences in the adhesive properties of the two drugs with the vehicle.
[187] Total lung deposition as a function of variations in flow rate (Q) is dependent not only on the aerodynamic distribution of aerosol particle size, but also on variations in inertial impaction that occur with changes in flow rate. In other words, for a given aPSD, the pulmonary dose is expected to decrease as the flow rate increases. In order to achieve in vivo flow rate independence, it is important to strike a balance of these two opposing factors. A simple way to explain the pulmonary dose dependence on both variables, ie, the particle size cutoff aerodynamic diameter, d, and the flow rate, Q, is to express aPSD in terms of a fraction cutoff point. of fine particle that incorporates both variables. Assuming that oropharyngeal losses are largely determined by inertial impaction, the cutoff point for pulmonary dose can be expressed in terms of the impaction parameter, d2Q. The d2Q cutoff point of 500 μm2-L/min was chosen to represent a range of inhalers, based on the fact that the best correlation with lung deposition is found in the fraction of particles with an aerodynamic size of less than 3 μm and one Medium resistance inhaler is typically tested at a flow rate of around 60 L/min.
[188] The % shift of FPFd2Q<500 going from 35 L/min to 47L/min was 4.6% for indacaterol and 8.1% for glycopyrrolate. Therefore, the formulation as a manipulated powder dramatically reduces the observed flow rate dependence on the anticipated pulmonary dose, where, for example, the total pulmonary deposition for PULMICORT™ TURBUHALER™ budesonide decreases from 28% to 15% going from one maneuver from forced inhalation to comfortable. This is consistent with what has been clinically observed for engineered particle monotherapies (see Duddu et al: Improved lung delivery from a passive dry powder inhaler using an engineered PulmoSphere™ powder. Pharm Res. 2002, 19:689-695).
[189] The high fine particle fractions observed are expected to lead to pulmonary releases in patients of >60% of the delivered dose. This in turn is expected to reduce the in vivo variability in pulmonary dose to ca. 10 to 20%. This compares with 30 to 50% for standardized micronized drug combinations (see Olsson B, Borgstrom L: Oropharyngeal deposition of drug aerosols from inhalation products. Respiratory Drug Delivery 2006, pp. 175-182).
[190] The formulation of the two actives into a single engineered particle virtually eliminates the variability associated with differences in adhesive properties between drug and vehicle. This enables the effective delivery of the two active ingredients to different targets in the same cell. EXAMPLE 5 X-ray powder diffraction study of dry powder formulations comprising spray dried particles comprising micronized indacaterol maleate crystals coated with a porous layer of amorphous glycopyrrolate and phospholipid
[191] Spray dried particles comprising fixed dose combinations of indacaterol maleate and glycopyrrolate were prepared using the procedure described in Example 2 (Table 7). The ratio of indacaterol maleate to glycopyrrolate was 3:1 in both formulations. The concentration of each active ingredient is expressed as a free base function. A vehicle formulation (batch V1) was also prepared. This formulation contains a 2:1 mol:mol ratio of DSPC:CaCl2.TABLE 7
[192] Composition of spray dried particles comprising fixed dose combinations of indacaterol maleate and glycopyrrolate used in XRPD studies

[193] The X-ray powder diffraction (XRPD) patterns of the test powders (see Figure 3) were measured using a SHIMADZU XRD-6000™ X-ray powder diffraction system with a graphite monochromator and a detector. flicker (Shimadzu Corporation, Japan). The samples were scanned from 3° to 40° 2θ, at 0.4° 2θ/minute, with a step size of 0.02° 2θ, using a Cu radiation source with a wavelength of 1.15 Á , operated at 40 kV and 40 mA. In this work, apertures receiving 0.5° divergence, 0.5° dispersion and 0.3 mm were used. A sample of each material was prepared by packing the concentrated powder into a chrome-plated copper sample container and a single sample was obtained from that sample. The environmental chamber over the X-ray equipment was purged with dry N2 gas during data acquisition.
[194] Figure 3 shows high angle powder diffraction patterns of the two fixed-dose combination formulations of indacaterol and glycopyrrolate. X-ray powder diffraction patterns of crude indacaterol material (highly crystalline) and a placebo formulation (DSPC:CaCl2) are provided for comparison. Both powders of the fixed dose combination exhibit diffraction peaks that are indicative of the presence of crystalline indacaterol, as shown by the concordance of the peak positions of the formulations with those in the indacaterol API powder standard. The powder pattern of each formulation also has a broad, conspicuous peak at 21.3° 2θ, which arises from DSPC. In addition to this peak, all other peaks can be assigned to indacateol, indicating that glycopyrrolate is amorphous. Therefore, the powder patterns of both formulations indicate that the two drugs are present in separate phases, where indacaterol is crystalline and glycopyrrolate is amorphous. DSPC is also present as a gel phase with its characteristic diffraction peak. Therefore, the two drugs and the hydrophobic excipient are effectively in separate phases in their own domains within the spray dried particles. crystalline indacaterol, amorphous glycopyrrolate and a hydrophobic excipient (DSPC or leucine)
[195] Several formulations comprising fixed-dose combinations of indacaterol maleate and glycopyrrolate are shown in Table 8. There are two main groups of formulations. The first group of formulations uses DSPC as the hydrophobic excipient and an emulsion-based raw material. The second group uses leucine as a hydrophobic excipient without an emulsion phase. Emulsion-based formulations are prepared by spray drying a base stock, comprising indacaterol maleate crystals in a submicron PFOB-in-water emulsion, in which the emulsion droplets are stabilized by a 2:1 mol:mol DSPC:CaCl2 ratio. Glycopyrrolate is dissolved in the continuous phase of the emulsion and is present as an amorphous solid in the spray dried particles. Formulation C3 adds 20 mM sodium maleate buffer (pH 5.7) to the DSPC base formulation. Increases in pH decrease the solubility of indacaterol, thereby limiting amorphous forms of indacaterol. Sodium maleate also serves as a glass stabilizing agent improving the physical and chemical stability of the amorphous phase. Formulation C4 contains added trehalose, an alternative vitreous stabilizing excipient. Formulation C5 contains trehalose and pH adjustment. Formulation C6 exploits fixed dose combinations comprising high concentrations of glycopyrrolate. Formulations C9 and C10 are leucine-based formulations that contain trisodium citrate and trehalose as vitreous stabilizing agents, respectively. Formulations containing DSPC were prepared by first creating a submicron emulsion of perflubron in water with an AVESTIN C-50™ homogenizer. The volume fraction of perflubron in the emulsion was 0.12 v/v. The glycopyrrolate and excipients are dissolved in the continuous phase of the emulsion and the micronized indacaterol maleate is dispersed in the continuous phase of the emulsion. The total solids content was 5% weight/volume. Leucine-based raw materials are prepared by dissolving excipients and glycopyrrolate in water. The micronized indacaterol is then added to the cooled solution and dispersed with an ULTRA TURRAX™ high shear mixer. The raw material to be spray dried had a solids content of 2.0% weight/volume. The formulations were spray dried in a laboratory scale spray dryer. The spray drying equipment consists of a dual-fluid atomizer, a drying chamber, a centrifugal separator, an adapter, an isolation valve and a 1 L manifold in a temperature-controlled housing. The target spray drying conditions were: inlet temperature = 97±3°C, outlet temperature = 60±3°C, manifold temperature = 60±3°C, drying air flow rate = 600±10 L/min, atomizer flow rate = 25±2 L/min, liquid feed rate = 10.0±0.5 mL/min. These spray drying conditions produced spray dried particles with a target density of about 0.05 g/ml.
[196] Fixed dose combination compositions comprising indacaterol maleate and glycopyrrolate

[197] The presence of dissolved indacaterol results in indacaterolamorph in the spray-dried drug product. Amorphous indacaterol is chemically less stable, with increased hydrolysis and enantiomer formation during storage. The presence of amorphous glycopyrrolate can also enhance degradation as glycopyrrolate can plasticize the amorphous indacaterol material. Spray-dried formulations comprising indacaterol can be effectively stabilized against chemical degradation by minimizing the dissolved fraction through process changes (eg, decreasing raw material temperature, increasing raw material solids content, or combination by atomization of particles with higher indacaterol content that comprise excipients only. Alternatively, the amorphous phase can be stabilized by the addition of a glass stabilizing excipient.
[198] The chemical stability of the formulations in Table 8 was evaluated by reversed-phase HPLC. The presence of a vitreous stabilizing excipient (eg, trehalose, trisodium citrate, sodium maleate) was necessary to effectively stabilize the amorphous phase within the spray dried particles of indacaterol/glycopyrrolate. After 3 months of storage of the powder concentrate packaged in an aluminum foil pouch at 40°C/75% relative humidity (RH), there was only minimal degradation observed in formulations containing sodium maleate. The total enantiomer content of indacaterol for C3 and C5 remained below 0.5%, while the total hydrolysis products of indacaterol remained below 0.1%. In these same formulations, no degradation of glycopyrrolate was observed after 3 months at 40°C/75% RH. In contrast, formulation C2 without glass stabilizing agent had an enantiomer content greater than 3% and a total hydrolysis greater than 0.4% after 3 months at 40°C/75% RH. Limited chemical degradation was also observed for formulations based on leucine (eg C10), where the content of indacaterol enantiomer remained less than 0.75% and total hydrolysis products less than 0.4%. No physical changes in the spray dried particles were noted during storage.
[199] Therefore, it has surprisingly been found that it is possible to manipulate spray dried particles, in which there are three separate phases (domains) that remain physically and chemically stable during storage. These include apparently incompatible crystalline and amorphous phases of two distinct drug substances and a gel phase of a hydrophobic excipient. EXAMPLE 7 Preparation of a fixed dose combination comprising indacaterol maleate, mometasone furoate and glycopyrrolate
[200] The composition of a fixed dose combination product comprising indacaterol maleate, mometasone furoate and glycopyrrolate is detailed in Table 9.TABLE 9
[201] A spray-dried powder composition comprising a fixed-dose combination comprising a long-acting beta agonist, a long-acting antimuscarinic, and a corticosteroid

[202] The spray dried powder is prepared by the emulsion spray drying process described previously in Example 2. Indacaterol maleate and mometasone furoate are dispersed as micronized crystals in the continuous phase of a submicron emulsion of perflubron in water. Glycopyrrolate is dissolved in the continuous phase of the emulsion. The continuous phase is comprised of 20 mM sodium maleate buffer (pH 5.5) prepared from maleic acid and sodium hydroxide. The raw material emulsion had a dispersed phase volume fraction of 0.18. The droplets are stabilized by a monolayer of distearoylphosphatidylcholine (DSPC) and calcium chloride. The ratio of DSPC:calcium chloride is 2:1 mol:mol. The total solids content in the raw material is 4.0%.
[203] The emulsion-based raw material complex comprising submicronic emulsion droplets, two dispersed APIs, one dissolved API and a buffer (glass stabilizing agent) is spray dried in a portable spray drying system in accordance with the process conditions described in Table 4. The resulting powder is comprised of particles comprising crystalline indacaterol and mometasone coated with amorphous glycopyrrolate and DSPC/CaCl2. The physicochemical and aerosol properties of the spray dried powder are controlled by the hollow and porous morphology of the particle and the low surface energy provided by the hydrophobic excipient DSPC which is concentrated at the particle interface.
[204] The various features and embodiments of the present invention referred to in the individual sections above apply, as appropriate, to other sections, mutatis mutandis. Consequently, characteristics specified in one section may be combined with characteristics specified in other sections as appropriate.
[205] Those skilled in the art will recognize, or be able to determine using nothing more than routine experimentation, various equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be covered by the following claims.

权利要求:
Claims (15)
[0001]
1. A dry powder formulation for inhalation characterized in that it comprises spray dried particles comprising a core of a first active ingredient in substantially crystalline form which is coated with a layer of a second active ingredient in substantially amorphous form which is dispersed in a pharmaceutically acceptable hydrophobic excipient.
[0002]
2. Formulation according to claim 1, characterized in that the active ingredients are selected from among bronchodilators, anti-inflammatory, antihistamines, decongestants and antitussive substances.
[0003]
3. Formulation according to claim 1 or 2, characterized by the fact that the first active ingredient is a β2 agonist and the second active ingredient is a steroid.
[0004]
4. Formulation according to claim 1 or 2, characterized by the fact that the first active ingredient is a β2 agonist and the second active ingredient is an antimuscarinic antagonist.
[0005]
5. Formulation according to claim 1 or 2, characterized in that the first active ingredient is a β2 agonist, the second active ingredient is an antimuscarinic antagonist, and the formulation also contains a third active ingredient, which is a steroid.
[0006]
6. Formulation according to any one of claims 1 to 5, characterized in that it further comprises a third active ingredient which is substantially amorphous and is dispersed in the hydrophobic excipient.
[0007]
7. Formulation according to claim 6, characterized in that the active ingredients are indacaterol or its salt, mometasone furoate and glycopyrrolate.
[0008]
8. Formulation according to any one of claims 1 to 7, characterized by the fact that the hydrophobic excipient is a phospholipid.
[0009]
9. Formulation according to any one of claims 1 to 8, characterized in that it is in powder form, the particles of the inhalable drug comprising 0.1 to 30% weight/weight of a first active ingredient in substantially crystalline drug which is coated with a roughened layer comprising 0.1% to 30% of a second active ingredient in substantially amorphous form which is dispersed in a hydrophobic excipient, wherein the particles have a mass median diameter (MMD ) between 1 and 10 microns, a mass median aerodynamic diameter (MMAD) between 1 and 5 microns and a roughness Sv greater than 1.5.
[0010]
10. Formulation according to claim 9, characterized in that the fine particle dose less than 3.3 μm is greater than 40% to minimize the interpatient variability associated with oropharyngeal deposition.
[0011]
11. Formulation according to claim 9, characterized in that the variability in the fraction of particles with a d2Q < 500 (expressed as mean variability) is less than 20% across a range of pressure drops in a inhaler. dry powder from 2 kPa to 6 kPa.
[0012]
12. Formulation according to claim 9, characterized in that the mass ratio of the first active ingredient/second active ingredient/optional third active ingredient in the fine particle dose is within 10% of the ratio of the nominal doses of the drugs .
[0013]
13. Process for preparing a dry powder formulation of spray dried particles containing a first active ingredient and a second active ingredient, characterized in that it comprises the steps of: (a) preparing a raw material comprising the second active ingredient dissolved in a solvent phase, a hydrophobic excipient and crystalline particles of the first active ingredient, said crystalline particles being substantially insoluble in said solvent phase; and (b) spray drying said raw material to provide the formulation, wherein said particles comprise a core of the first active ingredient in substantially crystalline form which is coated with a layer of the second active ingredient in substantially amorphous form, which is dispersed in a pharmaceutically acceptable hydrophobic excipient.
[0014]
14. Delivery system, characterized in that it comprises an inhaler and a dry powder formulation for inhalation as defined in any one of claims 1 to 12.
[0015]
15. Use of a dry powder formulation for inhalation, as defined in any one of claims 1 to 12, characterized in that it is for the preparation of a medicine for the treatment of an obstructive or inflammatory disease of the airways.

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同族专利:

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公开号 | 公开日

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JP6082049B2|2017-02-15|

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WO2012106575A1|2012-08-09|

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RU2629333C2|2017-08-28|

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AR085120A1|2013-09-11|

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CN103347501B|2015-11-25|

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BR112013019540A2|2016-10-04|

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JP2014507432A|2014-03-27|

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EP2670395A1|2013-12-11|

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US9050267B2|2015-06-09|

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CN103347501A|2013-10-09|

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MX2013008796A|2013-09-06|

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TWI519319B|2016-02-01|

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PT2670395E|2015-07-21|

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EP2670395B1|2015-03-25|

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JP2015187124A|2015-10-29|

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RU2013140706A|2015-03-10|

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KR101580728B1|2015-12-28|

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MX354109B|2018-01-16|

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PL2670395T3|2015-08-31|

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AU2012212094A8|2013-12-05|

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ES2539612T3|2015-07-02|

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US20130319411A1|2013-12-05|

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TW201309348A|2013-03-01|

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CA2825576C|2020-07-14|

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AU2012212094B2|2016-02-11|

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KR20130115380A|2013-10-21|

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JP5791737B2|2015-10-07|

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CA2825576A1|2012-08-09|

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AU2012212094A1|2012-08-09|

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-03-26| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-05-21| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2021-06-01| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-06-08| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2021-08-17| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 03/02/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201161439527P| true| 2011-02-04|2011-02-04|

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US61/439,527|2011-02-04|

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PCT/US2012/023727|WO2012106575A1|2011-02-04|2012-02-03|Dry powder formulations of particles that contain two or more active ingredients for treating obstructive or inflammatory airways diseases|

---