WO2019067708A1 - Procédé pour diminuer la taille de particules - Google Patents

Procédé pour diminuer la taille de particules Download PDF

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Publication number
WO2019067708A1
WO2019067708A1 PCT/US2018/053103 US2018053103W WO2019067708A1 WO 2019067708 A1 WO2019067708 A1 WO 2019067708A1 US 2018053103 W US2018053103 W US 2018053103W WO 2019067708 A1 WO2019067708 A1 WO 2019067708A1
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Prior art keywords
active agent
particle size
carrier
agent
particles
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PCT/US2018/053103
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English (en)
Inventor
Mukul C. Dalvi
Seah Kee Tee
Qi Li
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Teva Branded Pharmaceutical Products R&D, Inc.
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Publication of WO2019067708A1 publication Critical patent/WO2019067708A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • the embodiments generally relate to improved methods for the manufacture of dry powders for inhalation, such as powders for use in a dry powder inhaler device. More particularly, the aspects of the disclosure relate to methods for particle size reduction of an active agent using high shear mixing in the presence of coarse carrier particles.
  • Inhalation therapy is currently the best option for lung diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Pulmonary delivery allows the use of smaller drug doses and reduced systemic side effects.
  • pulmonary delivery is attractive as a route for systemic administration due to fast absorption by the massive surface area of the alveolar region, the abundant vasculature and thin air-blood barrier, and the avoidance of first pass metabolism. (Ibrahim et al., Medical Devices: Evidence and Research, 2015, 8: 131-139).
  • DPIs dry powder inhalers
  • pMDIs pressurized metered-dose inhalers
  • the aerodynamic diameter of the particles primarily influences this behavior, since deposition in the respiratory tract is controlled by a particle's aerodynamic size rather than its physical or geometric shape. Lung deposition improves substantially for particles less than 5 microns in aerodynamic diameter and decreases substantially for particles with effective aerodynamic diameters of greater than 5 microns. A drug particle size between 1 and 5 ⁇ is needed for entry into the deep lung by inhalation and particles of 1-2 ⁇ are most suitable for reaching the small airways, an important target for the treatment of asthma and COPD.
  • DPI drug formulations may be either fine powder drug blended with large carrier particles to prevent aggregation and increase powder flow prior to aerosolization, or may consist of drug alone. In all cases, the powder formulations travel along the airways to deposit in the targeted areas of the lung, and then dissolve to exert their pharmacological effect or are absorbed to reach systemic targets.
  • Powder blends for DPIs typically consist of micronized drug particles blended with an inactive excipient (lactose, mannitol, trehalose, sucrose, sorbitol, glucose) of larger sizes. These components are usually blended together to form an "interactive mixture" (or “ordered mixture”) wherein the finer drug particles are strongly adhered to the surface of the carrier particles.
  • Unoptimized powder blends can exhibit interparticulate cohesive forces which cause powder aggregates, making powder dispersion very difficult. Weak flow properties of the powder blend prevents uniform mixing and portioning into reservoirs, blisters, capsules, etc., resulting in dose variation.
  • agglomerates may form during the preparation of interactive mixtures (See, for example, U.S. Patent No. 8,512,753, the disclosure of which is incorporated herein by reference in its entirety). Agglomerates formation often can be dependent on various factors, including for example, cohesive and adhesive balance, particle size, the presence of large carrier particles, API concentrations, etc. In interactive mixtures, agglomerates may be broken down in the presence of large carrier particles and at low API concentrations as an example. However, if the API concentration increases, agglomeration of the cohesive API can be further facilitated.
  • agglomerates jeopardizes their dispersion onto the surface of coarse excipient particles and is detrimental to achieving good blend uniformity and hence a good accuracy of the dose.
  • the formation of agglomerates is particularly critical when a low-dosage strength active agent is used (i.e., an active ingredient with high potency which is present in the powder formulation in a very low concentration).
  • a method for reducing the particle size of powders useful in the preparation of an inhalation powder comprising an active agent and a carrier agent comprises (i) determining the initial particle size distribution of the active agent and carrier agent; (ii) mixing the active agent with the carrier agent to form a homogenous blend; wherein mixing the active agent with the carrier agent comprises three dimensional in situ mixing to reduce the particle size of the active agent.
  • Another embodiment involves a method of characterizing powders useful in the preparation of an inhalation powder comprising an active agent and a carrier agent that includes: (i) determining the initial particle size distribution of the active agent and carrier agent; (ii) mixing the active agent with the carrier agent to form a homogenous blend; and (iii) determining the particle size distribution of the active agent in the homogenous blend.
  • FIG. 1 is a graph of the particle size distribution profile of micronized fluticase propionate (Batch Number 43360-01210M).
  • FIG. 2 is a graph of the particle size distribution profile of micronized fluticase propionate (Batch Number 43360-01510M).
  • FIG 3. Is a graph of the particle size distribution profile of alpha-lactose monohydrate (Batch Number 602103).
  • FIG. 4 is a graph of the particle size distribution of micronized fluticasone propionate Batch No. 43360-01210M and low strength Fp inhalation blend G14-09-00 after high shear mixing, in accordance with one or more embodiments.
  • FIG. 5 is a graph of the particle size distribution of micronized fluticasone propionate Batch No. 43360-01510M and high strength Fp inhalation blend G14-31-00 after high shear mixing, in accordance with one or more embodiments.
  • FIG. 6 is a graph of the particle size distribution of micronized fluticasone propionate Batch No. 43360-01510M and low strength Fp inhalation blends 1A, IB, and
  • FIG. 7 is a graph of the particle size distribution of micronized fluticasone propionate Batch No. 43660-01510M and high strength Fp inhalation blends 2A, 2B, and
  • active agent includes any agent, drug, active pharmaceutical ingredient, composition of matter or mixture which provides a pharmacologic effect that can be demonstrated in- vivo or in-vitro.
  • excipient also “inactive ingredient” as used herein means any component other than an active ingredient.
  • batch means a specific quantity of a product that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during a same cycle of manufacture. Batch refers to the quantity of material and does not specify a mode of manufacture.
  • Dry powder refers to a powder composition that typically contains less than about 20% moisture, preferably less than 10% moisture, more preferably contains less than about 5-6% moisture, and most preferably contains less than about 3% moisture, depending upon the particular formulation.
  • a dry powder that is "suitable for pulmonary delivery” refers to a composition comprising solid (i.e., non-liquid) or partially solid particles that are capable of being (i) readily dispersed in/by an inhalation device and (ii) inhaled by a subject so that a portion of the particles reach the lungs to permit penetration into the alveoli. Such a powder is considered to be “respirable”.
  • Flowability is a bulk powder characteristic.
  • the term “flowable” means an irreversible deformation of a powder to make it flow due to the application of external energy or force.
  • "Aerosolized” or “aerosolizable” particles are particles which, when dispensed into a gas stream by either a passive or an active inhalation device, remain suspended in the gas for an amount of time sufficient for at least a portion of the particles to be inhaled by the patient, so that a portion of the particles reaches the lungs.
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” refers to the relatively non-toxic, inorganic and organic, acid and base addition salts of compounds disclosed herein. Representative salts include, for example, those listed in Berge et al, “Pharmaceutical Salts,” J. Pharm Sci, Vol. 66, pp. 1-19, (1977).
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p- toluenesulphonic, benzenesulphonic, isethionic, and naphthalenecarboxylic, such as l-hydroxy-2-naphthalenecarboxylic (i.e., xinafoic) acids.
  • Aerodynamic diameter denotes the diameter of a sphere of unit density which behaves aerodynamically as the particle of the test substance. It is used to compare particles of different sizes, shapes and densities and to predict where in the respiratory tract such particles may be deposited. The term is used in contrast to volume equivalent, optical, measured or geometric diameters which are representations of actual diameters which in themselves cannot be related to deposition within the respiratory tract.
  • the aerodynamic diameter, daer can be calculated from the equation: where d g is the geometric diameter, for example the Mass Median Aerodynamic Diameter" (MMAD), and p is the powder density. See, for example, U.S. Patent No. 9,539,211, the disclosure of which is incorporated herein by reference in its entirety.
  • MMAD Mass Median Aerodynamic Diameter
  • blend uniformity refers in general to a measure of the uniformity of a blend of powder.
  • FDA published a draft guidance document for analyzing blend uniformity in August 1999 (FDA, "Guidance for Industry; AND As: Blend Uniformity Analysis,” August 3, 1999, available at
  • An aspect of the disclosure provides a method for reducing the particle size of a powder particle useful in the manufacture of dry powders for inhalation comprising an active agent and a carrier agent.
  • the powders can be used, for example, in a dry powder inhaler device (DPI). More specifically, embodiments include methods for particle size reduction of a micronized active agent using high shear or tumbling mixing in the presence of coarse carrier particles.
  • the method can be used with any pharmaceutically active agent suitable for administration as a dry powder or as a dry powder blend.
  • the powder active pharmaceutical ingredient can be a bronchodilator.
  • the bronchodilator can be a Short- Acting Beta Adrenoceptor Agonist (SABA), such as albuterol, bitolterol, fenoterol, isoproterenol, levalbuterol, metaproterenol, pirbuterol or procaterol, a Long Acting Beta Adrenoceptor Agonist (LABA) such as arformoterol, bambuterol, clenbuterol, formoterol or salmeterol, or an Ultra Long Acting Beta Adrenoceptor Agonist (Ultra-LABA), such as abediterol, carmoterol, indacaterol, olodaterol or vilanterol.
  • SABA Short- Acting Beta Adrenoceptor Agonist
  • LAA Long Acting Beta Ad
  • the API may be an anticholinergic agent that blocks the activity of the muscarinic acetylcholine receptor, including a Short-Acting Muscarinic Antagonist (SAMA) such as ipratropium, or a Long-Acting Muscarinic Agent (LAMA), such as aclidinium, glycopyrronium, tiotropium, and umeclidinium.
  • SAMA Short-Acting Muscarinic Antagonist
  • LAMA Long-Acting Muscarinic Agent
  • the API may be an inhaled corticosteroid (ICS) such as, for example, budesonide, ciclesonide, flunisolide, beclomethasone, fluticasone, mometasone or triamcinolone.
  • ICS inhaled corticosteroid
  • the API is a pharmaceutically acceptable salt of any of the above-mentioned APIs.
  • the API is another powder API known in the art or later discovered, or mixtures of one or more of any of the above- mentioned APIs.
  • the active agent is fluticasone, which is preferably used in the form of fluticasone propionate (Fp).
  • the active agent is salmeterol, which is preferably used in the form of salmeterol xinafoate (Sx).
  • the active agent may be used in a substantially pure form, for example higher than 95 wt. %, more preferably higher than 98 wt. %, and even more preferably higher than 99 wt. %.
  • the active agent may contain low levels of residual solvent, for example less than 1 wt. %, preferably less than 0.5 wt. %.
  • the amount of active agent is typically present in an amount of at least 0.01 wt. % of the powder formulation.
  • the active agent can be present in an amount from about 0.1 to about 10 wt. %, preferably from about 0.1 to about 5 wt. %, and more preferably from about 0.1 to about 2 wt. %.
  • the active agent Prior to blending with the carrier agent, the active agent may include micronized particles wherein at least 90% of the particles, preferably at least 92%, and more preferably at least 95%, have a volume diameter (D90) less than 10 ⁇ , preferably less than 8 ⁇ , and more preferably, less than 6 ⁇ .
  • D90 volume diameter
  • the carrier agent can be any physiologically acceptable inert material of animal or vegetable origin.
  • the carrier agent is typically a sugar, sugar alcohol, or an amino sugar.
  • Sugars, sugar alcohols, and amino sugars are well known in the art and the embodiments are not restricted to any particular sugar, sugar alcohol or amino sugar.
  • the sugar is a monosaccharide such as arabinose, fructose, or glucose or a disaccharide such as lactose, maltose, saccharose, sucrose or trehalose.
  • the carrier agent can also be one or more polyalcohols, such as lactitol, maltitol, mannitol, sorbitol or xylitol, or an amino sugar, such as glucosamine.
  • the carrier agent is alpha-lactose monohydrate. Examples of commercially available alpha-lactose monohydrates include SpheroLac®, Pharmatose® and Lactohale®.
  • the carrier agent can be a mixture of fine carrier particles and coarse carrier particles, preferably of the same kind.
  • the fraction of fine carrier particles to coarse carrier particles in the pre-blend is in the range of 0.1 to 20 wt. %, preferably in the range of 0.1 to 10 wt. %, and more preferably in the range of 0.1 to 5 wt. %.
  • the amount of carrier agent can be present in an amount of from about 80 wt. % of the powder formulation.
  • the carrier agent can be present in an amount from about 80 to about 99.9 wt. %, preferably from about 90 to about 99.9 wt. %, and more preferably from about 95 to about 99.9 wt. %.
  • the particle size of the carrier does not substantially decrease with high shear mixing.
  • the particles of the active agent and the carrier agent can be provided within the particle size ranges provided herein prior to blending.
  • a number of techniques known to those skilled in the art for the production of solid materials of the required size can be used in certain aspects of the disclosure, including mechanical micronisation, milling, jet milling, grinding, rapid precipitation, freeze drying, lyophilization, rapid expansion of supercritical fluids, spray drying, and mixtures thereof.
  • the method may include determining that the particle sizes of both the active agent and the carrier agent before they are blended together to produce an inhalation powder.
  • the particle size of a spherical particle is generally measured by the dispersion and absorption of light (scattering pattern) generated by a laser using either wet or dry dispersion techniques.
  • a wet dispersion method individual particles are suspended in a liquid dispersant.
  • the dispersant is usually a flowing gas stream, most typically clean dry air.
  • Laser diffraction measures particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. The particle size can then be calculated using the principle that the angle of diffraction of the light is inversely proportional to the particle size.
  • Static light scattering techniques such as laser diffraction produce volume weighted particle size distribution.
  • D values The most widely used method of describing particle size distributions are D values
  • the DIO, D50 and D90 values are commonly used to represent the midpoint and range of particle sizes in a sample.
  • Computing D values relies on modelling all particles as spheres of equivalent volume, which may be considered interchangeable with mass.
  • a D- value can be thought of as a "mass division diameter.” It is the diameter which, when all particles are arranged in order of ascending mass, dividing the sample's respective mass into specified percentages.
  • the D10 value is the diameter at which 10% of a sample's mass is comprised of smaller particles
  • the D50 value is the diameter at which 50% of a sample's mass is comprised of smaller particles
  • the D90 value is the diameter at which 90% of a sample's mass is comprised of smaller particles.
  • the D50 is also known as the mass median diameter, as it divides the sample equally by mass. Since the primary result from laser diffraction is a volume distribution, the D50 cited is the volume median (also Dv50).
  • the particle size of the active agent and carrier agent can be measured by using a laser diffraction method. More particularly, the particle size of the active agent can be measured using a wet dispersion method using water as a dispersing agent on a Malvern Mastersizer 2000 Particle Size Analyzer equipped with Hydro 2000S dispersion cell unit. The wet dispersion technique is preferred for measuring particle size distribution (PSD) of a micronized active agent that is cohesive because it allows for separation of the particles.
  • PSD particle size distribution
  • the particle size of the carrier agent can be measured using a dry dispersion method using air as a dispersing agent on a Sympatec HELOS/BF Particle Size Analyzer equipped with the RODOS dispenser and VIBRI Feeder. The particle size distribution of the active agent and carrier particles are obtained using the measurements described above.
  • the particle size is expressed as mass aerodynamic diameter (MAD).
  • MAD mass aerodynamic diameter
  • MMAD mass median aerodynamic diameter
  • a powder for inhalation comprises micronized particles of an active agent and coarse particles of a physiologically acceptable carrier agent.
  • the device used for blending the active agent and carrier agent is preferably a high shear mixer, and more preferably a mixer that uses 3-dimensional Schatz geometry linkage.
  • Such mixers use a closed container that is set into a three dimensional movement that uses rotation, translation, and inversion according to the Schatz geometric theory, as described in, for example, Sarpale, S.A., et al., "Design and Analysis of Drive System of Schatz Geometry Shaker Mixer," IJEDR, 2016, 4(4): 512-535.
  • rotation of impeller blades at an angle to the geometric plane of the mixer can provide a shearing effect to mix the powder, and a chopper blade rotating at a vertical position can break up large
  • agglomerates that may be present in the blend.
  • Such mixers are known to those of skill in the art, and include, for example, the Turbula® Shaker Mixer (Glen Mills Inc.),
  • the blending process is a high energy input process, or high shear mixing.
  • the high energy mixing process is generally characterized by a mixing time of 5 to 120 minutes, preferably 5 to 30 minutes, and an impeller speed of 5 to 5000 rpm, preferably 50 to 500 rpm.
  • a preferred mixer for the high energy input process includes, but is not limited to, PharmaConnect® High Shear Mixer (GEA Process Engineering Inc.; Columbia MD, USA).
  • the blending process is a low energy input process, or tumbling mixing.
  • the low energy input process is generally characterized by a mixing time of 1 to 90 minutes, preferably 1 to 30 minutes, and an impeller speed of 1 to 150 rpm, preferably 10 to 100 rpm.
  • a preferred mixer for the low energy input process includes, but is not limited to, Turbula® Shaker-Mixer (Glen Mills Inc.; Clifton NJ, USA).
  • Dry powder formulations prepared according to the embodiments can be used with any type of DPI devices known in the art.
  • the DPI can be (i) a single dose inhaler, for the administration of pre-subdivided single doses of the active agent or (ii) a multidose dry powder inhaler, either with pre-subdivided single doses or pre-loaded with quantities of active ingredient for multiple.
  • DPIs are also categorized according on the basis of their required inspiratory flow rate (L/min) into (i) low-resistance devices (> 90 L/min); (ii) medium-resistance devices (ca. 60 L/min); and (iii) high-resistance devices (ca. 30 L/min).
  • the dry powder formulation of the instant invention is preferably administered with a RespiClick® (Teva Pharmaceutical Industries Ltd.) multi-dose inhaler.
  • the particle size was determined by laser diffraction using a Malvern MasterSizer 2000 Particle Size Analyzer equipped with Hydro 2000S dispersion cell unit apparatus. The parameters taken into consideration were Dv in microns of 10%, 50%, and 90% of the particles expressed as D10, D50 and D90 respectively, which correspond to the mass diameter assuming a size independent density for the particles. The relevant data are reported in Table 1.
  • FIG. 1 Histograms for micronized Fp Batch No. 43360-01210 and Batch No.43360- 01510 are shown in Figures 1 and 2, respectively.
  • the PSD for the two batches of micronized Fp was about the same with the exception of a slight difference in the spread in particle size distribution.
  • the PSD shows very small particles having a D50 value of 1.8 ⁇ .
  • the spread of the distributions is relatively narrow, with D90 values of 4.2 ⁇ . This indicates that substantially all of the powder by mass is less than 4.2 ⁇ .
  • a first low-dosage strength blend (1 kg) of fluticasone propionate and lactose carrier was prepared by high shear mixing using 0.49 wt. % of the API.
  • a second high- dosage strength blend (1 kg) of fluticasone propionate and lactose carrier was prepared by high shear mixing using 4.0 wt. % of the API.
  • the manufacturing process for preparation of the first and second blends was as follows. Alpha-Lactose monohydrate and fluticasone propionate were sieved prior to blending and dispensed separately into different stainless steel containers. The materials were added in the following order with 50% of the lactose, then fluticasone propionate and then the remaining 50% of the lactose such that the fluticasone propionate material was sandwiched between the two portions of lactose. The powders were then mixed in a high shear mixing blender. The components of the two powder blends and mixing conditions are summarized in Table 3 below.
  • Figure 4 shows the PSD of micronized Fp Batch No. 43360-01210 compared to low strength blend G14-0900 containing 0.49 wt. % active agent.
  • Figure 5 shows the PSD of micronized Fp Batch No. 43360-01510 compared to high strength blend G14-31- 00 containing 4.0 wt. % active agent. It was found that the particle size distribution of Fp in both the low strength and high strength blends was suitable for inhalation products, and in both instances the particle size of the Fp active ingredient was reduced. In other words, particle size reduction of fluticasone propionate in both low strength and high strength blends was achieved under simple conditions using high shear mixing in the presence of coarse carrier particles. As shown in Table 4 and Figures 4 and 5, the particle size reduction over the distribution can range from about 5% reduction to about 50%, from about 10% to about 40%, or from about 20% to about 30% of the original particle size of the powder.
  • Blending Condition A the stainless steel container of the Turbula® Shaker-Mixer was rotated in a figure of 8 motion at 50 rpm and the mixing time was 1 minute.
  • Blending Condition B the mixing time was increased from 1 minute to 10 minutes.
  • Blending Condition C the rotation of the container was increased from 50 rpm to 90 rpm and the mixing time was increased to 10 minutes.
  • the three high strength blends A2-C2 were prepared similarly using Blending Conditions A, B and C. The components of the six powder blends and mixing conditions are summarized in Table 4 below.
  • the fluticasone propionate/lactose blends of Example 3 were characterized in terms of the particle size distribution of the active agent.
  • Figure 6 is a graph of the particle size distribution of fluticasone propionate Batch No. 43360-01510M compared to Fp in low strength blends 1A, IB and 1C.
  • Figure 7 is a graph of the particle size distribution of fluticasone propionate Batch No. 43360-01510M compared to Fp in high strength blends 2A 2B and 2C. It was found that the particle size distribution of fluticasone propionate in both low strength and high strength blends was affected by the tumbling mixing parameters for the blending step. The best results were achieved with a tumbling speed of 90 rpm and a mixing time of 10 minutes.
  • the data obtained in the studies on fluticasone propionate/lactose blends indicates that particle size reduction of the API can be achieved and controlled by three dimensional mixing with a carrier agent comprising coarse carrier particles under either high sheer or tumbling mixing conditions.
  • the inventive method allows for the fine tuning of the particle size of the micronized active agent.
  • the inventive method is applicable to particle size reduction of other active agents in combination with lactose or other physiologically acceptable carrier agents.

Abstract

Des modes de réalisation de la présente invention concernent de façon générale des procédés d'amélioration de la fabrication de poudres sèches pour inhalation, telles que des poudres destinées à être utilisées dans un dispositif de type inhalateur de poudre sèche. L'invention concerne des procédés permettant de diminuer la taille des particules d'un agent actif en utilisant un mélange tridimensionnel en présence de particules de support grossières, et des procédés de caractérisation des poudres destinées à être utilisées dans la fabrication de mélanges de poudre sèche pour inhalation.
PCT/US2018/053103 2017-09-27 2018-09-27 Procédé pour diminuer la taille de particules WO2019067708A1 (fr)

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WO2022146255A1 (fr) * 2020-12-31 2022-07-07 Arven Ilac Sanayi Ve Ticaret Anonim Sirketi Procédé de préparation de compositions de poudre sèche pour inhalation

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