WO2022129069A1 - Pharmaceutical composition comprising epinephrine for aerosol administration - Google Patents

Pharmaceutical composition comprising epinephrine for aerosol administration Download PDF

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Publication number
WO2022129069A1
WO2022129069A1 PCT/EP2021/085723 EP2021085723W WO2022129069A1 WO 2022129069 A1 WO2022129069 A1 WO 2022129069A1 EP 2021085723 W EP2021085723 W EP 2021085723W WO 2022129069 A1 WO2022129069 A1 WO 2022129069A1
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Prior art keywords
pharmaceutical composition
aerosol
use according
liquid
epinephrine
Prior art date
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PCT/EP2021/085723
Other languages
French (fr)
Inventor
Dutch CHUNG
Leander Dittmann
Stephen MALCOLM
Pavel POSPISIL
Original Assignee
Philip Morris Products S.A.
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Publication of WO2022129069A1 publication Critical patent/WO2022129069A1/en

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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
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to an orally inhaled pharmaceutical composition
  • an orally inhaled pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof for use in the emergency treatment of allergic reactions including anaphylaxis and anaphylactic shock.
  • Anaphylaxis or anaphylactic shock is a severe allergic reaction that often requires immediate medical treatment. Anaphylaxis affects many of the body’s organs including the heart; lungs, skin and stomach as well as causing swelling of the mouth and throat.
  • the standard treatment of care for anaphylaxis is intramuscular delivery of epinephrine (also known as adrenaline) via injection.
  • Epinephrine is a catecholamine that stimulates the a- and p-adrenergic receptors of the sympathetic nervous system.
  • Epinephrine binds to these adrenergic receptors leading to relief of many life-threatening symptoms of anaphylaxis through relaxation of the smooth muscle in the bronchi of the lungs thereby opening up constricted airways; constriction of the blood vessels leading to decreased swelling of the tongue and throat; and increasing blood pressure and heart rate thereby preventing or reversing cardiovascular collapse.
  • administration by injection may not deliver epinephrine intramuscularly as intended but rather result in the active ingredient being deposited within the bone or subcutaneously.
  • Incorrectly injected epinephrine can delay or impair the effectiveness of the treatment during a time-critical period.
  • the use of a needle, particularly for children, has the potential to cause additional pain and/or damage to the bone if the needle over-penetrates beyond the intramuscular level. Further, injections tend to be painful and can be difficult to correctly self-administer.
  • epinephrine as an aerosol offers an alternative route of administration that is less painful and easier to self-administer.
  • Various publications describe suitable formulations for aerosol administration of epinephrine.
  • US2018126100 and US2019282497 describe epinephrine formulations for intra-nasal aerosol delivery and Epinephrine inhalers in emergency sets of patients with anaphylaxis; Schlegel et al (JDDG, Vol. 7, Issue 5, May 2009, p.
  • 420-425 describes two marketed formulations for aerosol delivery of epinephrine: a pressurized metered dose inhaler formulation (Primatene MistTM) and a handheld pump spray or liquid nebuliser formulation (InfectoKrupp ® Inhal).
  • Liquid nebuliser formulations require continuous delivery of the pharmaceutical composition to a subject which typically leads to longer periods of administration. In addition, they require higher device-loads of the pharmaceutical composition in order to achieve a targeted dosing of the active ingredient to the subject. Because anaphylaxis can be life threatening and stressful, the long duration required to administer a single dose using conventional nebulization poses additional health risks and complications, making liquid nebuliser formulations unsuitable for emergency treatment. In addition, due to the number of inhalations required for effective administration, patients can often experience gastrointestinal distress such as nausea and vomiting.
  • Formulations for pressurized metered dose inhalers such as Primatene MistTM require a propellant and the steps needed to administer them effectively are difficult for children to perform.
  • Nasal spray formulations such as those disclosed in US2018126100 and US2019282497, are unable to create an aerosol capable of delivering the active ingredient deep into the lung of a subject due the relatively large size of the particles they form.
  • an object of the present invention to provide an improved inhalable pharmaceutical composition that delivers epinephrine or a pharmaceutically acceptable salt thereof to a subject that is both easy to administer and achieves rapid systemic and local delivery of the active ingredient.
  • the present invention relates to a pharmaceutical composition for use in the treatment of an allergic reaction or symptom thereof comprising:
  • a solvent selected from water or a water/alcohol mixture characterised in that the pharmaceutical composition is orally administered as a liquid aerosol comprising liquid droplets generated by Rayleigh droplet train; interface-friction induced droplet break-up; direct atomization; or capillary wave breakup.
  • the pharmaceutical composition for use according to the present invention may be used to treat an allergic reaction selected from anaphylaxis or anaphylactic shock.
  • the pharmaceutical composition for use according to the present invention may be used in the emergency treatment of an allergic reaction to insect stings or bites, foods, drugs and other allergens as well as idiopathic or exercise induced anaphylaxis.
  • the pharmaceutical composition of the present invention enables the rapid delivery of epinephrine both locally and systemically to ensure fast onset of the drug in an emergency situation which may occur in the event of an allergic reaction, particularly in the event of anaphylaxis or anaphylactic shock.
  • the pharmaceutical composition for use according to the present invention may be administered as a treatment dose.
  • the pharmaceutical composition for use according to the present invention may be administered by oral inhalation.
  • the treatment dose may comprise at least about 0.001 mg, at least about 0.005 mg, at least about 0.01 mg, at least about 0.05 mg or at least about 0.1 mg of epinephrine or a pharmaceutically acceptable salt thereof.
  • the treatment dose may comprise no more than about 4 mg, no more than about 3 mg, no more than about 2 mg, no more than about 1 mg or no more than about 0.5 mg of epinephrine or a pharmaceutically acceptable salt thereof.
  • the treatment dose may comprise about 0.001 mg to about 4 mg, about 0.005 mg to about 3 mg, about 0.01 mg to about 2 mg, about 0.05 mg to about 1 mg or about 0.1 mg to about 0.5 mg of epinephrine or a pharmaceutically acceptable salt thereof.
  • the treatment dose may comprise any range from the given endpoints.
  • the pharmaceutical compositions of the present invention may enable effective low treatment doses of epinephrine.
  • the treatment dose may be administered as at least one fixed dose.
  • the treatment dose may be administered as one to eight fixed doses, alternatively as one to five fixed doses or as one to three fixed doses.
  • the fixed dose may have a volume of at least about 5 pL, at least about 10 pL, at least about 15 pL, at least about 20 pL, at least about 25 pL, at least about 30 pL, at least about 35 pL pr at least about 40 pL.
  • the fixed dose may have a volume of no more than about 300 pL, no more than about 250 pL, no more than about 200 pL, no more than about 150 pL, no more than about 100 pL, no more than about 75 pL, no more than about 50 pL or no more than about 45 pL.
  • the fixed dose may have a volume selected from about 5 pL to about 300 pL, about 10 pL to about 250 pL, about 15 pL to about 200 pL, about 20 pL to about 150 pL, about 25 pL to about 100 pL, about 30 pL to about 75 pL, about 35 pL to about 50 pL and about 40 pL to about 45 pL.
  • the fixed dose volume may comprise any range from the given endpoints.
  • the fixed does may be a metered dose.
  • the term “metered dose” refers to a fixed dose drawn from a bulk pharmaceutical composition reservoir.
  • the volume of fixed dose may minimise the number on fixed doses required to attain the therapeutic dose.
  • the pharmaceutical composition for use according to the present invention may be propellant-free.
  • Propellants conventionally used in medicinal aerosols include volatile hydrocarbons, haloalkanes or haloalkenes, with boiling points lower than room temperature (e.g. 20 e C).
  • Hydrofluoroalkanes (HFA), including HFA 134a (1 ,1 ,1 ,2, -tetrafluoroethane), HFA 227 (1 ,1 ,1 ,2,3,3,3-heptafluoropropane) or combinations thereof, are common. Consequently, pharmaceutical compositions for use according to the present invention may not include any of the preceding propellants.
  • a propellant free pharmaceutical composition, orally administered as a liquid aerosol has a lower aerosol velocity than a propellant based liquid aerosol which makes it easier for a patient to synchronize actuation and inhalation thus improving delivery of the active ingredient.
  • the liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV50 of at least about 3 pm, at least about 4 pm or at least about 5 pm.
  • the liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV50 of no more than about 8 pm, no more than 7 pm or no more than 6 pm.
  • the liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV50 selected from about 3 pm to about 8 pm, about 4 pm to about 7 pm and about 5 pm to about 6 pm.
  • the liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV90 of at least about 8 pm, at least about 9 pm, at least about 10 pm or at least about 11 pm;
  • the liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV90 of no more than about 15 pm, no more than about 14 pm, no more than about 13 pm or no more than about 12 pm.
  • the liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV90 selected from about 8 pm to about 15 pm, about 9 pm to about 14 pm, about 10 pm to about 13 pm and about 1 1 pm to about 12 pm.
  • the liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV10 of at least about 1 pm, at least about 1 .5 pm or at least about 1 .9 pm.
  • the liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV10 of no more than about 3 pm; no more than about 2.5 pm or no more than about 2.1 pm.
  • the liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV10 selected from about 1 pm to about 3 pm; about 1 .5 pm to about 2.5 pm and about 1 .9 pm to about 2.1 pm.
  • the particle size distribution of the liquid droplets may have any range from the given endpoints for each of DV10, DV50 and DV90.
  • the particle size distribution of the liquid droplets may be any combination of a DV50, a DV90 and a DV10 range or value referred to above.
  • the particle size distribution may be any combination of at least two of a DV50, a DV90 and a DV10 range or value referred to above.
  • the particle size distribution in the liquid aerosol facilitates the deposition of epinephrine or a pharmaceutically acceptable salt thereof throughout the respiratory tract. Larger particles are deposited in the mouth, throat and upper respiratory tract where they locally treat swelling and smaller particles deposit in the lung alveoli where they enter into the blood stream to systemically treat other allergic reaction symptoms.
  • the liquid droplets of the pharmaceutical composition for use according to the present invention are generated by Rayleigh droplet train or interface-friction induced droplet break-up.
  • the pharmaceutical composition for use according to the invention may comprise epinephrine or a pharmaceutically acceptable salt thereof in a concentration of at least about 0.01 mg/mL, at least about 0.02 mg/mL, at least about 0.03 mg/mL, at least about 0.04 mg/mL, at least about 0.05 mg/mL, at least about 0.06 mg/mL, at least about 0.07 mg/mL, at least about 0.08 mg/mL, at least about 0.09 mg/mL, at least about 0.1 mg/mL, at least about 0.12 mg/mL, at least about 0.13 mg/mL, at least about 0.14 mg/mL, at least about 0.15 mg/mL, at least about 0.16 mg/mL, at least about 0.17 mg/mL, at least about 0.18 mg/mL or at least about 0.2 mg/mL.
  • the pharmaceutical composition for use according to the invention may comprise epinephrine or a pharmaceutically acceptable salt thereof in a concentration of no more than about 200 mg/mL, no more than about 150 mg/mL, no more than about 100 mg/mL, no more than about 50 mg/mL, no more than about 25 mg/mL, no more than about 20 mg/mL, no more than about 15 mg/mL, no more than about 10 mg/mL, no more than about 5 mg/mL, no more than about 2.5 mg/mL, no more than about 2 mg/mL, no more than about 1.5 mg/mL, no more than about 1 mg/mL, no more than about 0.8 mg/mL, no more than about 0.6 mg/mL, no more than about 0.6 mg/mL, no more than about 0.4 mg/mL or no more than about 0.3 mg/mL.
  • the pharmaceutical composition for use according to the invention may comprise epinephrine or a pharmaceutically acceptable salt thereof in a concentration selected from about 0.01 mg/mL to about 200 mg/mL, about 0.02 mg/mL to about 150 mg/mL, about 0.03 mg/mL to about 100 mg/mL, about 0.04 mg/mL to about 50 mg/mL, about 0.05 mg/mL to about 25 mg/mL, about 0.06 mg/mL to about 20 mg/mL, about 0.07 mg/mL to about 15 mg/mL, about 0.08 mg/mL to about 10 mg/mL, about 0.09 mg/mL to about 5 mg/mL, about 0.1 mg/mL to about 2.5 mg/mL, about 0.12 mg/mL to about 2 mg/mL, about 0.13 mg/mL to about 1.5 mg/mL, about 0.14 mg/mL to about 1 mg/mL, about 0.15 mg/mL to about 0.8 mg/mL, about 0.16 mg/mL to about 0.6
  • the concentration may have any range from the given endpoints.
  • the epinephrine or a pharmaceutically acceptable salt thereof may be a free base or a salt of epinephrine.
  • the concentration of epinephrine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition may be increased by using a pharmaceutically acceptable salt that is more soluble in the solvent of the pharmaceutical composition.
  • the pharmaceutical composition for use according to the present invention may be used to treat an allergic reaction symptom selected from the group consisting of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhoea and abdominal cramps, involuntary voiding, wheezing, dyspnoea due to laryngeal spasm, pruritus, rashes, urticaria and angioedema.
  • the pharmaceutical composition according to the present invention may treat multiple symptoms of an allergic reaction simultaneously, particularly when the allergic reaction is anaphylaxis or anaphylactic shock.
  • the liquid aerosol of the pharmaceutical composition for use according to the present invention may be generated by a portable aerosol-generating device selected from the group consisting of a pneumatic or jet type aerosol generator, a vibration type aerosol generator, an ultrasonic type aerosol generator, and a compressed air type aerosol generator.
  • the present invention also provides a portable aerosol-generating device comprising a pharmaceutical composition, the pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof; and a solvent selected from water or a water/alcohol mixture, wherein the portable aerosol-generating device is selected from the group consisting of a pneumatic or jet type aerosol generator, a vibration type aerosol generator, an ultrasonic type aerosol generator, and a compressed air type aerosol generator.
  • the present invention also provides a kit comprising a pharmaceutical composition and a portable aerosol generating device, the pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof; and a solvent selected from water or a water/alcohol mixture, and the portable aerosol-generating device selected from the group consisting of a pneumatic or jet type aerosol generator, a vibration type aerosol generator, an ultrasonic type aerosol generator, and a compressed air type.
  • the present invention also provides a liquid aerosol comprising liquid droplets generated from a pharmaceutical composition by Rayleigh droplet train; interface-friction induced droplet break-up; direct atomization; or capillary wave breakup wherein the pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof; and a solvent selected from water or a water/alcohol mixture.
  • the present invention also provides a method comprising aerosolising a composition to form a liquid aerosol comprising liquid droplets, wherein the liquid aerosol is generated by Rayleigh droplet train; interface-friction induced droplet break-up; direct atomization; or capillary wave breakup, the composition comprising epinephrine or a pharmaceutically acceptable salt thereof and a solvent selected from water or a water/alcohol mixture.
  • the present invention also provides a method of treating a subject suffering from an allergic reaction or symptom thereof comprising administering by oral inhalation a pharmaceutical composition, comprising epinephrine or a pharmaceutically acceptable salt thereof and a solvent selected from water or a water/alcohol mixture, as a liquid aerosol comprising liquid droplets generated by Rayleigh droplet train; interface-friction induced droplet break-up; direct atomization; or capillary wave breakup.
  • a pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof and a solvent selected from water or a water/alcohol mixture, as a liquid aerosol comprising liquid droplets generated by Rayleigh droplet train; interface-friction induced droplet break-up; direct atomization; or capillary wave breakup.
  • the present invention also provides the use of epinephrine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an allergic reaction or symptom thereof wherein the epinephrine or a pharmaceutically acceptable salt thereof is orally administered as a liquid aerosol comprising liquid droplets generated from a pharmaceutical composition by Rayleigh droplet train; interface-friction induced droplet break-up; direct atomization; or capillary wave breakup wherein the pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof and a solvent selected from water or a water/alcohol mixture.
  • Fig. 1 a schematic representation of a liquid aerosol generated by Rayleigh droplet train
  • Fig. 2 a schematic representation of a liquid aerosol generated by a multi-nozzle Rayleigh droplet train
  • Fig. 3 a schematic representation of a liquid aerosol generated by interface-friction induced droplet break-up from a single jet
  • Fig. 4 a schematic representation of a liquid aerosol generated by interface-friction induced droplet break-up from (a) a single jet and (b) impinging jets
  • Fig. 5 a schematic representation of a liquid aerosol generated by capillary wave breakup
  • liquid aerosol comprising liquid droplets generated by Rayleigh droplet train; interface-friction induced droplet break-up; direct atomization; or capillary wave breakup ensures that the pharmaceutical composition of the present invention achieves rapid systemic and local delivery of epinephrine or its pharmaceutically acceptable salts.
  • epinephrine may be selected from citrate, halide (e.g. hydrochloride), sulfate, phosphate, acetate, maleate, succinate, ascorbate, carbonate, glutarate, mesylate, tartrate and lactate salts.
  • halide e.g. hydrochloride
  • sulfate phosphate
  • acetate maleate
  • succinate succinate
  • ascorbate carbonate
  • glutarate mesylate
  • tartrate and lactate salts Preferably the epinephrine may be in the form of a free base or a hydrochloride salt.
  • epinephrine hydrochloride is highly soluble in water. At room temperature and pressure, epinephrine hydrochloride has a solubility of up to 200 mg/mL in water. Epinephrine free base has a solubility of around 0.2 mg/mL in water at room temperature and pressure.
  • Epinephrine or its pharmaceutically acceptable salts may form a solution in a solvent selected from water or a mixture of water and alcohol.
  • the relative proportion of alcohol to water may be up to 70 percent by volume, up to 60 percent by volume, up to 50 percent by volume, up to 40 percent by volume, up to 30 percent by volume, up to 20 percent by volume or up to 10 percent by volume.
  • the alcohol is ethanol.
  • the pH of the pharmaceutical composition of the invention may be adjusted to a pH of 2 to 6, preferably 3 to 5, using suitable acids.
  • the pH may be adjusted using acids selected from inorganic or organic acids.
  • Particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and/or phosphoric acid.
  • Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid, and/or propionic acid. Adjusting the pH of the pharmaceutical composition may improve the solubility and stability of epinephrine or its pharmaceutically acceptable salts.
  • the pharmaceutical composition of the invention may comprise co-solvents and/or other excipients.
  • co-solvents are those which contain hydroxyl groups or other polar groups and may be selected from, but are not limited to, alcohols, particularly isopropyl alcohol, glycols, particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
  • the co-solvent may be used to control the viscosity of the pharmaceutical composition to achieve compatibility with the aerosol generating device and to attain the desired particle size distribution of the liquid droplets in the liquid aerosol.
  • the pharmaceutical composition of the invention may comprise 1 to 40% w/v, 5 to 30% w/v, 10 to 25% w/v; or 15 to 20% w/v of the co-solvent.
  • the pharmaceutical composition of the invention may comprise only ethanol as a co-solvent with water.
  • excipients may include surfactants selected from, but not limited to, soya lecithin, oleic acid, sorbitan esters (e.g. polysorbates), polyvinylpyrrolidone; stabilizers; complexing agents; antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical composition.
  • Flavourings, vitamins and/or other additives known in the art may also be used.
  • the excipients may also include pharmacologically acceptable salts, such as sodium chloride, as isotonic agents.
  • Antioxidants may be selected from, but are not limited to, ascorbic acid, vitamin A, vitamin E, tocopherols, and similar vitamins and provitamins occurring in the human body.
  • Preservatives may be used to protect the formulation from contamination with pathogens and improve the shelf life of the pharmaceutical composition.
  • Suitable preservatives may be selected from, but are not limited to, edetic acid (EDTA) or salts thereof such as disodium edetate, sodium metabisulfite, cetylpyridinium chloride, benzalkonium chloride, and benzoic acid or benzoates such as sodium benzoate.
  • EDTA edetic acid
  • salts thereof such as disodium edetate, sodium metabisulfite, cetylpyridinium chloride, benzalkonium chloride, and benzoic acid or benzoates such as sodium benzoate.
  • the pharmaceutical composition of the invention may comprise at least about 0.001 g/mL; at least about 0.005 g/mL; at least about 0.01 g/mL; at least about 0.05 g/mL; at least about 0.075 g/mL or at least about 0.1 g/mL of preservative.
  • the pharmaceutical composition of the invention may comprise no more than about 1 mg/mL; no more than about 0.8 mg/mL; no more than about 0.6 mg/mL; no more than about 0.5 mg/mL; no more than about 0.4 mg/mL or no more than about 0.3 mg/mL of preservative.
  • the pharmaceutical composition of the invention may comprise about 0.001 g/mL to about 1 mg/mL; about 0.005 g/mL to about 0.8 mg/mL; about 0.01 g/mL to about 0.6 mg/mL; about 0.05 g/mL to about 0.5 mg/mL; about 0.075 g/mL to about 0.4 mg/mL or about 0.1 g/mL to about 0.3 mg/mL of preservative.
  • a Rayleigh droplet train; interface-friction induced droplet break-up; direct atomization; or capillary wave breakup may be generated by an aerosol generator selected from the group consisting of a pneumatic or jet type aerosol generator, a vibration type aerosol generator, an ultrasonic type aerosol generator, and a compressed air type aerosol generator.
  • the liquid aerosol generated by Rayleigh droplet train may be generated by an aerosol generator comprising a single nozzle as shown in Figure 1 or multiple nozzles as shown in Figure 2.
  • the Rayleigh droplet train, or Rayleigh break-up is governed mainly by surface tension with other forces, e.g. friction forces, playing a minor role. As a result of the limited forces involved, the pinch-off of droplets may result in a relatively consistent droplet size distribution.
  • the liquid aerosol generated by interface-friction induced droplet break-up may be generated by an aerosol generator comprising a single nozzle as shown in Figures 3 and 4a or multiple nozzles as shown in Figure 4b.
  • the interface-friction induced droplet break-up occurs with an increase in the Reynolds number, e.g. an increase in the relative velocity of the liquid to the air. This increase in relative velocity results in an increase in friction forces or shear forces at the boundary between liquid and air and between the liquid and the nozzle which induces perturbations and turbulences, known as Kelvin- Helmholtz instability.
  • the different levels of friction induced turbulences and distortions result in a chaotic droplet break-up which reflects in a droplet size distribution that typically spans a wider range compared to Rayleigh break-up.
  • the liquid aerosol generated by capillary wave breakup may be generated by forces acting on the liquid, which may produce waves or ripples on the open liquid surface.
  • the capillary wave breakup may result from a destabilization of the capillary wave crests along the phase boundaries of fluids, such as the interface between liquid and air.
  • the crests of the generated capillary waves may disintegrate forming droplets, the characteristics of which depend on the liquid properties, such as surface tension and viscosity and the amplitude of the generated capillary wave, as shown in Figure 5.
  • SAW surface acoustic wave
  • the forces may come from a pressure wave travelling through a liquid towards the liquid surface wherein the pressure wave may be generated by the surface acoustic wave travelling along the surface of an acoustic wave substrate - for example, a piezo crystal with an interdigital transducer as wave emitter.
  • the pressure wave then gets refracted into the liquid once this travelling surface wave reaches the liquid surface.
  • capillary wave breakup may also be generated when there is a relative velocity of air versus liquid along the interface - for example the wind on a lake forming ripples.
  • Capillary waves that are a standing wave are often referred to as Faraday waves.
  • the liquid aerosol may be generated by interface-friction induced droplet break-up (aerodynamic perturbations) and/or by impinging at least two of the liquid jets (hydrodynamic perturbations).
  • the aerosol generators of the invention may enable the particle size distribution of the liquid droplets in the liquid aerosol to be adjusted to provide deposition of a therapeutic dose of epinephrine or a pharmaceutically acceptable salt thereof in the throat, upper respiratory tract, lower respiratory tract and lung alveoli of a subject.
  • the aerosol generator may form part of an aerosol generating device wherein the aerosol generating device comprises: an aerosol generator, a cartridge for containing the liquid pharmaceutical composition and an actuator.
  • the cartridge may be built into the aerosol generating device or it may be replaceable.
  • a kit according to the invention may comprise a separate cartridge comprising the pharmaceutical composition.
  • the cartridge may comprise a single therapeutic dose or multiple therapeutic doses of the pharmaceutical composition.
  • Multiple therapeutic doses may be at least about 2, at least about 3, at least about 4, at least about 5 or at least 10.
  • Multiple therapeutic doses may be no more than about 60, no more than about 50, no more than about 40, no more than about 30 or no more than about 20 doses.
  • Multiple therapeutic doses may be about 2 to about 60, about 3 to about 50, about 4 to about 40, about 5 to about 30 or about 10 to about 20 doses.
  • the cartridge comprising multiple therapeutic doses may comprise about 10 mL, about 9 mL, about 8 mL, about 7 mL, about 6 mL, about 5mL, about 4 mL, about 3mL, about 2 mL or about 1 mL of the pharmaceutical composition.
  • the aerosol generating device may be portable.
  • portable relates to a device that may be comfortably held in the hand and actuated with one hand.
  • the aerosol generating device may be mechanically primed and/or actuated in order to generate the liquid aerosol.
  • the term “mechanically” is intended to mean that no electrical power source is required to generate the liquid aerosol.
  • the term “primed” relates to the act of preparing the aerosol generating device for actuation and the terms “actuated” or “actuation” relate to the act of releasing the pharmaceutical composition as a liquid aerosol from the aerosol generating device.
  • the aerosol generating device may be actuated by hand or may be breath actuated.
  • Devices for generating liquid aerosols via Rayleigh droplet train are known in the art and include the inhaler developed by Medspray BV and disclosed in WO2014/137215.
  • Devices for generating liquid aerosols via capillary wave breakup include surface acoustic wave nebulizers.
  • Other devices for generating liquid aerosols include portable vibrating mesh nebulizers such as the DeeproTM nebulizer.
  • the aerosol generating device may operate at inhalation flow rates of about 10 L/min, about 20 L/min, about 30 L/min, about 40 L/min, about 50 L/min, about 60 L/min or greater than about 60 L/min.
  • Efficacy across a broad spectrum of flow rates may be important when treating subjects suffering from an allergic reaction or symptom thereof because the rate at which the subject may be able to inhale differs depending on the symptoms they are experiencing.
  • the aerosol generating device may meter the liquid aerosol as a fixed dose of the pharmaceutical composition upon actuation.
  • the fixed dose may have a volume of at least about 5 pL; at least about 10 pL; at least about 15 pL; at least about 20 pL; at least about 25 pL; at least about 30 pL; at least about 35 pL; or at least about 40 pL.
  • the fixed dose may have a volume of no more than about 300 pL; no more than about 250 pL; no more than about 200 pL; no more than about 150 pL; no more than about 100 pL; no more than about 75 pL; no more than about 50 pL; or no more than about 45 pL.
  • the fixed dose may have a volume selected from about 5 pL to about 300 pL; about 10 pL to about 250 pL; about 15 pL to about 200 pL; about 20 pL to about 150 pL; about 25 pL to about 100 pL; about 30 pL to about 75 pL; about 35 pL to about 50 pL; about 40 pL to about 45 pL.
  • the fixed dose may have any range from the given endpoints.
  • the fixed dose may have a volume of at least about 10 pL, about 15 pL, about 20 pL, about 25 pL, about 30 pL, about 35 pL, about 40 pL, about 45 pL or about 50 pL.
  • the volume of the fixed dose should ensure delivery of the treatment dose in less than 120 seconds, alternatively in less than about 90 seconds, preferably in less than about 60 seconds and most preferably in less than about 30 seconds.
  • the volume of the fixed dose may enable delivery of the treatment dose in no more than 8 fixed doses, alternatively in no more than 7 fixed doses, alternatively in no more than 6 fixed doses, alternatively in no more than 5 fixed doses, alternatively in no more than 4 fixed doses, preferably in no more than 3 fixed doses and more preferably in no more than 2 fixed doses.
  • Most preferably the treatment dose is delivered in one fixed dose.
  • the liquid aerosol may comprise liquid droplets having a particle size distribution suitable for deposition of epinephrine or a pharmaceutically acceptable salt thereof in the throat, upper respiratory tract, lower respiratory tract and lung alveoli of a subject.
  • traditional inhaled pharmaceutical compositions focus on ensuring that the size of the liquid droplets in the aerosol is sufficiently low to maximise delivery to the lung alveoli
  • the pharmaceutical composition of the present invention generates a liquid aerosol with a liquid droplet particle size distribution that facilitates delivery of epinephrine throughout the respiratory tract.
  • the pharmaceutical composition of the present invention generates an aerosol comprising liquid droplets having a DV90 of about 8 to about 15 pm; a DV50 of about 3 to about 8 pm and a DV10 of about 1 to about 3 pm.
  • the liquid aerosol according to the invention may comprise liquid droplets having a combination of the DV90, DV50 and DV10 values defined by the aforementioned ranges.
  • the particle size distribution of the liquid droplets may be any combination of a DV90 selected from 8, 9, 10, 1 1 , 12, 13, 14 and 15 pm; a DV50 selected from 3, 4, 5, 6, 7 and 8 pm; and a DV10 selected from 1 , 2 and 3 pm.
  • the liquid droplets may have a particle size distribution combining a DV90 of about 10 pm to about 13 pm; a DV50 of about 4 pm to about 6 pm and a DV10 of about 2 pm to about 3 pm.
  • the particle size distribution - defined as DV90, DV50 or DV10 - may be measured using techniques known in the art such as those defined in the section 4.2.1 .8 of the EMEA’s Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products (2006). Such methods include laser diffraction or impactor methods based on an Andersen cascade impactor (ACI), a next generation impactor (NGI) or a time-of-flight aerodynamic particle sizer (APS).
  • ACI Andersen cascade impactor
  • NTI next generation impactor
  • APS time-of-flight aerodynamic particle sizer

Abstract

The invention relates to a pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof for use in the emergency treatment of allergic reactions including anaphylaxis and anaphylactic shock through the oral inhalation of a liquid aerosol generated by Rayleigh droplet train; interface-friction induced; droplet break-up; direct atomization or capillary wave breakup.

Description

PHARMACEUTICAL COMPOSITION COMPRISING EPINEPHRINE FOR AEROSOL ADMINISTRATION
The present invention relates to an orally inhaled pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof for use in the emergency treatment of allergic reactions including anaphylaxis and anaphylactic shock.
Background
Anaphylaxis or anaphylactic shock is a severe allergic reaction that often requires immediate medical treatment. Anaphylaxis affects many of the body’s organs including the heart; lungs, skin and stomach as well as causing swelling of the mouth and throat. The standard treatment of care for anaphylaxis is intramuscular delivery of epinephrine (also known as adrenaline) via injection. Epinephrine is a catecholamine that stimulates the a- and p-adrenergic receptors of the sympathetic nervous system. Epinephrine binds to these adrenergic receptors leading to relief of many life-threatening symptoms of anaphylaxis through relaxation of the smooth muscle in the bronchi of the lungs thereby opening up constricted airways; constriction of the blood vessels leading to decreased swelling of the tongue and throat; and increasing blood pressure and heart rate thereby preventing or reversing cardiovascular collapse.
For some, administration by injection may not deliver epinephrine intramuscularly as intended but rather result in the active ingredient being deposited within the bone or subcutaneously. Incorrectly injected epinephrine can delay or impair the effectiveness of the treatment during a time-critical period. Moreover, the use of a needle, particularly for children, has the potential to cause additional pain and/or damage to the bone if the needle over-penetrates beyond the intramuscular level. Further, injections tend to be painful and can be difficult to correctly self-administer.
The delivery of epinephrine as an aerosol offers an alternative route of administration that is less painful and easier to self-administer. Various publications describe suitable formulations for aerosol administration of epinephrine. US2018126100 and US2019282497 describe epinephrine formulations for intra-nasal aerosol delivery and Epinephrine inhalers in emergency sets of patients with anaphylaxis; Schlegel et al (JDDG, Vol. 7, Issue 5, May 2009, p. 420-425) describes two marketed formulations for aerosol delivery of epinephrine: a pressurized metered dose inhaler formulation (Primatene Mist™) and a handheld pump spray or liquid nebuliser formulation (InfectoKrupp ® Inhal).
Liquid nebuliser formulations require continuous delivery of the pharmaceutical composition to a subject which typically leads to longer periods of administration. In addition, they require higher device-loads of the pharmaceutical composition in order to achieve a targeted dosing of the active ingredient to the subject. Because anaphylaxis can be life threatening and stressful, the long duration required to administer a single dose using conventional nebulization poses additional health risks and complications, making liquid nebuliser formulations unsuitable for emergency treatment. In addition, due to the number of inhalations required for effective administration, patients can often experience gastrointestinal distress such as nausea and vomiting.
Formulations for pressurized metered dose inhalers (pMDIs) such as Primatene Mist™ require a propellant and the steps needed to administer them effectively are difficult for children to perform.
Nasal spray formulations, such as those disclosed in US2018126100 and US2019282497, are unable to create an aerosol capable of delivering the active ingredient deep into the lung of a subject due the relatively large size of the particles they form.
Accordingly, it is an object of the present invention to provide an improved inhalable pharmaceutical composition that delivers epinephrine or a pharmaceutically acceptable salt thereof to a subject that is both easy to administer and achieves rapid systemic and local delivery of the active ingredient.
Summary of Invention
The present invention relates to a pharmaceutical composition for use in the treatment of an allergic reaction or symptom thereof comprising:
(a) epinephrine or a pharmaceutically acceptable salt thereof; and
(b) a solvent selected from water or a water/alcohol mixture, characterised in that the pharmaceutical composition is orally administered as a liquid aerosol comprising liquid droplets generated by Rayleigh droplet train; interface-friction induced droplet break-up; direct atomization; or capillary wave breakup.
The pharmaceutical composition for use according to the present invention may be used to treat an allergic reaction selected from anaphylaxis or anaphylactic shock.
Preferably, the pharmaceutical composition for use according to the present invention may be used in the emergency treatment of an allergic reaction to insect stings or bites, foods, drugs and other allergens as well as idiopathic or exercise induced anaphylaxis.
Advantageously, the pharmaceutical composition of the present invention enables the rapid delivery of epinephrine both locally and systemically to ensure fast onset of the drug in an emergency situation which may occur in the event of an allergic reaction, particularly in the event of anaphylaxis or anaphylactic shock. The pharmaceutical composition for use according to the present invention may be administered as a treatment dose. Preferably the pharmaceutical composition for use according to the present invention may be administered by oral inhalation.
The treatment dose may comprise at least about 0.001 mg, at least about 0.005 mg, at least about 0.01 mg, at least about 0.05 mg or at least about 0.1 mg of epinephrine or a pharmaceutically acceptable salt thereof.
The treatment dose may comprise no more than about 4 mg, no more than about 3 mg, no more than about 2 mg, no more than about 1 mg or no more than about 0.5 mg of epinephrine or a pharmaceutically acceptable salt thereof.
The treatment dose may comprise about 0.001 mg to about 4 mg, about 0.005 mg to about 3 mg, about 0.01 mg to about 2 mg, about 0.05 mg to about 1 mg or about 0.1 mg to about 0.5 mg of epinephrine or a pharmaceutically acceptable salt thereof. The treatment dose may comprise any range from the given endpoints. The pharmaceutical compositions of the present invention may enable effective low treatment doses of epinephrine.
The treatment dose may be administered as at least one fixed dose. The treatment dose may be administered as one to eight fixed doses, alternatively as one to five fixed doses or as one to three fixed doses. The fixed dose may have a volume of at least about 5 pL, at least about 10 pL, at least about 15 pL, at least about 20 pL, at least about 25 pL, at least about 30 pL, at least about 35 pL pr at least about 40 pL.
The fixed dose may have a volume of no more than about 300 pL, no more than about 250 pL, no more than about 200 pL, no more than about 150 pL, no more than about 100 pL, no more than about 75 pL, no more than about 50 pL or no more than about 45 pL.
The fixed dose may have a volume selected from about 5 pL to about 300 pL, about 10 pL to about 250 pL, about 15 pL to about 200 pL, about 20 pL to about 150 pL, about 25 pL to about 100 pL, about 30 pL to about 75 pL, about 35 pL to about 50 pL and about 40 pL to about 45 pL. The fixed dose volume may comprise any range from the given endpoints. The fixed does may be a metered dose. As used herein, the term “metered dose” refers to a fixed dose drawn from a bulk pharmaceutical composition reservoir. Advantageously, the volume of fixed dose may minimise the number on fixed doses required to attain the therapeutic dose.
The pharmaceutical composition for use according to the present invention may be propellant-free. Propellants conventionally used in medicinal aerosols include volatile hydrocarbons, haloalkanes or haloalkenes, with boiling points lower than room temperature (e.g. 20eC). Hydrofluoroalkanes (HFA), including HFA 134a (1 ,1 ,1 ,2, -tetrafluoroethane), HFA 227 (1 ,1 ,1 ,2,3,3,3-heptafluoropropane) or combinations thereof, are common. Consequently, pharmaceutical compositions for use according to the present invention may not include any of the preceding propellants. A propellant free pharmaceutical composition, orally administered as a liquid aerosol, has a lower aerosol velocity than a propellant based liquid aerosol which makes it easier for a patient to synchronize actuation and inhalation thus improving delivery of the active ingredient.
The liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV50 of at least about 3 pm, at least about 4 pm or at least about 5 pm.
The liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV50 of no more than about 8 pm, no more than 7 pm or no more than 6 pm.
The liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV50 selected from about 3 pm to about 8 pm, about 4 pm to about 7 pm and about 5 pm to about 6 pm.
The liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV90 of at least about 8 pm, at least about 9 pm, at least about 10 pm or at least about 11 pm;
The liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV90 of no more than about 15 pm, no more than about 14 pm, no more than about 13 pm or no more than about 12 pm.
The liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV90 selected from about 8 pm to about 15 pm, about 9 pm to about 14 pm, about 10 pm to about 13 pm and about 1 1 pm to about 12 pm.
The liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV10 of at least about 1 pm, at least about 1 .5 pm or at least about 1 .9 pm.
The liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV10 of no more than about 3 pm; no more than about 2.5 pm or no more than about 2.1 pm.
The liquid droplets of the pharmaceutical composition for use according to the present invention may have a particle size distribution comprising a DV10 selected from about 1 pm to about 3 pm; about 1 .5 pm to about 2.5 pm and about 1 .9 pm to about 2.1 pm.
The particle size distribution of the liquid droplets may have any range from the given endpoints for each of DV10, DV50 and DV90. The particle size distribution of the liquid droplets may be any combination of a DV50, a DV90 and a DV10 range or value referred to above. The particle size distribution may be any combination of at least two of a DV50, a DV90 and a DV10 range or value referred to above. Advantageously, the particle size distribution in the liquid aerosol facilitates the deposition of epinephrine or a pharmaceutically acceptable salt thereof throughout the respiratory tract. Larger particles are deposited in the mouth, throat and upper respiratory tract where they locally treat swelling and smaller particles deposit in the lung alveoli where they enter into the blood stream to systemically treat other allergic reaction symptoms.
Preferably, the liquid droplets of the pharmaceutical composition for use according to the present invention are generated by Rayleigh droplet train or interface-friction induced droplet break-up.
The pharmaceutical composition for use according to the invention may comprise epinephrine or a pharmaceutically acceptable salt thereof in a concentration of at least about 0.01 mg/mL, at least about 0.02 mg/mL, at least about 0.03 mg/mL, at least about 0.04 mg/mL, at least about 0.05 mg/mL, at least about 0.06 mg/mL, at least about 0.07 mg/mL, at least about 0.08 mg/mL, at least about 0.09 mg/mL, at least about 0.1 mg/mL, at least about 0.12 mg/mL, at least about 0.13 mg/mL, at least about 0.14 mg/mL, at least about 0.15 mg/mL, at least about 0.16 mg/mL, at least about 0.17 mg/mL, at least about 0.18 mg/mL or at least about 0.2 mg/mL.
The pharmaceutical composition for use according to the invention may comprise epinephrine or a pharmaceutically acceptable salt thereof in a concentration of no more than about 200 mg/mL, no more than about 150 mg/mL, no more than about 100 mg/mL, no more than about 50 mg/mL, no more than about 25 mg/mL, no more than about 20 mg/mL, no more than about 15 mg/mL, no more than about 10 mg/mL, no more than about 5 mg/mL, no more than about 2.5 mg/mL, no more than about 2 mg/mL, no more than about 1.5 mg/mL, no more than about 1 mg/mL, no more than about 0.8 mg/mL, no more than about 0.6 mg/mL, no more than about 0.6 mg/mL, no more than about 0.4 mg/mL or no more than about 0.3 mg/mL.
The pharmaceutical composition for use according to the invention may comprise epinephrine or a pharmaceutically acceptable salt thereof in a concentration selected from about 0.01 mg/mL to about 200 mg/mL, about 0.02 mg/mL to about 150 mg/mL, about 0.03 mg/mL to about 100 mg/mL, about 0.04 mg/mL to about 50 mg/mL, about 0.05 mg/mL to about 25 mg/mL, about 0.06 mg/mL to about 20 mg/mL, about 0.07 mg/mL to about 15 mg/mL, about 0.08 mg/mL to about 10 mg/mL, about 0.09 mg/mL to about 5 mg/mL, about 0.1 mg/mL to about 2.5 mg/mL, about 0.12 mg/mL to about 2 mg/mL, about 0.13 mg/mL to about 1.5 mg/mL, about 0.14 mg/mL to about 1 mg/mL, about 0.15 mg/mL to about 0.8 mg/mL, about 0.16 mg/mL to about 0.6 mg/mL, about 0.17 mg/mL to about 0.6 mg/mL, about 0.18 mg/mL to about 0.4 mg/mL and about 0.2 mg/mL to about 0.3 mg/mL. The concentration may have any range from the given endpoints. The epinephrine or a pharmaceutically acceptable salt thereof may be a free base or a salt of epinephrine. The concentration of epinephrine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition may be increased by using a pharmaceutically acceptable salt that is more soluble in the solvent of the pharmaceutical composition. The pharmaceutical composition for use according to the present invention may be used to treat an allergic reaction symptom selected from the group consisting of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhoea and abdominal cramps, involuntary voiding, wheezing, dyspnoea due to laryngeal spasm, pruritus, rashes, urticaria and angioedema. Advantageously, the pharmaceutical composition according to the present invention may treat multiple symptoms of an allergic reaction simultaneously, particularly when the allergic reaction is anaphylaxis or anaphylactic shock.
The liquid aerosol of the pharmaceutical composition for use according to the present invention may be generated by a portable aerosol-generating device selected from the group consisting of a pneumatic or jet type aerosol generator, a vibration type aerosol generator, an ultrasonic type aerosol generator, and a compressed air type aerosol generator.
The present invention also provides a portable aerosol-generating device comprising a pharmaceutical composition, the pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof; and a solvent selected from water or a water/alcohol mixture, wherein the portable aerosol-generating device is selected from the group consisting of a pneumatic or jet type aerosol generator, a vibration type aerosol generator, an ultrasonic type aerosol generator, and a compressed air type aerosol generator.
The present invention also provides a kit comprising a pharmaceutical composition and a portable aerosol generating device, the pharmaceutical composition comprising epinephrine or a pharmaceutically acceptable salt thereof; and a solvent selected from water or a water/alcohol mixture, and the portable aerosol-generating device selected from the group consisting of a pneumatic or jet type aerosol generator, a vibration type aerosol generator, an ultrasonic type aerosol generator, and a compressed air type.
The present invention also provides a liquid aerosol comprising liquid droplets generated from a pharmaceutical composition by Rayleigh droplet train; interface-friction induced droplet break-up; direct atomization; or capillary wave breakup wherein the pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof; and a solvent selected from water or a water/alcohol mixture.
The present invention also provides a method comprising aerosolising a composition to form a liquid aerosol comprising liquid droplets, wherein the liquid aerosol is generated by Rayleigh droplet train; interface-friction induced droplet break-up; direct atomization; or capillary wave breakup, the composition comprising epinephrine or a pharmaceutically acceptable salt thereof and a solvent selected from water or a water/alcohol mixture.
The present invention also provides a method of treating a subject suffering from an allergic reaction or symptom thereof comprising administering by oral inhalation a pharmaceutical composition, comprising epinephrine or a pharmaceutically acceptable salt thereof and a solvent selected from water or a water/alcohol mixture, as a liquid aerosol comprising liquid droplets generated by Rayleigh droplet train; interface-friction induced droplet break-up; direct atomization; or capillary wave breakup.
The present invention also provides the use of epinephrine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an allergic reaction or symptom thereof wherein the epinephrine or a pharmaceutically acceptable salt thereof is orally administered as a liquid aerosol comprising liquid droplets generated from a pharmaceutical composition by Rayleigh droplet train; interface-friction induced droplet break-up; direct atomization; or capillary wave breakup wherein the pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof and a solvent selected from water or a water/alcohol mixture.
Figures
Fig. 1 : a schematic representation of a liquid aerosol generated by Rayleigh droplet train
Fig. 2: a schematic representation of a liquid aerosol generated by a multi-nozzle Rayleigh droplet train
Fig. 3: a schematic representation of a liquid aerosol generated by interface-friction induced droplet break-up from a single jet
Fig. 4: a schematic representation of a liquid aerosol generated by interface-friction induced droplet break-up from (a) a single jet and (b) impinging jets
Fig. 5: a schematic representation of a liquid aerosol generated by capillary wave breakup
Detailed description
The formation of a liquid aerosol comprising liquid droplets generated by Rayleigh droplet train; interface-friction induced droplet break-up; direct atomization; or capillary wave breakup ensures that the pharmaceutical composition of the present invention achieves rapid systemic and local delivery of epinephrine or its pharmaceutically acceptable salts.
Pharmaceutically acceptable salts of epinephrine may be selected from citrate, halide (e.g. hydrochloride), sulfate, phosphate, acetate, maleate, succinate, ascorbate, carbonate, glutarate, mesylate, tartrate and lactate salts. Preferably the epinephrine may be in the form of a free base or a hydrochloride salt. In contrast to epinephrine free base, epinephrine hydrochloride is highly soluble in water. At room temperature and pressure, epinephrine hydrochloride has a solubility of up to 200 mg/mL in water. Epinephrine free base has a solubility of around 0.2 mg/mL in water at room temperature and pressure.
Epinephrine or its pharmaceutically acceptable salts may form a solution in a solvent selected from water or a mixture of water and alcohol. The relative proportion of alcohol to water may be up to 70 percent by volume, up to 60 percent by volume, up to 50 percent by volume, up to 40 percent by volume, up to 30 percent by volume, up to 20 percent by volume or up to 10 percent by volume. Preferable the alcohol is ethanol.
Preliminary studies indicate that the percentage of ethanol in the solvent can influence the size of the liquid droplets generated in the initial aerosol and the size of the liquid droplets as they pass through the respiratory tract.
The pH of the pharmaceutical composition of the invention may be adjusted to a pH of 2 to 6, preferably 3 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid, and/or propionic acid. Adjusting the pH of the pharmaceutical composition may improve the solubility and stability of epinephrine or its pharmaceutically acceptable salts.
The pharmaceutical composition of the invention may comprise co-solvents and/or other excipients. Preferred co-solvents are those which contain hydroxyl groups or other polar groups and may be selected from, but are not limited to, alcohols, particularly isopropyl alcohol, glycols, particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. Advantageously, the co-solvent may be used to control the viscosity of the pharmaceutical composition to achieve compatibility with the aerosol generating device and to attain the desired particle size distribution of the liquid droplets in the liquid aerosol.
The pharmaceutical composition of the invention may comprise 1 to 40% w/v, 5 to 30% w/v, 10 to 25% w/v; or 15 to 20% w/v of the co-solvent.
Preferably, the pharmaceutical composition of the invention may comprise only ethanol as a co-solvent with water.
Further excipients may include surfactants selected from, but not limited to, soya lecithin, oleic acid, sorbitan esters (e.g. polysorbates), polyvinylpyrrolidone; stabilizers; complexing agents; antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical composition. Flavourings, vitamins and/or other additives known in the art may also be used. The excipients may also include pharmacologically acceptable salts, such as sodium chloride, as isotonic agents. Antioxidants may be selected from, but are not limited to, ascorbic acid, vitamin A, vitamin E, tocopherols, and similar vitamins and provitamins occurring in the human body.
Preservatives may be used to protect the formulation from contamination with pathogens and improve the shelf life of the pharmaceutical composition. Suitable preservatives may be selected from, but are not limited to, edetic acid (EDTA) or salts thereof such as disodium edetate, sodium metabisulfite, cetylpyridinium chloride, benzalkonium chloride, and benzoic acid or benzoates such as sodium benzoate.
The pharmaceutical composition of the invention may comprise at least about 0.001 g/mL; at least about 0.005 g/mL; at least about 0.01 g/mL; at least about 0.05 g/mL; at least about 0.075 g/mL or at least about 0.1 g/mL of preservative.
The pharmaceutical composition of the invention may comprise no more than about 1 mg/mL; no more than about 0.8 mg/mL; no more than about 0.6 mg/mL; no more than about 0.5 mg/mL; no more than about 0.4 mg/mL or no more than about 0.3 mg/mL of preservative.
The pharmaceutical composition of the invention may comprise about 0.001 g/mL to about 1 mg/mL; about 0.005 g/mL to about 0.8 mg/mL; about 0.01 g/mL to about 0.6 mg/mL; about 0.05 g/mL to about 0.5 mg/mL; about 0.075 g/mL to about 0.4 mg/mL or about 0.1 g/mL to about 0.3 mg/mL of preservative.
A Rayleigh droplet train; interface-friction induced droplet break-up; direct atomization; or capillary wave breakup may be generated by an aerosol generator selected from the group consisting of a pneumatic or jet type aerosol generator, a vibration type aerosol generator, an ultrasonic type aerosol generator, and a compressed air type aerosol generator.
The liquid aerosol generated by Rayleigh droplet train may be generated by an aerosol generator comprising a single nozzle as shown in Figure 1 or multiple nozzles as shown in Figure 2. The Rayleigh droplet train, or Rayleigh break-up, is governed mainly by surface tension with other forces, e.g. friction forces, playing a minor role. As a result of the limited forces involved, the pinch-off of droplets may result in a relatively consistent droplet size distribution.
The liquid aerosol generated by interface-friction induced droplet break-up may be generated by an aerosol generator comprising a single nozzle as shown in Figures 3 and 4a or multiple nozzles as shown in Figure 4b. When a single nozzle aerosol generator is used, the interface-friction induced droplet break-up occurs with an increase in the Reynolds number, e.g. an increase in the relative velocity of the liquid to the air. This increase in relative velocity results in an increase in friction forces or shear forces at the boundary between liquid and air and between the liquid and the nozzle which induces perturbations and turbulences, known as Kelvin- Helmholtz instability. The different levels of friction induced turbulences and distortions result in a chaotic droplet break-up which reflects in a droplet size distribution that typically spans a wider range compared to Rayleigh break-up. The liquid aerosol generated by capillary wave breakup may be generated by forces acting on the liquid, which may produce waves or ripples on the open liquid surface. The capillary wave breakup may result from a destabilization of the capillary wave crests along the phase boundaries of fluids, such as the interface between liquid and air. The crests of the generated capillary waves may disintegrate forming droplets, the characteristics of which depend on the liquid properties, such as surface tension and viscosity and the amplitude of the generated capillary wave, as shown in Figure 5.
An example of capillary wave breakup is surface acoustic wave (SAW) breakup. In SAW, the forces may come from a pressure wave travelling through a liquid towards the liquid surface wherein the pressure wave may be generated by the surface acoustic wave travelling along the surface of an acoustic wave substrate - for example, a piezo crystal with an interdigital transducer as wave emitter. The pressure wave then gets refracted into the liquid once this travelling surface wave reaches the liquid surface.
In the natural world, capillary wave breakup may also be generated when there is a relative velocity of air versus liquid along the interface - for example the wind on a lake forming ripples.
Capillary waves that are a standing wave, are often referred to as Faraday waves.
When multiple nozzles are used, the liquid aerosol may be generated by interface-friction induced droplet break-up (aerodynamic perturbations) and/or by impinging at least two of the liquid jets (hydrodynamic perturbations).
The aerosol generators of the invention may enable the particle size distribution of the liquid droplets in the liquid aerosol to be adjusted to provide deposition of a therapeutic dose of epinephrine or a pharmaceutically acceptable salt thereof in the throat, upper respiratory tract, lower respiratory tract and lung alveoli of a subject.
The aerosol generator may form part of an aerosol generating device wherein the aerosol generating device comprises: an aerosol generator, a cartridge for containing the liquid pharmaceutical composition and an actuator.
The cartridge may be built into the aerosol generating device or it may be replaceable. A kit according to the invention may comprise a separate cartridge comprising the pharmaceutical composition. The cartridge may comprise a single therapeutic dose or multiple therapeutic doses of the pharmaceutical composition.
Multiple therapeutic doses may be at least about 2, at least about 3, at least about 4, at least about 5 or at least 10.
Multiple therapeutic doses may be no more than about 60, no more than about 50, no more than about 40, no more than about 30 or no more than about 20 doses.
Multiple therapeutic doses may be about 2 to about 60, about 3 to about 50, about 4 to about 40, about 5 to about 30 or about 10 to about 20 doses. The cartridge comprising multiple therapeutic doses may comprise about 10 mL, about 9 mL, about 8 mL, about 7 mL, about 6 mL, about 5mL, about 4 mL, about 3mL, about 2 mL or about 1 mL of the pharmaceutical composition.
The aerosol generating device may be portable. As used herein, the term “portable” relates to a device that may be comfortably held in the hand and actuated with one hand.
The aerosol generating device may be mechanically primed and/or actuated in order to generate the liquid aerosol. The term “mechanically” is intended to mean that no electrical power source is required to generate the liquid aerosol. The term “primed” relates to the act of preparing the aerosol generating device for actuation and the terms “actuated” or “actuation” relate to the act of releasing the pharmaceutical composition as a liquid aerosol from the aerosol generating device. The aerosol generating device may be actuated by hand or may be breath actuated.
Devices for generating liquid aerosols via Rayleigh droplet train are known in the art and include the inhaler developed by Medspray BV and disclosed in WO2014/137215.
Devices for generating liquid aerosols via interface-friction induced droplet break-up are known in the art and include Boehringer Ingelheim’s Respimat® inhaler and the inhaler developed by Softhale NV and disclosed in WO2019/180022.
Devices for generating liquid aerosols via capillary wave breakup include surface acoustic wave nebulizers.
Other devices for generating liquid aerosols include portable vibrating mesh nebulizers such as the Deepro™ nebulizer.
The aerosol generating device may operate at inhalation flow rates of about 10 L/min, about 20 L/min, about 30 L/min, about 40 L/min, about 50 L/min, about 60 L/min or greater than about 60 L/min.
Efficacy across a broad spectrum of flow rates may be important when treating subjects suffering from an allergic reaction or symptom thereof because the rate at which the subject may be able to inhale differs depending on the symptoms they are experiencing.
The aerosol generating device may meter the liquid aerosol as a fixed dose of the pharmaceutical composition upon actuation.
The fixed dose may have a volume of at least about 5 pL; at least about 10 pL; at least about 15 pL; at least about 20 pL; at least about 25 pL; at least about 30 pL; at least about 35 pL; or at least about 40 pL.
The fixed dose may have a volume of no more than about 300 pL; no more than about 250 pL; no more than about 200 pL; no more than about 150 pL; no more than about 100 pL; no more than about 75 pL; no more than about 50 pL; or no more than about 45 pL.
The fixed dose may have a volume selected from about 5 pL to about 300 pL; about 10 pL to about 250 pL; about 15 pL to about 200 pL; about 20 pL to about 150 pL; about 25 pL to about 100 pL; about 30 pL to about 75 pL; about 35 pL to about 50 pL; about 40 pL to about 45 pL. The fixed dose may have any range from the given endpoints.
Alternatively, the fixed dose may have a volume of at least about 10 pL, about 15 pL, about 20 pL, about 25 pL, about 30 pL, about 35 pL, about 40 pL, about 45 pL or about 50 pL.
The volume of the fixed dose should ensure delivery of the treatment dose in less than 120 seconds, alternatively in less than about 90 seconds, preferably in less than about 60 seconds and most preferably in less than about 30 seconds. The volume of the fixed dose may enable delivery of the treatment dose in no more than 8 fixed doses, alternatively in no more than 7 fixed doses, alternatively in no more than 6 fixed doses, alternatively in no more than 5 fixed doses, alternatively in no more than 4 fixed doses, preferably in no more than 3 fixed doses and more preferably in no more than 2 fixed doses. Most preferably the treatment dose is delivered in one fixed dose.
The liquid aerosol may comprise liquid droplets having a particle size distribution suitable for deposition of epinephrine or a pharmaceutically acceptable salt thereof in the throat, upper respiratory tract, lower respiratory tract and lung alveoli of a subject. Whereas traditional inhaled pharmaceutical compositions focus on ensuring that the size of the liquid droplets in the aerosol is sufficiently low to maximise delivery to the lung alveoli, the pharmaceutical composition of the present invention generates a liquid aerosol with a liquid droplet particle size distribution that facilitates delivery of epinephrine throughout the respiratory tract.
The pharmaceutical composition of the present invention generates an aerosol comprising liquid droplets having a DV90 of about 8 to about 15 pm; a DV50 of about 3 to about 8 pm and a DV10 of about 1 to about 3 pm. The liquid aerosol according to the invention may comprise liquid droplets having a combination of the DV90, DV50 and DV10 values defined by the aforementioned ranges. For example, the particle size distribution of the liquid droplets may be any combination of a DV90 selected from 8, 9, 10, 1 1 , 12, 13, 14 and 15 pm; a DV50 selected from 3, 4, 5, 6, 7 and 8 pm; and a DV10 selected from 1 , 2 and 3 pm. In one embodiment the liquid droplets may have a particle size distribution combining a DV90 of about 10 pm to about 13 pm; a DV50 of about 4 pm to about 6 pm and a DV10 of about 2 pm to about 3 pm.
The particle size distribution - defined as DV90, DV50 or DV10 - may be measured using techniques known in the art such as those defined in the section 4.2.1 .8 of the EMEA’s Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products (2006). Such methods include laser diffraction or impactor methods based on an Andersen cascade impactor (ACI), a next generation impactor (NGI) or a time-of-flight aerodynamic particle sizer (APS).

Claims

CLAIMS:
1. A pharmaceutical composition for use in the treatment of an allergic reaction or symptom thereof comprising:
(a) epinephrine or a pharmaceutically acceptable salt thereof; and
(b) a solvent selected from water or a water/alcohol mixture, characterised in that the pharmaceutical composition is orally administered as a liquid aerosol comprising liquid droplets generated by Rayleigh droplet train; interface-friction induced droplet break-up; or capillary wave breakup.
2. The pharmaceutical composition for use according to claim 1 , wherein the allergic reaction is selected from anaphylaxis or anaphylactic shock.
3. The pharmaceutical composition for use according to any preceding claim, wherein the pharmaceutical composition is administered as a treatment dose.
4. The pharmaceutical composition for use according to claim 3, wherein the treatment dose comprises 0.001 mg to 4 mg, 0.005 mg to 3 mg, 0.01 mg to 2 mg, 0.05 mg to 1 mg or 0.1 mg to 0.5 mg of epinephrine or a pharmaceutically acceptable salt thereof.
5. The pharmaceutical composition for use according to any one of claims 3 to 4, wherein the treatment dose is at least one fixed dose.
6. The pharmaceutical composition for use according to any one of claims 3 to 5, wherein the treatment dose is one to eight fixed doses.
7. The pharmaceutical composition for use according to claims 5 to 6, wherein the fixed dose has a volume selected from 5 pL to 300 pL, 10 pL to 250 pL, 15 pL to 200 pL, 20 pL to 150 pL, 25 pL to 100 pL, 30 pL to 75 pL, 35 pL to 50 pL, 40 pL to 45 pL.
8. The pharmaceutical composition for use according to any preceding claim, wherein the liquid droplets have a DV50 selected from 3 to 8 pm, 4 to 7 pm or 5 to 6 pm.
9. The pharmaceutical composition for use according to any preceding claim, wherein the liquid droplets have a DV90 selected from 8 to 15 pm, 9 to 14 pm, 10 to 13 pm or 1 1 to 12 pm. The pharmaceutical composition for use according to any preceding claim, wherein the liquid droplets have a DV10 selected from 1 to 3 pm; 1 .5 to 2.5 pm or 1 .9 to 2.1 pm. The pharmaceutical composition for use according to any preceding claim, wherein the epinephrine or a pharmaceutically acceptable salt thereof has a concentration selected from 0.01 mg/mL to 200 mg/mL, 0.02 mg/mL to 150 mg/mL, 0.03 mg/mL to 100 mg/mL, 0.04 mg/mL to 50 mg/mL, 0.05 mg/mL to 25 mg/mL, 0.06 mg/mL to 20 mg/mL, 0.07 mg/mL to 15 mg/mL, 0.08 mg/mL to 10 mg/mL, 0.09 mg/mL to 5 mg/mL, 0.1 mg/mL to 2.5 mg/mL, 0.12 mg/mL to 2 mg/mL, 0.13 mg/mL to 1 .5 mg/mL, 0.14 mg/mL to 1 mg/mL, 0.15 mg/mL to 0.8 mg/mL, 0.16 mg/mL to 0.6 mg/mL, 0.17 mg/mL to 0.6 mg/mL, 0.18 mg/mL to 0.4 mg/mL and 0.2 mg/mL to 0.3 mg/mL. The pharmaceutical composition for use according to any preceding claim, wherein the liquid aerosol is generated by a portable aerosol-generating device selected from the group consisting of a pneumatic or jet type aerosol generator, a vibration type aerosol generator, an ultrasonic type aerosol generator, and a compressed air type aerosol generator. A portable aerosol-generating device comprising a pharmaceutical composition according to claims 1 to 12, wherein the portable aerosol-generating device is selected from the group consisting of a pneumatic or jet type aerosol generator, a vibration type aerosol generator, an ultrasonic type aerosol generator, a surface acoustic wave nebulizer and a compressed air type aerosol generator. A kit comprising a pharmaceutical composition according to claims 1 to 12 and a portable aerosol generating device according to claim 13. A method comprising aerosolising a pharmaceutical composition according to claims 1 to 12 to form a liquid aerosol comprising liquid droplets, wherein the liquid aerosol is generated by Rayleigh droplet train; interface-friction induced droplet break-up or capillary wave breakup.
PCT/EP2021/085723 2020-12-17 2021-12-14 Pharmaceutical composition comprising epinephrine for aerosol administration WO2022129069A1 (en)

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