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WO2025229354A1 - Aérosol comprenant du sulfate de salbutamol et du dipropionate de béclométhasone - Google Patents

Aérosol comprenant du sulfate de salbutamol et du dipropionate de béclométhasone

Info

Publication number
WO2025229354A1
WO2025229354A1 PCT/GB2025/050959 GB2025050959W WO2025229354A1 WO 2025229354 A1 WO2025229354 A1 WO 2025229354A1 GB 2025050959 W GB2025050959 W GB 2025050959W WO 2025229354 A1 WO2025229354 A1 WO 2025229354A1
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WO
WIPO (PCT)
Prior art keywords
formulation
salbutamol
ethanol
beclomethasone dipropionate
formulations
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/GB2025/050959
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English (en)
Inventor
Sanjeeva DISSANAYAKE
Anne BRINDLEY
Rudi Mueller-Walz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Senari Pharma Ltd
Original Assignee
Senari Pharma Ltd
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Filing date
Publication date
Application filed by Senari Pharma Ltd filed Critical Senari Pharma Ltd
Publication of WO2025229354A1 publication Critical patent/WO2025229354A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • This invention relates inter alia to pressurised pharmaceutical formulations containing salbutamol and beclomethasone dipropionate (BDP), metered dose inhalers containing them and their use in therapy, particularly for the treatment of asthma and chronic obstructive pulmonary disease (COPD).
  • BDP salbutamol and beclomethasone dipropionate
  • COPD chronic obstructive pulmonary disease
  • pMDIs Pressurised metered dose inhalers
  • Reliever drugs like salbutamol known as albuterol in the US
  • corticosteroid drugs like beclomethasone dipropionate are given by pMDIs, either alone or in a fixed- dose combination for improved patient convenience and compliance.
  • Salbutamol most commonly used in the form of salbutamol sulphate, is a short-acting agonist of p2 adrenergic receptors which are prevalent on airway smooth muscle. Importantly, airway smooth muscle is found in greatest density in the large and medium-sized airways but is absent from the alveoli. Binding induces relaxation of smooth muscle and hence bronchodilation and as such salbutamol is one of the most common rescue/reliever drugs used to alleviate bronchospasm in asthma or COPD patients.
  • Beclomethasone dipropionate is a corticosteroid drug, more specifically a glucocorticoid, that binds to the glucocorticoid receptor almost universally expressed in vertebrate cells. Binding initiates a signalling cascade which culminates in the up-regulation of anti-inflammatory, and repression of pro- inflammatory, protein expression and hence induces suppression of chronic inflammation. Airway inflammation occurs throughout the lung in asthma and COPD, but the greatest contribution to airway surface area is the alveoli. In asthma alveolar eosinophilic inflammation is associated with symptom expression and exacerbations. In COPD, pathophysiological abnormalities (inflammation, fibrosis and gas trapping) are primarily centred on the distal lung. Exacerbation rates are higher in the COPD patient subgroup with eosinophilic inflammation, and this subgroup of COPD patients exhibit the greatest exacerbation risk reduction in response to glucocorticoid treatment.
  • the particle size of the drug particles delivered by pMDIs is the dominant physico-chemical parameter that facilitates targeting of different areas of the lungs. Particle size is measured ex-vivo as Aerodynamic Particle Size Distribution (APSD) of the drugs and expressed by surrogate parameters of Mass Median Aerodynamic Diameter (MMAD), Fine Particle Dose (FPD, an expression of the potentially inhalable or “respirable” drug mass), and FPF (FPD as a percentage of the total delivered dose).
  • APD Aerodynamic Particle Size Distribution
  • MMAD Mass Median Aerodynamic Diameter
  • FPD Fine Particle Dose
  • FPD an expression of the potentially inhalable or “respirable” drug mass
  • FPF FPD as a percentage of the total delivered dose
  • FPD data may be collected using the Next Generation Impactor (NGI), a high-performance cascade impactor that enables classification of aerosol particles into size fractions for testing of pressurised metered dose inhalers and other drug delivery devices.
  • NGI Next Generation Impactor
  • aerosolised samples pass through the NGI in a saw tooth pattern and through a series of nozzles containing progressively reducing jet diameters. Particle separation and sizing is achieved by successively increasing the velocity of the airstream as it passes through each, resulting in the collection of progressively finer particles. Samples may then be analysed via microscopy or chemical analyses to determine the mass of material deposited at each stage.
  • Optimal MMAD values for salbutamol (e.g. as sulphate) and beclomethasone dipropionate are about 2.2-3 pm and about 1-1.5 pm, respectively.
  • the optimal MMAD for beclomethasone dipropionate may be slightly higher within this range than when a “press and breath” inhaler device is used.
  • Target mean FPD values for salbutamol and beclomethasone dipropionate, in a formulation having a nominal dose (i.e. target delivered dose) of 90/40 pg/actuation ex-actuator respectively, are about 40-48 pg and about 18-22 pg, respectively.
  • a product known by the brand name Qvar Redihaler is available at two strengths (40 and 80 pg beclomethasone dipropionate /actuation ex-actuator).
  • the formulations comprise beclomethasone dipropionate solubilised in a mixture of ethanol and liquefied HFA134a.
  • the RedihalerTM device is a breath-actuated inhaler device.
  • a product known by the brand name Proventil HFA with strength 100 pg salbutamol /actuation exactuator comprises salbutamol sulphate in suspension, ethanol, oleic acid and HFA134a.
  • a product known by the brand name Clenil Compositum is manufactured by Chiesi and comprises salbutamol sulfate in suspension, beclomethasone dipropionate in solution, ethanol, oleic acid and HFA134a.
  • the nominal dose of the product is 100/250 pg/actuation (salbutamol/ beclomethasone dipropionate) ex-actuator.
  • a product known by the brand name Salbair-B is manufactured by Lupin and comprises levosalbutamol (the active L-isomer of salbutamol) sulfate in suspension, beclomethasone dipropionate solubilised in a mixture of ethanol and liquefied HFA propellant, assumed to be HFA134a.
  • the nominal dose of this product is 50/50 pg/actuation (salbutamol/ beclomethasone dipropionate) ex-actuator.
  • a product known by the brand name Aerocort is manufactured by Cipla and comprises levosalbutamol sulfate in suspension and beclomethasone dipropionate solubilised in a mixture of ethanol and liquefied HFA134a.
  • the nominal dose of this product is 50/50 pg/actuation (salbutamol/ beclomethasone dipropionate) ex-actuator.
  • HFA hydrofluoroalkane
  • the propellant HFA1234ze (trans- 1,3,3,3-tetrafluoroprop-1- ene, herein abbreviated as 1 , 3,3,3- tetrafluoropropene) has low global warming potential and has been described as a potential propellant for use in pMDIs (US2016/0324778).
  • W02023/039103 (Kindeva Drug Delivery) describes metered dose inhaler formulations comprising greater than 70% by weight of HFO-1234ze(E), ethanol and at least one active pharmaceutical ingredient suspended in the formulation to form a suspension. Examples are provided of formulations containing HFO-1234ze(E), ethanol and salbutamol sulfate in suspension.
  • the objective of the present invention is the provision of a fixed-dose combination salbutamol- beclomethasone dipropionate formulation for a pMDI using a propellant without global warming potential and which has suitable properties for treating or preventing lung disorders.
  • the invention provides a pharmaceutical aerosol formulation comprising: (i) salbutamol sulfate in suspension and beclomethasone dipropionate in solution in the formulation as active ingredients (ii) liquefied 1 ,3,3,3-tetrafluoropropene as propellant (iii) ethanol and (iv) optionally a surfactant.
  • Figure 1 shows the relationship between ethanol content (% w/w) and BDP FPD (pg) (Span 85 containing formulations S1-S3, S4-S6) (see Examples section 4.2.1)
  • Figure 2 shows the relationship between ethanol content (% w/w) and salbutamol FPD (pg) (Span 85 containing formulations S1-S3, S4-S6) (see Examples section 4.2.1)
  • Figure 3 shows the relationship between Span 85 content (% w/w) and BDP MMAD (pm) (Surfactant- free formulations S7, S60, S61 & Span 85-containing formulations S3, S8-12, S33-S41 , S62) (see Examples section 4.2.1 and 4.2.4)
  • Figure 4 shows the relationship between Span 85 content (% w/w) and salbutamol MMAD (pm) (Surfactant-free formulations S7, S60, S61 & Span 85-containing formulations S3, S8-12, S33-S41 , S62) (see Examples section 4.2.1 and 4.2.4)
  • Figure 5 shows the relationship between Tween 80 content (% w/w) and BDP MMAD (pm) (Surfactant-free formulations S7, S60, S61 & Tween 80-containing formulations S13-16, S42-48) (see Examples section 4.2.2 and 4.2.4)
  • FIG 6 shows the relationship between Tween 80 content (% w/w) and salbutamol MMAD (pm) (Surfactant-free formulations S7, S60, S61 & Tween 80-containing formulations S13-16, S42-48) (see Examples section 4.2.2 and 4.2.4)
  • Figure 7 shows the relationship between total Span 85/Tween 80 content (% w/w) and BDP MMAD (pm) (Surfactant-free formulations S7, S60, S61 & Span 85/Tween 80-containing formulations S17- 29, S49-59) (see Examples section 4.2.3 and 4.2.4)
  • Figure 8 shows the relationship between total Span 85/Tween 80 content (% w/w) and salbutamol FPD (pm) (Surfactant-free formulations S7, S60, S61 & Span 85/Tween 80-containing formulations S17-29, S49-59) (see Examples section 4.2.3 and 4.2.4)
  • the formulation comprises a surfactant.
  • the surfactant may be a non-ionic surfactant such as a polysorbate e.g. polysorbate 20, polysorbate 60 or polysorbate 80 (sometimes known as Tween 80), a sorbitan fatty acid ester e.g. sorbitan oleate, sorbitan trioleate (sometimes known as Span 85), sorbitan monolaurate or sorbitan monostearate.
  • a poloxamer such as poloxamer 124 and poloxamer 188.
  • the surfactant may be an ionic surfactant such as oleic acid.
  • the surfactant is sorbitan trioleate. In another preferred embodiment the surfactant is polysorbate 80. In another preferred embodiment the surfactant is a mixture of sorbitan trioleate and polysorbate 80
  • the formulation does not contain any surfactant.
  • the formulation contains ethanol to aid solubilising agent of the beclomethasone dipropionate in the formulation.
  • the presence of ethanol also modifies the vapour pressure of the formulation.
  • the concentration of ethanol is 5-16% w/w e.g. 6-16% w/w e.g. 6-15% w/w e.g. 7-14% w/w e.g. 8- 13% w/w e.g. 9-12% w/w.
  • the concentration of ethanol is 5-16% w/w e.g. 6-16% w/w e.g. 6-15% w/w e.g. 7-14% w/w e.g. 8-13% w/w e.g. 9-12% w/w e.g. about 10 % w/w.
  • the concentration of ethanol is 6-12.5% w/w e.g. 7-11% w/w e.g. 8.5-10% w/w e.g. about 9.5 % w/w.
  • the concentration of ethanol is 7-13 % w/w e.g. 8-11.5% w/w e.g. 9-10.5 % w/w.
  • the concentration of ethanol is 5-13% w/w e.g. 6-13% w/w e.g. 6-11% w/w e.g. 7-11% w/w e.g. 8-10% w/w e.g. about 9% w/w.
  • the concentration of surfactant in the formulation if present, is 0.002-1.0% e.g. 0.005-0.2% e.g. 0.005-0.03% w/w.
  • the aforesaid ranges are the total amount of surfactant.
  • the concentration of sorbitan trioleate is 0.002-0.90% w/w e.g. 0.005-0.2% w/w e.g. 0.005-0.015% w/w e.g. about 0.01 % w/w.
  • the concentration of polysorbate 80 is 0.002-0.50% w/w e.g. 0.002-0.33 % w/w e.g. 0.005-0.20% w/w e.g. 0.005-0.03% w/w e.g. about 0.02 % w/w or about 0.025 % w/w.
  • the concentration of sorbitan trioleate is 0.002-0.40% w/w e.g. 0.002-0.10% w/w e.g. 0.002-0.05% w/w e.g. 0.002-0.01% w/w e.g. about 0.005% w/w and the concentration of polysorbate 80 is 0.002-0.40% % w/w e.g. 0.002-0.17 % w/w e.g. 0.002-0.10% w/w e.g. 0.002-0.01 % w/w e.g. about 0.01% w/w.
  • the formulation contains a mixture of sorbitan trioleate and polysorbate 80 as surfactant
  • the total concentration of surfactant is 0.004-0.80% w/w e.g. 0.004-0.27% w/w e.g. 0.004-0.15% w/w e.g. 0.004-0.02% w/w e.g. about 0.015% w/w.
  • the concentration of salbutamol sulfate and beclomethasone dipropionate in the formulation is related to the desired dose to be delivered and the metering volume of the valve used with the pressurised metered dose inhaler.
  • the ex-actuator target delivered dose is mathematically related to the metering volume (e.g. for a target delivered dose of 40 pg of beclomethasone dipropionate from a 63 pL valve (delivering about 74.5 mg of formulation) the concentration of beclomethasone dipropionate would be 0.0671 % w/w, however, it may be desirable to reduce or increase (more typically to increase) the concentration to allow for possible losses in the system or to otherwise modify the performance.
  • the reduction in concentration from the mathematically calculated value may be up to 15% e.g. up to 10% e.g. up to 5%.
  • the increase in concentration from the mathematically calculated value may be up to 30% e.g. 5, 10, 15, 20, 25 or 30%.
  • beclomethasone dipropionate there is an increase and the increase is up to 15% e.g. up to 10% e.g. 2-5% such as about 3%.
  • an increase of 3% to the mathematically calculated value in the example given above would lead to a beclomethasone dipropionate concentration of 0.0691 % w/w.
  • the mathematically calculated value of the concentration of salbutamol (as salbutamol sulfate) would be 0.161 % w/w.
  • the increase is up to 30% e.g. 10-30%.
  • E.g. 15-20% such as about 17%.
  • an increase of 17% to the mathematically calculated value in this example would lead to a salbutamol (as salbutamol sulfate) concentration of 0.188 % w/w.
  • the concentration of salbutamol sulfate in the formulation is 0.12-0.65 % w/w.
  • concentration of salbutamol sulfate in the formulation is 0.32-0.65 % w/w e.g. 0.33-0.58 % w/w e.g. 0.35-0.55 % w/w .
  • concentration of salbutamol sulfate in the formulation is 0.16-0.33 % w/w e.g. 0,16-0.30 % w/w e.g.
  • the concentration of salbutamol sulfate in the formulation is 0.12-0.26 % w/w e.g. 0.13-0.23 % w/w e.g. 0.14-0.22 % w/w e.g. 0.18-0.19 % w/w.
  • the concentration of salbutamol sulfate in the formulation is suitably 0.16-0.60 % w/w.
  • the concentration of salbutamol sulfate in the formulation is suitably 0.15-0.61 % w/w.
  • the concentration of salbutamol sulfate in the formulation is suitably 0.15-0.69 % w/w.
  • the concentration of salbutamol sulfate in the formulation is suitably 0.16-0.53 % w/w.
  • the salbutamol sulfate is present in the formulation in suspension.
  • the salbutamol sulfate is present in particulate form.
  • the particles of salbutamol sulfate have particle size distribution with a Dv10 of 0.3-1 pm, Dv50 of 1-3 pm and Dv95 of 3-6 pm as determined by laser light scattering e.g. using a Coulter LS Particle Size Analyzer.
  • salbutamol sulfate in particulate form of an appropriate particle size distribution can be prepared by milling, suitably micronisation.
  • the concentration of beclomethasone dipropionate in the formulation is 0.04-0.27 % w/w.
  • the concentration of beclomethasone dipropionate in the formulation is 0.10-0.27% w/w e.g 0.12-0.25 % w/w e.g. 0.13- 0.23 % w/w.
  • the concentration of beclomethasone dipropionate in the formulation is 0.05-0.14% w/w e.g. 0.06-0.13 % w/w e.g. 0.06- 0.12 % w/w e.g.
  • the concentration of beclomethasone dipropionate in the formulation is 0.04-0.11 % w/w e.g 0.05-0.10 % w/w e.g. 0.05-0.09 % w/w e.g. 0.06-0.07 % w/w.
  • the concentration of beclomethasone dipropionate in the formulation is suitably 0.04-0.24 % w/w.
  • the concentration of beclomethasone dipropionate in the formulation is suitably 0.06-0.20 % w/w.
  • the concentration of beclomethasone dipropionate in the formulation is suitably 0.04-0.31 % w/w.
  • the concentration of beclomethasone dipropionate in the formulation is suitably 0.04-0.27 % w/w.
  • the pharmaceutical aerosol formulation consists essentially of e.g. consists of (i) salbutamol sulfate in suspension and beclomethasone dipropionate in solution in the formulation as active ingredients (ii) liquefied 1 ,3,3,3-tetrafluoropropene as propellant (iii) ethanol and (iv) optionally a surfactant.
  • the formulation comprises, consists essentially of or consists of 0.18-0.19 % w/w salbutamol sulfate in suspension, 0.06-0.07 % w/w beclomethasone dipropionate in solution, 9-12 % w/w e.g. about 10% w/w ethanol, 0.005-0.015% w/w e.g. about 0.01% w/w sorbitan trioleate and liquefied 1 ,3,3,3-tetrafluoropropene (qs).
  • This formulation may, for example, be suitable for use with a 63 pL valve.
  • the formulation comprises, consists essentially of or consists of 0.23-0.25 % w/w salbutamol sulfate in suspension, 0.08-0.10 % w/w beclomethasone dipropionate in solution, 9- 12 % w/w e.g. about 10% w/w ethanol, 0.005-0.015% w/w e.g. about 0.01 % w/w sorbitan trioleate and liquefied 1 ,3,3,3-tetrafluoropropene (qs).
  • This formulation may, for example, be suitable for use with a 50 pL valve.
  • the formulation comprises, consists essentially of or consists of 0.18-0.19 % w/w salbutamol sulfate in suspension, 0.06-0.07 % w/w beclomethasone dipropionate in solution, 8.5- 10% w/w e.g. about 9.5% w/w ethanol, 0.005-0.03% w/w e.g. about 0.02% w/w or about 0.025% w/w polysorbate 80 and liquefied 1 ,3,3,3-tetrafluoropropene (qs).
  • This formulation may, for example, be suitable for use with a 63 pL valve.
  • the formulation comprises, consists essentially of or consists of 0.23-0.25 % w/w salbutamol sulfate in suspension, 0.08-0.10 % w/w beclomethasone dipropionate in solution, 8.5- 10% w/w e.g. about 9.5% w/w ethanol, 0.005-0.03% w/w e.g. about 0.02% w/w or about 0.025% w/w polysorbate 80 and liquefied 1 ,3,3,3-tetrafluoropropene (qs).
  • This formulation may, for example, be suitable for use with a 50 pL valve.
  • the formulation comprises, consists essentially of or consists of 0.18-0.19 % w/w salbutamol sulfate in suspension, 0.06-0.07 % w/w beclomethasone dipropionate in solution, 9-10.5 % w/w e.g. about 9.5% w/w ethanol, 0.002-0.01% w/w e.g. about 0.005% w/w sorbitan trioleate, 0.002-0.01% w/w e.g. about 0.01% w/w polysorbate 80 and liquefied 1 ,3,3,3-tetrafluoropropene (qs).
  • This formulation may, for example, be suitable for use with a 63 pL valve.
  • the formulation comprises, consists essentially of or consists of 0.23-0.25 % w/w salbutamol sulfate in suspension, 0.08-0.10 % w/w beclomethasone dipropionate in solution, 9-10.5 % w/w e.g. about 9.5% w/w ethanol, 0.002-0.01% w/w e.g. about 0.005% w/w sorbitan trioleate, 0.002-0.01 % w/w e.g. about 0.01 % w/w polysorbate 80 and liquefied 1 ,3,3,3-tetrafluoropropene (qs).
  • This formulation may, for example, be suitable for use with a 50 pL valve.
  • the formulation comprises, consists essentially of or consists of 0.18-0.19 % w/w salbutamol sulfate in suspension, 0.06-0.07 % w/w beclomethasone dipropionate in solution, 8-10% w/w e.g. about 9% w/w ethanol and liquefied 1 ,3,3,3-tetrafluoropropene (qs).
  • This formulation may, for example, be suitable for use with a 63 pL valve.
  • the formulation comprises, consists essentially of or consists of 0.23-0.25 % w/w salbutamol sulfate in suspension, 0.08-0.10 % w/w beclomethasone dipropionate in solution, 8-10% w/w e.g. about 9% w/w ethanol and liquefied 1 ,3,3,3-tetrafluoropropene (qs).
  • This formulation may, for example, be suitable for use with a 50 pL valve.
  • Beclomethasone dipropionate can be used in its anhydrous or hydrated form (i.e. comprising one molecule of water of hydration).
  • the beclomethasone dipropionate is used as anhydrous beclomethasone dipropionate for minimizing the level of free water in the formulation.
  • the ethanol as used in the formulation is anhydrous ethanol, i.e. dehydrated alcohol for minimizing the level of free water in the formulation.
  • Suitably formulations of the invention are chemically stable.
  • Suitably formulations are chemically stable such that there is a reduction in purity of salbutamol sulfate of less than 0.2% e.g. less than 0.15% e.g. less than 0.1% after storage for 6 months at 25 °C and 60% RH.
  • Suitably formulations are chemically stable such that there is a reduction in purity of salbutamol sulfate of less than 0.5% e.g. less than 0.3% e.g. less than 0.2% after storage for 12 weeks at 40 °C and 75% RH.
  • Suitably formulations are chemically stable such that there is a reduction in purity of beclomethasone dipropionate of less than 0.3% e.g.
  • formulations are chemically stable such that there is a reduction in purity of beclomethasone dipropionate of less than 1.0% e.g. less than 0.8% e.g. less than 0.6% after storage for 12 weeks at 40 °C and 75% RH. Purity may be determined as reportable % area as described in Example 4.2.5. The aforesaid percentage figures are by weight.
  • the invention further provides a canister containing a plurality of doses of a formulation as described herein and fitted with a metering valve.
  • the plurality of doses may be, for example, 60 to 200 doses including a suitable overage.
  • the metering valve may, for example, have a volume of 20-70 pL, and metering valves of volume 25 pL, 50 pL or 63 pL are most suitable since they are readily available from commercial suppliers. Metering valve volumes of 50 pL- 63 pL are preferred due to their superior performance when used with formulations of the invention. In one embodiment the metering valve volume is 50 pL In another embodiment the metering valve volume is 63 pL
  • Canisters generally comprise a container capable of withstanding the vapour pressure of the formulation, such as plastic or plastics coated glass bottle or preferably a metal can, for example an aluminium can which may optionally be anodised, lacquer-coated and/or plastics coated, which container is closed with a metering valve. It may be preferred that canisters be coated with a fluorocarbon polymer as described in WO 96/32151 , for example, a co-polymerof polyethersulphone (PES) and polytetrafluoroethylene (PTFE). Another polymer for coating that may be contemplated is FEP (fluorinated ethylene propylene).
  • the metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate gaskets to prevent leakage of the formulation through the valve.
  • Valve seals will preferably be manufactured of a material which is inert to and resists extraction into the contents of the formulation, especially since the contents include ethanol.
  • the seals may comprise any suitable elastomeric material such as for example low density polyethylene, chlorobutyl, black and white butadiene-acrylonitrile rubbers, butyl rubber, ethylenepropylene diene terpolymer (EPDM) rubber and neoprene.
  • Valve materials especially the material of manufacture of the metering chamber, will preferably be manufactured of a material which is inert to and resists distortion by contents of the formulation, especially since the contents include ethanol.
  • Particularly suitable materials for use in manufacture of valve components e.g.
  • the metering chamber include metals, e.g. stainless steel, polyesters e.g. polybutyleneterephthalate (PBT) and polyacetals (POM), especially PBT.
  • Materials of manufacture of the metering chamber and/or the valve stem may desirably be fluorinated, partially fluorinated or impregnated with fluorine containing substances in order to resist drug deposition.
  • Thermoplastic elastomer valves as described in WO92/11190 and valves containing ethylene-propylene diene terpolymer (EPDM) rubber as described in WO95102651 are especially suitable. Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Aptar Pharma, France (eg.
  • DF10, DF30, DF31 , DF60 Bespak Ltd, UK (eg. BK300, BK356, BK357) and 3M-Neotechnic Ltd, UK (eg. 3MTM Retention valve or SpraymiserTM).
  • the invention also provides a metered dose inhaler comprising a canister fitted with a metering valve and installed in a channelling device comprising an actuator adapted for topical administration of the formulation to the lung.
  • the actuator is activated by pressing the bottom of the canister into the housing with the subject required to coordinate depression of the canister with inhaling through the mouthpiece (so called “press and breath” inhalers).
  • the inhaler is breath-actuated such that the actuation (canister depression) occurs when the subject inhales through the mouthpiece.
  • the invention provides a method of treating or preventing an inflammatory disorder of the lung which comprises administering to a human subject in need thereof by inhalation a metered dose of a formulation as described herein.
  • the invention also provides a metered dose of a formulation as described herein for use in treating or preventing an inflammatory disorder of the lung when administered by inhalation.
  • the invention also provides use of a metered dose of a formulation as described herein for the manufacture of a medicament for treating or preventing an inflammatory disorder of the lung when administered by inhalation.
  • the disorder is asthma or COPD.
  • the beclomethasone dipropionate is administered with a MMAD of 1-4 e.g. 1-2 e.g. 1-1.5 e.g. 1.2-1.5 pm.
  • the delivered dose of beclomethasone dipropionate is 30-50 pg e.g. 32-48 pg e.g. 34-46 pg per inhalation.
  • the fine particle dose of beclomethasone dipropionate is 16-24 pg e.g. 17-23 pg e.g. 18-22 pg per inhalation.
  • the fine particle fraction of beclomethasone dipropionate is more than 40% e.g. more than 50% e.g. 50- 60% per inhalation.
  • the salbutamol (as salbutamol sulfate) is administered with a MMAD of 1-5 e.g. 2-4 e.g. 2-3 e.g. 2.2-3 pm.
  • the delivered dose of salbutamol is 67-113 pg e.g. 72-108 pg e.g. 76-104 pg per inhalation.
  • the fine particle fraction of salbutamol is more than 35% e.g. more than 40% e.g. 40-50% per inhalation.
  • aerosol particle size distribution parameters e.g. delivered dose, fine particle mass, fine particle fraction and MMAD
  • pharmacopoeias such as the European Pharmacopoeia and the United States Pharmacopoeia, e.g. NGI and DUSA apparatuses e.g. as described therein and in the Examples below.
  • an aliquot of the liquified formulation is added to an open canister under conditions which are sufficiently cold that the formulation does not vaporise, and then a metering valve crimped onto the canister.
  • each filled canister is check- weighed, coded with a batch number and packed into a tray for storage before release testing.
  • Suitable channelling devices comprise, for example a valve stem receptacle and a cylindrical or cone-like passage through which medicament may be delivered from the filled canister via the metering valve to the mouth of a subject i.e. a mouthpiece.
  • valve stem is seated in a nozzle block which has an orifice leading to an expansion chamber.
  • the expansion chamber has an exit orifice which extends into the mouthpiece.
  • Actuator (exit) orifice diameters in the range 0.1-0.45 mm are generally suitable eg. 0.15, 0.22, 0.25, 0.30, 0.33 or 0.42 mm.
  • the dimensions of the orifice should not be so small that blockage of the jet by particulate drug occurs.
  • Actuator jet lengths are typically in the range 0.30- 1.7 mm eg. 0.30, 0.65 or 1.50 mm for buccal administration.
  • the precise shape and dimensions of the actuator will be adapted to the needs of the specific formulation to be applied for topical administration to the lung as appropriate.
  • the canister and metering valve may be incorporated into a breath-actuated inhaler device.
  • breath-actuated devices common to breath-actuated devices is that the patients’ inspiratory force triggers a loaded mechanical system to release the metered dose from the metering valve or another device component into the channeling component and the inhalation airflow.
  • the nozzle block design and exit orifice diameter may be similar for conventional press and breathe and breath-actuated pressurised metered dose inhalers, with the latter the canister is not manually depressed. Instead, the valve metering chamber fills in the resting position as for conventional pressurised metered dose inhalers but canister depression is effected e.g., by means of a lever mechanism or opening of the mouthpiece cover.
  • the dose is however not released from the device further to canister depression as, e.g., the metering valve orifice is obstructed or, e.g., the dose released from the metering chamber is held in a secondary kinked retention valve.
  • the metered dose is released as, e.g., the obstruction to the metering valve orifice is lifted or, e.g., the dose retention valve straightens
  • the dose is thus released into the patient’s airstream in a breath-synchronised manner.
  • breath-actuated devices are sold under the brand names K-halerTM, EasibreatheTM, AutohalerTM and RedihalerTM.
  • a pharmaceutical aerosol formulation comprising: (i) salbutamol sulfate in suspension and beclomethasone dipropionate in solution in the formulation as active ingredients (ii) liquefied 1 , 3,3,3- tetrafluoropropene as propellant (iii) ethanol and (iv) optionally a surfactant.
  • a formulation according to clause 1 which contains a surfactant which is a non-ionic surfactant.
  • a formulation according to clause 2 which contains a mixture of sorbitan trioleate and polysorbate 80 as non-ionic surfactant.
  • a formulation according to clause 8 wherein the concentration of ethanol is 6-16% w/w e.g. 6-15% w/w e.g. 7-14% w/w e.g. 8-13% w/w e.g. 9-12% w/w.
  • a formulation according to clause 8 wherein the concentration of ethanol is 5-13% w/w e.g. 6- 13% w/w e.g. 6-11 % w/w e.g. 7-11 % w/w e.g. 8-10% w/w e.g. about 9% w/w. 14.
  • a canister according to clause 18 which has an internal surface in contact with the formulation which is plasma treated and/or coated or lined with a drug deposition resistive material such as a polymer.
  • a metered dose inhaler comprising a canister according to clause 18 or clause 19 installed in a channelling device comprising an actuator adapted for topical administration of the formulation to the lung.
  • a method of treating or preventing an inflammatory disorder of the lung which comprises administering to a human subject in need thereof by inhalation a metered dose of a formulation according to any one of clauses 1 to 17.
  • Clenil Compositum (beclomethasone dipropionate I salbutamol (as sulfate) combination 250/100 pg metered dose) marketed in Italy and elsewhere (Chiesi Farmaceutici)
  • Salbair-B beclomethasone dipropionate /levosalbutamol (as sulfate) combination 50/50 pg metered dose) (Lupin) marketed in India.
  • Aerocort beclomethasone dipropionate /levosalbutamol (as sulfate) combination 50/50 pg metered dose) (Cipla) marketed in India.
  • Example formulations shown in Table 1 were prepared.
  • Aerosol formulations were prepared as follows:
  • the manufacturing method employed for the development of spray formulations is detailed below.
  • the surfactant (Span 85, Tween 80 or a combination thereof), if applicable, and ethanol were weighed into amber glass vials and stirred for ca. 5 minutes at 500 rpm until visually homogenous.
  • BDP was added and stirred at 500 rpm for ca. 10 minutes until the drug dissolves.
  • Salbutamol sulphate was then be added and stirred at 500 rpm for ca. 10 minutes.
  • the premix containing ethanol, active ingredients and surfactant(s) (where applicable) was added to the canister with rapid stirring to achieve homogeneity.
  • the canister containing the formulation was crimped followed by the addition of propellant and shaken to mix the constituents of the formulation.
  • the canister was stored inverted following manufacture for a minimum of 14 days post-manufacture to allow equilibration of the valve and formulation. Dose priming by actuating twice to waste was performed prior to inversion (with canister shaking for 10 seconds at 2 shakes per second before each actuation).
  • Example formulations were packaged in canisters with a 63 pL, 50 pL or 25 pL metering valve, with an appropriate concentration chosen for the APIs to achieve the target delivered dose.
  • Valve 63 pL, 50 pL or 25 pL B357 Inverted Use Cut Edge Can Metering Valve, EPDM/PBT (supplier Bespak)
  • NGI and DUSA Example formulations and Reference products were assessed using the Next Generation Impactor (NGI) and Dose Unit Sampling Apparatus (DUSA).
  • NGI Next Generation Impactor
  • DUSA Dose Unit Sampling Apparatus
  • the NGI was used to assess Aerodynamic Particle Size Distribution (APSD), the DUSA to assess Delivered Dose and Delivered Dose Uniformity (DD and DDU, respectively)
  • canisters were stored inverted at ambient temperature for at least 14 days to facilitate formulation/valve equilibration. Based on the learnings from the earlier experiments, dose priming was performed by actuating twice to waste prior to inversion (with canister shaking for 10 seconds at 2 shakes per second before each actuation).
  • the Next Generation Impactor is a particle classifying cascade impactor designed specifically for the pharmaceutical industry for testing pMDIs, dry powder inhalers (DPIs), nebulizers and nasal sprays.
  • the NGI is one of the official instruments for determining APSD as documented in pharmacopoeias such as the European Pharmacopoeia and the United States Pharmacopoeia.
  • the main components of the NGI are the induction port, the impactor itself comprising the impactor stages, and the vacuum pump.
  • the induction port (an aluminium or stainless-steel tube with a 90° bend) serves to simulate the mouth and throat of a patient and direct the airflow through the impactor to which it is connected.
  • the vacuum pump creates an airflow through the impactor stages, reproducing at the induction port the peak flow generated by the act of inspiration. The flow is kept constant at 30 L/min for the duration of the test.
  • the impactor itself comprises three main parts:
  • the cup tray containing eight removable impaction cups used to collect the aerosol and classify the aerosol particles according to their aerodynamic size prior to HPLC analysis.
  • the bottom frame used to support the cup tray, which allows the insertion and removal of collection cups from the impactor, and provides the structure for a clamping and sealing mechanism.
  • the lid containing the inter-stage passageways and the seal body which incorporates different sized nozzles for different cups, and facilitates the impaction of aerosol particles of pre-defined size ranges on the different collection cups.
  • the parts are assembled and connected to the vacuum pump.
  • the pump is switched on and once the constant airflow of 30 L/min is established at the induction port, the pMDI is shaken and attached to the induction port using a rubber mouthpiece adaptor for an airtight seal.
  • the pMDI is actuated by depressing the canister to deliver the aerosol from the metering valve. Then the pMDI is removed and the shaking-insertion-actuation-removal cycle is repeated 9 further times to collect a total of 10 actuations in the NGI, which are required because of the quantitation limits of the HPLC method.
  • the whole apparatus is dissembled and the drug deposited in the 7 sizing cups and the micro-orifice collector/filter stage of the NGI, the induction port and the pMDI actuator is washed off using adequate amounts of solvent and collected for quantification of the drug mass by HPLC methods such as described in detail in the HPLC methods section below.
  • the Dosage Unit Sampling Apparatus is a dose-collecting apparatus specified in various pharmacopoeiae, e.g. the European Pharmacopoeia and the United States Pharmacopoeia, to sample and test pMDIs. It is used to perform the tests for DD and DDU as specified by the relevant compendial standards.
  • the DUSA consists of a standardised collection tube and associated cap with a mouthpiece adaptor and a filter holder into which a filter is placed. These parts are assembled and connected to a vacuum pump. The pump is switched on and once a constant airflow of 28.3 L/min is established, the pMDI is shaken and attached to the mouthpiece adaptor to form an airtight seal. The pMDI is actuated by pressing the canister bottom to deliver the aerosol from the metering valve through the actuator into the DUSA. The pMDI is removed, shaken again, re-attached to the DUSA mouthpiece adaptor and actuated a second time as a full dose is comprised of 2 actuations.
  • the DUSA test is performed at the beginning, middle and end of inhaler usage as defined by the nominal number of actuations within the pMDI.
  • HPLC Method 1 which was mostly used to perform the determination of Example formulations is summarised in Table 2 below.
  • HPLC Methods 2, 3 and 4 summarised in Tables 3-5 below were mostly used to perform NGI analyses of the commercialised Reference products in contrast to the methods employed to analyse Example formulations S1-S65, as the Reference products were analysed at a different time.
  • HPLC Method 3 was also used in the valve investigation studies.
  • HPLC Method 5 summarised in Table 6 below was used in the chemical stability studies upon storage. Salbutamol sulfate was always quantified as salbutamol free base. Accordingly, FPD, FPF, DD and MMAD values are referred to as values based on salbutamol not salbutamol sulfate.
  • Table 7A NGI results for Qvar Redihaler 40 ng (beclomethasone dipropionate)
  • Table 7B NGI results for Proventil HFA 90 ng (salbutamol sulfate)
  • Tables 7C, 7D and 7E The results of testing certain combination Reference products (see section 2.2.2) are shown in Tables 7C, 7D and 7E below.
  • Table 7C shows the result of FPD, DD, FPF and MMAD testing for Clenil Compositum by two CDMOs on three batches.
  • Table 7D shows the result of FPD, DD, FPF and MMAD testing for Salbair B by one CDMO on two batches.
  • Table 7E shows the result of FPD, DD, FPF and MMAD testing for Aerocort by one CDM on two batches.
  • the optimal (i.e. target) MMAD for salbutamol is approximately 2-3 pm especially 2.2-3 pm; and the optimal (i.e. target) MMAD for beclomethasone dipropionate is approximately 1-1.5 pm especially 1.2-1.5 pm respectively.
  • the combination Reference products can be seen to have low FPF compared to the monotherapy Reference products.
  • valve volume With a view to investigating the effect of valve volume in order to guide later studies, various formulations were tested to determine the delivered dose, the final particle dose and the MMAD. In a first set of experiments, 63 pL and 25 pL valves were compared.
  • Fine particle dose (FPD) data generated with an NGI are presented in Table 9.
  • Mass median aerodynamic (MMAD) data generated with an NGI are presented in Table 10.
  • the 63 pL valve and the 50 pL valve were considered similar and superior to the 25 pL valve.
  • the 63 pL valve also demonstrated lower actuator/valve deposition than the 25 pL valve (data not shown). Most further studies were performed with the 63 pL valve. 4.2 Studies to investigate Example formulations
  • Table 12 shows the result of FPD, DD and MMAD testing and Table 13 shows the results of DDU testing. A 63 pL valve was used except where indicated.
  • E - content fill estimated on the basis of presumptive concentration within the formulation and initially estimated shot weight (77.1 mg). Incremental I decremental changes in API content calculated against E *50 pL metering valve, with requisite higher API content (see Table 1). All other formulations used 63 pL valve
  • the inset figure presents the relationship between BDP MMAD and Span 85 over a more limited, closer to optimal, Span 85 range.
  • Table 12 and Figures 1 and 2 show that the FPD values of BDP and SS in Span 85 containing formulations decrease with increasing ethanol levels.
  • Tables 12 and 13 and Figures 3 and 4 show the coarsening effect of increasing Span 85 content on BDP and salbutamol MMAD values, implying an optimal Span 85 level of less than around 0.2 % w/w especially less than around 0.015% w/w.
  • Table 14 shows uniformity of DD for both BDP and salbutamol at start, middle and end of canister life for Span 85-containing formulations.
  • the totality of the data indicate that a salbutamol sulfate concentration of 0.18-0.19 % w/w, beclomethasone di propionate concentration of 0.06-0.07 % w/, ethanol content of 9-12 % w/w, sorbitan trioleate content of 0.005-0.015% w/w and liquefied 1 ,3,3,3-tetrafluoropropene (qs) achieve close to optimal formulation performance in conjunction with a 63 pL metering valve.
  • S means Start (doses 1 and 2)
  • M means Middle (doses 60 and 61)
  • E means End (doses 119 and 120)
  • Table 15 shows the result of FPD, DD and MMAD testing and Table 16 shows the results of DDU testing.
  • a 63 pL valve was used in all cases. HPLC Method 1 was used.
  • E - content fill estimated on the basis of presumptive concentration within the formulation and initially estimated shot weight (77.1 mg). Incremental I decremental changes in API content calculated against E
  • Tween 80 content and BDP MMAD for Tween 80 containing formulations based on the data presented in Table 15, is presented in Figure 5 which also includes data for three non-surfactant formulations (containing 9.5% to 11.0% w/w ethanol).
  • Tween 80 content and salbutamol MMAD for Tween 80 containing formulations based on the data in Table 15, is presented in Figure 6 which also includes data for three non-surfactant formulations (containing 9.5% to 11.0% w/w ethanol).
  • Table 15 and Figures 5 and 6 show the coarsening effect of increasing Tween 80 content on BDP and AS MMAD values, implying an optimal Tween 80 level of less than around 0.2 % w/w especially less than around 0.03% w/w.
  • Table 16 shows uniformity of DD for both BDP and salbutamol at start, middle and end of canister life for Tween 80-containing formulations.
  • the totality of the data indicate that a salbutamol sulfate concentration of 0.18-0.19 % w/w, beclomethasone dipropionate concentration of 0.06-0.07 % w/, ethanol content of 8.5-10 % w/w, polysorbate 80 content of 0.005-0.03% w/w and liquefied 1 ,3,3,3-tetrafluoropropene (qs) achieve close to optimal formulation performance in conjunction with a 63 pL metering valve.
  • close to optimal FPD performance, and thus clinically meaningful formulations may also be attained with considerably lower (e.g., down to 6% w/w) or higher (e.g., up to 12.5% w/w) ethanol concentrations.
  • S means Start (doses 1 and 2)
  • M means Middle (doses 60 and 61)
  • E means End (doses 119 and 120)
  • Table 17 shows the result of FPD, DD and MMAD testing and Table 18 shows the results of DDU testing.
  • a 63 pL valve was used in all cases.
  • E - content fill estimated on the basis of presumptive concentration within the formulation and initially estimated shot weight (77.1 mg). Incremental I decremental changes in API content calculated against E
  • Table 17 and Figures 7 and 8 show the coarsening effect of increasing Span 85/Tween 80 content on BDP and salbutamol MMAD values, implying an optimal total Span 85/Tween 80 content of less than around 0.15 % w/w especially less than around 0.02% w/w.
  • Table 18 shows uniformity of DD for both BDP and salbutamol at start, middle and end of canister life.
  • the totality of the data indicate that a salbutamol sulfate concentration of 0.18-0.19 % w/w, beclomethasone dipropionate concentration of 0.06-0.07 % w/, ethanol content of 9-10.5 % w/w, sorbitan trioleate content of 0.002-0.01% w/w polysorbate 80 content of 0.002-0.01% w/w and liquefied 1 ,3,3,3-tetrafluoropropene (qs) achieve close to optimal formulation performance in conjunction with a 63 pL metering valve.
  • E - content fill estimated on the basis of presumptive concentration within the formulation and initially estimated shot weight (77.1 mg). Incremental / decremental changes in API content calculated against E
  • & Average means the average of the values at the S, M and E sampling locations.
  • S means Start (doses 1 and 2)
  • M means Middle (doses 60 and 61)
  • E means End (doses
  • Table 19 shows the result of FPD, DD and MMAD testing and Table 20 shows the results of DDU testing. A 63 pL valve was used in all cases.
  • E - content fill estimated on the basis of presumptive concentration within the formulation and initially estimated shot weight (77.1 mg). Incremental I decremental changes in API content calculated against E
  • Table 20 shows uniformity of DD for both BDP and salbutamol at start, middle and end of canister life.
  • the totality of the data indicate that a salbutamol sulfate concentration of 0.18-0.19 % w/w, beclomethasone dipropionate concentration of 0.06-0.07 % w/, ethanol content of 8-10 % w/w, and liquefied 1 ,3,3,3-tetrafluoropropene (qs) achieve close to optimal formulation performance in conjunction with a 63 pL metering valve.
  • close to optimal FPD performance, and thus clinically meaningful formulations may also be attained with considerably lower (e.g., down to 5% w/w or 6% w/w) or higher (e.g., up to 13% w/w) ethanol concentrations.
  • & Average means the average of the values at the S, M and E sampling locations.
  • S means Start (doses 1 and 2)
  • M means Middle (doses 60 and 61)
  • E means End (doses 119 and 120)
  • the % area of SS and BDP ranged from ca. 99.84 - 99.87% area (for salbutamol) and ca. 99.48 - 99.52% area (for BDP).
  • formulations of the invention in at least some embodiments demonstrate one or more of the following favourable properties:
  • the FPF expresses the fraction of the delivered (ex-actuator) dose that is comprised of the fine particle dose ( ⁇ 5 pm). It is thus expressed as a percentage and may be considered to reflect the “efficiency” of a formulation in that particles of less than 5 pm in diameter are generally considered to be “respirable” whilst coarser particles exhibit a greater predisposition to oropharyngeal deposition where they do not contribute to the intended effect (in the lung) but may elicit local or systemic adverse effects of the medication. Thus, an ideal inhaled formulation would have a FPF of 100%, although such formulations do not currently exist.
  • the FPF values for formulations S63, S65 and S64 ranged from ⁇ 53 to 55% for the beclomethasone dipropionate component and ⁇ 43 to 47% for the salbutamol component (see Tables 13, 15 and 19).
  • These FPF values are similar to those of the monotherapy Reference products Qvar RediHaler 40 pg; and Proventil HFA 90 pg (see Tables 7A & 7B above).
  • FPF values for beclomethasone dipropionate and salbutamol for many other compositions of the invention also exceed those of the combination Reference products, this being particularly the case when the ethanol concentration used was relatively low within the suitable ranges.
  • Example 3 of that disclosure states that “increasing ethanol levels beyond 5% by weight, resulted in no further benefit in mean ex-actuator delivered dose, whilst resulting in a significant and undesirable reduction in FPM and FPF. Therefore, it was learned that the most beneficial level of ethanol in the composition to provide maximum benefit to both delivered dose and FPM/FPF is between 2% and 5% ethanol by weight in HFO-1234ze(E) suspensions of salbutamol sulfate.”

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Abstract

L'invention concerne une formulation d'aérosol pharmaceutique comprenant : (i) du sulfate de salbutamol en suspension et du dipropionate de béclométhasone en solution dans la formulation en tant que principes actifs, (ii) du 1,3,3,3-tétrafluoropropène liquéfié en tant qu'agent propulseur, (iii) de l'éthanol et (iv) éventuellement un tensioactif.
PCT/GB2025/050959 2024-05-03 2025-05-02 Aérosol comprenant du sulfate de salbutamol et du dipropionate de béclométhasone Pending WO2025229354A1 (fr)

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WO1996032151A1 (fr) 1995-04-14 1996-10-17 Glaxo Wellcome Inc. Inhalateur doseur de propionate fluticasone
WO2004019985A1 (fr) * 2002-08-29 2004-03-11 Cipla Ltd Produits et compositions pharmaceutiques comprenant des agents anticholinergiques specifiques, des agonistes beta-2 et des corticosteroides
GB2456028A (en) * 2008-11-14 2009-07-01 Consort Medical Plc A medicament dispenser with an HFO propellant
US20160324778A1 (en) 2004-04-29 2016-11-10 Honeywell International Inc. Medicament delivery formulations, devices and methods
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Publication number Priority date Publication date Assignee Title
WO1992011190A2 (fr) 1990-12-21 1992-07-09 Minnesota Mining And Manufacturing Company Dispositif pour administrer un aerosol
WO1996032151A1 (fr) 1995-04-14 1996-10-17 Glaxo Wellcome Inc. Inhalateur doseur de propionate fluticasone
WO2004019985A1 (fr) * 2002-08-29 2004-03-11 Cipla Ltd Produits et compositions pharmaceutiques comprenant des agents anticholinergiques specifiques, des agonistes beta-2 et des corticosteroides
US20160324778A1 (en) 2004-04-29 2016-11-10 Honeywell International Inc. Medicament delivery formulations, devices and methods
GB2456028A (en) * 2008-11-14 2009-07-01 Consort Medical Plc A medicament dispenser with an HFO propellant
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