US20140060531A1 - Aerosol inhalation device - Google Patents

Aerosol inhalation device Download PDF

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Publication number
US20140060531A1
US20140060531A1 US14/012,392 US201314012392A US2014060531A1 US 20140060531 A1 US20140060531 A1 US 20140060531A1 US 201314012392 A US201314012392 A US 201314012392A US 2014060531 A1 US2014060531 A1 US 2014060531A1
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United States
Prior art keywords
actuator
orifice
tubular element
longitudinal axis
nozzle block
Prior art date
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Abandoned
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US14/012,392
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English (en)
Inventor
Gaetano Brambilla
Robert Johnson
Daivd Andrew Lewis
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Chiesi Farmaceutici SpA
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Chiesi Farmaceutici SpA
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Application filed by Chiesi Farmaceutici SpA filed Critical Chiesi Farmaceutici SpA
Publication of US20140060531A1 publication Critical patent/US20140060531A1/en
Assigned to CHIESI FARMACEUTICI S.P.A. reassignment CHIESI FARMACEUTICI S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRAMBILLA, GAETANO, JOHNSON, ROBERT, LEWIS, DAVID ANDREW
Priority to US15/276,291 priority Critical patent/US10737044B2/en
Abandoned legal-status Critical Current

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    • 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
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/0021—Mouthpieces therefor
    • 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
    • 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
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0233—Conductive materials, e.g. antistatic coatings for spark prevention
    • 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
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0238—General characteristics of the apparatus characterised by a particular materials the material being a coating or protective layer
    • 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
    • A61M2209/00—Ancillary equipment
    • A61M2209/06—Packaging for specific medical equipment

Definitions

  • the present invention relates to the field of inhalers for medicaments and in particular to an improvement of aerosol devices for transferring to the respiratory system of a patient and in particular to the lungs, by oral inhalation, a metered dose of a medicament contained in a pressurised dispensing container.
  • pMDIs are aerosol delivery systems designed to deliver a medicament formulated with a pressure liquefied propellant gas and optionally at least one suitable additive. pMDIs are designed to meter a predetermined amount of the medicament, completely dissolved (in solution) or in form of micronized solid particles dispersed or suspended in the formulation and to dispense the dose as an inhalable aerosol cloud or plume.
  • FIG. 1 A conventional pMDI is shown in FIG. 1 .
  • the pMDI comprises an actuator 1 comprising, in its vertical hollow portion, a housing adapted to receive a canister 2 .
  • the canister 2 contains a formulation wherein the medicament is in solution or in suspension with a low boiling point propellant system optionally comprising at least one suitable pharmaceutically acceptable additive.
  • the canister 2 is normally provided with a metering valve having a hollow valve stem 3 for measuring discrete doses of the medicament formulation. The dose is dispensed as an inhalable cloud or plume 4 .
  • Typical actuators 1 have a nozzle assembly or nozzle block 5 which receives the hollow valve stem 3 of the aerosol canister 2 .
  • the nozzle block 5 defines the walls of the valve stem receptacle 13 , expansion chamber or sump 6 , and orifice 7 which ends in an aperture 8 having an enlarging frusto-conical section terminating in a cylindrical parallel sided portion.
  • the orifice 7 through its aperture 8 serves to propel the aerosol formulation into the mouthpiece portion, towards a mouthpiece opening 10 and assists in atomization of the aerosol formulation.
  • the orifice 7 has been provided such that its longitudinal axis is aligned with a longitudinal axis 9 of the actuator mouthpiece portion, so that the aerosol exits the orifice in a mean direction towards a mouthpiece opening 10 .
  • the longitudinal axis of the orifice 7 in the nozzle block 5 aligned with the longitudinal axis 9 of the mouthpiece portion, is normally located at an angle greater or equal to 90°, preferably in the range from approximately 90° to approximately 120°, and more preferably from approximately 90° to approximately 110° to the direction of the longitudinal axis of the hollow valve stem 3 of the aerosol canister 2 . Therefore when the canister 2 is actuated, the formulation containing the propellant moves down the stem 3 and expands within the expansion chamber 6 before being propelled through the orifice 7 from its aperture 8 towards the mouthpiece opening 10 . The formulation, therefore, is atomized in a direction extending at an angle from approximately 90° to approximately 120° and preferably 110° with respect to the longitudinal axis of the aerosol canister 2 .
  • the medicament is discharged in response to the user actuation performed by moving the canister relative to the valve stem, in the same time the medicament is inhaled by the user through the mouthpiece opening, creating an airflow entering from the spaces between the external walls of the canister and the internal walls of the vertical portion of the actuator, located upstream from the mouthpiece portion.
  • inhalers of this type are normally designed to be as small as practical for the convenience of users, the distance between the point at which the medicament is fired into the airflow and the patient's mouth is usually quite small so that there is little distance to reduce the inertia of the particles of medicament, with the result that coarse, non-respirable (>9 ⁇ m aerodynamic diameter) aerosol particles may impact and deposit in the mouth, throat and pharynx walls.
  • GB-A-2279879 and EP-A-0839544 disclose inhalers in which air inlets are arranged such that during inhalation an air flow is created which has a component directed away from the mouthpiece towards the aerosol spray.
  • the reverse airflow component is intended to create turbulence and slow the velocity of the medicament particles.
  • EP-A-862921 discloses similar devices comprising also a flow controller manually depressible to unseal the air inlets.
  • W0 93/05837 and U.S. Pat. No. 4,972,830 disclose inhalers in which the passage which directs the pressurised medicament from the canister to the chamber has particular configurations to reduce the velocity of the spray and enhance dispersion of the medicament in the airflow.
  • EP-A-0412648 discloses an inhaler in which a frusto-conical diverter with a small orifice is positioned in the path of the spray before the mouthpiece. Aerosol droplets are said to predominantly pass through the small orifice, decelerate and be inhaled while the propellant gas is predominantly diverted away from the mouthpiece out of the inhaler.
  • WO 00/50112 relates to actuators arranged as to inhibit airflow due to patient in the vicinity of the orifice of the nozzle block.
  • WO 2008/023014 wherein the actuator outlet, through which the user inhales, has a substantially closed rear end section which partitions the outlet from the housing such that, on inhalation, an air flow is drawn substantially from an outer peripheral surface of the outlet;
  • outlet includes at least one flow path which provides for a substantially annular air flow as to provide a sheathing air flow
  • nozzle outlet coupled or integrally formed with the actuator outlet, is present as a separately-formed component from the nozzle block and may be provided with one or more air inlets of different shapes positioned around the orifice outlet of the nozzle block.
  • the actuator is designed such that atomized spray may be emitted from the orifice with a longitudinal axis which coincides with the longitudinal axis of the canister.
  • the correct use of this actuator depends on the inspiratory effort and timing of the patient, moreover the manufacture of such a device is more complex and expensive than a conventional pMDI.
  • EP-A2-0132352 U.S. Pat. No. 3,361,306, and US-A1-2012/0085345 describe devices for dispensing medicaments from pressurised containers having an outlet spout provided internally with an outlet member having a small (capillary passage) arranged at one end to receive contents discharged from the pressurised container and terminating at the other hand in an outlet directed towards the outlet end of the spout. But these devices are not intended for oral inhalation of drugs for the treatment of lung or pulmonary diseases but simply consist in spray applicator devices for local treatment of conditions of the nose, mouth or throat.
  • PSD particle size distribution
  • an actuator for an aerosol inhalation device comprising:
  • a housing adapted to receive an aerosol canister containing a pressurised medicament formulation, provided with a metering valve having a hollow valve stem, a mouthpiece portion terminating in a mouthpiece opening through which the user inhales, wherein the longitudinal axis of the mouthpiece portion is located at an angle greater or equal to 90° to the direction of the longitudinal axis of the hollow valve stem;
  • a nozzle block defining a valve stem receptacle, an expansion chamber or sump, and an orifice to propel the aerosol formulation towards the mouthpiece opening characterized by the presence of a tubular element extending in the mouthpiece portion from the orifice aperture in a longitudinal axis substantially aligned with a longitudinal axis of the actuator mouthpiece portion and substantially coinciding with the orifice longitudinal axis.
  • tubular element is positioned to enclose the orifice aperture within a recess.
  • the tubular element is configured such that one of its terminal openings may be close fit to the nozzle block external surface, around the orifice aperture, so as to be in a continuous flow path with the orifice.
  • the tubular element is configured such that one of its terminal openings is in a tight fit with the nozzle block external surface, around the orifice aperture, so as to be in a continuous flow path with the orifice.
  • the tubular element may be welded to the nozzle block external surface, around the orifice aperture.
  • the tubular element may be formed on the lateral part of a shaped hollow cylindrical object suitable to be tightly fitted to the outside of the nozzle block, covering its lateral surfaces so as the tubular element is in a continuous flow path with the orifice.
  • tubular element, the nozzle block, the housing for the aerosol canister and the mouthpiece portion form a single piece moulded actuator.
  • the tubular element has an internal diameter from 2 to 15 mm, preferably from 3 to 12 mm, even more preferably from 5 to 7 mm, and the particularly preferred diameter is equal to about 6 mm.
  • the tubular element has a length, i.e. the distance between its apertures, from 2 to 20 mm, preferably from 3 to 15 mm, even more preferably from 8 to 12 mm, and the particularly preferred lengths are equal to about 9, 10, and 11 mm.
  • the tubular element may also have a conventional thickness for this kind of devices known to the skilled in the art, however, suitable tubular element thickness may be from 0.1 to 3 mm or more, preferably from 0.2 to 2 mm, more preferably from 0.8 to 1.2 mm and most preferably of 1 mm.
  • the tubular element or the shaped hollow cylindrical object comprising in its lateral side a tubular element, suitable to be tightly fitted to the outside of the nozzle block, may be formed of the same material as the nozzle block or of a different material specifically suited to its purposes.
  • a shaped hollow cylindrical object suitable to be tightly fitted to the outside of the nozzle block of an actuator for pMDI inhalers, covering its lateral surfaces and comprising in its lateral side a tubular element so as that the tubular element is in a continuous flow path with the nozzle block orifice.
  • an inhaler comprising the actuator of any one aspect or embodiment described herein, and a canister having a metering valve and containing a pressurised medicament formulation.
  • the canister comprises a valve stem to be fitted into the valve stem receptacle formed in the nozzle block.
  • a metered-dose inhaler actuator comprising a housing having a mouthpiece portion and a canister receiving portion configured to receive a canister.
  • the actuator further comprises a nozzle block disposed within the housing and defining a valve stem receptacle configured to receive a valve stem of the canister, an orifice in fluid communication with the valve stem receptacle to propel the aerosol formulation towards the mouthpiece opening and a tubular element extending in the mouthpiece portion from the orifice aperture in a longitudinal axis substantially aligned with a longitudinal axis of the actuator mouthpiece portion and substantially coinciding with the orifice longitudinal axis.
  • a kit of parts comprising an actuator of an aerosol inhalation device, the shaped hollow cylindrical object suitable to be tightly fitted to the outside of the nozzle block and an aerosol canister containing a pressurised medicament formulation.
  • a method in which an actuator of any one aspect or embodiment described herein is used for dispensing an aerosol formulation from a canister.
  • the method may be used to dispense the aerosol formulation without interaction with a human or animal body.
  • the method may, for example, be used to dispense an aerosol formulation when priming a metered dose inhaler.
  • Another aspect of the present invention is the use of an actuator comprising a tube element according to any aspect or embodiment described herein for the reduction of the non-respirable dose and consequent potential oro-pharyngeal deposition of the dispensed aerosol formulation on actuation of the inhaler.
  • tubular element manipulates the airflow internal to the mouthpiece portion of the actuator, creating an area of low velocity immediately after the orifice aperture and altering the expansion dynamics of the flashing liquid emitted by the orifice which results in significant advantages over the prior art.
  • Non-respirable fraction is often associated with systemic side effects and oral candidiasis and dysphonia (in case of inhaled corticosteroid treatment).
  • PSD particle size distribution
  • An actuator according to the present invention may remove the requirement for add-on devices, spacers or holding chambers such as the VolumaticTM and AeroChamber PlusTM, which prevent a large proportion of the coarse particles from the dose reaching the patient, but produce dramatically changes in the PSD with respect to “actuator only” products. This reduces the need to carry such add-on devices which are cumbersome and is an additional factor considering patient compliance.
  • the patient generated airflow is identical to that generated in a conventional MDI actuator without the tubular element according to the present invention. Duration of plume and manner of patient use are also unaffected.
  • the aerosol formulation may be an aerosol solution formulation or an aerosol suspension formulation.
  • the aerosol formulation may contain at least one active ingredient in a propellant or in a propellant/solvent system and, optionally, further excipients.
  • an optional low volatility component such as glycerol may be present.
  • any eventual deposits of the medicament in the tubular element or in the mouthpiece portion of the actuator may be removed through conventional washing or cleaning techniques.
  • FIG. 1 is a schematic longitudinal sectional view of a conventional pressurized metered dose inhaler (pMDI) according to the prior art.
  • pMDI pressurized metered dose inhaler
  • FIG. 2 is a schematic longitudinal sectional view of a pMDI actuator of an embodiment of the present invention.
  • FIG. 3A is a schematic longitudinal sectional view of a pMDI actuator of another embodiment of the present invention, representing the hollow shaped hollow cylindrical object (in black), comprising in its lateral side a tubular element, suitable to be tightly fitted to the outside of the nozzle block.
  • FIG. 3B is an enlarged view of the actuator of FIG. 3A in the part comprising the hollow cylindrical object of FIG. 3A .
  • FIG. 3C is a front view of the pMDI actuator of FIG. 3A .
  • FIG. 4 is an enlarged sectional view of a portion of a pMDI actuator according to an embodiment wherein projections indicating the diameter (D) and the length (L) of the tubular element are shown.
  • FIG. 5 is an enlarged sectional view of a portion of a pMDI actuator according to an embodiment wherein the internal diameter of the tube element was wider than the conical portion of the nozzle block of the actuator.
  • FIGS. 6 to 15 and FIGS. 18 to 19 represent graphics or images of the results of the tests performed in the Examples.
  • FIG. 16A is a schematic longitudinal sectional view of a pMDI actuator of an embodiment of the present invention, representing a single piece moulded actuator plus nozzle tube element with a smoothed gradient between the frusto-conical section of the orifice aperture and the tube opening.
  • FIG. 16B is a front view of the pMDI actuator of FIG. 16A .
  • FIG. 17A is a schematic longitudinal sectional view of a pMDI actuator of an embodiment of the present invention, representing a single piece moulded actuator plus nozzle tube element with a stepped feature between the orifice aperture and the tube opening.
  • FIG. 17B is an enlarged view of the stepped actuator of FIG. 17A in the part of the tube element.
  • FIG. 17C is a front view of the stepped actuator of FIG. 17A .
  • FIGS. 20(A) , 20 (B), 20 (C), and 20 (D) represent alternative embodiments of the tube element according to the present invention.
  • active drug active drug
  • active ingredient active ingredient
  • active compound active compound
  • active substance active substance
  • therapeutic agent therapeutic agent
  • nozzle block or “nozzle assembly” are used synonymously to define an almost cylindrical element, which accommodates the valve stem of the aerosol canister and directs the emitted dose towards the mouthpiece. It rigidly extends in the actuator housing adapted to receive the canister from a central internal position of its base.
  • aligned when referring to two axes means “coinciding or parallel to each other”.
  • substantially aligned with it is meant that the axes deviate by less 30 degrees, preferably less than 15 degrees, more preferably less than 5 degrees, even more preferably less than 3 degrees, even more preferably less than 2 degrees, even more preferably less than 1 degree.
  • substantially coinciding with it is meant that the axes deviate by less 30 degrees, preferably less than 15 degrees, more preferably less than 5 degrees, even more preferably less than 3 degrees, even more preferably less than 2 degrees, even more preferably less than 1 degree, and that the axes are offset by no more than 10 mm, preferably no more than 5 mm, more preferably no more than 2 mm, even more preferably no more than 1 mm, even more preferably no more than 0.5 mm, even more preferably no more than 0.1 mm.
  • longitudinal axis refers to a center longitudinal axis of the respective concavity of component.
  • Respirable fraction also termed “fine particle fraction” refers to an index of the percentage of active particles which would reach the deep lungs in a patient.
  • the respirable fraction is calculated by the ratio between the “respirable dose” and the “delivered dose.” They are evaluated in vitro using a Multistage Cascade Impactor such as an Andersen Cascade Impactor (Apparatus 1, United States Pharmacopoeia—USP34-NF29) fitted with a USP throat, also defined as induction port, according to procedures reported in common Pharmacopoeias.
  • a Multistage Cascade Impactor such as an Andersen Cascade Impactor (Apparatus 1, United States Pharmacopoeia—USP34-NF29) fitted with a USP throat, also defined as induction port, according to procedures reported in common Pharmacopoeias.
  • the “delivered dose” is determined from the cumulative deposition in the apparatus, while the “respirable dose,” also defined as “fine particle dose,” is calculated from the deposition on Stages 3 (S3) to filter (AF) corresponding to particles ⁇ 4.7 microns.
  • non-respirable dose is the amount of larger aerosol particles which, upon inhalation, impact within the mouth and throat of the patient and may be swallowed, potentially causing side effects. It is determined by the amount of the emitted aerosol particles blocked at the level of the USP throat.
  • FIG. 2 is a schematic cross-sectional view, taken along the center symmetry plane, of an actuator ( 1 ) for a pMDI inhaler according to the invention comprising a housing adapted to receive an aerosol canister containing a pressurized medicament formulation, provided with a metering valve and a hollow valve stem, a mouthpiece portion terminating in a mouthpiece opening 10 through which the user inhales, a nozzle block 5 defining a valve stem receptacle 13 , an expansion chamber or sump 6 , and an orifice 8 to propel the aerosol formulation towards the mouthpiece opening characterized by the presence of a tubular element 11 extending in the mouthpiece portion from the orifice aperture in a longitudinal axis 9 aligned with a longitudinal axis of the actuator mouthpiece portion and coinciding with the orifice 8 longitudinal axis, wherein said tubular element is positioned to enclose the orifice aperture within a recess.
  • the tubular element 11 is configured such that one of its terminal openings may be close fit or in a tight fit to the with the nozzle block 5 external surface, around the orifice aperture 8 , so as to be in a continuous flow path with said orifice.
  • One of the terminal openings of the tubular element 11 may be secured to the nozzle block external surface, around the orifice aperture to be in a continuous flow path with said orifice, using a suitable joining procedure such as welding, soldering or other suitable techniques such as by a chemical bonding process among which adhesive bonding.
  • Adhesive bonding may be performed by depositing a suitable liquid adhesive or glue around the juncture circumference of one terminal opening of the tubular element and around the orifice aperture, optionally followed by curing the adhesive, e.g. with UV light.
  • the tubular element 11 may be formed on the lateral part of a shaped hollow cylindrical object 12 suitable to be tightly fitted to the outside of the nozzle block 5 , covering its lateral surfaces, so as the tubular element 11 is in a continuous flow path with the orifice 8 .
  • the hollow cylindrical object 12 and the tubular element 11 may be moulded in one piece, as a single unit, or, in alternative, they may be joined together around the lateral opening of the cylindrical object 12 , at the level of the orifice aperture 8 , and one of the terminal opening of the tubular element 11 , using a suitable joining procedure such as welding, soldering or other suitable techniques such as by a chemical bonding process as described above.
  • tubular element 11 , the nozzle block 5 , the housing for the aerosol canister and the mouthpiece portion of the actuator 1 may be molded in one piece, as a single unit through single injection molding tools.
  • the injection molding using the suitable tool permits manufacturing in a single piece an actuator plus nozzle tube element with a smoothed gradient between the frusto-conical section of the orifice aperture 8 and the tube opening, as shown in FIGS. 16A-16B , or with a stepped feature between the orifice aperture 8 and the tube opening, as shown in FIGS. 17A to 17C .
  • Actuation of the metering valve of the aerosol canister allows one dose of the formulation to be released from the valve through the stem 3 , and propelled towards the mouthpiece opening passing respectively through the intermediate sump 6 , orifice 7 and tubular element 11 .
  • the tubular element 11 has a substantially cylindrical shape, opened at the two bases and with an internal diameter from 2 to 15 mm, preferably from 3 to 12 mm, even more preferably from 5 to 7 mm and a particularly preferred diameter is equal to about 6 mm.
  • the tubular element 11 has a length, i.e. the distance between its apertures, from 2 to 20 mm, preferably from 3 to 15 mm, even more preferably from 8 to 12 mm and particularly preferred lengths are equal to about 9, 10 and 11 mm.
  • Tubular elements with manufacturing tolerances of ⁇ 0.2 mm and preferably of ⁇ 0.1 mm with respect to a given diameter and/or length are acceptable and may be considered included in the present invention.
  • the tubular element 11 may also have a conventional thickness for this kind of devices known to the skilled in the art; however, suitable tubular element thickness may be from 0.1 to 3 mm or more, preferably from 0.2 to 2 mm, more preferably from 0.8 to 1.2 mm and most preferably 1 mm In this case, manufacturing tolerances of from ⁇ 0.05 to ⁇ 0.2 are acceptable and are also included in the present invention.
  • FIG. 20(A) to (D) comprise tubular elements with a substantially cylindrical shape wherein non-parallel tubes as well as parallel tubes with an outer lip are provided and which may be categorized by the following geometric profiles:
  • Lipped Tubes ( FIG. 20A ): represented by parallel tubes consisting of various designs and features surrounding the exit orifice.
  • the lipped tubes consisted of a range of parallel tubes ( FIGS. 5-11 ) with either a lip of varied thickness (T), step length (S) and a smooth or a stepped feature around the exit orifice;
  • Elliptical Tubes ( FIG. 20D ): represented by elliptical shaped tubes with various internal features such as oval or circular section or with internal partial obstructed airflow features.
  • the actuator 1 , the nozzle block 5 , the tubular element 11 and/or the shaped cylindrical object 12 may be formed of different materials and with different specifications which are suited for their specific purposes.
  • suitable materials include metal materials such as aluminium, aluminium alloy or stainless steel; but also plastic polymeric materials, such as thermoplastic resins, optionally UV curable, including different grades of polypropylene (PP) the material of first choice in general for the pMDI actuators, polyethylene (i.e.
  • HDPE high density PE
  • fluorinated polymers such as polytetrafluoroethylene (PTFE); acrylonitrile-butadiene-styrene (ABS); polyacrylate such as polymethyl methacrylate (PMMA); polycarbonate (PC); polyamide (i.e. nylon); polyester such as polyethylene terephthalate (PET).
  • PTFE polytetrafluoroethylene
  • ABS acrylonitrile-butadiene-styrene
  • PMMA polymethyl methacrylate
  • PC polycarbonate
  • polyamide i.e. nylon
  • polyester such as polyethylene terephthalate (PET).
  • PET polyethylene terephthalate
  • the plastic polymeric materials may be coated with antistatic agents by means of a molding or a coating process.
  • the lateral surface of the tubular element 11 may be continuous or in alternative, perforated by one or more holes of optimised shapes (for instance round, square or rhomboid) and dimensions, disposed linearly or opposed each other and at different lengths and positions with respect to its opening in the mouthpiece portion of the actuator.
  • optimised shapes for instance round, square or rhomboid
  • the lateral inner surface of the tubular element 11 may also present different alternative surface textures, in fact it may be smooth or wrinkled, with different degrees of roughness, to optimise the performance of the device.
  • the tubular element 11 , the shaped hollow cylindrical object 12 suitable to be tightly fitted to the outside of the nozzle block and comprising in its lateral side a tubular element 11 , or a single piece moulded actuator comprising the tubular element 11 , the nozzle block 5 , the housing for the aerosol canister 2 and the mouthpiece portion 9 are suitable for use in dispensing of a drug formulation to a patient through conventional pMDI inhalation devices.
  • the pMDI inhalation devices are known in the art. Said devices comprise a canister fitted with a metering valve.
  • Part or the entire canister may be made of a metal, for example aluminium, aluminium alloy, stainless steel or anodized aluminium.
  • the canister may be a plastic can or a plastic-coated glass bottle.
  • the metal canisters may have part or all of their internal surfaces lined with an inert organic coating.
  • preferred coatings are epoxy-phenol resins, perfluorinated polymers such as perfluoroalkoxyalkane, perfluoroalkoxyalkylene, perfluoroalkylenes such as poly-tetrafluoroethylene (Teflon), fluorinated-ethylene-propylene (FEP), polyether sulfone (PES) or fluorinated-ethylene-propylene polyether sulfone (FEP-PES) mixtures or combination thereof.
  • Other suitable coatings could be polyamide, polyimide, polyamideimide, polyphenylene sulfide or their combinations.
  • canisters having their internal surface lined with FEP-PES or Teflon may be used.
  • canisters made of stainless steel may be used.
  • the canister is closed with a metering valve for delivering a daily therapeutically effective dose of the active ingredient.
  • the metering valve assembly comprises a ferrule having an aperture formed therein, a body molding attached to the ferrule which houses the metering chamber, a stem consisting of a core and a core extension, an inner- and an outer-seal around the metering chamber, a spring around the core, and a gasket to prevent leakage of propellant through the valve.
  • the gasket seal and the seals around the metering valve may comprise elastomeric material such as EPDM, chlorobutyl rubber, bromobutyl rubber, butyl rubber, or neoprene. EPDM rubbers are particularly preferred.
  • the metering chamber, core and core extension are manufactured using suitable materials such as stainless steel, polyesters (e.g. polybutyleneterephthalate (PBT)), or acetals.
  • the spring is manufactured from stainless steel eventually including titanium or other inert metal alloys.
  • the ferrule may be made of a metal, for example aluminium, aluminium alloy, stainless steel or anodized aluminium. Suitable valves are available from manufacturers such as Valois, Bespak plc and 3M-Neotechnic Ltd.
  • the pMDI is actuated by a metering valve capable of delivering a volume of 25 to 100 ⁇ l preferably 40 to 70 ⁇ l and optionally about 50 ⁇ l, or about 63 ⁇ l per actuation.
  • valve stem is seated in a nozzle block which has an orifice leading to an expansion chamber.
  • the expansion chamber has an exit orifice 8 which extends into the mouthpiece.
  • Actuator (exit) orifices having a diameter in the range 0.15 to 0.45 mm and a length from 0.30 to 1.7 mm are generally suitable.
  • an orifice having a diameter from 0.2 to 0.44 mm is used, e.g. 0.22, 0.25, 0.30, 0.33, or 0.42 mm.
  • actuator orifices having a diameter ranging from 0.10 to 0.22 mm, in particular from 0.12 to 0.18 mm, such as those described in WO 03/053501, which is incorporated herein by reference in its entirety.
  • the use of said fine orifices may also increase the duration of the cloud generation and, hence, may facilitate the coordination of the cloud generation with the slow inspiration of the patient.
  • the canister contains an aerosol formulation which may be an aerosol solution formulation or an aerosol suspension formulation.
  • the aerosol formulation may contain at least one active ingredient in a propellant or in a propellant/solvent system and, optionally, further pharmaceutical acceptable additive or excipient.
  • the at least one active ingredient of the formulation may be any pharmaceutical active ingredient known in the art, administrable by inhalation alone or in combination for separate, sequential or simultaneous use.
  • the active ingredient is known for prophylaxis or treatment of respiratory diseases and their symptoms, and in particular in diseases characterized by obstruction of the peripheral airways as a result of inflammation and presence of mucus, such as asthma of all types, chronic obstructive pulmonary disease (COPD), bronchiolitis, chronic bronchitis, emphysema, acute lung injury (ALI), cystic fibrosis, rhinitis, and adult or acute respiratory distress syndrome (ARDS).
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • bronchiolitis chronic bronchitis
  • ALI acute lung injury
  • cystic fibrosis rhinitis
  • ARDS adult or acute respiratory distress syndrome
  • the at least one active ingredient is selected from the class of the beta-2 agonists, inhaled corticosteroids, anti-muscarinic agents, phosphodiesterase IV inhibitors, and combinations thereof.
  • beta-2 agonist is selected from the group of salbutamol, (R)-salbutamol (levalbuterol) fenoterol, formoterol, arformoterol, carmoterol (TA-2005), indacaterol, milveterol, vilanterol (GSK 642444), terbultaline, salmeterol, bitolterol, and metaproterenol in form of single stereoisomers, diastereoisomeric mixtures, and a pharmaceutically acceptable salt thereof or hydrate thereof.
  • the inhaled corticosteroid is selected from the group of beclometasone dipropionate, fluticasone propionate, fluticasone furoate, butixocort, mometasone furoate, triamcinolone acetonide, budesonide and its 22R-epimer, ciclesonide, flunisolide, loteprednol, and rofleponide.
  • the anti-muscarinic agent is selected from the group of methscopolamine, ipratropium, oxitropium, tiotropium, glycopyrronium, aclidinium, umeclidinium, trospium and a salt thereof with a pharmaceutical acceptable counter ion.
  • phosphodiesterase IV inhibitor is selected from the group of cilomilast, piclomilast, roflumilast, tetomilast, CHF 6001 and a pharmaceutically acceptable salt thereof.
  • active ingredients may be selected from the group of beclometasone dipropionate, fluticasone propionate, fluticasone furoate, mometasone furoate and budesonide alone or in combination with one or more active ingredient selected from salbutamol, formoterol, salmeterol, indacaterol, vilanterol, glycopyrronium, tiotropium, aclidinium, umeclidinium and a salt thereof.
  • the most preferred active ingredients are selected from beclometasone dipropionate, budesonide, formoterol fumarate, beclometasone dipropionate-salbutamol sulphate combination, beclometasone dipropionate-formoterol fumarate combination and beclometasone dipropionate-formoterol fumarate-glycopyrronium bromide combination.
  • the propellant may be any pressure-liquefied propellant and is preferably a hydrofluoroalkane (HFA) or a mixture of different HFAs, more preferably selected from the group consisting of HFA 134a (1,1,1,2-tetrafluoroethane), HFA 227 (1,1,1,2,3,3,3-heptafluoropropane), and mixtures thereof.
  • HFA hydrofluoroalkane
  • HFA 227 1,1,1,2,3,3,3-heptafluoropropane
  • the solvent which may be incorporated into the formulation has generally a higher polarity than that of the propellant and may include one or more substances such as a pharmaceutically acceptable alcohol, in particular ethanol, a polyol, such as propylene glycol or polyethylene glycol, or mixtures thereof.
  • a pharmaceutically acceptable alcohol in particular ethanol
  • a polyol such as propylene glycol or polyethylene glycol, or mixtures thereof.
  • the solvent is selected from the group of lower branched or linear alkyl (C 1 -C 4 ) alcohols such as ethanol and isopropyl alcohol.
  • the co-solvent is ethanol.
  • the at least one pharmaceutically active ingredient of the formulation is substantially completely and homogeneously dissolved in the propellant/solvent, system, i.e. the composition is preferably a solution formulation.
  • the formulation may comprise other pharmaceutical acceptable additives or excipients known in the art which are substantially inert materials which are non-toxic and do not interact in negative manner with other components of the formulation.
  • the formulation may comprise one or more co-solvents, surfactants, carbohydrate, phospholipid, polymer, wetting agent, stabilizers, lubricants, or low volatility components.
  • an acid which may be organic or inorganic acid (mineral acids) which may be selected from pharmaceutically acceptable monoprotic or polyprotic acid, such as (but not limited to): hydrogen halides (hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.) phosphoric acid, nitric acid, sulphuric acid, and halogen oxoacids.
  • mineral acids organic or inorganic acid
  • phosphoric acid such as (but not limited to): hydrogen halides (hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.) phosphoric acid, nitric acid, sulphuric acid, and halogen oxoacids.
  • Low volatility components are useful in order to increase the mass median aerodynamic diameter (MMAD) of the aerosol particles upon actuation of the inhaler and/or to improve the solubility of the active ingredient in the propellant/solvent system.
  • MMAD mass median aerodynamic diameter
  • the low volatility component when present, has a vapor pressure at 25° C. lower than 0.1 kPa, preferably lower than 0.05 kPa.
  • low-volatility components are esters such as isopropyl myristate, ascorbyl myristate, tocopherol esters; glycols such as propylene glycol, polyethylene glycol, glycerol; and surface active agents such as saturated organic carboxylic acids (e.g. lauric, myristic, stearic acid) and unsaturated carboxylic acids (e.g. oleic or ascorbic acid).
  • the amount of low volatility component may vary from 0.1 to 10% w/w, preferably from 0.5 to 5% (w/w), more preferably from 1 and 2% (w/w).
  • an amount of water comprised between 0.005 and 0.3% (w/w) may optionally be added to the formulations in order to favorably affect the solubility of the active ingredient without increasing the MMAD of the aerosol droplets upon actuation.
  • FIGS. 3 b and 4 show the basic premise of the design and the respective diameter D and length L of the geometries tested.
  • the smallest internal diameter of 3 mm is less than the diameter of the orifice cone therefore was chamfered to prevent an impact surface and potential dead space from being created.
  • the largest tube diameters required a step detail to enable the extra width to be catered for, as the internal diameter was wider than the nozzle block of the actuator ( FIG. 5 ).
  • tubular elements were manufactured in UV Curable Acrylic Plastic. All prototype tubes were fitted on actuators with 0.30 mm orifice diameter.
  • the actuator prototypes based on FIGS. 2 to 5 were produced and tested with respect to a conventional actuator of FIG. 1 with 0.30 mm orifice diameter.
  • Drug delivery characterization of the prototypes, in conjunction with the BDP 250 formulation, was determined with an Andersen Cascade Impactor (Apparatus 1, United States Pharmacopoeia—USP34-NF29) fitted with a USP throat, also defined as induction port, according to procedures reported in common Pharmacopoeias, at a flow rate of 28.3 ( ⁇ 5%) L min ⁇ 1 .
  • Drug deposition in each stage and in the induction port was quantified by UPLC/MS (Ultra-Performance Liquid Chromatography/Mass Spectrometry).
  • Aerosol characteristics determined include mass median aerodynamic diameter (MMAD), i.e., the diameter around which the mass aerodynamic diameters of the emitted particles are distributed equally; the delivered dose (DD) determined from the cumulative deposition in the apparatus, the fine particle dose (FPD) or respirable dose corresponding to the amount of particles of diameter ⁇ 4.7 ⁇ m; the fine particle fraction (FPF) which is the percent ratio between the FPD and the DD.
  • MMAD mass median aerodynamic diameter
  • DD delivered dose
  • FPD fine particle dose
  • FPF fine particle fraction
  • the range of tubular element geometries manufactured in phase 1 is reported in Table 2 and their drug delivery characteristics, analysed using the BDP 250 formulation of Table 1.
  • Phase 1 Prototype numbers for the geometries of tubular elements (prototypes 184-194). Length, L (mm) Prototypes 3 5 10 15 Internal Diameter, 3 184 186 188 191 D (mm) 6 185 187 189 192 9 190 193 12 194
  • Phase 2 Prototype numbers for the geometries of tubular elements (prototypes 197-211). Length, L (mm) Prototypes 8 9 10 11 12 Diameter, D 5 197 200 203 206 209 (mm) 6 198 201 204 207 210 7 199 202 205 208 211
  • FIGS. 6 and 7 present data from both phases 1 and 2 and demonstrate correlations between the length/diameter ratio (L/D) of the tubular element, the induction port deposition and FPD respectively.
  • FIG. 7 shows that as the ratio is increased to greater than 2, the FPD begins to drop significantly, shifting the particle size distribution of the emitted aerosol particles away from that of the BDP 250 formulation emitted from a conventional actuator. This may be because the cone angle of the plume is restricted to such a degree that an increased number of the finer particles are impacted and retained on the tubular element in addition to the coarse fraction.
  • Table 4 below presents combined data sets of phases 1 and 2, which best match the particle size distribution of the tested formulation (BDP 250: Table 1). All of these tube geometries reduce induction port deposition by a similar mass with respect to the same formulation delivered through a conventional actuator while maintaining constant the performance in term of Fine particle dose, MMAD and GSD (Geometric Standard Deviation). Similar reduction in induction port deposition from the selected prototypes suggests that potential slight differences in the final prototype geometry, caused by tolerances in the materials used in manufacture, will not affect the performance of the device.
  • a range of single molded actuators plus tubular elements of 10 mm length and 6 mm diameter with smoothed or stepped nozzle tube features as shown in FIGS. 16A-B and in FIGS. 17A-C were manufactured and tested in their performances.
  • An actuator fitted with one of the preferred tube element i.e. Prototype 204 of Example 1A
  • a 10 mm length (L) and 6 mm internal diameter (D) was tested to challenge the robustness of the concept.
  • Through-can-life testing was carried out to assess the drug delivery performance of the prototype, in particular when no patient washing is performed, i.e. a “worst case” scenario.
  • the plume temperature profile was also measured, to determine whether the presence of the nozzle tube could potentially reduce the “cold-freon” effect.
  • Prototype 204 was coupled with a new, un-primed can containing the solution formulation of beclometasone dipropionate 250 ⁇ g/dose (BDP 250 of Table 1).
  • BDP 250 of Table 1
  • Four doses were delivered to a waste Dose Unit Sampling Apparatus (DUSA; Copley Instruments, UK) every five minutes and all shot weights recorded. The five minute period allowed the ethanol to evaporate and the area around the orifice and nozzle tube to dry; this could be expected to occur between doses in everyday patient use.
  • a microscope photograph was taken of the orifice aperture and tubular element. Andersen Cascade Impactor (ACI) testing was carried out at beginning, middle and end of can-use-life. Following the exhaustion of the can, the device was washed to determine the ease with which the layer of deposit within the recessed nozzle could be removed.
  • ACI Andersen Cascade Impactor
  • FIG. 8 presents the shot weight data for the through-can-life investigation.
  • the mean shot weight was 52.6 ⁇ 1.3 mg, calculated from all shot weights (199) excluding the priming shot 1. All shot weights (excluding priming) are well within ⁇ 15% of the mean recorded shot weight.
  • the microscope pictures of FIG. 9 show a gradual accumulation of non-volatile material, assumed to be mostly drug and glycerol particles, on the lower surface of the tubular element. This build up, however, does not block the orifice aperture and may be easily removed by washing the actuator with warm water, according to the washing procedures suggested for similar marketed products.
  • Plumes of the emitted aerosols were collected into a DUSA and temperature profiles were recorded by thermocouples (Omega, UK, K-Type, response time 3 ms) mounted 20 mm from the inlet of the DUSA. Data was collected continually by a PC using Dasylab Data Acquisition Software, to ensure that the entire plume temperature profile was captured, according to Brambilla, G. et al., “Plume Temperature Emitted from Metered Dose Inhalers,” Int. J. Pharm., 405(1-2), 9-15, 2011, which is incorporated herein by reference in its entirety. Mean minimum plume temperature, (MMPT), for each test condition is reported as the mean ⁇ standard deviation of the lowest temperatures from each of five replicate plumes.
  • MMPT Mean minimum plume temperature
  • the presence of the recessed tube element causes an overall increase in the plume temperature profile, compared with a conventional actuator (0.30 mm orifice diameter) as shown in FIG. 10 .
  • the mean minimum plume temperature, MMPT, for the prototype is 0.9 ⁇ 0.4° C., compared with ⁇ 5.9 ⁇ 1.9° C. without the nozzle tube.
  • a warmer plume may cause less discomfort to the patient, which could have a more positive effect on patient compliance.
  • a tube element according to the invention also demonstrated a robust performance through-can-life, with consistent shot weight data and particle size distribution at beginning, middle and end of life of the canister.
  • the plume temperature profile is also favourable when compared to a conventional pressurised metered dose inhaler actuator without tube element.
  • Drug delivery data was collected for the marketed Clenil Modulite range, purchased in a pharmacy, which includes the dose strengths: BDP 250, 200, 100, and 50 ⁇ g/50 ⁇ l.
  • Data were also collected for Fostair, another marketed product, purchased in a pharmacy, based on a combination of the active ingredients beclometasone dipropionate and formoterol fumarate dihydrate 100 ⁇ g-6 ⁇ g, respectively per 50 ⁇ l actuation of a pressurised inhalation solution including ethanol, hydrochloric acid and norflurane (HFA 134a.
  • the Fostair formulation does not contain glycerol.
  • FIG. 15 and Table 8 demonstrate that an actuator with the tube element prototype 204 also functions effectively with the Fostair marketed formulation.
  • the delivered dose is reduced from 89 to 49 ⁇ g and 5.4 to 2.9 ⁇ g for BDP and formoterol respectively, as induction port deposition is decreased.
  • tube elements of dimensions corresponding to prototype 204 were manufactured in the following materials: aluminium, polytetrafluoro ethylene (PTFE), polypropylene (PP), stainless steel, nylon. They have been tested in an actuator with 0.32 orifice diameter using the BDP 250 formulation of Table 1 (Example 1A).
  • Drug delivery investigations on the actuator according to the present invention characterized by the presence of a tubular element, were also performed with a pressurized metered dose inhaler containing a combination of two active ingredients wherein a first active ingredient is dissolved in the formulation and micronized particles of a second active ingredient are dispersed in the formulation.
  • the actuator according to the present invention results in an almost 50% reduction in the non-respirable dose both for beclometasone dipropionate and salbutamol.
  • Pertinent choice of the orifice sizes allows aerosol plume to match more closely the fine particle dose of the conventional, marketed product.

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US20170143915A1 (en) * 2014-05-14 2017-05-25 The Technology Partnership Plc Aerosolisation engine for liquid drug delivery background
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PE20150523A1 (es) 2015-05-07
US10737044B2 (en) 2020-08-11
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EA033581B1 (ru) 2019-11-06
TN2015000073A1 (en) 2016-06-29

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