EP1689474A2 - Inhalateur portable fonctionnant au gaz - Google Patents

Inhalateur portable fonctionnant au gaz

Info

Publication number
EP1689474A2
EP1689474A2 EP04820761A EP04820761A EP1689474A2 EP 1689474 A2 EP1689474 A2 EP 1689474A2 EP 04820761 A EP04820761 A EP 04820761A EP 04820761 A EP04820761 A EP 04820761A EP 1689474 A2 EP1689474 A2 EP 1689474A2
Authority
EP
European Patent Office
Prior art keywords
drug
inhaler
chamber
gas
spacer
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.)
Withdrawn
Application number
EP04820761A
Other languages
German (de)
English (en)
Other versions
EP1689474A4 (fr
Inventor
Stephan C. Gamard
Bryan R. Bielec
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.)
Praxair Technology Inc
Original Assignee
Praxair Technology Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US10/726,627 external-priority patent/US20050121025A1/en
Application filed by Praxair Technology Inc filed Critical Praxair Technology Inc
Publication of EP1689474A2 publication Critical patent/EP1689474A2/fr
Publication of EP1689474A4 publication Critical patent/EP1689474A4/fr
Withdrawn legal-status Critical Current

Links

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
    • A61M15/00—Inhalators
    • A61M15/0086—Inhalation chambers
    • 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
    • A61M11/001—Particle size control
    • A61M11/002—Particle size control by flow deviation causing inertial separation of transported particles
    • 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
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/06—Sprayers or atomisers specially adapted for therapeutic purposes of the injector type
    • 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
    • A61M15/0005—Details of inhalators; Constructional features thereof with means for agitating the medicament
    • A61M15/0006—Details of inhalators; Constructional features thereof with means for agitating the medicament using rotating means
    • A61M15/0008—Details of inhalators; Constructional features thereof with means for agitating the medicament using rotating means rotating by airflow
    • 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
    • A61M15/0013—Details of inhalators; Constructional features thereof with inhalation check valves
    • A61M15/0015—Details of inhalators; Constructional features thereof with inhalation check valves located upstream of the dispenser, i.e. not traversed by the product
    • 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
    • A61M15/0031—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 by bursting or breaking the package, i.e. without cutting or piercing
    • 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
    • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
    • 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
    • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
    • A61M15/0046—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier
    • A61M15/005—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier the dosages being arranged on a cylindrical surface
    • 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
    • A61M15/0068—Indicating or counting the number of dispensed doses or of remaining doses
    • 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
    • A61M15/0086—Inhalation chambers
    • A61M15/0088—Inhalation chambers with variable volume
    • 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
    • A61M15/0091—Inhalators mechanically breath-triggered
    • A61M15/0096—Hindering inhalation before activation of the dispenser
    • 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
    • A61M11/005—Sprayers or atomisers specially adapted for therapeutic purposes using ultrasonics
    • 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
    • A61M15/0085—Inhalators using ultrasonics
    • 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
    • A61M21/00—Other devices or methods to cause a change in the state of consciousness; Devices for producing or ending sleep by mechanical, optical, or acoustical means, e.g. for hypnosis
    • A61M2021/0005—Other devices or methods to cause a change in the state of consciousness; Devices for producing or ending sleep by mechanical, optical, or acoustical means, e.g. for hypnosis by the use of a particular sense, or stimulus
    • A61M2021/0016—Other devices or methods to cause a change in the state of consciousness; Devices for producing or ending sleep by mechanical, optical, or acoustical means, e.g. for hypnosis by the use of a particular sense, or stimulus by the smell sense
    • 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
    • A61M2202/025—Helium
    • 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
    • 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
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0205—Materials having antiseptic or antimicrobial properties, e.g. silver compounds, rubber with sterilising agent
    • 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
    • A61M2205/58—Means for facilitating use, e.g. by people with impaired vision
    • A61M2205/583—Means for facilitating use, e.g. by people with impaired vision by visual feedback
    • A61M2205/584—Means for facilitating use, e.g. by people with impaired vision by visual feedback having a color code
    • 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
    • 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 or packages with special means for dispensing contents for delivery of liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant for a product delivered by a propellant
    • B65D83/44—Valves specially adapted therefor; Regulating devices
    • B65D83/52—Valves specially adapted therefor; Regulating devices for metering
    • B65D83/54—Metering valves ; Metering valve assemblies

Definitions

  • This invention relates to the field of inhalers used to administer a drug to a patient through the patient's lungs and, more particularly, to an improved gas inhaler.
  • Heliox is defined as a gas mixture of helium and oxygen whose physical properties are summarized in Table 1 depending on the concentration of Helium. Table 1: Physical properties of Heliox at 273 K, 1 atmosphere.
  • ambient air is defined as that air which normally exists around us which is either inhaled and exhaled from the environment, or, pumped into a mechanical hand held device from the environment and then inhaled.
  • aerosolization is primarily defined as the generation and then breakup of a liquid sheet into primary and satellite droplets, generally 1 micron to 20 microns in size, although the physical form of particles in an aerosol as used herein may be liquid drops or solid dry powder particles.
  • fluidization is defined as the deagglomeration of a compact mass of drug in micronized dry powder form manufactured with a preferred particle size range of 1 micron to 5 microns into a cloud, with the objective being the generation of particles in the preferred 1-10 micron range, and more preferably in the 1-3 micron range.
  • heterodisperse aerosol or
  • heterodisperse particle cloud shall be defined as a deliverable form of a liquid drug formulation or dry powder drug formulation, such that there are particles of many different sizes.
  • Drug particles may be absorbed from the lung primarily by alveolar macrophages.
  • fine particle dose shall mean particles that are preferably about 5 ⁇ m or less, generally 3 ⁇ m or less, and more preferably 2 ⁇ m or less.
  • respirable fraction RF is a dose fraction of aerosolized drug particles small enough in diameter to escape the filtration machinery of the airways and be deposited in the lungs.
  • the intravenous needle method of administering therapeutic drugs in liquid form in the arm or femorally results in the dilution and loss of administered drug potency as the blood passes through the venous system back to the heart, then to the lungs, and finally into the- arterial circulation for delivery.
  • Intra-muscular needle injection adds a pathway where part of the administered dose can be lost.
  • gas driven jet needle-less injection where the drug substance must go through the skin, into the muscle, (usually and primarily) into the venous blood system, and then into the arterial system.
  • a bolus of drug delivered to the target is less diluted, and, therefore, less drug needs to be deposited in-vivo at the site or entry point of administration (the alveoli) .
  • Delivery of drugs via the lungs is the optimal approach to treat diseases in the lung.
  • drugs delivered via the lungs for other than respiratory diseases go rapidly and directly into the arterial blood, then to the heart, and then to the other critical organs such as brain, liver and kidneys, and receptor sites residing thereon. This reduces the effect of dilution on the administered therapeutic dose in the bloodstream.
  • Pulmonary drug delivery can, depending on the drug and disease: a) improve the efficacy of .
  • a drug improves the bioavailability of a drug, which is particularly important for biological compounds such as peptides and proteins; c) improve targeting to an organ or receptor site thus reducing unwanted side effects (which is an important consideration with, for example, anticancer agents) ; and d) mimic the biopattern of a disease, or circadian rhythm, e.g., as in the case of sustained- release anti-hypertensives designed to peak coinciding with the early morning blood pressure surge.
  • a new method of pulmonary drug delivery for an existing drug can extend its therapeutic indications, lower cost, and facilitate a more rapid time to market.
  • U.S. Patent No. 6,125,844 discloses an apparatus for portable gas-assisted dispensing of medication not using a fluorocarbon propellant.
  • the apparatus comprises a pressurized supply of gas containing therapeutic gas or mixture of therapeutic gases, and one or more drugs mixed therein, connected to a pressure regulator, wherein the pressure regulator is connected to a gas release switch which is connected to a breath activator.
  • the objective with any method and technology involving inhalers is: a) to generate particles of the optimum size range for deep lung delivery, and b) to get any administered particles past the larger airways where they will be lost to turbulence and impaction and into the middle (for treating respiratory diseases) and deep (for delivering drugs to the target area where they can enter the arterial blood) lung.
  • drugs administered via the lungs are not subject to prior first pass hepatic metabolism. They are also less subject to reacting with or being affected by fewer receptors prior to reaching their intended target either in the lungs or systemically, resulting in a reduced amount of drug being needed, if the particle size and delivery to the target location in the lungs are optimized.
  • particulate drug dispensed by conventional inhalers is delivered in this range.
  • Large molecule drugs such as peptides and - • proteins which are now possible due to genetic • '• engineering, do not pass easily through the airway surface because it is lined with a ciliated mucus- covered cell layer of some depth, making it highly impermeable.
  • the alveoli however, have a thin single cellular layer enabling absorption into the bloodstream.
  • the alveoli are the door to the arterial blood and are at the base of the lungs. So, to reach the alveoli, a particulate drug must be administered in small size particles, and the inhalation must be moderated, slow, and deep.
  • the first two are the principle methods that apply to the deposition of large particles. Diffusion, is the primary factor of deposition of smaller * particles in peripheral regions of the lung. The optimum size particles of drug for delivery to
  • the alveoli are in the range generally of 1-3 microns, and usually particles less than 2 microns reach the alveoli.
  • the diameter of therapeutically usable particles is generally between 0.5 and 5 microns. Particles 1-5
  • Heliox has also been used to administer a liquid drug using a nebulizer, which is a different type of device for pulmonary drug administration lasting 10-60 minutes. That is distinct from "puffs" received through an inhaler. Additionally, in both cases, the systems in which Heliox were used were designed for the physical properties of air and not Heliox, and so were not optimized for Heliox. Prior art and medical publications pertaining to inhalers, address other factors but do not focus on the specific gas involved in the transport of particles into the lung. In the case of DPIs, the gas is always assumed to be, or stated specifically to be, air.
  • MDI is a metered dose inhaler consisting of a propellant generating a vapor pressure and a drug in suspension or solution form, where, when the device is activated, the vapor pressure of said propellant pushes a predetermined amount of liquid drug through a nozzle generating an aerosol for inhalation.
  • MDIs contain suspensions or solutions of a drug, a propellant, and a surfactant that: acts as a lubricant to stop particles from aggregating and to reduce clogging of the aerosol nozzle.
  • MDIs rely on the use of propellants that have a high vapor pressure.
  • the higher the vapor pressure the faster a liquid containing a drug can be pushed out of a nozzle, and thus a thinner liquid sheet is formed, and smaller particles are produced.
  • Vapor pressure is therefore directly related to the velocity generated and the fraction of fine or desirable small particles generated.
  • the drug crystals are initially enclosed within large propellant droplets whose mass median diameter may exceed 30 ⁇ m.
  • This velocity is much higher than an inhalation velocity by a user.
  • the result can be impaction of particles in the oropharyngeal area.
  • a spacer which is discussed later, is a solution to this problem, i.e., reducing the velocity of the "cloud” of particles prior to inhalation.
  • Another technique is to use the "open-mouth” method that implies activating the device a few cms away from an open mouth. MDIs containing a suspension require that they be shaken before use. MDIs containing a solution need not be. This presents a problem to patients using more than one type of drug, i.e., one in suspension and one in solution, as the patient may shake the wrong MDI, or not shake the MDI that needs to be shaken before use.
  • DPI is a dry powder inhaler consisting of a drug in micronized dry powder form provided in a compact shape and contained in a unit dose container or reservoir, which is fluidized by the flow of a gas and inhaled by the patient.
  • Micronized dry powder formulations are very soluble and quickly dissolve in the fluid layer on the surface of the deep lung before passing through the thin single cellular layer of the alveoli. They are then deposited in the alveolar region and can be absorbed into the bloodstream without using what are commonly referred to as penetration enhancers. Dry powder aerosols can carry approximately five times more drug in a single breath than metered dose inhaler (MDI) systems and many more times than;-liquid or nebulizer systems . Micronized dry powder drugs used in inhalers are usually produced with an original particle range of 1- 10 microns. An individual dose as loaded can take from 5 mg to 20 mg of dry powder drug.
  • MDI metered dose inhaler
  • This multitude of constituents in a MDI increases the work involved in production of the product and its packaging, can effect formulation stability, can cause aerosolization problems by clogging the nozzle, and may require either the shaking or non-shaking of the MDI Inhaler before use.
  • DPI devices providing compressed gas or propeller/impeller assisted fluidization, basing the fluidization on the patient's inhalation produces a major variability in dosing and particle size formation.
  • the velocity, ramp up rate, and continuous event of this inhalation are variables that can effect the fluidization of the powdered drug and the effective delivery of the optimum size particles to the deep lung.
  • Some DPIs use compressed air generated by a pumping mechanism, which the patient utilizes, whereby the pressure is released for fluidization of the powder drug when the system is actuated.
  • the pressure, and therefore velocity, of a gas that can be generated by a hand pump or an inhaler device is far less than that available from a compressed gas cartridge.
  • the uniformity of fluidization of the dry powder would therefore be less using a manual hand pump, with the possibility therefore of generating larger percentages of larger size particles, which result in the variable and inconsistent loss of drug in the oropharyngeal and upper bronchi .
  • the higher the velocity of the gas hitting the dry powder the greater the amount of powder dislodged and the turbulence induced, which can create a cloud of particles for inhalation.
  • Heliox is supplied at 2,200 psig and requires a two- stage pressure regulator to reduce the pressure for administering to patients.
  • Gas flow within the tracheobronchial tree is complex and depends on many factors. For a given pressure gradient, the volumetric flow rate of a gas is inversely proportional to the square root of its density.
  • substituting helium for nitrogen in inhaled gas mixtures results in increased gas flow rates because the density of helium is much lower than that of nitrogen. Resistance to the flow of gas within the tracheobronchial tree results from convective acceleration and friction.
  • the efficacy of Heliox in respiratory therapy occurs because it is a low-density gas.
  • the rate of diffusion of a gas through a narrow orifice is inversely proportional to the square root of its density (Graham's Law).
  • Gramham's Law When an area of stenosis occurs in the airway, there is resistance to flow at the site of the stenosis. The resistance varies directly with gas density. Downstream from the stenosis, airflow becomes turbulent.
  • helium for nitrogen in inspired air, resistance at stenotic areas is reduced and turbulence downstream from the stenosis is either reduced or eliminated.
  • a laminar flow normally exists in airways that are generally less than 2 mm in diameter.
  • Turbulent flow has been observed in the upper respiratory tract, the glottis, and the central airways. This upper portion of the airway, especially the throat, and the main bronchioles, are considered to be the region where the turbulent intensity is sensitive to the gas density. Since airway resistance in turbulent flow is directly related to the density of the gas, Heliox, with its lower density than nitrogen or oxygen, results in lower airway resistance. Heliox further lowers airway resistance by reducing the Reynolds number, such that some areas of turbulent flow are converted to laminar flow. The higher flow rate of Heliox has the ability to stay laminar at velocities under which air would be turbulent. Heliox does not need to be laminar to provide higher flow rates and its benefits persist under turbulent conditions.
  • helium is less viscous than air, so it flows faster.
  • the absolute viscosity of helium is slightly higher than that of air, and its kinematic viscosity (absolute viscosity divided by density) is about seven times that of air.
  • helium is more viscous than air.
  • the linear relationship between helium concentration and resistance to flow is predictable on the basis of fluid mechanics.
  • Heliox is more beneficial because of its lower density. Compared to air, it flows at a higher flow rate for fixed pressure gradient, or needs a lower pressure gradient or work of breathing (or patient inhalation effort) for a given flow rate. This is valid even in turbulent conditions.
  • There is medical literature where Heliox has been provided to a patient prior to dosing with an Inhaler based on a CFC based propellant.
  • There is also a study where a small volume of Heliox (40-70ml) was delivered as bolus but with a shallow breath during pulmonary administration of a particulate to see if the entrained particles would diffuse deeper into the lungs by themselves within the Heliox gas.
  • an inhaler for medical purposes where the main carrier gas is Heliox or helium.
  • One embodiment of the invention is an inhaler for introducing a drug into a user, said inhaler comprising: a first chamber adapted for containing first a compressed gas at a first pressure; a second chamber in selective communication with said first chamber, said second chamber adapted for containing a second compressed gas at a second pressure lower than the first pressure, said first and second chambers cooperating so as to yield said second pressure of said compressed gas within said second chamber; a means to administer two different volumes of gas in successive applications from the second chamber; • ⁇ a storage section coupled to said second chamber, said storage section adapted for containing a drug and operating such that a portion of said second compressed gas can fluidize and aerosolize said drug to thereby produce a drug cloud; and a mouthpiece coupled to said storage section, said mouthpiece adapted for receiving said drug cloud and convey said drug cloud to a user.
  • the inhaler is comprised of three mostly independent parts: a high-pressure canister, a drug delivery holder, and a spacer.
  • the three parts can be separable from each other or affixed in a non-separable way.
  • the canister can have a resealable, refilling opening and the drug holder can be removable and have a resealable refilling means.
  • the high pressure canister holds pressurized Heliox or helium and delivers two constant volumes of gas at a fixed pressure independently of the inside pressure of the canister. One volume of gas can go directly to the spacer to purge it from ambient air, while the second, smaller, volume of gas will interact with the drug.
  • the drug drum holds several doses of drug in liquid or powder form that will be nebulized or liquefied using the second volume of gas from the canister. Finally a spacer is used to hold and mix the two volumes of gas from the canister and opens up to the patient. Alternatively, only one volume of gas can be released by the canister to purge and nebulize the drug in one process .
  • the user would also have a bigger, high-pressurized helium/Heliox cylinder at home and would refill his small inhaler canister with a simple process after a certain number, 10 for instance, of uses.
  • This idea is novel to inhalers and would allow the patient to use their inhalers for months at a time without a refill from health care providers.
  • the drug drum could be allowed to contain a much higher number of doses. Refilling the cartridge could be done with no or very little modification to the current proposed cartridge and gas delivery designs .
  • the canister's maximum pressure is 500 psig.
  • An E-cylinder is typically filled up to 2,200 psig for a total content of 623 liters for 100% helium or 708 liters for pure oxygen.
  • an E-cylinder to refill the canister with a basic regulator set up for a delivery of 500 psig would allow refilling the canister with 1,600 doses or 480 liters based on the content for the helium E-cylinder.
  • the in-home Heliox tank would have a standard regulator set up for a delivery of 500 psig.
  • the easiest way to refill the canister is to have a separate valve on the canister for refilling purposes only.
  • the valve could be similar to a standard one-way refilling valve as used on footballs for instance and located on top or on the side of the canister to avoid any interference with the metering chamber inside the canister. For aesthetic and safety reasons, it is preferable that no extension protrudes from the cylinder.
  • the valve would only open if the proper stem from the in-home refilling tank is inserted and, due to the regulator of the home cylinder, would refill the portable cylinder to exactly 500 psig, or 10 doses.
  • the operation would only require the user to push the cylinder on the valve stem and would last a few seconds.
  • a pressure gage on the home cylinder would let the user know when the inside pressure falls below 500 psig, the pressure when the cylinder would be considered having reached the end of its usable life.
  • a counter device would let the user know how many refills are available in the home cylinder.
  • the whole refilling system would only require the regulator on top of a standard medical cylinder along with the specific valve stem and the pressure gage or dose counter. This clearly limits the overall cost of the device. Renting the home cylinder to the user would further reduce the costs by reusing the device and refilling it in specialized facilities in a similar fashion to existing Oxygen cylinders.
  • Fig. 1 is a side view of an inhaler, diff ser, and spacer in accordance with the invention
  • Fig. 2 side view of a piston-chamber assembly to deliver the two volumes of gas
  • Fig. 3 is a an alternative to Fig. 2 to deliver the two volumes of gas using two gas orifices, one being a calibrated orifice
  • Fig. 4 is side view of a drug drum assembly
  • Fig. 4A is a sectional r view of A-A of the drum of Figure 4 used to hold a drug in accordance with the invention
  • Fig. 5 is an alternative to Fig. 4.
  • Fig. 6 is a side view showing the engagement of the drum and an equalization chamber
  • Fig. 1 is a side view of an inhaler, diff ser, and spacer in accordance with the invention
  • Fig. 2 side view of a piston-chamber assembly to deliver the two volumes of gas
  • Fig. 3 is a an alternative to Fig. 2 to deliver the two volumes of gas using
  • FIG. 7 is an enlarged side view of a tube containing a liquid drug
  • Fig. 8 is an enlarged side view of an alternative embodiment of a tube containing a liquid drug
  • Fig. 9 is a side view of a tube adapted to be coupled to a fixed nozzle
  • Fig. 10 is a side view of an alternative coupling of a tube with a fixed nozzle
  • Fig. 11 is a side view of a spacer in accordance with the invention
  • Fig. 12 is a side view of another embodiment of an inhaler and diffuser in accordance with the invention.
  • Inhaler 30 comprises a high pressure chamber 32 coupled to an equalization chamber 34.
  • High pressure chamber 32 is a small, cold rolled, low carbon steel container containing gas 52 compressed to a pressure between about 30 psig and about 1600 psig, preferably between 100 psig and about 500 psig.
  • Gas 52 is a gas preferably containing from 0% to 100% of helium, the balance if needed being oxygen. Other compressed gases could also be used. It is preferred that the gas that is-.,used be a dry gas.
  • the high pressure storage allows Heliox to be stored in a container preferably 10 cc to 100 cc in volume but still provide sufficient gas for a large number of inhalations. For example, 100 cc of Heliox at 200 atmosphere will expend 200 times in volume to a volume of 20 liters when the gas is released to atmospheric pressure.
  • the storage pressure in chamber 32 should be significantly higher than the regulating pressure. When the supply pressure of the compressed Heliox falls below the pressure required to fluidize the powder (or aerosolize a liquid) to the uniform standard established, then the inhaler should become inoperative, and a cut off mechanism is thus desirable.
  • the chamber could have a resealable, refilling opening 31 to which a user can couple the canister to a larger high-pressurized Heliox tank.
  • High pressure chamber 32 includes a housing 36 defining a third chamber 38. Housing 36 includes an opening 40 on a top portion thereof and a gas passage 42 on a side. Third chamber 38 communicates with both high pressure chamber 32 and equalization chamber 34. Equalization chamber 34 is needed to produce a consistent volume of gas throughout the lifecycle of the high-pressure canister 32 independent of its inside pressure. This is achieved with the help of a simple regulator via the diaphragm plate 56.
  • Equalization chamber 34 includes a housing 58 having a gasket 46 disposed therein.
  • Gasket 46 includes a gas passage 48 on a side thereof for allowing gas disposed in third chamber 38 to communicate with second chamber 34.
  • a piston 44 is slidably mounted within gasket 46 and within housing 36.
  • Piston 44 includes a communication opening 50. Piston 44 is pushed downwards with a spring 60 located inside chamber 38 to allow gas communication between chambers 32 and 34. When the canister 32 is separated from the inhaler, the spring 60 is pushing the piston 44 sealing the canister by closing the opening 42.
  • Communication opening 50 is designed to selectively allow gas 52 stored in high pressure chamber 32 to communicate with gas 54 stored in equalization chamber 34.
  • a pressure plate 56 is also disposed within housing 58. One side of pressure plate 56 is coupled to piston 44.
  • piston 44 has a communication opening 50 that selectively allows high pressure chamber 32 to communicate with equalization chamber 34 through gas passages 42 and 48 when passages 42, 48 are aligned with communication opening 50.
  • Gas 52 applies pressure against a small area defined by the top of piston 44. The net force from gas 52 pressing on piston 44 is the pressure of the gas multiplied by the surface area of the top of piston 44.
  • This net force applied by the high-pressure side of high pressure chamber 32 on piston 44 works with the biasing force of spring 60 and against the force applied by gas 54 on pressure plate 56.
  • the spring constant of spring 60 and the surface area of pressure plate 56 are chosen so that when equalization chamber 34 has received sufficient pressure to utilize inhaler 30, the force applied by gas 54 on pressure plate 56 will exceed that of the force produced by gas 52 on piston 44 on the high- pressure side of the device and the force of the spring 60. At such a time, the force applied by gas 54 will cause piston 44 to move upward within housings 58 and 36. As piston 44 moves upwardly, communication opening 50 will move away from gas passage 48 effectively stopping any additional high-pressure Heliox 52 from entering equalization chamber 34.
  • the spring 60 will push the piston 44 downwards to allow gas passage from chamber 32 to chamber 34 no matter what the pressure is inside chamber 32. Since the surface of the pressure plate 56 is quite important, the two main forces rebalancing the piston are the spring force and the : . ⁇ pressure force from the equalization chamber 34.
  • the spring constant of spring 60 and the area of pressure plate 56 are thus selected for a specific pressure rating so that a patient will always receive the same volume of gas and dosage for their applications, independent of the pressure change in high-pressure chamber 32.
  • gas 54 is dispensed (i.e., inhaler 30 has been actuated and the medication in inhaler 30 is delivered to the patient)
  • the pressure exerted by gas 54 on pressure plate 56 is lower and the high-pressure Heliox 52 along with the spring 60 will force piston 44 downwardly thereby repeating the cycle described above until equalization chamber 34 once again has a desired pressure of gas therein.
  • An alternative to this delivery system can be done using a mechanical actuation by the user.
  • the piston 44 will allow the gas to escape from the high-pressure gas passage 42 and be stored into a secondary chamber.
  • the amount of gas released into equilibrium chamber 34 is then defined by the volume of this secondary chamber.
  • the gas is released from this chamber into the equilibration chamber 34 when the high-pressure cylinder 32 is returned to its original position.
  • the housing 58 could be used as the secondary chamber.
  • the high-pressure Heliox 52 can be stored at, for example, 1,600 psig.
  • Equalization chamber 34 effectively decompresses this gas so that it has a pressure of, for example, 32 to 200 psig. Using 22 ml of the 200 psig Heliox, the gas will expand to 300 ml at a pressure of one atmosphere. This is a sufficient amount of gas for drug delivery in one inhalation.
  • the equalization chamber 34 can be part of the separable high-pressure canister 32.
  • Equalization chamber 34 contains a fixed volume of pressurized gas 54. This gas will be released in two widely different volumes to the rest of the inhaler. The first volume released is around 270 ml of gas; the second is roughly l/10 th that value, or 30 ml. It is proposed here that the creation of the two volumes occurs in separate activation, either triggered manually by the user (i.e. pressing a trigger twice or at two positions) or sequentially inside the device.
  • the drawings will cover 2 different embodiments of the invention: mainly either delivering two volumes of gas using a two-chamber piston (Fig. 2), or with the use of two gas orifices, one being a calibrated orifice (Fig. 3).
  • Option 1 The two-volume delivery can be done first by having two-chambers as seen in Figure 2.
  • the novelty aspect lies in the presence of two internal chambers and a unique piston shape, selectively isolating the chambers.
  • Option 1 also allows for the delivery of the two-volumes of gas to be an inside component of the high-pressure canister 32.
  • the two-volume delivery can be inherent to the canister design where the two chambers are an internal mechanism of the canister, along with the equalization chamber. It is for that reason that the valve assembly has been designed to closely resembles existing MDI canister design. If the two-volume delivery is thought of belonging to the inhaler instead, the piston shape can be changed to ease its manufacturing.
  • Equalization chamber 201 includes an internal housing 203 defining two different size chambers 204 and 205. Housing 203 includes an opening 208 on top for communication with the equalization chamber. First chamber 204 communicates with second chamber 205 via opening 209, and the outside via the opening 210 in the main piston 202.
  • Second chamber 205 communicates with both equalization chamber 201 and the first chamber 204 via the openings 208 and 209 in housing 203.
  • a piston 202 is slidably mounted within the gasket 203.
  • Piston 202 includes a communication opening 210 comprising of a hollow passage terminated at the bottom of the piston.
  • the communication opening 210 is designed to selectively allow gas stored in chamber 204 to communicate with"the outside of the canister.
  • the unique shape of the .piston 202 allows for the two- process operation. At rest, piston 202 is pushed downwards by spring 206 located inside the housing 203, isolating the chambers with an isolation ring.
  • Communication openings 208 and 209 are opened allowing filling of the second and third chamber 204 and 205 from the equalization chamber 201.
  • piston 202 is sliding upward relative to the chamber 201.
  • the opening 210 is now communicating with chamber 204, releasing the first initial large volume of gas.
  • piston 202 pushes against the isolation ring surrounding opening 209, closing opening 209 and isolating chamber 204 from chamber 205. All the gas in chamber 204 will leave until equilibrium is reached with the outside of the canister.
  • the piston 202 is moved further up. Gas can now flow from chamber 204 to chamber 205 via opening 209, and to the outside via opening 210.
  • the valve 311 is encased inside a casket 312 which has two gas passages 315A and 315B connecting the high-pressure gas from the canister 301 to the rest of the inhaler.
  • 315B is a calibrated orifice that will allow a very small known flow rate to the inhaler. For instance a .004" diameter orifice will allow a volume in one-half second of 21 ml for pure helium at 200 psig while 315A is a larger orifice, sealed by the secondary piston 313. Piston 313 is pushed against the casket 312 by the large diameter of the valve 311.
  • valve 311 When the valve 311 is first pushed up, it pushes up piston 302, releasing high-pressure gas from the canister 301 to the outside via openings 309 and 310.
  • the hollow diameter of piston 311 is now at the same level as the secondary piston 313. Aided by the spring 314, the piston 313 slides towards the valve 311 opening channel 315A.
  • High-pressure gas flows via both orifices 315A and 315B producing the large amount of gas needed for the purge bolus.
  • the valve 311 When the second volume of gas is desired, the valve 311 is pushed farther up. Due to the expansion in the valve .diameter, the piston 313 is pushed back against 312 sealing orifice 315A.
  • drum section 64 includes a housing 65 that contains a rotating drum 66 and includes gas passage 62.
  • An elastic material 67 is disposed between drum section 66 and housing 65 so that drum 66 can rotate freely within housing 65 but still retain drugs stored therein.
  • Drum 66 is made of plastic or coated plastic to decrease or eliminate static electricity, which can lead to agglomeration of particles of an injected drug.
  • Drum 66 includes a plurality of tubes 68, 70 that are substantially cylindrical and extend longitudinally therethrough.
  • Drum 66 further includes a substantially cylindrical bore 72 also extending longitudinally therethrough.
  • Tubes 68 contain a powdered drug formulation to be administered to a patient, whereas tubes 70 are empty and hollow to allow communication of gas 54 from equalization chamber 34 to a spacer 96 so that spacer 96 can be rapidly filled with several hundred ml of Heliox prior to injection of the fluidized dry powder drug formulation into spacer 96.
  • Fig. 1 shows an embodiment where drum 66 includes tubes 68 and so an attached spacer is not pre-purged.
  • Fig. 4 shows an embodiment of drum 66 that includes tubes 70.
  • Fig. 4A shows a cross sectional view along line A- A of Fig. 4.
  • tubes 70 are empty and have a diameter that is larger than the diameter of tubes 68.
  • Tubes 68 contain a powdered medication 76.
  • the diameter of each tube 68 is dependent on the volume and weight of dry powder of a specific drug to be delivered.
  • Both tubes 68 and 70 are packed within rotating drum 66 so as to maximize the amount of doses available per rotating drum.
  • a preferred arrangement is for the drug filled tubes and hollow empty tubes to be arranged in pairs vertical to each other.
  • Micronized dry powder drugs can be made in particle ranges from preferably slightly smaller than 1 micron to 5 microns.
  • a fluidized particle range of less than 1 micron to 3 microns is most beneficial for optimal drug delivery to the deep lung for systemic diseases.
  • particle sizes should be optimized for both the delivery system, i.e. the inhaler design, and the targeted location in the lung.
  • Therapeutic drugs to treat the upper or middle lung for respiratory diseases can be up to 5 microns in size in their final fluidized and delivered form. Referring to Fig. 4, when rotating drum 66 is to be used, drum 66 is placed upon spindle 78 so that spindle 78 is inserted into bore 72 and drum 66 is coaxial with spindle 78.
  • rotating drum 66 is selectively placeable upon and removable from spindle 78.
  • a plurality of ducts 80 are disposed between gas passage 62 and both tubes 68 and 70 so as to provide a gaseous communication between these elements.
  • Two ducts 80 may be used to feed Heliox from equalization chamber 34 to spacer 96 with gas flow occurring through ducts 80 first to tubes 70 and then to corresponding tubes 68. After the allocated number .of tubes per one concentric ring has been emptied, the ducts are moved to a different concentric ring and corresponding tubes. This can be accomplished through a simple appendage on drum 66 engaging a switch, or, a contact switch operated by low level current.
  • one duct 80 may provide gas to both tubes 68, 70 which is on an assembly that moves, and which changes position moving from one concentric ring of tubes to the other. For example, this can be done by a set of gears (not shown) . The multidose barrel will rotate after
  • tubes 68 shown in dark indicate tubes that still have medication 86a and 86b within them.
  • Tubes 68 that are open indicate tubes that no longer have medication to be dispensed within them.
  • only one duct 80 at a time need be coupled to a corresponding tube 68. This is because spindle 78 is used to provide communication of gas 54 with spacer 96. Additional ducts 80 could be used for a different concentric ring of tubes 68.
  • the embodiment of Fig. 5 would increase the number of tubes containing drug powder or liquid in rotating drum 66, raising the multi-unit dose capacity of a single disposable plastic barrel.
  • ducts 80 would act as a source of propellant and fluidizing energy for the drug in the tubes.
  • Each duct is activated by a mechanical means when the ducts are to be utilized.
  • a single Heliox source needle can change position to access each circular row of drug bearing tubes in succession.
  • a clear sealed plastic overlay 86 is disposed on the front 86a and back 86b of drum 66 covering all tubes 68.
  • Plastic overlay 86 contains and protects the dry powdered drug 76 from moisture, provides an anti-microbial barrier, and keeps tubes 68 clean and moisture free for pre-dose generation of Heliox gas injection into the spacer 96.
  • Plastic overlay 86 will have a surface strength marginally less then the pressure of gas 54.
  • gas , 54 is injected into drug filled tube 68, plastic overlay 86a bursts inward into tube 68.
  • a buildup of pressure from Heliox 54 then occurs in tube 68, and explosively blows plastic overlay 86b existing on the spacer side of tube 68 thereby fluidizing powder 76 into the environment of the spacer.
  • the engagement of rotating drum 66 with ducts 80 is illustrated with reference to Fig. 6.
  • Rotating drum 66 includes a receptacle 88 for hermetically receiving duct 80 therein.
  • Rotating drum 66 can be designed so that plastic overlay 86a covers the entire front of rotating drum 66 and receptacle 88 is affixed over plastic overlay 86a.
  • receptacle 88 may have a plastic membrane similar to plastic overlay 86 built into it.
  • Duct 80 includes beveled portions 90 made of a strong but pliable material so that when ducts 80 are inserted into receptacle 88, a small amount of physical pressure is required to maintain a tight friction based seal between receptacle 88 and duct 80 during injection of the Heliox gas.
  • Receptacle 88 further has a trapezoidal shaped appendage 92 designed to accept duct 80 on a hermetic fitting basis at the pressure required for operation and drug powder fluidization.
  • tubes 68 may contain, instead of powdered drug 76, a liquid drug 69 disposed therein.
  • a micropore aerosol nozzle 71 is disposed in tube 68 at an end opposite duct 80.
  • plastic overlay 86 keeps liquid drug 69 within tube 68 until it is desired that liquid drug 69 be administered.
  • a space 85 is provided between aerosol nozzle 71 and plastic overlay 86B. Space 85 could be 0.25 inches or larger.
  • Aerosol nozzle 71 is a hard structure with micropores.
  • Plastic overlay 86B will expand and stretch before it ruptures so it should not lay on top of the aeroso'l nozzle 71.
  • Space 85 will also prevent plastic overlay 86 from sticking over aerosol holes in aerosol nozzle 71 when plastic overlay 86 ruptures.
  • tube 68 is divided into a liquid container part 68a and gas conveyer part 68b.
  • Liquid drug 69 is contained within liquid container part 68a through the use of plastic overlays 86a,b.
  • Tube 68 further includes a friction seat 124 that is designed to selectively mate with a fixed nozzle 126 of spacer 96.
  • spindle 78 is shown as the conduit for compressed gas 54. It should be clear though that tubes 70 could also be used in a drum 66 that has a friction seat 124 which mates with a friction nozzle 126. In the embodiments shown, where a fixed nozzle is implemented, when drum 66 rotates to align a new drug to be administered, drum 66 is moved forward toward spacer 96 and press fitted therein. This forward performed movement may be accomplished mechanically or manually by the patient. In all of the embodiments discussed above, when gas 54 is applied to:.tube 68, the application causes an explosion of plastic overlay 86a blowing into chamber 68.
  • Disposable multidose drum 66 is designed so that it can only be inserted onto spindle 78 on which it rotates in the correct manner. That is, a position where the front of the drum 66 is inserted correctly juxtaposed to where the Heliox source (s) ducts are located.
  • An activating trigger 94 is disposed on drum section 64.
  • Trigger 94 can have several stops like a multi-action pistol trigger, or may have an activating button plunger with the same multi-action inducing activities. When trigger 94 is depressed, drum 66 is rotated about spindle 78 to a correct position for the next dose.
  • inhalation port door 98 coupled to a mouth piece 99 of spacer 96 closes, thereby inhibiting a user from inhaling gas disposed within spacer 96.
  • inhalation port door 98 could be first left open so that the air in spacer 96 is more efficiently purged out (as discussed immediately below) . Thereafter, inhalation port door 98 is closed as above.
  • Yet another embodiment includes using a combination pressure/vacuum port (not shown) which opens to let air out during the purging phase and closes during the drug delivery phase.
  • a quantity of 230-270ml of Heliox gas is injected into spacer 96 from equalization chamber 34 to gas passage 62, through tubes 70 or spindle 78, through another gas passage 63 (not shown in figures) in housing 65 and finally through a compressed gas input port of spacer 96.
  • the air in spacer 96 is pushed out or purged through a pressure port 100 so as to assure as close to a 100% Heliox is present in the ambient spacer environment as possible.
  • the Heliox gas provides both a spacer environment for settling of the heavier undesirable particles, and provides a large bolus front wave of gas in which the desired fine particle fraction will be entrained during inhalation.
  • inhaler 30 When the process of filling spacer 96 with gas 54 ends, inhaler 30, based on a sequence automated or* manually activated by trigger 94, shoots 30 to 70 ml of gas 54 obtained via the options presented in figures 2 and 3 into tube 68 containing the drug formulation.
  • the gas fluidizes powder drug 76 (or aerosolizes drug 69) , driving the drug through drug input port 68 into spacer 96, and causes turbulence which helps to further fluidize and deagglomerate the drug.
  • one port could be used to deliver both the compressed gas alone, and a combination of the compressed gas and drug.
  • Heliox gas 54 used to aerosolize drug 76 or 69 may be provided in two pulses, of, for example, 60% and then 40% of the total intended volume. This procedure assures all powder 76 from tube 68 is injected into spacer 96, and further adds turbulence to spacer 96 so that the particles are kept separated. At a pre-determined period of time thereafter, e.g. 0.5 to 5 seconds, a mechanical timer opens inhalation port 98 so that the patient can inhale cloud of particles. A combination of a spring, gear and wire (not shown) attached to trigger 94 can be used to make inhalation port door 98 close when trigger 94 is depressed. Depressing trigger 94 also activates the Heliox purge at the same time.
  • a vacuum/pressure valve 104 will close automatically until inhalation door 98 opens and will equalize the pressure inside spacer 96 until the patient has finished inhaling. As the patient inhales cloud of particles, a vacuum begins to form in spacer 96. At a certain pressure, vacuum/pressure valve 104 opens allowing ambient air into spacer 96. By opening vacuum/pressure valve 104, the patient may continue a steady deep inhalation of room air following the Heliox bolus, slug or gas front entraining particle cloud.
  • Vacuum/pressure valve 104 also ensures that larger particles that may settle on the bottom of spacer 96 do not get inhaled by a user.
  • Vacuum/pressure valve 104 can be opened/closed automatically. For example, it can be made of a piece of flexible metal strip. At atmospheric pressure, the strip will line up perfectly with the wall of spacer 96. When the Heliox builds up excess pressure during purging, vacuum pressure valve 104 will coil upward, keeping the Heliox in. When inhalation port door 98 is opened by the trigger wire, the pressure will drop to normal. During the drug delivery, the patient will breathe in much larger volume of gases (500 ml to 1.5 liters) than the 230-270 ml.
  • Spacer 96 provides the following benefits: ;: a) slows down the velocity of the Heliox gas plus drug formulation injected into the spacer; b) allows sufficient turbulence to keep the small desirable particles suspended and separated; c) allows the heavier particles unsuitable for pulmonary drug delivery to settle out or be trapped in the spacer; and d) provides a bolus, slug or initial front of gas plus drug formulation that is 100% Heliox, followed, thereafter, by air as part of the same continuous breath.
  • Spacer 96 may be further provided with a scented receptacle 110 disposed on an upper and outer part of the spacer near to where a patient's nose would be.
  • Receptacle 110 may be a scented strip containing essence of vanilla, mint, or another scent, and is placed near the nose to make the use of the inhaler pleasant for children and older adults who dominate the usage population.
  • Spacer 96 should be constructed of a plastic, or provided with an inner coating, that eliminates the generation of static electricity. This is because static electricity imparted to the drug particles injected into the spacer could result in clumping and adversely affect the dose delivered to the patient.
  • spacer 96 it is desirable for spacer 96 to incorporate in its inhalation port door 98 an apparatus to prevent the accidental exhalation by the patient into spacer 96 prior to inhalation, so as to avoid mixing of exhaled gases with the Heliox and suspended drug cloud of particles, and to avoid agglomeration of the particles due to exhaled moisture. It is also desirable for inhalation port door 98 to be closed upon introduction of the Heliox ambient atmosphere and Heliox plus drug formulation into spacer 96, so that only Heliox is in spacer 96 and a minimal amount of that Heliox is lost external to spacer 96.
  • Spacer 96 can be made of rough materials on its surface. The rough surface serves two different purposes.
  • a diffuser 112 is disposed between spacer 96 and drum section 64. Diffuser 112 includes an impact ball 114 at a portion of diffuser 112 that is proximate to gas passage.
  • Impact ball 114 is used to reduce the initial high velocity of highly turbulent gas and drug that enters diffuser 112. When gas and drug is injected into diffuser 112, a high-energy flow may concentrate in the center of the unit. Impact ball 114 helps avoid this channeling effect.
  • Diffuser 112 is shaped as an expansion cone to slow down the gas-powder mixture. The size of diffuser 112 is dependent on the desired gas-powder mixture velocity hitting the back of the throat. The velocity should be low enough so that the flow is laminar. At an inhalation flow rate of 60
  • the Reynolds number is 670 for pure helium compared to 5,400 for air. Using a certain mix of helium and air changes the Reynolds number accordingly, as shown in Table 2. Even if the Reynolds number is low enough so that it falls into a laminar category, the flow might still be turbulent due to the roughness of the surface for instance. Spacer 96 can be combined with diffuser 112 so that the large particles can drop out of particle cloud in spacer 96. Table 2 : Effect of concentration of helium on flow regime .
  • Ultrasonic nebulization uses the excitation of a piezoelectric crystal vibrated at high frequency to create waves in the liquefied drug solution placed directly above the crystal. The oscillation waves then disrupt the surface and create a geyser-like behavior at the surface, nebulizing the drug that is then carried by the Heliox gas passing above the surface on its way to the spacer.
  • a cut off pressure valve which, when the pressure in equalization chamber 34 is insufficient to provide sufficient Heliox volume to fill spacer 96 and a pressure wave to optimally fluidize or aerosolize the drug, the inhaler will cease to function.
  • a cut off switch could be comprised of a pin hook that is effective to disengage trigger 94. Pin hook could be coupled to a spring that could be in turn coupled to a diaphragm. Thus, when the pressure in equalization chamber 34 is high enough, the diaphragm would be pushed towards equalization chamber 34 thereby elongating the spring. This elongation of the spring clears the hook from trigger 94 and allows trigger 94 to operate.
  • a pressure activated flag or signal could be implemented to tell the user that a cartridge needs to be replaced. Since it is critical that patients have access to medication when needed, a counting method is desired concerning the number of doses remaining.
  • a counting method can be placed above or by each drug tube in drum 66, with an indicator for indicating the number of doses left.
  • Each application of trigger 94 will rotate drum 66 once and when the medication is empty,-, the indicator on drum 66 would indicate that there is no medication left in the device.
  • a clear label with black letters stating the drug and potency and a color band coding system can be affixed to the outside of each drum.
  • tubes 1, 2, 3, 4 may contain a sequential medication group and tubes 5, 6, 7, 8 a repeat of the same medication group with each dose, for example, within tubes 1-4 to be inhaled every 6 hours.
  • classes of drugs being investigated and formulated for pulmonary administration include, but are not limited to, those for chronic obstructive lung diseases such as the classes of agents commonly referred to as anticholinergic agents, beta-adrenergic agents, corticosteroids, antiproteinases, and mucolytics, and include such specific drugs.
  • controlled release drugs such as those that are liposome based and which are designed for pulmonary drug delivery to treat respiratory and systemic diseases over a period of time due to the chronic nature of the illness or the mode in which the illness responds to medication, or the mode in which the medication operates, may be administered by the invention.
  • Existing DPIs use the patient's inhalation alone, the patient's inhalation assisted by a propeller, or compressed air generated by a hand pump in a DPI, to fluidize the dry powder drug formulation.
  • One DPI also uses compressed air in a plastic pillow that contains the dry powder drug formulation as an aid to fluidization.
  • the present invention offers several advantages over these approaches to fluidizing a dry powder drug formulation.
  • a factory produced compressed Heliox source can be produced as a desiccated dry gas, eliminating this problem in humid climates. This in turn, would cause variability in the fluidization, deagglomeration, and post clumping of dry powder drug formulations, which in turn effects the fine particle fraction available for pulmonary administration and effective therapy.
  • a factory-produced source of pressurized Heliox also provides the advantage of a high velocity gas stream, which provides the advantage of a more forceful impact on and fluidization of a dry powder drug formulation, compared to the force generated by inhaled air, battery powered propeller assisted air, or hand pumped compressed air.
  • Heliox is a much better liquid aerosolizing/atomizing agent because of its high velocity of release and it does not have the same cooling characteristics of liquid CFCs .
  • the multidose insert containing multiple sealed unit doses of liquid drug, or a reservoir multidose liquid drug source is stored separately from the compressed gas.
  • the propellant and drug formulation are stored together, along with many other additional additive ingredients.
  • the MDI must be shaken before each use to try to achieve a uniform consistent dosing. Additionally, temperature changes can make the drug compound, which is packaged with the propellant, come out of solution.
  • This provides a unique gas environment for a) a differential settling of heavier particles than air, and b) a large volume bolus of Heliox plus a desired fine particle fraction which is then inhaled by the patient, followed on a continuous inhalation basis with air, with the Heliox and particles being the inhaled tidal gas front.
  • the spacer also can have laminar flow shelves, which help induce the laminar flow of Heliox plus entrained particles from the "cloud" of fluidized powder or aerosolized liquid drug formulation upon inhalation by the patient. • . -..The spacer reduces the velocity of the gas stream to an acceptable cloud of particles, the undesirable particles settle out, and the resulting cloud of remaining particles that are of the desired particle size range can be inhaled.
  • the laminar flow shelves aid in the introduction of a laminar flow out of the spacer of the helium gas and entrained particles. Then, upon inhalation, it is highly desirable to keep the particles of the desired size range from settling. With viscous drag greater than the gravitational settling velocity, the fine solid particles can be suspended indefinitely without settling. On the other hand, additional viscous drag will cause an excess pressure drop. It is therefore, desirable to control the viscosity.
  • the ability of this invention to generate initial high turbulent flow and provide rapid flow deceleration is important to the performance of the inhaler for powdered drug delivery.
  • a high pressure chamber and an equalization chamber are provided so that Heliox gas can be stored efficiently under a high pressure and also be used as a propellant to fluidize or aerosolize a drug at a lower pressure.
  • Using a mechanical way to systemically provide two widely different volumes of gas allows to create first a bolus of gas then a second volume of gas to fluidize, nebulize the drug, independently of a variable user activation.
  • Heliox as a propellant, a drug fluidized or aerosolized by this propellant has a better chance of navigating the airways and reaching desired portions of the lung.
  • the main costs of the inhaler are the drug and the manufacturing/parts.
  • the cost of Heliox, while being an expensive gas by itself, is less than the other costs.
  • Providing the user with an in-home mean to refill his canister allows him to continue using his inhaler for longer periods of time without going to the pharmacy or doctor. The higher cost of the inhaler would then be paid for by the longer use.

Abstract

L'invention concerne un inhalateur renfermant un gaz comprimé, tel que du gaz Heliox dans une première chambre qui communique avec une chambre d'égalisation possédant une pression inférieure à la pression du gaz dans la première chambre comprimée. Ledit inhalateur présente aussi une chambre de stockage de médicament qui est couplée de manière amovible à ladite chambre d'égalisation fonctionnant de manière qu'une partie du gaz comprimé provenant de la chambre d'égalisation fluidifie et introduit un aérosol dans le médicament, afin de produire un nuage de médicament qui peut être injecté dans un espace, où il peut être inhalé par un utilisateur.
EP04820761A 2003-12-04 2004-11-18 Inhalateur portable fonctionnant au gaz Withdrawn EP1689474A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US10/726,627 US20050121025A1 (en) 2003-12-04 2003-12-04 Portable gas operating inhaler
US10/845,411 US7461649B2 (en) 2003-12-04 2004-05-14 Portable gas operating inhaler
PCT/US2004/038477 WO2005060480A2 (fr) 2003-12-04 2004-11-18 Inhalateur portable fonctionnant au gaz

Publications (2)

Publication Number Publication Date
EP1689474A2 true EP1689474A2 (fr) 2006-08-16
EP1689474A4 EP1689474A4 (fr) 2012-09-12

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EP04820761A Withdrawn EP1689474A4 (fr) 2003-12-04 2004-11-18 Inhalateur portable fonctionnant au gaz

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EP (1) EP1689474A4 (fr)
BR (1) BRPI0417154A (fr)
CA (1) CA2549174C (fr)
WO (1) WO2005060480A2 (fr)

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WO2015001561A1 (fr) 2013-07-03 2015-01-08 MEway Pharma LTD Inhalateur-doseur et méthodes relatives à celui-ci

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DE102009011315B3 (de) * 2009-03-03 2010-09-16 Andrea Drollinger Inhalatorvorrichtung
US9364622B2 (en) * 2012-04-20 2016-06-14 Fsc Laboratories, Inc. Inhalation devices and systems and methods including the same
CN110115790B (zh) * 2018-02-07 2021-08-06 心诚镁行动医电股份有限公司 雾化器组件及其气流主要导引件
WO2023242262A1 (fr) * 2022-06-15 2023-12-21 Universidad De Zaragoza Procédé de génération d'un aérosol micro- ou nanoparticulaire inhalable à partir d'un matériau biocompatible pulvérisé à sec

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WO1994005357A1 (fr) * 1992-09-03 1994-03-17 Maansson Sven Systeme d'administration de medicaments
WO1997037708A1 (fr) * 1996-04-09 1997-10-16 Vivorx Pharmaceuticals, Inc. Inhalateur a poudre seche
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WO2002002167A1 (fr) * 2000-07-01 2002-01-10 Glaxo Group Limited Valve de contenant d'aerosol
WO2003045483A2 (fr) * 2001-11-23 2003-06-05 Innovata Biomed Limited Systeme
WO2003094694A2 (fr) * 2002-05-08 2003-11-20 Medihale Ltd. Appareil a main d'inhalotherapie et procede d'utilisation

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US4114615A (en) * 1975-12-12 1978-09-19 Aktiebolaget Draco Aerosol inhalation device
WO1994005357A1 (fr) * 1992-09-03 1994-03-17 Maansson Sven Systeme d'administration de medicaments
WO1997037708A1 (fr) * 1996-04-09 1997-10-16 Vivorx Pharmaceuticals, Inc. Inhalateur a poudre seche
US6125844A (en) * 1998-04-30 2000-10-03 Westwood Biomedical Portable oxygen based drug delivery system
WO2002002167A1 (fr) * 2000-07-01 2002-01-10 Glaxo Group Limited Valve de contenant d'aerosol
WO2003045483A2 (fr) * 2001-11-23 2003-06-05 Innovata Biomed Limited Systeme
WO2003094694A2 (fr) * 2002-05-08 2003-11-20 Medihale Ltd. Appareil a main d'inhalotherapie et procede d'utilisation

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Publication number Priority date Publication date Assignee Title
WO2015001561A1 (fr) 2013-07-03 2015-01-08 MEway Pharma LTD Inhalateur-doseur et méthodes relatives à celui-ci

Also Published As

Publication number Publication date
WO2005060480A2 (fr) 2005-07-07
BRPI0417154A (pt) 2007-03-06
CA2549174C (fr) 2010-04-06
CA2549174A1 (fr) 2005-07-07
EP1689474A4 (fr) 2012-09-12
WO2005060480A3 (fr) 2006-07-06

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