WO2017089404A1 - Composition pharmaceutique - Google Patents

Composition pharmaceutique Download PDF

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Publication number
WO2017089404A1
WO2017089404A1 PCT/EP2016/078564 EP2016078564W WO2017089404A1 WO 2017089404 A1 WO2017089404 A1 WO 2017089404A1 EP 2016078564 W EP2016078564 W EP 2016078564W WO 2017089404 A1 WO2017089404 A1 WO 2017089404A1
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Prior art keywords
weight
formulation
glycopyrronium
pharmaceutical aerosol
aerosol formulation
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PCT/EP2016/078564
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English (en)
Inventor
Rudi Mueller-Walz
Jan Kendall De Kruif
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Jagotec Ag
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Publication of WO2017089404A1 publication Critical patent/WO2017089404A1/fr

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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
    • A61K9/008—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present invention relates to a pharmaceutical aerosol formulation for use in a metered dose inhaler (MDI) comprising a triple combination of formoterol, fluticasone and glycopyrronium, suspended in HFA propellant and the use of such formulations in the treatment of chronic respiratory diseases such as COPD and asthma.
  • MDI metered dose inhaler
  • 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 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 drugs may act to treat two different symptoms.
  • Combination therapy is beneficial particularly in the treatment of chronic respiratory diseases such as asthma or COPD where disease management involves preventing disease progression, treating symptoms and also preventing and treating exacerbations of the disease.
  • chronic respiratory diseases such as asthma or COPD
  • one drug may treat acute airway constriction while another may reduce or prevent inflammation of the airways.
  • treatment with multiple drugs involves the use of multiple inhalers to administer different active agents, often more than once a day, resulting in a complicated treatment plan which may lead to poor patient compliance. This results in under treatment of the patients and consequently a reduction in their quality of life.
  • prophylactic therapies which are important in the long term management of the conditions but which patients may be less likely to take regularly due to lack of immediate improvement in their symptoms.
  • prophylactic therapies which are important in the long term management of the conditions but which patients may be less likely to take regularly due to lack of immediate improvement in their symptoms.
  • fluticasone propionate and formoterol fumarate dihydrate has previously been successfully formulated, as Flutiform ® , despite the technical difficulties in producing a stable aerosol suspension formulation in HFA propellant of two potent and moisture sensitive drugs, particularly with regards to formoterol, and ensuring that stability is maintained during exposure to moist conditions during storage and use.
  • Glycopyrrolate (glycopyrronium bromide) is even more hydrophilic than formoterol and has a LogP of -1.0, in comparison to 2.2 for formoterol.
  • glycopyrronium bromide tends to interact with water molecules and it is very difficult to stabilise these hydrophilic particles in the nonpolar environment of liquefied propellants and propellants mixtures (i.e. in the organic phase) to form a stable suspension formulation for pressurised metered dose inhaler. It is also known that glycopyrronium bromide is notorious for forming amorphous phase material when subjected to an air-jet mill for grinding coarse crystalline particles to the small particle size required for inhalation. Amorphous material is thermodynamically unstable and characterised by the fact that the molecules are not fixed at regular points to form a crystal lattice or crystal phase but they are more irregularly located and exhibit a higher molecular mobility.
  • a first aspect of the present invention provides a pharmaceutical aerosol formulation for use in a metered dose inhaler (MDI) which comprises: formoterol or a pharmaceutically acceptable salt, solvate or derivative thereof; fluticasone or a pharmaceutically acceptable salt, solvate, ester or derivative thereof; glycopyrronium or a pharmaceutically acceptable salt or derivative thereof; and HFA propellant; wherein the formoterol, fluticasone and glycopyrronium are suspended in the HFA propellant.
  • MDI metered dose inhaler
  • Formoterol is a long acting beta 2 agonist and may be present in the composition as a free base or as a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts of formoterol include, for example, salts of inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric acids and of organic acids such as maleic, fumaric, tartaric, citric, benzoic, 4-methoxybenzoic, 2- or 4- hydroxybenzoic, 4-chlorobenzoic, p-toluenesulphonic, methanesulphonic, ascorbic, salicylic, acetatic, succinic, lactic, tricarballylic, hydroxy-naphthalene-carboxylic, gluconic or oleic acids.
  • the preferred form of formoterol for use in the present invention is the salt formoterol fumarate, preferably in its dihydrate form as formoterol fumarate dihydrate.
  • the formoterol is present in an amount of 0.003-0.04% by weight, more preferably 0.004 to 0.03%> by weight, most preferably 0.005-0.02%) by weight, based on the total weight of the formulation.
  • Further advantageous ranges of formoterol in the present invention are 0.001 to 0.04%> by weight, more preferably 0.002 to 0.03%) by weight, even more preferably 0.003 to 0.02% by weight.
  • Fluticasone a corticosteroid
  • Fluticasone is also present as an active agent in the triple combination formulation, preferably as an ester of fluticasone such as fluticasone propionate or fluticasone furoate, preferably as fluticasone propionate.
  • the fluticasone is present in an amount of 0.01-0.6%) by weight; more preferably 0.02 to 0.5% by weight, even more preferably 0.03 to 0.4% by weight, most preferably 0.05 to 0.4%> by weight, based on the total weight of the formulation.
  • Glycopyrronium a long acting muscarinic antagonist
  • the glycopyrronium may be present in an amount of 0.005- 0.07% by weight, preferably 0.006-0.05% by weight, more preferably 0.008-0.03% by weight, based on the total weight of the formulation.
  • the glycopyrronium may be present in an amount of 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06% or 0.07% by weight, based on the total weight of the formulation.
  • the formulation therefore provides a triple suspension formulation combination of formoterol, fluticasone and glycopyrronium in HFA propellant which may be administered to a patient via a single MDI device, thereby providing improved patient compliance while delivering the therapeutic benefits of a triple combination of a long acting beta agonist, inhaled corticosteroid and muscarinic antagonist.
  • the present invention is advantageous in comparison to the administration of separate formulations for each active agent or the separate administration of a mono formulation of glycopyrronium and Flutiform® because the glycopyrronium in the triple formulation is more stable than when formulated in a mono formulation.
  • the triple combination of formoterol, fluticasone and glycopyrronium of the present invention is formulated as a suspension formulation in a hydrofluoroalkane (HFA) propellant.
  • HFA 227 and HFA 134a are well known HFA propellants for aerosol formulations and these propellants may be used on their own or in combination, but the triple combination of the present invention is preferably formulated as a suspension in HFA 227.
  • Suspension formulations comprise active agents in fine particle powder form, which are then suspended in a liquefied propellant or propellant blend.
  • the suspension formulation is then stored in a sealed canister with sufficient pressure to maintain the propellant in liquid form.
  • the metering valve of the metered dose inhaler is actuated then a dose is delivered in rapidly deployed fine droplets.
  • the particle size of these small droplets must be small enough that they can be inhaled into the lungs of the patient, when delivered using an inhalation device such as a metered dose inhaler (MDI).
  • MDI metered dose inhaler
  • 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 Diameter (MMAD)) of about
  • MMAD Mass Median Aerodynamic Diameter
  • 1 to ⁇ preferably in the range of 1 to 6 ⁇ , even more preferably in the range of 1 to 4 ⁇ , in order to be capable of penetrating into the lungs and exerting the intended pharmacological effect.
  • the particle size of the active agents should not be larger than ⁇ and preferably not larger than
  • the amount of active drug deployed in the fine inhalable particle droplets is called the fine particle dose (FPD) or the fine particle fraction (FPF), which is defined as the percentage of the fine particle dose relative to the total amount of released active compound. Both are determined by the measurement of the aerodynamic particle size distribution with a cascade impactor or liquid impinger. These are routine tests for which the methods and apparatus are described in the pharmacopeias. For example, formulations of the present invention meet the requirement set out in Chapter ⁇ 601> of the United States Pharmaceopeia (USP) 32 or in the inhalants monograph 2.9.18 of the European
  • the fine particle fraction of each of formoterol, fluticasone and glycopyrronium in the formulation of the first aspect of the invention is not less than 20%, preferably not less than 30%, more preferably not less than 40%>.
  • the fine particle fraction of each of formoterol, fluticasone and glycopyrronium is not less than 20%, preferably not less than 30%, more preferably not less than 40% after storage for 1 month at 40°C and 75% relative humidity, preferably after storage for 3 months at 40°C and 75% relative humidity, more preferably after storage for 6 months at 40°C and 75% relative humidity. It is important for the FPF of all three drugs to be at a similar level because they all act on receptors located at a similar area of the lung. If the FPF of one active agent is at a lower level than this could potentially be addressed by increasing the dose of that active agent, but that would lead to increased amounts of drug being absorbed systemically by swallowing or absorption into the bloodstream, with a consequent increase in side effects. It is therefore
  • the fine particle fraction of the glycopyrronium in the formulation of the first aspect of the invention is not less than 20%, more preferably not less than 30%, even more preferably not less than 40%).
  • the fine particle fraction of the glycopyrronium is not less than 20%, more preferably not less than 30%, even more preferably not less than 40% after storage for 1 month at 40°C and 75% relative humidity, preferably after storage for 3 months at 40°C and 75% relative humidity, more preferably after storage for 6 months at 40°C and 75% relative humidity.
  • the present invention therefore further provides the use of a combination of glycopyrronium, formoterol and fluticasone in a pharmaceutical suspension formulation for maintaining the FPF of glycopyrronium during storage of the pharmaceutical formulation. It has now been found that it is possible to successfully formulate a stable triple formulation despite the issues associated with the presence of amorphous content in glycopyrromum and the damaging effect of this amorphous content on the stability of glycopyrromum. For example, it is known that even an amorphous content of as little as 1% by weight on the surface of the glycopyrromum has a detrimental effect on the stability of this active agent in a suspension formulation in HFA propellant.
  • a stable pharmaceutical aerosol suspension formulation for use in a metered dose inhaler comprising formoterol or a pharmaceutically acceptable salt, solvate or derivative thereof, fluticasone or a pharmaceutically acceptable salt, solvate, ester or derivative thereof, glycopyrromum or a pharmaceutically acceptable salt or derivative thereof and HFA propellant, wherein the amorphous content of the glycopyrromum is in the range of not more than 6% by weight, preferably not more than 5% by weight, more preferably not more than 4% by weight, even more preferably not more than 3% by weight.
  • the stability of the formulation is determined by the maintenance of the FPF and FPD during storage and exposure to environmental moisture, as defined above. It is known that the raw material of micronised glycopyrromum bromide has a high proportion of particles in the sub-micron size range of around 30-40% vol% as measured by laser diffraction (e.g. using a Malvern Mastersizer). This is due to the fragility of the glycopyrromum which leads to a high percentage of very small particles when the raw material is subjected to micronisation. A high sub- micron particle dose or fraction (i.e.
  • a high amount of particles smaller than 1 micron is generally disadvantageous because these sub-micron particles penetrate deep into the lung to the alveoli and therefore do not interact with the receptors in the lung (e.g. muscarinic receptors for glycopyrrolate); this fraction of the formulation therefore cannot exert its desired effect on the lung tissue. Instead, the sub-micron particles are either absorbed into the bloodstream or exhaled. If the active agent is absorbed into the bloodstream then it may result in an undesired systemic effect and therefore cause side effects that would not occur if the active agent interacted solely with the pharmacological target in the lung.
  • the sub-micron dose of glycopyrromum bromide can be significantly reduced when formulated in accordance with the present invention. Therefore, preferably the sub- micron fraction of glycopyrromum of the first or second aspects of the present invention is at least 20%, preferably at least 30%>, preferably at least 40%>, more preferably at least 50%> lower at initial than the sub-micron particle fraction of an equivalent mono formulation of glycopyrronium bromide.
  • An equivalent mono formulation contains the same amounts of glycopyrronium and all other non- therapeutic components of the formulation such as ethanol and HFA propellant and is prepared in the same way as a triple formulation in accordance with the present invention, but lacks formoterol and fluticasone.
  • the invention therefore further provides the use of a combination of glycopyrronium, formoterol and fluticasone in a pharmaceutical suspension formulation for reducing the sub-micron particle fraction of glycopyrronium, preferably for reducing the sub-micron particle fraction to a level lower than that seen in an equivalent mono formulation of glycopyrronium.
  • the aerodynamic particle size distribution (APSD) of the glycopyrronium bromide when present in the triple formulation according to the present invention superimposes on top of the APSD profile for fluticasone propionate.
  • This is advantageous because it is indicative of the fact that the glycopyrronium bromide and fluticasone propionate are delivered to and deposit at the same site in the lungs, which can maximise any synergistic action between the two drugs.
  • the aerodynamic particle size distribution of the glycopyrronium bromide and fluticasone propionate relative to their delivered doses is substantially the same.
  • the aerodynamic particle size distribution is substantially the same within ⁇ 35% on each impactor stage, preferably within 30% on each impactor stage, more preferably ⁇ 25% on each impactor stage, preferably within ⁇ 20% on each stage, even more preferably within ⁇ 15% on each impactor stage.
  • the triple formulation of the present invention can therefore provide a steroid sparing effect due to synergistic action of fluticasone and glycopyrronium.
  • a patient uncontrolled on Flutiform ® (a formulation identical to the present invention but lacking glycopyrronium) may receive effective treatment from a formulation of the present invention in which the dose of fluticasone and formoterol is lower than used in the Flutiform ® formulation.
  • a cromone may advantageously be included in the formulation, such as sodium cromoglycate (disodium cromoglycate or DCSG) or nedocromil sodium.
  • the cromone is provided in a sub-therapeutic amount, such that it does not have a biological or clinical effect and is pharmaceutically inactive.
  • a therapeutic dose of an active agent may be determined by those of ordinary skill in the art with due consideration to factors such as the potency, route of administration and mechanical system used to administer the drug, and therefore a non- therapeutic dose would also be determined by the skilled person based on similar factors.
  • the minimum dose required to achieve an effect for sodium cromoglycate would be either known to the skilled person or easily determined, as this agent has been used in the treatment of asthma as an active agent for more than 30 years (for example, as Intal ® ).
  • the cromone is preferably present in an amount of 0.01 -0.1% by weight, more preferably 0.02 to 0.08% by weight, more preferably 0.03 to 0.05%> by weight, more preferably 0.03 to 0.04%) by weight, based on the total weight of the formulation.
  • a cromone such as sodium cromoglycate aids the stabilisation of the formulation, particularly against hydrolysis by competitive water absorption and acts to stabilise the fine particle fraction in the formulation by competitively binding free water present within the propellant phase.
  • the sodium cromoglycate is particularly effective at scavenging moisture and protecting the amorphous content of the glycopyrronium from the action of free water, thereby avoiding the formation of lumps of hard crystals and consequently assisting with maintenance of the FPF during storage of the formulation.
  • the present invention therefore provides in a third aspect the use of sodium cromoglycate in the preparation of a stable pharmaceutical aerosol suspension formulation for a metered dose inhaler comprising formoterol or a pharmaceutically acceptable salt, solvate or derivative thereof, fluticasone or a pharmaceutically acceptable salt, solvate, ester or derivative thereof, glycopyrronium or a pharmaceutically acceptable salt or derivative thereof and HFA propellant.
  • the active agents of the present formulation are present in the formulation as separate individual particles that tend to associate in such a way as to form floccules, which comprise a loosely held mass or aggregation of discrete fine particles held together in a network-like fragile structure, suspended in the propellant.
  • the specific amounts of each solid component in the formulation are selected so that the floccules formed have a density substantially the same as that of the HFA propellant.
  • the aggregates formed by the floccules tend to break up easily under the application of small amounts of sheer stress, such as gentle agitation of the canister and reform an extended network of particles after the force is removed. Flocculation therefore imparts a structure of the suspension with virtually no increase in viscosity.
  • the floccules will settle rapidly, usually to a high sediment volume and may be easily re-suspended even after standing for prolonged periods of storage, for example after 3, 6, 9, 12, 18 months or longer.
  • the floccules of the present formulation have a density to match that of the density of the liquefied propellant in which they are placed. This gives the floccules the ability to remain in suspension without the tendency to cream, float or sink.
  • the suspension formulation of the present invention may therefore remain in a viable formulation for an extended period of time and results in a robust product with an extended shelf life and improved reliability of the end product.
  • the tendency to form these floccules may provide enhanced uniformity in the suspension and less fluctuation in the local homogeneity which then results in a product which may have reduced deviation in the delivered dose.
  • the inventors have surprisingly found that the same ratio of the four solid components is found in each sample, and that the concentration of each component present in the delivered dose is also maintained.
  • the tendency of formulations according to the present invention to associate to form floccules results in all the active ingredients remaining associated right up until the moment they are dispensed from the MDI and enter the patient's respiratory system. This provides for a formulation with an improved quality and improved ability to adhere to a calculated dose.
  • the floccules afford an increased stability to the suspension formulation. This increased stability of the suspension means that the ingredients associate together in preference to associating with the internal surfaces of the canister or metering valve of the inhaler.
  • the formulation may also include a wetting agent, which may be an alcohol, diol or polyol, such as ethanol, propylene glycol, glycerol, butandiol or mixtures thereof.
  • a wetting agent which may be an alcohol, diol or polyol, such as ethanol, propylene glycol, glycerol, butandiol or mixtures thereof.
  • the wetting agent is ethanol, more preferably anhydrous ethanol.
  • wetting agent employed having regard to the concentrations of the fluticasone, formoterol and glycopyrronium employed, and the other components of the formulation, such as the HFA propellant and sodium cromoglycate. If the wetting agent is a solvent for one or more of the drug substances then the wetting agent must be employed in an amount which avoids solubilisation or partial solubilisation of the drug substances or any excipients intended to be held in suspension, to ensure that a suspension formulation is achieved.
  • the balance is made yet more complicated by the presence of three drug substances with differing physical properties and solubility.
  • the wetting agent is employed in an amount of 0.01 to 3% by weight, preferably 0.05 to 2.5% by weight and more preferably 1 to 2 % by weight, based on the total weight of the formulation.
  • the effect of the amorphous content of the glycopyrronium may also or alternatively be minimised by the use of a conditioning step.
  • a conditioning step For example, by using a rotor stator homogeniser in the production of the formulation, the solid material is suspended and kept in motion, thereby preventing agglomeration of the particles while they recrystallize due to exposure to and interaction with free water in the HFA and ethanol.
  • a further aspect of the invention therefore provides a method of producing a stable pharmaceutical formulation according to the first aspect of the invention and wherein the glycopyrronium has an amorphous content of between 1 and 5 wt% comprising the step of using a rotor stator homogeniser to disperse the solid materials in the liquefied HFA propellant.
  • a pharmaceutical aerosol formulation for use in a metered dose inhaler which comprises 0.003 to 0.04%> by weight formoterol fumarate dihydrate, 0.01 to 0.6%) by weight fluticasone propionate, 0.005 to 0.07% by weight glycopyrronium bromide, 0.01 to 3%) by weight ethanol and 0.01 to 0.1 % by weight sodium cromoglycate, with the remainder comprising HFA 227 propellant.
  • a particularly preferred formulation comprises 0.007%> by weight of formoterol fumarate dihydrate, 0.179%) fluticasone propionate, 0.011%, 0.022%> or 0.45% by weight glycopyrronium bromide, 0.034%) sodium cromoglycate, 1.43% by weight of anhydrous ethanol, with the remainder comprising HFA 227.
  • Alternative preferred formulations comprise 0.007% by weight of formoterol fumarate dihydrate, 0.036%, 0.071% or 0.357% by weight fluticasone propionate, 0.011%, 0.022% or 0.45% by weight glycopyrronium bromide, 0.034%> sodium cromoglycate, 1.43% by weight of anhydrous ethanol, with the remainder comprising HFA 227.
  • a further preferred formulation comprises 0.014%> formoterol fumarate, 0.357%) fluticasone propionate, 0.011%, 0.022%> or 0.45% by weight glycopyrronium bromide, 0.034%> sodium cromoglycate, 1.43% by weight of anhydrous ethanol, with the remainder comprising HFA 227.
  • the dose of formoterol fumarate dihydrate, fluticasone propionate and glycopyrronium contained within an aerosol suspension formulation according to the present invention may be varied to provide a desired therapeutic effect.
  • Nominal doses of formoterol fumarate dihydrate may range from about 3 to about 20 micrograms
  • nominal doses of fluticasone propionate may range from about 25 to about 500 micrograms
  • nominal doses of the active moiety of glycopyrronium may range from about 5 to about 50 micrograms.
  • nominal dose is a target dose for a drug substance contained in a metered dose inhaler.
  • Metered dose inhalers of the present invention typically will contain a plurality of nominal doses such that a single inhaler may treat patients over several days or weeks depending on the total number of nominal doses loaded into a canister.
  • the actual dose metered from a metered dose inhaler and the delivered dose are expected to be slightly lower than the nominal dose, but within strictly regulated limits.
  • the nominal dose may be administered by one or more actuations of the metered dose inhaler, preferably by two actuations.
  • the aerosol formulation is delivered to the patient in two actuations in a preferred aspect of the invention.
  • the formulation may be administered to the patient 1 , 2 or 3 times a day, but preferably the formulation is administered to the patient twice a day.
  • Particularly preferred doses of formoterol fumarate dihydrate delivered in one actuation are 5 micrograms of formoterol fumarate dihydrate, 25, 50, 125 or 250 micrograms of fluticasone propionate and 6.25, 12.5 or 25 micrograms of the active moiety of glycopyrronium or alternatively 10 micrograms of formoterol fumarate dihydrate, 250 micrograms of fluticasone propionate and 6.25, 12.5 or 25 micrograms of the active moiety of glycopyrronium.
  • the nominal dose of formoterol fumarate dihydrate comprises 10 micrograms of formoterol fumarate dihydrate, 50, 100, 250 or 500 micrograms of fluticasone propionate and 12.5, 25 or 50 micrograms of the active moiety of glycopyrronium or alternatively the nominal dose of formoterol fumarate dihydrate comprises 20 micrograms of formoterol fumarate dihydrate, 500 micrograms of fluticasone propionate and 12.5, 25 or 50 micrograms of the active moiety of glycopyrronium.
  • glycopyrronium could be used in the formulation, as determined by therapeutic requirements, such as 5, 5.25, 5.5, 5.75, 6, 6.5, 6.75, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 13, 13.5, 14, 15, 20, 25, 30, 35, 40, 45 or 50 micrograms per actuation.
  • a pharmaceutical aerosol formulation contained in a metered dose inhaler comprising 0.007% by weight of formoterol fumarate dihydrate, 0.179%) by weight of fluticasone propionate, 0.011%>, 0.22 or 0.45%> by weight of glycopyrronium bromide, 0.0343%) of sodium cromoglycate, 1.43% by weight of anhydrous ethanol and HFA 227 ad 100%; and wherein the nominal dose of formoterol fumarate is 10 ⁇ g, the nominal dose of fluticasone propionate is 250 ⁇ g and the nominal dose of the active moiety of glycopyrronium is 12.5, 25 or 50 ⁇ g wherein each dose comprises two actuations of the formulation.
  • a pharmaceutical aerosol formulation contained in a metered dose inhaler comprising 0.007%) by weight of formoterol fumarate dihydrate, 0.036% by weight fluticasone propionate, 0.011%, 0.022% or 0.045% by weight glycopyrronium bromide, 0.034%) sodium cromoglycate, 1.43% by weight of anhydrous ethanol, with the remainder comprising HFA 227, wherein the nominal dose for formoterol fumarate is 10 ⁇ g, the nominal dose of fluticasone propionate is 50 ⁇ g and the nominal dose of the active moiety of glycopyrronium is 12.5, 25 or 50 ⁇ g wherein each dose comprises two actuations of the formulation.
  • a pharmaceutical aerosol formulation contained in a metered dose inhaler comprising 0.007%) by weight of formoterol fumarate dihydrate, 0.071% by weight fluticasone propionate, 0.011%, 0.022% or 0.045% by weight glycopyrronium bromide, 0.034%) sodium cromoglycate, 1.43% by weight of anhydrous ethanol, with the remainder comprising HFA 227, wherein the nominal dose for formoterol fumarate is 10 ⁇ g, the nominal dose of fluticasone propionate is 100 ⁇ g and the nominal dose of the active moiety of glycopyrronium is 12.5, 25 or 50 ⁇ g wherein each dose comprises two actuations of the formulation.
  • a pharmaceutical aerosol formulation contained in a metered dose inhaler comprising 0.007%) by weight of formoterol fumarate dihydrate, 0.357%) by weight fluticasone propionate, 0.011% or 0.022%) or 0.045%) by weight glycopyrronium bromide, 0.034%) sodium cromoglycate, 1.43% by weight of anhydrous ethanol, with the remainder comprising HFA 227, wherein the nominal dose for formoterol fumarate is 10 ⁇ g, the nominal dose of fluticasone propionate is 500 ⁇ g and the nominal dose of the active moiety of glycopyrronium is 12.5, 25 or 50 ⁇ g wherein each dose comprises two actuations of the formulation.
  • a pharmaceutical aerosol formulation contained in a metered dose inhaler comprising 0.014%) by weight of formoterol fumarate dihydrate, 0.357% by weight fluticasone propionate, 0.011%, 0.022%, or 0.045% by weight glycopyrronium bromide, 0.034%> sodium cromoglycate, 1.43% by weight of anhydrous ethanol, with the remainder comprising HFA 227, wherein the nominal dose for formoterol fumarate is 20 ⁇ g, the nominal dose of fluticasone propionate is 500 ⁇ g and the nominal dose of the active moiety of glycopyrronium is 12.5, 25 or 50 ⁇ g wherein each dose comprises two actuations of the formulation.
  • a pharmaceutical aerosol formulation as described above for use in the treatment or prevention of a chronic respiratory disease such as COPD or asthma.
  • a pharmaceutical aerosol formulation as described above in the manufacture of a medicament for the treatment or prevention of a chronic respiratory disease such as COPD or asthma.
  • a method of treating or preventing a chronic respiratory disease such as COPD or asthma comprising the step of administering to a patient in need thereof a pharmaceutical aerosol formulation as described above.
  • Figure 1 shows the aerodynamic particle size distribution of the formulation of formoterol fumarate dihydrate, fluticasone propionate and glycopyrronium bromide contained in pouched inhalers from Example 1 , determined by Andersen Cascade Impactor.
  • Example 1 is based on an aerosol suspension formulation according to the present invention comprising formoterol fumarate dihydrate, fluticasone propionate, glycopyrronium bromide, sodium cromoglycate, ethanol and HFA 227 propellant.
  • aerosol suspension formulation comprising formoterol fumarate dihydrate, fluticasone propionate, glycopyrronium bromide, sodium cromoglycate, ethanol and HFA 227 propellant.
  • Aerodynamic particle size determination was performed on pouched inhalers from Example 1 using an Andersen Cascade Impactor as described in USP ⁇ 601>, which consists of 9 stages, 8 collection plates and a final filter. The test was performed on five inhalers. For each determination a defined number of actuations was delivered into the Andersen Cascade Impactor at an air flow-rate of 28.3 litres per minute. The amount of formoterol fumarate dihydrate, fluticasone propionate and of glycopyrronium bromide on each stage, on the filter, and possible wall losses are determined by liquid chromatography with UV detection.
  • the stages of the Andersen Cascade Impactor are numbered 0, 1 , 2, 3, 4, 5, 6, 7 and F. Stage F contains the filter.
  • Inhalers from Example 1 were subjected to a stability investigation and measurements were taken at initial and following exposure to conditions of 40 °C / 75 %RH for 1 month, 3 months and 6 months. Results of percentage target assay and determination of mean delivered dose, mean fine particle dose, mean sub-micron particle dose, and total percentage water content are displayed in Table 1. It can be seen that inhalers containing the formulation according to the invention exhibit superior drug product stability. In particular the mean delivered dose and fine particle dose are maintained during storage for 6 months at accelerated condition of 40 °C / 75 %RH and the desired performance target is achieved. These results obtained under accelerated conditions are indicative of the results of long term storage under normal conditions at 25°C and 60% relative humidity.
  • micron particle FP 3.2 FP: 3.3 FP: 3.3 FP: 3.0
  • Table 1 Stability results of the suspension formulation of formoterol fumarate dihydrate (FF), fluticasone propionate (FP), glycopyrronium bromide (GB), sodium cromoglycate, ethanol and HFA 227 following exposure to 40 °C / 75 % H for up to 6 months.
  • Canisters containing formulations with the amounts of formoterol fumarate dihydrate, fluticasone propionate, glycopyrronium bromide, sodium cromoglycate, anhydrous ethanol and HFA 227 shown in Table 2 were prepared in the same way as described in Example 1. Inhalers were then subjected to a stability investigation under the same conditions as used in Example 3 and the FPF and FPD were determined.
  • 016AP01 (% by 023AP01 (% by 033AP01 (% by
  • Table 2 Amounts of each ingredient present in three different strength h formulations.
  • Table 3 FPF and FPD results at initial and after storage for three different strength formulations.
  • the results displayed in Table 3 provide further evidence of the superior drug product stability of formulations according to the invention.
  • the fine particle fraction and fine particle dose are maintained during storage for 3 months at accelerated condition of 40 °C / 75 %RH.
  • Example 1 1.34 g of glycopyrronium bromide and 4.11 g of sodium cromoglycate were weighed and dispensed into a pressure -resistant batch vessel. 171 g of anhydrous ethanol and 11.8 kg of HFA 227 were added. All other conditions are as Example 1. The relevant properties of the formulation was measured as described in Example 2. Stability testing was conducted as described in Example 3. Results of percentage target assay and determination of mean delivered dose, mean fine particle dose, mean sub-micron particle dose, and total percentage water content were compared to results obtained for glycopyrronium bromide in the formulation of Example 1 and are displayed in Table 4.
  • the mean delivered dose is lower than for the triple formulation, the mean fine particle dose decreases during storage, while the fine particle dose for the triple formulation is maintained and the sub particle fraction is much higher than that of the glycopyrronium bromide in the triple formulation.
  • glycopyrronium bromide in a suspension formulation of glycopyrronium bromide, formoterol fumarate, fluticasone propionate, sodium cromoglycate, ethanol and HFA 227 following exposure to the same conditions.
  • Example 6 1.9 kg of ethanol anhydrous and 128 kg of HFA227 were loaded into a pressure -resistant batch vessel. 468 g of fluticasone, 18.7 g of formoterol, 29.6 g of glycopyrronium and 45 g of sodium cromoglycate were loaded into a drug addition vessel connected to the batch vessel. The materials were transferred into the batch vessel during homogenisation using a rotor-stator homogeniser Koruma Disho L60. A minimum of 9000 canisters were filled using a Pamasol Macromat pressure-filling line after suspension preparation. All filled canisters were subjected to an equilibration period and thereafter processed further by function testing, weight check, and actuator assembly and pouching.
  • glycopyrronium bromide 1.34 g was weighed into a pressure-resistant batch vessel. 8.6 g of ethanol anhydrous and 1.2 kg of HFA227 were added and the formed slurry was passed through a Avestin Emulsiflex high-pressure homogeniser until the appropriate fine particle size of glycopyrronium for inhalation (i.e., having a MMAD of 1 to 4 ⁇ ) was achieved.
  • the concentrate formulation was connected to a batch vessel loaded with 0.86 g of formoterol fumarate dihydrate, 21.4 g of fluticasone propionate, and 4.11 g of sodium cromoglycate and flushed in by addition of the remainder of anhydrous ethanol and HFA 227 to make up a batch of 12 kg.
  • the resulting suspension was stirred heavily using an internal stirrer and re -circulated between batch vessel and the pressure-filling equipment.
  • a minimum of 900 canisters was filled after suspension preparation. All filled canisters are subjected to an equilibration period and thereafter processed further by function testing, weight check, and actuator assembly and pouching.

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Abstract

La présente invention concerne une formulation d'aérosol pharmaceutique destinée à être utilisée dans un inhalateur-doseur comprenant : a) du formotérol ou un sel, un solvate ou un dérivé pharmaceutiquement acceptable de celui-ci; b) de la fluticasone ou un sel, un solvate, un ester ou un dérivé pharmaceutiquement acceptable de celle-ci; c) du glycopyrronium ou un sel ou un dérivé pharmaceutiquement acceptable de celui-ci; et d) un propulseur HFA; a), b) et c) étant en suspension dans le propulseur HFA.
PCT/EP2016/078564 2015-11-25 2016-11-23 Composition pharmaceutique WO2017089404A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020031148A1 (fr) * 2018-08-10 2020-02-13 Tykhonivska Nataliya Composition pharmaceutique, produit médicinal et procédé de traitement de maladies obstructives broncho-pulmonaires
WO2020084549A1 (fr) * 2018-10-25 2020-04-30 Glenmark Specialty S.A. Composition de nébulisation comprenant du glycopyrrolate et du formotérol
WO2022023515A1 (fr) * 2020-07-31 2022-02-03 Chemo Research , S.L. Polythérapie destinée à une administration par inhalation

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Publication number Priority date Publication date Assignee Title
AU2013203244A1 (en) * 2009-10-16 2013-05-02 Jagotec Ag Improved formulations
WO2014118532A1 (fr) * 2013-01-31 2014-08-07 Prosonix Limited Compositions pharmaceutiques contenant des particules cristallines multi-composant appropriées pour être utilisées dans un traitement par inhalation
US20140308214A1 (en) * 2011-02-17 2014-10-16 Cipla Limited Pharmaceutical Composition
WO2015101575A1 (fr) * 2013-12-30 2015-07-09 Chiesi Farmaceutici S.P.A. Composition stable pressurisée de solution pour aérosol d'une combinaison de bromure de glycopyrronium et de formotérol

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Publication number Priority date Publication date Assignee Title
AU2013203244A1 (en) * 2009-10-16 2013-05-02 Jagotec Ag Improved formulations
US20140308214A1 (en) * 2011-02-17 2014-10-16 Cipla Limited Pharmaceutical Composition
WO2014118532A1 (fr) * 2013-01-31 2014-08-07 Prosonix Limited Compositions pharmaceutiques contenant des particules cristallines multi-composant appropriées pour être utilisées dans un traitement par inhalation
WO2015101575A1 (fr) * 2013-12-30 2015-07-09 Chiesi Farmaceutici S.P.A. Composition stable pressurisée de solution pour aérosol d'une combinaison de bromure de glycopyrronium et de formotérol

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020031148A1 (fr) * 2018-08-10 2020-02-13 Tykhonivska Nataliya Composition pharmaceutique, produit médicinal et procédé de traitement de maladies obstructives broncho-pulmonaires
WO2020084549A1 (fr) * 2018-10-25 2020-04-30 Glenmark Specialty S.A. Composition de nébulisation comprenant du glycopyrrolate et du formotérol
WO2022023515A1 (fr) * 2020-07-31 2022-02-03 Chemo Research , S.L. Polythérapie destinée à une administration par inhalation

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