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WO2017033032A1 - Composition pharmaceutique à inhaler - Google Patents

Composition pharmaceutique à inhaler Download PDF

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Publication number
WO2017033032A1
WO2017033032A1 PCT/GB2016/052680 GB2016052680W WO2017033032A1 WO 2017033032 A1 WO2017033032 A1 WO 2017033032A1 GB 2016052680 W GB2016052680 W GB 2016052680W WO 2017033032 A1 WO2017033032 A1 WO 2017033032A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
active agent
active agents
micronised
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PCT/GB2016/052680
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English (en)
Inventor
Rudi Mueller-Walz
Morgan FRIDEZ
Maria BALAXI
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Jagotec AG
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Jagotec AG
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    • 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
    • A61K9/0012—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
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • 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 present invention relates to a pharmaceutical composition for inhalation comprising a first active agent and a second active agent, wherein the aerodynamic particle size distribution of the first and second active agents relative to their delivered doses is substantially the same.
  • Drugs for the treatment of respiratory diseases and disorders are frequently administered directly to the lungs via inhalation.
  • the inhalation route may also be used for the delivery of systemically acting drugs.
  • Administration via inhalation can increase the therapeutic index, reduce side effects of the drugs compared to administration by other routes (such as orally or intravenously), can result in a rapid speed of onset of the drugs, and in improved patient compliance.
  • Administration by inhalation may be in the form of either dry powders or aerosol formulations, which are inhaled by the patient either through use of an inhalation device or nebuliser.
  • single active agents may be employed to treat a specific disease or disorder
  • the use of combinations of drugs is often advantageous.
  • low-dose therapy using one drug may not be sufficient to control asthma symptoms, but adding treatment with another drug having a different mechanism of action may significantly improve symptoms compared with simply increasing a patient's dose of a single drug, while also reducing side effects.
  • a combination of drugs may also have a synergistic effect, leading to enhanced patient treatment.
  • the two drugs may act to treat two different symptoms; for example one drug may treat the airway constriction while the other may reduce or prevent inflammation of the airways.
  • Formulating two active agents in a single formulation for administration from a single inhalation device is particularly advantageous for improving patient compliance.
  • the particle size of the deployed formulation must be small enough that it can be inhaled into the lungs of the users. Therefore, the particles of the formulation need to be in the micrometer size range, i.e. having a mean aerodynamic particle diameter (measured as Mass Median Aerodynamic
  • the particle size of the active agents should not be larger than 1 ⁇ and preferably not larger than 5 ⁇ .
  • Various methods may be used to form such fine particles for inhalation which are known to the skilled person.
  • the most widely used method of producing particles of a drug compound in the micrometer size range is a particle reduction technique called micronisation, using an air jet mill. Jet milling is a highly effective technology for reducing the particle size of drugs where the size of the particles is relevant to the effective delivery.
  • Air jet mills grind materials by using a high speed jet of compressed air or inert gas which accelerates particles fed into the grinding chamber. Particle reduction is achieved by the impact of particles colliding into each other at high speed and reducing themselves by attrition and collision.
  • Air jet mills are usually designed to output particles below a certain size; the compressed air or gas jet exits the mill through an outlet at the center of the grinding chamber and draws the micronised particles with it. Larger, i.e. oversized particles are held in the grinding chamber by centrifugal force and continue the milling process until the desired micrometer size is achieved, allowing them to escape the grinding chamber. Particles leaving the mill can eventually be separated from the gas stream by c3 clonic separation. Due to this design, a narrow particle size distribution of the resulting product can be achieved.
  • the resulting particle size distribution of micronised drug compound depends on several parameters, such as the diameter of the air jet mill, the grinding gas pressure, the feeding gas pressure and the feeding rate.
  • drug compound specific characteristics are also important for the result and need to be considered, such as the starting particle size range of the un-micronised compound, hardness, friability, temperature sensitivity (softening at higher temperature), or polymorph stability.
  • Oxygen or moisture sensitivity of the drug compound may also demand the use of inert gas as a feeding and grinding media.
  • each specific drug compound may require its defined individual set of process parameters.
  • the different microfine drug powders as constituents of the combination drug product are therefore normally manufactured and micronised separately, and only combined at a later stage of preparation of the finished drug product.
  • separate preparation of the two active agents may result in differing behaviour in the finished drug product and therefore different delivery or deposition at different locations in the lungs may well occur.
  • a pharmaceutical composition for inhalation comprising a first active agent and a second active agent, wherein the aerodynamic particle size distribution (APSD) of the first and second active agents relative to their delivered doses is substantially the same.
  • the aerodynamic particle size distribution relative to the delivered dose is preferably substantially the same within ⁇ 25% on each impactor stage, preferably within ⁇ 20% on each impactor stage, more preferably within ⁇ 15% on each impactor stage, more preferably within ⁇ 10% on each impactor stage.
  • cascade impactors may be used as an instrument to determine the aerodynamic particle size distribution of airborne drug particles delivered from inhaled formulations.
  • Cascade impactors separate the drug particles contained in the formulation into fractions on the basis of differences in inertia, which is a function of particle density, shape, and velocity.
  • ACI Andersen Cascade Impactor
  • NTI Next Generation Impactor
  • Both types of cascade impactors include a number of stages, each with a specified number of nozzles of known diameter, with nozzle size and total nozzle area decreasing with stage number.
  • a vacuum pump draws the inhaled formulation isokinetically through the stages.
  • Cascade impactors thus segregate the drug dose delivered by an inhaled formulation into several size classes and give the Aerodynamic Particle Size Distribution (APSD) of the inhaled formulation.
  • the APSD represents an in- vitro surrogate of the particulate aerosol delivered to the lungs, and it is agreed that inhaled formulations with similar APSD will behave similarly in-vivo and are delivered to the same regions of the lung. In reverse, for two drug compounds that are intended to exhibit a synergistic pharmacological effect it is imperative for them to be targeted to the same region in the lung by having the same or at least similar APSD.
  • Measurement of the APSD with a cascade impactor also determines the amount of active drug deployed in fine, inhalable particles which is the fine particle dose (FPD) or the fine particle fraction (FPF), defined as the percentage of the fine particle dose relative to the total amount of released active compound.
  • FPD fine particle dose
  • FPF fine particle fraction
  • the measurement of the FPD and FPF is carried out by routine tests for which the methods and apparatus are described in the pharmacopeias.
  • formulations of the present invention meet the requirement set out in Chapter ⁇ 601> of the United States Pharmacopeia (USP) 32 or in the inhalants monograph 2.9.18 of the European Pharmacopeia (Ph.Eur.), 6 th edition 2009.
  • the first and second active agents belong to different classes of
  • a formulation according to the first aspect of the invention may comprise the combination of a long acting beta 2 agonist and a long acting muscarinic antagonist.
  • a formulation according to the first aspect of the invention may comprise the combination of a long acting beta 2 agonist and a corticosteroid.
  • a further option for a formulation according to the first aspect of the invention comprises the combination of a long acting muscarinic antagonist and a corticosteroid.
  • Another option comprises the combination of a muscarinic antagonist- beta 2 agonist in combination with a corticosteroid.
  • a formulation according to the first aspect of the invention comprises a methylxanthine and a corticosteroid.
  • methylxanthine is selected from the group consisting of theophylline,
  • the inhaled corticosteroid is selected from the group consisting of beclometasone, beclomethasone dipropionate, budesonide, fluticasone, flunisolide, mometasone, triamcinolone, ciclesonide, prednisone, prednisolone, methyl prednisolone, naflocort, deflazacort, halopredone acetate, fluocinolone acetonide, fluocinonide, clocortolone, tipredane, prednicarbate,
  • alclometasone dipropionate halometasone, rimexalone, deprodone propionate, triamcinolone, betamethasone, fludrocortisone, desoxycorticosterone, rofleponide, etiprendnol dicloacetate, GW-685698, GW-799943, NCX-1010, NCX-1020, NO-dexamethasone, PL-2146, NS-126, ZK- 216348 or a pharmaceutically acceptable salt or derivative thereof.
  • the long acting beta 2 agonist is selected from the group consisting of arformoterol, formoterol, salmeterol, bambuterol, carmoterol, indacaterol, olodaterol, vilanterol, or a pharmaceutically acceptable salt thereof.
  • the long acting muscarinic antagonist is selected from the group consisting of glycopyrronium, tiotropium, aclidinium, umeclidinium, oxitropium, ipratropium, or a
  • the muscarinic antagonist- beta 2 agonist is selected from the group consisting of THRX-198321 or GSK961081 or pharmaceutically acceptable salts or derivatives thereof.
  • the phosphodiesterase IV inhibitor is selected from the group consisting of apremilast, ciclamilast, cilomilast, ibudilast, piclamilast, roflumilast, BAY 19-8004, CI-1044, SCH 351591 or a pharmaceutically acceptable salt or derivative thereof.
  • the phosphodiesterase V inhibitor is selected from the group consisting of avanafil, benzamidenafil, lodenafil,
  • mirodenafil mirodenafil, sildenafil, tadalafil, udenafil, vardenafil, zaprinast, T-1032, icariin or a
  • the leukotriene receptor antagonist is selected from the group consisting of montelukast, zafirlukast and zilueton or a pharmaceutically acceptable salt or derivative thereof.
  • active agents comprise theophylline and fluticasone propionate; fluticasone propionate and formoterol fumarate; fluticasone propionate and salmeterol xinafoate; budesonide and formoterol fumarate; and beclometasone dipropionate and formoterol fumarate.
  • the first and second active agents have a synergistic pharmacological effect.
  • the present invention is particularly advantageous in relation to synergistic
  • synergistic effect may occur between theophylline and inhaled corticosteroids or between long acting beta 2 agonists and corticosteroids and result in enhanced pulmonary efficacy.
  • This synergy can be achieved using doses of the drugs which were less effective when administered alone, but which are formulated such that they co-deposit in the lungs to maximise the synergistic effect between the two drugs.
  • the pharmaceutical composition of the first aspect may also include a third active agent.
  • third active agents which may be included in the composition are long-acting beta 2 agonists, muscarinic antagonists or muscarinic antagonist- beta 2 agonists.
  • the third active agent belongs to a different class of pharmacological active agents, i.e. the first, second and third active agents all exert their effects via different pharmacological mechanisms.
  • the pharmaceutical composition of the first aspect of the invention may be formulated as a dry powder for inhalation. Such a formulation may optionally include a carrier.
  • Suitable examples of carriers to be used in a pharmaceutical composition according to a first aspect are mono or di saccharides, such as glucose, lactose, lactose monohydrate, sucrose or trehalose, sugar alcohols such as mannitol or xylitol, polylactic acid or cyclodextrin, glucose, trehalose.
  • the carrier is alpha lactose monohydrate.
  • the dry powder may be formulated for administration by a dry powder inhaler.
  • a dry powder inhaler may be a multi dose dry powder inhaler which comprises a reservoir from which individual therapeutic dosages can be withdrawn on demand through actuation of the device.
  • multi dose dry powder inhalers may contain a plurality of capsules or blisters containing single or multiple pre-dosed units.
  • magnesium stearate may be included in a pharmaceutical composition according to the first aspect of the invention, which may improve the flowability of the formulation. This is particularly useful if the composition is a dry powder formulation for inhalation.
  • the amount of magnesium stearate used is preferably in the range of 0.001 to 10% by weight, more preferably 0.01 to 5% by weight, more preferably 0.1 to 2% by weight, more preferably 0.5% to 1% by weight, based on the total formulation.
  • the composition may be formulated as a suspension formulation for inhalation.
  • a formulation may include a propellant, preferably a HFA propellant, such as HFA134a or HFA227.
  • Suspension formulations according to the invention may be formulated for administration by a pressurised metered dose inhaler.
  • a metered dose inhaler typically consists of a canister for storing an aerosol formulation under pressure, which is sealed at one end with a metering valve. The canister and valve are held in an actuator, which comprises means for actuating the metering valve through which may be dispensed a precisely fixed dose of the aerosol formulation, and a mouth-piece through which a dispensed dose of the aerosol formulation is directed into the mouth of a patient.
  • a wetting agent and a co-solvent or either one of those may also be included in a suspension formulation.
  • a suitable wetting agent or co-solvent is an alcohol, more particularly ethanol, diols or polyols, such as propylene glycol, glycerol, butandiol or mixtures thereof.
  • the wetting agent is ethanol and more preferably dehydrated ethanol.
  • the amount of ethanol used within the formulation is typically adjusted according to its role. For example, if the wetting agent is a solvent for one or both of the drug substances, the wetting agent should be employed in an amount that avoids solubilisation or partial solubilisation of the drug substances or any excipients intended to be held in suspension.
  • the suspension formulation may be formulated for delivery by a nebuliser.
  • the formulation is therefore formulated as an aerosol liquid, which is dispersed in a gas phase (typically, air).
  • a gas phase typically, air
  • the pharmaceutical composition of the first aspect is obtainable or obtained by co-micronising the two active agents. It has been found that a perfectly superimposing APSD or near perfectly superimposing APSD of the delivered doses of both drugs can be achieved when both drugs are co-micronised rather than prepared separately. Co-micronisation of two active drugs to achieve co-deposition in the lungs for exerting a synergistic effect or to target a specific area of the lungs for treatment is particularly advantageous.
  • the first and second active agents may be mixed prior to co-micronisation, or may be mixed and co-micronised as a one step process. Both the first and second active agents are preferably co- micronised starting from an unmicronised form, or in some instances one active agent may be provided already in micronised form and then co-micronised together with the other active agent. Where the first and second active agents are mixed prior to co-micronisation, this blending step provides an important way of ensuring that the same ratio of the two active agents is micronised as is required to deliver the correct safe and efficacious dose of either drug and to achieve an ordered mixture, and is particularly useful when the two active agents are cohesive and so do not easily mix.
  • the mixing may be carried out by sieving or blending (for example using a tumble blender or high shear mixer).
  • the homogeneity of the blend of the two active agents is ensured by the interparticulate adhesive forces and the blending process may be more or less complex depending on the physicochemical characteristics of the drug entities.
  • the first and second active agents are co-micronised as a one step process, preferably pre-defined ratios of the amounts of each active agent may be fed (either via one feeder or separate feeders) and directly mixed in a micronisation chamber.
  • the micronisation may be carried out using mechanical grinding, preferably using an air jet mill. Manipulation of the process parameters set for the micronisation in the air jet mill results in the desired particle size of the micronised particles of both drugs to target the site of action being obtained. These process parameters can be determined by the skilled person to provide the appropriate results.
  • compositions which include a first active agent, second active agent and third active agent are obtainable by co-micronising all three active agents.
  • two of the active agents may be co-micronised in a first step and the other active agent may be added subsequently, for example co-micronisation of the first and second active agents and subsequent addition of micronised third active agent; co-micronisation of the first and third active agents and subsequent addition of the micronised second active agent; or co-micronisation of the second and third active agents and subsequent addition of the micronised first active agent.
  • two of the active agents are co-micronised to form a co-micronised mixture, and the third active agent is then co-micronised with the mixture.
  • Co-micronising only two of the active agents together may be particularly advantageous if they have a synergistic action but the other does not, or if two are required for targeting one area of the lung and the other is required in a different part of the lung.
  • the skilled person would be able to determine the appropriate order for co-micronisation of the three active agents depending on the particle size, shape, hardness, roughness and/or friability of each active agent.
  • a carrier is present in the formulation, this is preferably mixed or blended with the co- micronised first and second active agents, i.e. the carrier is added in a separate step subsequent to micronisation.
  • the magnesium stearate is preferably co-micronised with the first active agent and the second active agent.
  • the invention therefore includes a pharmaceutical composition which is obtainable or obtained by co-micronising a first active agent, second active agent and magnesium stearate.
  • the magnesium stearate is preferably co-micronised with the first, second and third active agents.
  • the magnesium stearate is preferably co-micronised at the same time as the two active agents.
  • a method of making a pharmaceutical composition for inhalation comprising co-micronising a first active agent, a second active agent and optionally magnesium stearate.
  • the co-micronised first and second active agents and optional magnesium stearate are mixed with a carrier.
  • the co-micronised first and second active agents and optional magnesium stearate are co-micronised with a third active agent.
  • a pharmaceutical composition of the first aspect of the invention for use in the treatment of a respiratory disease preferably a respiratory disease selected from the group consisting of asthma, severe asthma, paediatric asthma, COPD, cystic fibrosis, pulmonary hypertension, pulmonary arterial hypertension, interstitial lung disease, alveolar hypoventilation disorders, respiratory distress syndrome, asthma- COPD overlap syndrome (ACOS) or idiopathic pulmonary fibrosis.
  • a respiratory disease preferably a respiratory disease selected from the group consisting of asthma, severe asthma, paediatric asthma, COPD, cystic fibrosis, pulmonary hypertension, pulmonary arterial hypertension, interstitial lung disease, alveolar hypoventilation disorders, respiratory distress syndrome, asthma- COPD overlap syndrome (ACOS) or idiopathic pulmonary fibrosis.
  • a method of treating a respiratory disease comprising administering an effective amount of a pharmaceutical composition of the first aspect of the invention to a patient in need of treatment, preferably wherein the respiratory disease is selected from e group consisting of asthma, severe asthma, paediatric asthma, COPD, cystic fibrosis, pulmonary hypertension, pulmonary arterial
  • Figure 1 shows theophylline co-micronisation
  • Figure 2 shows Grinding principle of the spiral jet mill (Alpine Hosokawa AS). Picture from http ://www.hosokawamicron. co.jp.
  • Figure 3 shows the jet mill working area.
  • Figure 4 shows process manufacture No. 4 (process for comparison).
  • Figure 5 shows process manufacture No. 5 (process for comparison).
  • Figure 6 shows process manufacture No. 9 (example process according to the invention).
  • Figure 7 shows process manufacture No. 10 (example process according to the invention).
  • Figure 8 shows process manufacture No. 12 (process for comparison).
  • Figure 9 shows the particle size distribution of theophylline (TP) & fluticasone propionate (FP) co-micronised with the optimized settings, measured with Malvern Mastersizer Micro Plus.
  • Figure 10 shows particle size distribution of TP & FP co-micronised with the optimized settings, measured with Malvern Mastersizer Micro Plus.
  • FIG 11 shows the fine particle fraction (FPF) results of the different batches.
  • Figure 12 shows the aerodynamic particle size distribution of TP and FP, measured by NGI for batch 010AG01, which was manufactured by micronising TP alone (for comparison).
  • Figure 13 shows the aerodynamic particle size distribution, measured by NGI for batch 014AG01, which was manufactured by co-micronising TP and FP.
  • Figure 14 shows the aerodynamic particle size distribution, measured by NGI for batch 015AG01, which was manufactured by co-micronising TP, FP and magnesium stearate (MgS).
  • Figure 15 shows the aerodynamic particle size distribution, measured by NGI for batch Oi l AGO 1 , which was manufactured by micronising TP alone (for comparison).
  • Figure 16 shows the aerodynamic particle size distribution, measured by NGI, for batch 019AG01, which was manufactured by co-micronising TP with FP and MgS.
  • Figure 17 shows the aerodynamic particle size distribution, measured by NGI, for batch 080AG01, which was manufactured by co-micronising TP with FP and MgS.
  • Figure 18 shows the aerodynamic particle size distribution, measured by NGI, for batch 081AG01, which was manufactured by co-micronising TP with FP and MgS.
  • Figure 19 shows the aerodynamic particle size distribution, measured by NGI, for batch 082AG01, which was manufactured by co-micronising TP with FP and MgS.
  • Figure 20 shows the aerodynamic particle size distribution, measured by NGI during stability storage for batch 080AG02, manufactured by co-micronising TP with FP and MgS.
  • Figure 21 shows the aerodynamic particle size distribution, measured by NGI during stability storage for batch 081 AG02, manufactured by co-micronising TP with FP and MgS.
  • Figure 22 shows the aerodynamic particle size distribution, measured by NGI during stability storage for batch 082AG02, manufactured by co-micronising TP with FP and MgS.
  • Figure 23 shows the particle size distribution by laser diffraction with Sympatec Helos of batch 076 ABO 1 before co-micronisation of TP with FP and MgS.
  • Figure 24 shows the particle size distribution by laser diffraction with Sympatec Helos of batch 076A301 after co-micronisation of TP with FP and MgS.
  • the examples are based on the combination of anhydrous theophylline (TP) and the inhaled corticosteroid fluticasone propionate (FP) and the co-micronisation of these two active agents.
  • Theophylline is a bronchodilator drug given orally in the treatment of asthma and is therefore not commercially available as microfine particles suitable for inhalation.
  • the methods and procedures used can be applied to any combination of two or three active agents according to the invention.
  • Example 1 Preparation of formulations containing 250 ⁇ 6 fluticasone propionate and either 500ue or 3000u.g theophylline and APSD testing The following two formulations of different strengths were prepared, comprising theophylline anhydrous, fluticasone propionate, magnesium stearate (MgS) and lactose monohydrate, in the amounts shown in Table 1 below.
  • Target 50 ( ⁇ g TP / 25( ⁇ g FP 3000 ⁇ g TP / 250 ⁇ g FP
  • Theophylline anhydrous was micronised alone for use in comparative blends in a process comprising sieving followed by jet milling. The micronised theophylline was then blended with fluticasone propionate, lactose and (optionally) magnesium stearate.
  • Micronisation was carried out using an Alpine Hosokawa 50 AS spiral air jet mill with a Fritsch vibratory feeder added.
  • the jet milling was operated at the range shown in Table 2.
  • the ratio of the injector pressure to the grinding pressure was kept high enough to avoid the powder being blown back to the feeding funnel.
  • the working area is shown in Figure 3.
  • Capsule filling was done manually (25mg ⁇ 8%) under controlled laboratory conditions. Filled capsules were stored into 30ml HDPE bottles. Stability samples were packed into Alu/Alu blisters. Table 3 provides details of the batches manufactured, including details of whether theophylline was micronised alone (with optional magnesium stearate) or co-micronised with fluticasone propionate (again, with optional magnesium stearate) and the subsequent blending process used.
  • Table 3 Blends manufactured. Processes 4, 5, 9, 10 and 12 are detailed in Figures 4, 5, 6, 7 & 8.
  • Preparation of batch 014AG01 involved pre-blending theophylline anhydrous with fluticasone propionate in the ratio 2:1 (see table 4).
  • Preparation of batches 015AG01 and 019AG01 involved pre-blending of theophylline with fluticasone propionate in the 2 ratios corresponding to the 50( ⁇ g TP /25( ⁇ g FP and to the 300( ⁇ g TP /25( g FP strengths (see Table 6).
  • Magnesium stearate KN 12041 5.0 g 2.8 g The co-micronisation was performed according to the process described in Figure 1 and with the jet milling parameters shown in Table 7.
  • Particle size distribution was measured with a Malvern Mastersizer Micro Plus.
  • the particle size distribution batch 014AG01 (co-mi cronised TP and FP) co-micronised with optimised settings is shown in Figure 9.
  • the particle size distribution of batches 015AG01 and 019AG01 (co-micronised TP, FP and MgS) co-micronised with optimised settings is shown in Figure 10.
  • NGI Next Generation Impactor
  • MOC micro-orifice collector
  • Table 8 APSD results of the different batches manufactured, measured by NGI
  • Tables 9 and 10 below show the percentage difference between the percentage delivered dose for TP and FP for the different batches.
  • Table 9 % difference between % delivered dose for TP and FP for the 500 ⁇ g 125( ⁇ g batches manufactured.
  • Table 10 % difference between % delivered dose for TP and FP for the 3000 ⁇ g / 250 ⁇ g batches manufactured.
  • the percentage difference for the batches 010AG01 and 011 AG01 is greatly increased compared to the percentage difference for the batches 015 AGO 1 and 019AG01 of the present invention and the values for 010AG01 and 011 AG01 do not fall within the 25% difference in APSD relative to delivered doses for TP and FP of the present invention. In contrast the results for 015AG01 and 019AG01 do fall within this percentage difference.
  • Figures 12, 13, 14, 15 and 16 show the APSD profiles of both actives overlaid. It is evident that the profiles for theophylline and fluticasone are similar when the APIs are co-micronised together. When theophylline is micronised alone, the deposition profiles of the two actives differ.
  • Inhalation capsules filled with powder blends manufactured with co-micronised APIs showed significantly higher product performance compared to powder blends manufactured with APIs micronised using standard techniques. Moreover, aerodynamic particle size (measured by NGI) was similar for the two APIs when these were co-micronised, which would result in co- deposition of the two APIs in the lungs.
  • Example 2 Preparation of formulations containing 150 ⁇ fluticasone propionate and ⁇ . 2000u.g or 4000ug theophylline
  • Three formulations of different strengths were prepared, comprising theophylline anhydrous, fluticasone propionate, magnesium stearate and lactose monohydrate, with the target dose of the active agents being in the following amounts.
  • Lactose monohydrate and 1% by weight magnesium stearate were also present in all
  • the formulations were prepared in accordance with the invention and as described above in Example 1 by co-micronising TP, FP and MgS and subsequently blending the co-micronised components with lactose monohydrate.
  • a MC 100 spiral jet mill using nitrogen at 10 bar as micronisation gas was used instead of the Alpine Hosokawa 50 AS spiral air jet mill.
  • Example 3 Stability of formulations of Example 2
  • Example 2 The batches of formulations prepared in accordance with the invention in Example 2 were stored at 40°C and 75% rh and were analysed at TO, after 1 month and after 3 months to determine the APSD, using a NGI as described in Example 1.
  • Example 4 particle size distribution of the blends
  • a 600 g batch 076 ABO 1 of theophylline, fluticasone and magnesium stearate as provided by the different manufacturers was prepared for co-micronisation in the ratio 1000 : 150 : 250 using a tumble blending process.
  • the mixture was tested for drug content and homogeneity and found conform to the requirements given by Ph. Eur. 2.9.40. Uniformity of Dosage Units).
  • the particle size distribution of a sample before co-micronisation was analysed by laser diffraction using a Sympatec Helos particle analyser with Rodos/Vibri dry dispersion unit at 3 bar feeding pressure.
  • the particle size distribution curve confirmed the presence of the different particle entities (Figure 23).
  • Micronisation of the batch was performed on a MC 100 spiral jet mill using nitrogen at 10 bar as micronisation gas.
  • the laser diffraction particle analysis of the co-micronised batch showed a mono-modal Gaussian particle size distribution which confirmed that both drug substances and magnesium stearate were micronised to similar size below 10 microns (Figure 24).
  • the 10th, 50th (median) and 90th percentile of the measured volume distribution curves are given in Table 11 below.
  • Table 11 10th, 50th and 90th percentile of particle size distribution curve of theophylline- fluticasone-magnesium stearate batch 076AB01 before and after micronisation
  • the particle size measurement of micronised the theophylline-fluticasone-magnesium stearate mixture confirmed that all components were micronised to a similar size whereas the particle size measurement of the non-micronised mixture showed the presence of different particle entities.

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Abstract

La présente invention concerne une composition pharmaceutique à inhaler comprenant un premier agent actif et un second agent actif, la granulométrie aérodynamique des premier et second agents actifs par rapport aux doses de chacun d'entre eux qui sont administrées étant sensiblement la même.
PCT/GB2016/052680 2015-08-27 2016-08-30 Composition pharmaceutique à inhaler Ceased WO2017033032A1 (fr)

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CN107320709A (zh) * 2017-09-04 2017-11-07 上海市中医医院 一种治疗小儿哮喘的中药组合物
WO2020100040A1 (fr) * 2018-11-12 2020-05-22 3M Innovative Properties Company Formulation d'uméclidinium et de vilantérol et inhalateur
US20210161804A1 (en) * 2018-06-07 2021-06-03 Kindeva Drug Delivery L.P. Fluticasone and vilanterol formulation and inhaler
CN117224482A (zh) * 2023-09-07 2023-12-15 苏州易合医药有限公司 一种用于治疗ipf疾病的吸入制剂及其制备方法

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WO2007068443A1 (fr) * 2005-12-12 2007-06-21 Jagotec Ag Préparations de poudre pour inhalation
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WO2013109218A1 (fr) * 2012-01-16 2013-07-25 Mahmut Bilgic Formulations en poudre sèche comprenant du carmotérol et de la ciclésonide
WO2013109219A1 (fr) * 2012-01-16 2013-07-25 Mahmut Bilgic Formulations en poudre sèche comprenant du tiotropium et du carmotérol
WO2013109220A1 (fr) * 2012-01-16 2013-07-25 Mahmut Bilgic Formulations en poudre sèche comprenant du tiotropium, du formotérol et du budésonide
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US20060257324A1 (en) * 2000-05-22 2006-11-16 Chiesi Farmaceutici S.P.A. Pharmaceutical solution formulations for pressurised metered dose inhalers
WO2007068443A1 (fr) * 2005-12-12 2007-06-21 Jagotec Ag Préparations de poudre pour inhalation
WO2008000482A1 (fr) * 2006-06-30 2008-01-03 Novartis Ag Compositions à inhaler à base d'un sel de glycopyrronium
EP2881108A1 (fr) * 2009-10-16 2015-06-10 Jagotec AG Formulations d'aérosol médicinal améliorées
WO2013109218A1 (fr) * 2012-01-16 2013-07-25 Mahmut Bilgic Formulations en poudre sèche comprenant du carmotérol et de la ciclésonide
WO2013109219A1 (fr) * 2012-01-16 2013-07-25 Mahmut Bilgic Formulations en poudre sèche comprenant du tiotropium et du carmotérol
WO2013109220A1 (fr) * 2012-01-16 2013-07-25 Mahmut Bilgic Formulations en poudre sèche comprenant du tiotropium, du formotérol et du budésonide

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107320709A (zh) * 2017-09-04 2017-11-07 上海市中医医院 一种治疗小儿哮喘的中药组合物
US20210161804A1 (en) * 2018-06-07 2021-06-03 Kindeva Drug Delivery L.P. Fluticasone and vilanterol formulation and inhaler
WO2020100040A1 (fr) * 2018-11-12 2020-05-22 3M Innovative Properties Company Formulation d'uméclidinium et de vilantérol et inhalateur
CN117224482A (zh) * 2023-09-07 2023-12-15 苏州易合医药有限公司 一种用于治疗ipf疾病的吸入制剂及其制备方法

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