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WO2025046496A1 - Administration nasale et pulmonaire de médicament - Google Patents

Administration nasale et pulmonaire de médicament Download PDF

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Publication number
WO2025046496A1
WO2025046496A1 PCT/IB2024/058393 IB2024058393W WO2025046496A1 WO 2025046496 A1 WO2025046496 A1 WO 2025046496A1 IB 2024058393 W IB2024058393 W IB 2024058393W WO 2025046496 A1 WO2025046496 A1 WO 2025046496A1
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WO
WIPO (PCT)
Prior art keywords
drug
gas
energy source
canister
chamber
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/IB2024/058393
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English (en)
Inventor
Dominic Schiller
William Samuel Hunter
David Alexander Vodden Morton
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.)
Envirohale Malta Holdings Ltd
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Envirohale Malta Holdings Ltd
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Filing date
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Publication of WO2025046496A1 publication Critical patent/WO2025046496A1/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
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/02—Sprayers or atomisers specially adapted for therapeutic purposes operated by air or other gas pressure applied to the liquid or other product to be sprayed or atomised
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/003—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using capsules, e.g. to be perforated or broken-up
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/003—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using capsules, e.g. to be perforated or broken-up
    • A61M15/0033—Details of the piercing or cutting means
    • A61M15/0041—Details of the piercing or cutting means with movable piercing or cutting means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0065—Inhalators with dosage or measuring devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D83/00—Containers or packages with special means for dispensing contents
    • B65D83/14—Containers for dispensing liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D83/00—Containers or packages with special means for dispensing contents
    • B65D83/14—Containers for dispensing liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant
    • B65D83/44—Valves specially adapted for the discharge of contents; Regulating devices
    • B65D83/52—Metering valves; Metering devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D83/00—Containers or packages with special means for dispensing contents
    • B65D83/14—Containers for dispensing liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant
    • B65D83/60—Containers for dispensing liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant with contents and propellant separated
    • B65D83/66—Containers for dispensing liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant with contents and propellant separated initially separated and subsequently mixed, e.g. in a dispensing head
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/08—Inhaling devices inserted into the nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/02—Gases
    • A61M2202/0208—Oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/02—Gases
    • A61M2202/0225—Carbon oxides, e.g. Carbon dioxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/02—Gases
    • A61M2202/0266—Nitrogen (N)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/04—Liquids
    • A61M2202/0468—Liquids non-physiological
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/82—Internal energy supply devices
    • A61M2205/8218—Gas operated
    • A61M2205/8225—Gas operated using incorporated gas cartridges for the driving gas

Definitions

  • This invention relates to nasal and pulmonary drug delivery. More particularly it relates to novel drug delivery devices and methods of delivering drugs via the nasal and oral pulmonary routes. It also relates to a power source comprising a canister of up to 50ml, more preferably up to 35ml and typically from 10 to 22ml with a gas volume metering valve designed to deliver from 0.1ml to 5ml, more preferably 0.2 to 2.5ml of a propellant gas at a pressure of from 2- 10 Bar.
  • drug includes both prescription pharmaceuticals (including biologics) and other functional actives delived to a user and includes both the pure form, salts and formulations thereof.
  • approved drug in contrast, is limited to a regulatory approved drug (including a biologic), namely one approved by e.g. the United States Food and Drug Administration (FDA), European Medicines Agency (EMA), or another national government agency.
  • FDA United States Food and Drug Administration
  • EMA European Medicines Agency
  • FIG. 1 A simple pressurised metered dose inhaler of the art, is illustrated in Fig 2, and comprises as the propellant power source, a liquid (and a gas headspace) which is mixed with the drug in the form of a suspension or solution.
  • a metered dose is delivered on actuation and the device can include a mouthpiece or a nasal adapter. The aerosol is created by expansion of the liquid propellant.
  • the pMDI is an active device, delivering a single dose in a fast plume (about 100m/s at point of generation) over a period of microseconds.
  • the pMDI creates the fast moving plume from the expansion of the evaporating propellant at the actuator orifice.
  • the velocity and timing are known challenges in patient coordination of inhalation with firing the device.
  • the patient needs to coordinate the actuation of the fast spray with their steady slow inhalation.
  • HFA propellants existing as liquids in the compressed state can act as solvents within the cannister, and a significant concern with all such materials is the potential to extract and leach chemicals from polymeric valve materials.
  • the propellants are in contact with all internal canister and valve components, and are also in contact with the drug substances and excipients, all of which which must be proven to not cause adhesion, create contaminants and degradation products and cause swelling of gaskets. [0017] All these issues are either not or are less relevant for the current invention where the drug is metered external to the cannister, and the propellant is a gas and not a liquid. [0018] A major driver of technology in this sector has been legislation.
  • HFA152a is an alternative HFA propellant which has 138 times the GWP of CO 2 .
  • the problem with such alternate propellants is that they will take extensive time and cost to re-validate.
  • Such re-validation needs to be performed with each one of the wide range of pharmaceutical compounds they need to be re-formulated with.
  • HFA-152a and HF0-1234ze(E) are reported with pharmacological and toxic effects - Sellers, Allergy Asthma Clin Immunol (2017) 13:30, DOI 10.1186/s13223-017-0202-0.
  • Current pressurised metered dose asthma inhaler (pMDI) propellants (HFAs) are not inert pharmacologically, with the compound family having smooth muscle relaxant effect and anaesthetic effects.
  • New propellant HFA152a has been associated with deaths through abuse caused by deliberate inhalation of this gas from consumer aerosols -
  • the climate is Changing for Metered-Dose Inhalers and Action is Needed, J.Pritchard, Drug Design, Development and Therapy 2020:143043–3055.
  • the new HFAs are very different in physicochemical properties, more combustible, and chemically very stable. Thus, they are polyfluoroalkyl substances (PFAS), “forever” chemicals, which are also associated with significant environmental impact issues, and if degraded by heat produce dangerous products such as hydrogen fluoride (HF).
  • PFAS polyfluoroalkyl substances
  • HF hydrogen fluoride
  • PFAS The Organization for Economic Cooperation and Development (OECD) define PFAS to include medical grade fluorinated gases that can be used as propellants. Germany, the Netherlands, Denmark, Norway and Sweden have proposed restrictions on PFAS in Europe, which will likely involve a more stringent timeline in regulations banning their use - A. Lee, “Developing the Next Generation of Inhalers” Technology Networks July 2023. [0026] pMDIs have been cheaper to produce than current DPIs, so there is concern over affordability to switch patients into DPIs.
  • Applicant has a unique power source, containing an aerial gas adsorbed on an adsorbent in a canister.
  • the aerial propellant gas can aerosolise a unit dose of a powder or a liquid which are contained separate of the power source.
  • the aerial propellant gas has zero GWP.
  • Dry Powder Inhalers [0028] Dry powder inhalers take multiple forms. [0029] Passive devices (all current commercial DPI devices) rely on a patients inhalation efforts to entrain, disperse and deliver the powder to the airways. [0030] Active devices employ mechanical or electrical technology, in addition to patient inhalation to entrain, disperse and deliver the powder to the airways. [0031] Devices are further split into “carrier” based systems, which can deliver a single dose or multiple doses from a reservoir, and “agglomerate” based systems.
  • Single dose devices include capsule based formulations such as Aerolizer ® (Novartis) and Handihaler ® (Boehringer Ingelheim) and Multi-dose devices. These multi-dose devices include devices with multiple unit doses, such as, the Diskhaler ® and Diskus ® (Glaxo Smith Kline) and reservoir devices, such as, the Turbohaler (Astra Zeneca) and the Pulvinal ® (Cheisi). [0033] Obviously the designs vary with type, but common essential features are: • An inlet through which air is drawn; • A metered dosing chamber, where the powdered drug is stored prior to actuation; and • An outlet from which the dose is delivered to the user.
  • a device for delivering a drug to a user via the nasal or pulmonary route comprising a propellant energy source to deliver the drug, which propellant energy source is or comprises an aerial gas that is stored in a canister separate of the drug, at a pressure of at least 2 Bar, adsorbed on an adsorbent where it is released therefrom to dispense the drug, which device is absent of a bag-on-valve.
  • the invention is based around the fact that gases can be adsorbed under pressure onto an adsorbant e.g. activated carbon and the greater volumes stored create a power source that can be exploited.
  • gases can be adsorbed under pressure onto an adsorbant e.g. activated carbon and the greater volumes stored create a power source that can be exploited.
  • an adsorbant e.g. activated carbon
  • the greater compressibility of carbon dioxide approximately X10 when adsorbed onto activated carbon at e.g 10 bar
  • a canister filled with 25 cm 3 of activated carbon and charged with carbon dioxide to reach a pressure of about 10 barg adsorbs about 2.3 g of carbon dioxide (approximately 1.3 litres of gas).
  • the combination product further comprises a mechanism for releasing a sufficient volume of the propellant at a speed that delivers/ aerosolizes a unit dose of drug.
  • It may also comprises a drug releasing mechanism for releasing a unit dose of formulated drug into a dose metering chamber from which it is delivered.
  • the key to each device type is the use of the power source, an aerial gas adsorbed on an adsorbent in a canister.
  • benefits such as: o Compact design; o Ease of use by the patient o Simpler and lower cost design; o Greater consistency of discharge; and o An ability to deliver larger doses than conventionally achieved using the prior art devices may be achieved.
  • valve is actuated by the interaction of the cannister and the actuator typically via the valve stem.
  • the gas flow can be controlled by known means, e.g. orifice and conduit size and the use of e.g. reducers, which can alter the flow rate from the chamber.
  • Fig 1 is an illustration of a range of prior art inhalers, the drugs typically used therewith, dose range limitations and the form (powder, suspension, solution);
  • Fig 2 is an illustrative example of a prior art pressurised metered dose inhaler, its metering valve and adapters for nasal or pulmonary delivery;
  • Fig 3 is an illustrative example of a prior art powder inhaler device (passive) with a reservoir delivering multiple doses via a metering mechanism;
  • Fig 4 is an illustration of an alternative prior art powder inhaler device (active) with a pump and a mechanism for piercing blisters;
  • Fig 5 is an illustration of a prior art soft mist inhaler device and its “uniblock” component;
  • Fig 6 is an illustration of a prior art nebuliser;
  • Fig 7a is an illustration of an exemplary press
  • the canister (45) is housed at a proximal (21) end of the device (20) remote from a distal (22) end, which is the end of the device where an aerosol plume (60), on actuation of the device, exits the device (20).
  • the device (20) comprises canister retaining walls (23) and an end face (24) through which a valve stem (43) of the canister (45) passes.
  • gas is released from the canister and can cause a unit dose (U) of the formulated drug (30) to be dispensed.
  • U unit dose
  • the gas can be dispensed in a “metered” fashion, with a volume (V) of e.g. from 0.1 to 5 ml, more particularly 0.2 to 2.5ml, at a pressure (P) of e.g.2 to 10 Bar which has been demonstrated (Example 1) to effectively aerosolise a high dose (up to 50mg) of an exemplary powder (Example 2).
  • the gas release mechanism (50) comprises a chamber (52) in operative communication with the canister (45) and device (20) (See Fig 7b which is applicable to the claimed invention) allowing a known volume of gas, at a given pressure, to be dispensed on actuation of the device (pressing on the canister results in the valve stem being depressed opening the valve – compare e.g. Fig 7c and 7d) and the chamber (52) to be refilled with aerial gas (21) as it is desorbed from the adsorbent (42).
  • a metered dose of aerial gas (41) is released on actuation of a metering valve (51) and is directed from a valve stem (53) along a first conduit (25) to, in the example illustrated, a drug dosing chamber (80) holding a unit (U) dose of a drug (30), which is dispensed in an arosolised plume (60) as the gas travels from upstream of the drug (30) though the dosing chamber (80) where it picks up the drug (in the example illustrated a powder) and carries it along a second conduit (27) to an exit orifice (28) where it leaves the device as a plume (60).
  • a drug releasing mechanism (70) in this embodiment comprises a piercing mechanism (72) releases the drug (30) from a capsule whereupon it is aerosolised by the gas as it passes from the first conduit (25) through the dosing chamber (80) and out via the second conduit (27) and exit orifice (28).
  • Fig 7a illustrates the delivery of a single unit dose
  • the drug releasing mechanism (70) could dispense multiple doses using, for example, a carousel, as disclosed in WO200117595 (ML Labs) or alternatively Relenza Rotadisc patient instructions available at: https://www.medicines.org.uk/emc/files/pil.3809.pdfDiskhaler or could be a chamber that is dry powder inhaler: Focussed in vitro proof of principle evaluation of a new chemical entity for asthma”, International Journal of Pharmaceutics 239 (2002) 149–156, illustrated in Figure 1 therein as a detailed view of the Clickhaler metering cone.
  • Fig 7b illustrates a standard pMDI metering mechanism (50), also applicable to the present invention, and comprises a metering valve (51) fitted to a canister (45) and actuator device (20). It comprises a metering chamber (52) and valve stem (53) leading to an exit orifice (28).
  • Figs 7c and 7d illustrate an exemplary and modified metering mechanism (50) which has a metering chamber (52) with a larger volume capacity than existing pMDIs. It too comprises a metering valve (51) and valve stem (53), the metering valve comprising a gas entry orifice (54) which allows the chamber to be filled from the canister (45) when at rest (Fig 7c) and a gas exit orifice (55) which allows the gas to exit the chamber (51) when the device (20) is actuated (Fig 7d).
  • a typical pMDI canister has a volume of between 10 to 22ml and the metering mechanism (50) dispenses a liquid and not an aerial gas (21).
  • the metering chamber only needs to have a capacity of 20 to 100 ⁇ l.
  • the mechanism (50) employed to deliver, if desired, a metered dose of the pressurised aerial gas is several orders of magnitude larger at 0.1ml to 5ml, more typically 0.5ml to 2.5ml. This is because the aerial gases expansion is wholly dependent on the pressure at which it is stored.
  • the gas metering mechanism (50) comprises a metering valve (51), a gas chamber (52), a valve stem (53), a gas entry orifice (54) which is open in an at rest position (7c) and a gas exit orifice (55) which is closed in the rest position.
  • gas entry orifice (54) When actuated, gas entry orifice (54) is closed and gas exits via gas orifice (55) via the valve stem (53).
  • Fig 8a - c compares the equilibrium adsorption isotherms of respectively: • Oxygen • Nitrogen; and • Carbon dioxide at 25oC and pressures of from 1 to 10 bar for different adsorbents including granulated activated carbon (GAC) - Pure (and functionalised). What it shows is that significant adsorption can be achieved for each of these gases, with the greatest adsorbtion being for carbon dioxide.
  • GAC granulated activated carbon
  • Fig 9 from WO2008064293, compares the content discharge from a canister of carbon dioxide when adsorbed v as a compressed gas. What it demonstrates is that an adsorbed gas makes it easier to manage “controlled” dosing.
  • the canister may be of the same dimensions as for a prior art (10 to 50ml, typically 10 to 22ml).
  • an exemplary drug for use in a modified pMDI inhaler of the invention is Salbutamol.
  • Salbutamol is a drug used for asthma treatment.
  • a prior art device may contain the drug and propellant in a cansiter with an internal volume of 20 ml, which is sufficient to administer up to 100-200 metered doses of medication.
  • a similarly-dimensioned canister using an activated carbon absorbant, and compressed to ⁇ 2 to 10 bar with CO 2 as the propellant gas may also be used to dispense a very significant number of doses of powder from pierced capsules.
  • the dimensions, familiar shape, and portability of existing asthma inhalers may be potentially carried over to a similar design, but using a zero GWP propellant.
  • a standard metering valve is shown in the embodiment in Figs 7b, a metering valve as such may not be required with the Applicant’s invention. For this embodiment all that is required is to pass a sufficient minimum volume of gas to dispense the e.g.
  • salbutamol from e.g. a pierced capsule to dispense a repeatable dose of the drug
  • minimum gas volume may not be require to be precisely metered.
  • the minimum gas volume varies depending on the mass of powder in the exemplary capsule. For capsules containing from 10 to 50 mg of powder, the Applicant has found such minimum gas volume may be in the range of 1-10 ml of gas (at atmospheric pressure). [00143] Furthermore, the Applicants have determined that a number of alternative aerial gases may be used as illustrated by the data in Figure 8.
  • a prior art pressurised metered dose inhaler (200) is a combination product (210) comprising a device (220), a drug (230) and a power source (240) or propellant (241).
  • the drug (230) and propellant (241) – a liquid, typically a hydrofluroalkane (HFA), are retained together in a sealed canister (245) under pressure (P).
  • HFA hydrofluroalkane
  • the device (220) has an actuator body (222), a first opening (224) that receives the canister (245), and a second opening (226) out of which the aerosolised (260) drug (230) exits the device (220).
  • the device (220) has a metering mechanism (250) for delivering a metered dose comprising a metering valve (252), actuator (254), actuator seat (256) and actuator nozzle (258).
  • Actuation of the device results in the delivery of a metered dose, the liquid propellant expanding and aerosolising the drug which is dispensed through an appropriate adapter (90) (nasal (92) or mouthpiece (94)).
  • the device is powered by the release of an aerial gas from an adsorbent from a canister which delivers a unit dose of drug which is housed separate of the propellant.
  • V volume
  • Q flow rate
  • the drug can take the form of a powder, suspension, dispersion or emulsion, or solution.
  • a prior art dry powder inhaler (300) is a combination product (310) comprising a device (320), a drug (330) and a power source (340) such as a mechanical spring (342).
  • the drug (330) is stored in a bulk chamber (380) which is delivered to a metering chamber (382).
  • the device (320) has a body (322).
  • An overcap (324) at one end houses the power source (340) and the drug (330) is fed from the bulk chamber (380) into a metering chamber (382) of a drug metering mechanism (350).
  • Channels (326) in the device ensure that when a user inhales, air is drawn across the device and aerosolised (360) drug (330) exits the device (320).
  • a device can be modified by way of the invention such that a unit dose of a powdered drug (330) is released from a chamber actively (as opposed to passively) using an aerial gas dispensed from a power souce (40) as illustrated in Figs 7a to 7d.
  • a prior art active dry powder inhaler (400) is a combination product (410) comprising a device (420), a drug (435) and a power source (440) in the form of a pump (442) and integral air reservoir (444).
  • the drug (435) is stored in a chamber (480) in a unit dose form such as a blister (434) and is released from the chamber by a blister piercing mechanism (470).
  • the device (420) has a body (422), a first opening (424) which receives the pump (442), and a second opening (426) out of which the aerosolised (460) drug (435) exits the device (420).
  • Such a device can be modified by way of the invention such that a unit dose of a powdered drug (435) is released from a chamber actively (as opposed to passively) using an aerial gas dispensed from a power source (440) as exemplified in Figs 7a to 7d which replaces the pump and integral air resevoir.
  • a power source 440
  • a prior art active soft mist inhaler (500) is a combination product (510) comprising a device (520), a drug (530) and a power source (540) in the form of a spring (542) which drives a unit dose of drug (530) from a chamber (580) through a uniblock (528) where it is aerosolised (560).
  • the device (520) has a body (522), a first end (524) which houses the spring (542) and a second opening (526) out of which the aerosolised (560) drug (530) exits the device (520), the dose being held in a chamber (580) intermediate the two with the uniblock (528) positioned beyond the dosing chamber.
  • the uniblock (528) comprises a nozzle outlet (5281), filter structure (5282), silicon wafer (5283) and glass (5284).
  • a unit dose of a powdered drug (530) is released from its chamber actively using an aerial gas dispensed from a power souce (40) as exemplified in Figs 7a to 7d which replaces the spring (542).
  • a power souce 40
  • t dose delivery time
  • a representative prior art neubuliser (600) comprises a device (620), a drug (630) and a power source (640) – pressurised gas from a compressor (electric).
  • the drug (630) is stored in a resevoir (680) and is aerosolised.
  • the device (620) has a body (622).
  • the device (620) has a body (622), an air inlet (624) and an air outlet (628) or mouthpiece out of which the aerosolised (660) drug (630) exits the device (620).
  • the device further comprises a baffle arrangement (626) to assist aerosolization and break up.
  • Such a device can be modified by way of the invention such that the drug (630) is caused to arosolise using an aerial gas dispensed from a power source (40) as exemplified in Figs 7a to 7d as opposed to air driven electrically through a compressor. Thus, it does not require mains electric or batteries for operation.
  • a powder particle containing Fluorescein formulation suitable for nasal delivery was prepared based on the methodology of Suhaidi et al (2023) - Bulk Flow Optimisation of Amorphous Solid Dispersion Excipient Powders through Surface Modification. Pharmaceutics, 15. [00166] The particles when dissolved in artificial mucus would fluoresce brightly under UV light in a clear nasal cast. As the particles were for nasal delivery a particle size distribution with the largest proportion of the particles in the range 10 ⁇ m to 40 ⁇ m was prepared. [00167] A blend of 90% Maltodextrin, 5% L-leucine, and 5% Fluorescein produced a powder with particle diameter in the correct size range for nasal delivery, and with good flowability.
  • the particles formulated became a bright green colour under UV.
  • the power source can aerosolise particles, whether for nasal or pulmonary delivery
  • the larger, heavier nasal particles size range 10 to 40 ⁇ m
  • lighter, smaller pulmonary particles size range 2 to 10 ⁇ m
  • the rig (700) comprises an air inlet (710), an adjustable regulator (720) and a solenoid valve (730) which is connected to an electrician controller (750) linked to a computer (760) via a relay (740).
  • a pierced capsule (30) is placed in a chamber (770) – see also Fig 11 and a controlled pulse of air is released such that the drug (30) is delivered as a plume (60) out of an insufflator nozzle (780) onto a plate inside a conical funnel (790) where it can be visualised under UV.
  • Nasal powder dispensing device [00170] Dry powder inhalers (DPIs) for pulmonary inhalation therapy are devices somewhat similar to nasal powder delivery devices as they both release dry powder particles from a reservoir into an aerosol plume for delivery to the patient.
  • DPIs may release drugs in powder from either i) capsules; ii) multi-dose strips, or iii) bulk powder reservoirs.
  • capsule-based DPIs There are several capsule-based DPIs on the market and they have some advantages over powder reservoir devices as the capsule and blister packaging protects the powder contents from moisture.Furthermore, capsule filling lines are widely used and deployed in the pharmaceutical industry.
  • Capsule-based DPIs also have good dose-to-dose consistency (Islam & Gladki, 2008).
  • Well-known capsule-based DPIs which have been on the market for many years include the Breezhaler® (Novartis, Basel, Switzerland); the HandiHaler® (Boeringer Ingelheim, Germany); the Twister® (Aptar, IL, USA); and the Rotahaler® (Cipla, Mumbai, India). Consequently, Applicant chose a nasal powder delivery device which used Fluorescein dyed particles loaded into capsules for testing.
  • the Plastiape RS01 is another example of a commercial capsule-based DPI (hereon called cDPIs).
  • the capsule loading, piercing, and powder dispensing arrangement (70) comprises two hollow stainless steel piercing spikes (72) which penetrate each of the opposite domed ends of a size 3 gelatin capsule (Fig 11).
  • the piercing spikes create holes in the capsule of diameter 1.15 mm (Martinelli, F., Balducci, A. G., Rossi, A., Sonvico, F., Colombo, P., & Buttini, F.(2015). “pierce and inhale” design in capsule based dry powder inhalers: Effect of capsule piercing and motion on aerodynamic performance of drugs. International Journal of Pharmaceutics, 487, 197–204). Users deploy these hollow spikes by depressing two opposed spring-loaded buttons. Whilst the passive method of oral inhalation to induce powder delivery does not suit a nasal delivery device the RS01 device does have a capsule piercing arrangement which is be suitable for capsule emptying.
  • a manual “squeeze bulb” powder insufflator was procured (Sheehy House Insufflator, Grace Medical, Memphis USA).
  • the manual "squeeze bulb” was replaced by a programmable air pulse source as part of a test rig described earlier with reference to Fig 10.
  • capsules were filled with 10, 20, 30, 40 and 50 mg of the fluorescent powder blend. Five repeated tests were made at each of the 10 mg mass increments. Hence a total of 25 capsules were tested.
  • Each capsule had its domed ends pierced using an RS01 device shown in Fig 11 having a dosing chamber (70) with a piercing mechanism (72) in which a capsule is placed.
  • Fig 12 shows a plot of the capsule emptying performance (emitted dose) using a single 200ms burst of air applied via the test rig. This chart demonstrates effective capsule emptying performance for each mass increment. Only one relatively poor emptying result (60%) for 1 of the 25 capsules tested (40 mg powder mass) measured, which caused the lower percentage. [00177] A photograph of the plume (60) emitted is illustrated in Fig 13.

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Abstract

La présente invention concerne un dispositif (20) destiné à administrer un médicament (30) à un utilisateur par voie nasale ou pulmonaire. Le dispositif peut être un aérosol doseur sous pression (200), un inhalateur de poudre sèche active (300/400), un inhalateur de nuage (500) ou un nébuliseur (600). Le dispositif (20) comprend une source d'énergie propulsive (40) pour administrer un médicament (30), ladite source d'énergie propulsive (40) étant ou comprenant un gaz aérien (41) qui est stocké dans une cartouche (45) séparée du médicament, à une pression d'au moins 2 bars, adsorbé sur un adsorbant (42) d'où il est libéré pour délivrer le médicament (30). Le dispositif comprend un mécanisme de diffusion de gaz (50) doté d'une chambre de dosage (52) qui a une capacité supérieure à celle d'un aérosol doseur sous pression traditionnel rempli d'un agent propulseur HFC. Le gaz aérien (41) est libéré de la chambre lors de l'actionnement et se déplace le long d'un conduit (25) pour déplacer, depuis une chambre de dosage (80), une dose d'un médicament (30) qui est aérosolisé et sort du dispositif sous forme de panache (60) par l'intermédiaire d'un second conduit (27) et d'une sortie (28).
PCT/IB2024/058393 2023-08-30 2024-08-29 Administration nasale et pulmonaire de médicament Pending WO2025046496A1 (fr)

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Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001017595A1 (fr) 1999-09-04 2001-03-15 Innovata Biomed Limited Dispositif d'administration
US6257233B1 (en) 1998-06-04 2001-07-10 Inhale Therapeutic Systems Dry powder dispersing apparatus and methods for their use
WO2001078696A3 (fr) 2000-04-17 2002-03-14 Vectura Ltd Ameliorations au niveau des formulations a utiliser dans des dispositifs d'inhalation
US20050263151A1 (en) * 2004-03-05 2005-12-01 Boehringer Ingelheim International Gmbh Powder inhaler having a nozzle with a plurality of channels
US20060049215A1 (en) 2004-06-12 2006-03-09 Lim Walter K System and method for providing a reserve supply of gas in a pressurized container
WO2006056812A1 (fr) 2004-11-23 2006-06-01 Vectura Limited Formulations de poudre seche pour inhalateur comprenant des particules modifiees en surface avec des additifs anti-adherants
WO2008053253A2 (fr) 2006-11-03 2008-05-08 Vectura Limited Dispositifs inhalateurs et compositions pharmaceutiques sur mesure
US20080116228A1 (en) * 2006-11-22 2008-05-22 Calgon Carbon Corporation Carbon Filled Pressurized Container and Method of Making Same
US20090235924A1 (en) * 2008-03-17 2009-09-24 Boehringer Ingelheim International Gmbh Reservoir and nebulizer
EP2327921A1 (fr) * 2003-12-03 2011-06-01 Chemviron Carbon Limited Stockage de gaz et utilisation pour distribution de fluides
US20140048566A1 (en) 2004-01-23 2014-02-20 Kbig Limited Method of manufacturing a product dispensing system
US20160129205A1 (en) * 2014-11-09 2016-05-12 Sipnose Ltd. Device and method for aerosolized delivering of substance to a natural orifice of the body
US20200024065A1 (en) * 2017-03-01 2020-01-23 Simply Breathe Ltd Gas storage devices
WO2020021473A1 (fr) 2018-07-27 2020-01-30 Simply Breathe Ltd Technologie de poche sur vanne
WO2024033662A1 (fr) 2022-08-12 2024-02-15 Cambridge Healthcare Innovations Limited Appareil d'amplification de pression négative et inhalateur

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4049158A (en) * 1975-11-13 1977-09-20 S. C. Johnson & Son, Inc. Pressurized container-dispensers and filling method
CA2617486A1 (fr) * 2005-08-08 2007-02-15 Novartis Ag Recipient isole pour dispositif d'inhalation a doses mesurees
WO2007135438A1 (fr) * 2006-05-24 2007-11-29 Kbig Limited Système de distribution de produit
CA3111516C (fr) * 2011-03-03 2023-05-23 Impel Neuropharma, Inc. Dispositif d'administration de medicament par voie nasale
US20140117054A1 (en) * 2012-11-01 2014-05-01 Calgon Carbon Corporation Carbon blends for enhanced gas storage
KR101978554B1 (ko) * 2016-05-17 2019-05-16 한양대학교 산학협력단 비강-뇌 약물전달장치
GB2599207B (en) * 2018-07-27 2023-02-01 Simply Breathe Holdings Ltd Bag on valve technology
CN113473967B (zh) * 2019-01-03 2022-09-09 英倍尔制药公司 经鼻药物递送装置

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6257233B1 (en) 1998-06-04 2001-07-10 Inhale Therapeutic Systems Dry powder dispersing apparatus and methods for their use
WO2001017595A1 (fr) 1999-09-04 2001-03-15 Innovata Biomed Limited Dispositif d'administration
WO2001078696A3 (fr) 2000-04-17 2002-03-14 Vectura Ltd Ameliorations au niveau des formulations a utiliser dans des dispositifs d'inhalation
EP2327921A1 (fr) * 2003-12-03 2011-06-01 Chemviron Carbon Limited Stockage de gaz et utilisation pour distribution de fluides
US20140048566A1 (en) 2004-01-23 2014-02-20 Kbig Limited Method of manufacturing a product dispensing system
US20050263151A1 (en) * 2004-03-05 2005-12-01 Boehringer Ingelheim International Gmbh Powder inhaler having a nozzle with a plurality of channels
US20060049215A1 (en) 2004-06-12 2006-03-09 Lim Walter K System and method for providing a reserve supply of gas in a pressurized container
WO2006056812A1 (fr) 2004-11-23 2006-06-01 Vectura Limited Formulations de poudre seche pour inhalateur comprenant des particules modifiees en surface avec des additifs anti-adherants
WO2008053253A2 (fr) 2006-11-03 2008-05-08 Vectura Limited Dispositifs inhalateurs et compositions pharmaceutiques sur mesure
WO2008064293A2 (fr) 2006-11-22 2008-05-29 Calgon Carbon Corporation Contenant sous pression rempli de carbone et procédé de fabrication de celui-ci
US20080116228A1 (en) * 2006-11-22 2008-05-22 Calgon Carbon Corporation Carbon Filled Pressurized Container and Method of Making Same
US20090235924A1 (en) * 2008-03-17 2009-09-24 Boehringer Ingelheim International Gmbh Reservoir and nebulizer
US20160129205A1 (en) * 2014-11-09 2016-05-12 Sipnose Ltd. Device and method for aerosolized delivering of substance to a natural orifice of the body
US20200024065A1 (en) * 2017-03-01 2020-01-23 Simply Breathe Ltd Gas storage devices
WO2020021473A1 (fr) 2018-07-27 2020-01-30 Simply Breathe Ltd Technologie de poche sur vanne
WO2024033662A1 (fr) 2022-08-12 2024-02-15 Cambridge Healthcare Innovations Limited Appareil d'amplification de pression négative et inhalateur

Non-Patent Citations (25)

* Cited by examiner, † Cited by third party
Title
"Development of Respimat® Soft MistTM Inhaler and its clinical utility in respiratory disorders", MEDICAL DEVICES: EVIDENCE AND RESEARCH, vol. 4, 2011, pages 145 - 155
"Inhaled drug delivery for the targeted treatment of asthma", ADVANCED DRUG DELIVERY REVIEWS, vol. 198, 2023, pages 114858
"Novel Platforms for drug delivery Applications", WOODHEAD PUBLISHING SERIES IN BIOMATERIALS, 2023, pages 568 - 606
A. LEE: "Developing the Next Generation of Inhalers", TECHNOLOGY NETWORKS, July 2023 (2023-07-01)
ASC OMEGA, vol. 7, 2022, pages 18409 - 18428
EHRICK,J. D., SHAH, S. A., SHAW, C., KULKARNI, V. S., COOWANITWONG, I., DE, S., & SUMAN, J.D.: "Considerations for the development of nasal dosage forms. Sterile Product Development: Formulation, Process", QUALITY AND REGULATORY CONSIDERATIONS, 2013, pages 99 - 144
ELKINS, M. R.ANDERSON, S. D.PERRY, C. P.DAVISKAS, E.CHARLTON, B.: "Inspiratory flows and volumes in subjects with non-cf bronchiectasis using a new dry powder inhaler device", OPEN RESPIR MED, vol. 8, 2014, pages 8 - 13
FARKAS, D., HINDLE, M., & LONGEST, P. W.: "Development of an inline dry powder inhaler that requires low air volume", JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY, vol. 31, 2017, pages 255 - 265
FRONTIERS | HALF A CENTURY OF TECHNOLOGICAL ADVANCES IN PULMONARY DRUG DELIVERY: A PERSONAL PERSPECTIVE
FRONTIERS IN DRUG DELIVERY, 13 April 2022 (2022-04-13)
INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 239, 2002, pages 149 - 156
ISLAM, N.GLADKI, E.: "Dry powder inhalers (dpis)-a review of device reliability and innovation", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 360, 2008, pages 1 - 11, XP022853120, DOI: 10.1016/j.ijpharm.2008.04.044
J ALLERGY CLIN IMMUNOL PRACT., vol. 10, no. 7, July 2022 (2022-07-01), pages 1813 - 1824
J.PRITCHARD, DRUG DESIGN, DEVELOPMENT AND THERAPY, vol. 14, 2020, pages 3043 - 3055
J.PRITCHARD: "The Climate is Changing for Metered-Dose Inhalers and Action is Needed", DRUG DESIGN, DEVELOPMENT AND THERAPY, vol. 14, 2020, pages 3043 - 3055, XP055795957, DOI: 10.2147/DDDT.S262141
KUBLIK, H.VIDGREN, M. T.: "Nasal delivery systems and their effect on deposition and absorption", ADVANCED DRUG DELIVERY REVIEWS, vol. 29, 1998, pages 157 - 177, XP055248105, DOI: 10.1016/S0169-409X(97)00067-7
MARTINELLI, F., BALDUCCI, A. G., ROSSI, A., SONVICO, F., COLOMBO, P., & BUTTINI,F.: "pierce and inhale" design in capsule based dry powder inhalers:Effect of capsule piercing and motion on aerodynamic performance of drugs", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 487, 2015, pages 197 - 204, XP029158446, DOI: 10.1016/j.ijpharm.2015.04.003
ON DRUG DELIVERY, 24 April 2023 (2023-04-24), pages 13
ON DRUG DELIVERY, pages 13 - 17
PHARMACEUTICAL TECHNOLOGY, 26 August 2024 (2024-08-26)
RESPIRATORY DRUG DELIVERY, vol. 2, 2022
SELLERS, ALLERGY ASTHMA CLIN IMMUNOL, vol. 13, 2017, pages 30
STEINTHEIL, J AEROSOL MED PULM DRUG DELIVERY, vol. 30, no. 1, February 2017 (2017-02-01), pages 20 - 41
SUHAIDI ET AL.: "Bulk Flow Optimisation of Amorphous Solid Dispersion Excipient Powders through Surface Modification", PHARMACEUTICS, 2023, pages 15
WILKINSONWOODCOCK, BR J CLIN PHARMACOL., vol. 88, 2022, pages 3016 - 3022

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