EP1148905A2 - Inhalateur a air comprime pour administration intra-pulmonaire d'aerosols a base de poudres de liposomes, et poudres pour aerosols correspondantes - Google Patents

Inhalateur a air comprime pour administration intra-pulmonaire d'aerosols a base de poudres de liposomes, et poudres pour aerosols correspondantes

Info

Publication number
EP1148905A2
EP1148905A2 EP00912355A EP00912355A EP1148905A2 EP 1148905 A2 EP1148905 A2 EP 1148905A2 EP 00912355 A EP00912355 A EP 00912355A EP 00912355 A EP00912355 A EP 00912355A EP 1148905 A2 EP1148905 A2 EP 1148905A2
Authority
EP
European Patent Office
Prior art keywords
powder aerosol
compressed air
liposomes
liposomal
anspmch
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Withdrawn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
EP00912355A
Other languages
German (de)
English (en)
Inventor
Julia Eva Diederichs
Wolfgang Koch
Hubert Lödding
Regina Reszka
Horst Windt
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.)
Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
Original Assignee
Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
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
Application filed by Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV, Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft filed Critical Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
Publication of EP1148905A2 publication Critical patent/EP1148905A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier 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
    • A61M15/00—Inhalators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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
    • 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
    • A61M15/0086—Inhalation chambers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/0012—Apparatus for achieving spraying before discharge from the apparatus
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/02—Spray pistols; Apparatus for discharge
    • B05B7/06—Spray pistols; Apparatus for discharge with at least one outlet orifice surrounding another approximately in the same plane
    • B05B7/062—Spray pistols; Apparatus for discharge with at least one outlet orifice surrounding another approximately in the same plane with only one liquid outlet and at least one gas outlet
    • B05B7/066—Spray pistols; Apparatus for discharge with at least one outlet orifice surrounding another approximately in the same plane with only one liquid outlet and at least one gas outlet with an inner liquid outlet surrounded by at least one annular gas outlet
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites

Definitions

  • the invention relates to a compressed air inhaler for pulmonary application of an active ingredient-carrying or an unloaded liposomal powder aerosol.
  • the invention is preferably intended for use on active ingredient-carrying liposomal powder aerosols.
  • the invention is equally applicable to unloaded liposomes, for example to liposomes made from special lipids such as surfactant lipids, which can themselves be active ingredients.
  • the invention further relates to the active ingredient-carrying or unloaded powder aerosols which can be used in the compressed air inhaler.
  • Liposomes are becoming increasingly important as an application form for active ingredients.
  • active ingredient-bearing liposome formulations are lyophilized.
  • these liposome lyophilisates are hygroscopic and thus cause difficulties in application if they are to be given as dry powder.
  • the storage of liposome lyophilisates is always problematic if it cannot be carried out in a sealed container under vacuum.
  • the lyophilisates are reconstituted with water or physiological saline and given, for example, as an intravenous injection. It is also possible to encapsulate the liposome lyophilisates or to compress them into tablets in order to provide oral dosage forms.
  • Liposomes that contain active substances can also be used to treat broncho-pulmonary diseases such as asthma, bronchitis or lung cancer.
  • the results so far on the use of liposomes for drug accumulation in the lungs are promising.
  • the liposome-mediated pulmonary drug application extends the length of time of the active ingredient in the lungs and increases the therapeutic efficiency while significantly reducing the extrapulmonary side effects.
  • the prolonged retention time of the liposomes in the airways noticeably affects the pharmacokinetics of the encapsulated material.
  • toxicity studies show no histological changes in the lungs in vivo and no toxic effects on healthy volunteers, which demonstrates that the pulmonary application of liposomes is well tolerated.
  • US 4,895,719 describes dry liposome powders, which are produced by spray drying, are suspended in fluorohydrocarbons, which simultaneously serve as propellants, and are atomized and inhaled under pressure.
  • the propellant gas evaporates in the device and in the oral cavity.
  • the air in the device and in the oral cavity is saturated with water vapor, and the propellant gas is immediately replaced by water due to the hygroscopicity of the formulation, so that an aqueous aerosol is inhaled in this case.
  • EP 0 223 831 B1 describes a system for applying a water-soluble medicament to the respiratory tract, which uses liposomes to encapsulate the medicament and provides an unspecified device for atomizing a defined amount of liposome using ultrasound or pneumatically for inhalation.
  • liposomal aerosol formulations are not without problems.
  • an ultrasonic nebulizer there is a progressive increase in the temperature of the aerosol in the so-called "holding chamber". This increase in temperature causes the encapsulated material to be released as a function of the phase transition temperature of the lipids used.
  • a release of the active ingredient was also observed. This phenomenon is attributed to the shear forces during nebulization.
  • the energy input is not very effective, so that a large proportion of large, non-inhalable drops is created. These drops flow back into the reservoir.
  • the liposome dispersion recirculates more than ten times and is redispersed each time before it leaves the nebulizer as an inhalable aerosol.
  • the repeated dispersion process can cause stability problems, particularly for substances that are susceptible to mechanical stress.
  • the vaporization process vaporizes a significant amount of water from the liposome dispersion because the nebulizing air is dry and the aerosol droplets with a large surface area promote evaporation. The liposome concentration therefore increases in the course of the nebulization time and consequently also the inhaled dose.
  • nebulizers Uniformity of the dose is therefore difficult for liposomes in conventional nebulizers.
  • the efficiency of the inhaled therapeutic aerosol depends on various factors, which are mainly related to the particle size of the aerol.
  • Commercial nebulizers generate an average droplet size of 5 ⁇ m.
  • Such an aerol is deposited in the upper airways.
  • numerous bronchopulmonary diseases manifest in deeper areas of the lungs, it would be desirable to be able to adapt the particle size spectrum.
  • the object of the invention was therefore to provide an inhaler with which the pulmonary application of liposomes is made possible without forced breathing maneuvers and with which the active substance can be brought to the desired site of action in sufficient quantity without the active substance escaping.
  • Another object of the invention was to provide suitable aerosol formulations for application in this inhaler.
  • the compressed air inhaler for pulmonary application of an active ingredient-carrying or an unloaded liposomal powder aerosol comprises a container for an aqueous liposome dispersion in which the liposomes are dispersed in water, which is pumped with an atomizing nozzle and with a drying unit such as a nebulizing chamber for spray drying of the liposomes is connected which is followed by a mouthpiece, the atomizing nozzle having separate feeds for the compressed air and the liposome dispersion.
  • the compressed air inhaler according to the invention allows, starting from an aqueous liposome dispersion, the in vivo production of a powder aerosol, so that on the one hand no forced breathing maneuvers by the patient are necessary and on the other hand no problems arise in handling the dry liposome powder.
  • the aqueous liposome dispersion has a low toxicity and a high stability of the liposomes compared to organic media and is easy to produce with the possibility of scaling up.
  • Fig. 1 is a schematic representation of a compressed air inhaler according to the invention.
  • FIG. 2 shows the schematic sectional illustration of a nozzle body in the compressed air inhaler according to FIG. 1.
  • the compressed air inhaler essentially consists of a nozzle body 1 with a compressed air supply 16 and a liquid supply 14, an expansion and drying vessel (vaporizing chamber) 17 and an aerosol outlet (mouthpiece) 18.
  • the liquid Feed 14 is connected to a liquid metering device 19 and a container 20 for the aqueous liposome dispersion.
  • the feed 16 is connected to a pressure reducer, not shown.
  • the nozzle body 1 forms a two-substance nozzle in which the liquid supplied is atomized with the aid of the compressed air supplied, which can be regulated at the level of the pressure.
  • the active ingredient is usually dissolved in the liquid supplied, for example water or ethanol, and is present as a dispersion in the present case (liposomes).
  • the air flow rate and the liquid flow rate can be set independently of one another.
  • the nozzle body 1 essentially consists of a central cavity 2, into which an injection body 3 is concentrically introduced, which has a central bore 4 for supplying the liquid and from an outlet opening 5 of the nozzle body 1 via a fixation device screw 15 is adjustable spaced, and which has an annular Bohmng 6 with outlet openings 7 in the cavity 2 of the nozzle body 1.
  • a feed 9 for the compressed air is introduced parallel to the wall 10, which meets a boring 11 perpendicular thereto, which is connected to the annular boring 6 of the injection body 2.
  • the Bohmng 11 is closed to the outside with a blind plug 12.
  • the compressed air is over z. B. a hose olive 13 is introduced into the compressed air supply 16.
  • the generated drops can be separated from the atomizing air before entering the drying vessel 17 by integrating a virtual impactor.
  • the mist droplets Due to the evaporation of the supplied liquid in the drying chamber 17, which is usually water or ethanol and which functions as a solvent for the active substance or as a dispersing medium for the liposomes, the mist droplets are reduced in diameter until they dry completely.
  • C mass concentration of the active ingredient (dispersion concentration of the liposomes in the aqueous solution).
  • the diameter is reduced by a factor of 4.6.
  • particles with an average size of, for example, 1.7 ⁇ m or at a higher pressure of, for example, 0.9 ⁇ m can emerge at the outlet of the drying chamber 17 of the inhaler (aerosol outlet 18, for example a mouthpiece).
  • the drying vessel 17 (or evaporation vessel) is dimensioned in such a way that complete evaporation is ensured without any significant droplet losses on the walls.
  • the drying vessel 17 is equipped with semi-permeable membranes for an increased liquid throughput for drying the mist. There may be a drying agent on the outside of this membrane (s) to absorb the water vapor. In another variant, the outside of the membrane is washed with dry air.
  • An optimal high active substance aerosol concentration is achieved by the independent adjustment of the liquid and compressed air flow.
  • the liquid is subjected to the dispersion process only once.
  • a recirculation of the dispersion and an associated concentration enrichment or a structural change of the active ingredient particles through repeated exposure to high shear forces is avoided.
  • the drops are dried immediately after they are created.
  • the compressed air inhaler is designed as a pocket device for convenient use by the patient at any location.
  • the veining chamber 17 can be made very small in its function as a drying section, for example as a hose.
  • the invention also relates to the method for treating pulmonary diseases by using the compressed air inhaler according to the invention.
  • the invention further relates to liposomal and nanoparticulate powder aerosols according to claims 7-27.
  • powder aerosols have the following properties: It is a dry powder without the presence of a cryoprotector.
  • the individual powder particles are spherical and have an amorphous or crystalline structure. They are variable in size from 0.5 - 10 ⁇ m. As a result, the deposition location can be determined to a certain depth of the lungs in accordance with the illness to be treated. They consist of dry loose liposome or nanoparticle aggregates or of individual liposomes or nanoparticles.
  • the composition of the powder aerosol can vary within a wide range.
  • liposomal powder aerosol consists, for example, of phospholipids and cholesterol in varying proportions, of natural or artificial pulmonary surfactant or of cationic amphiphiles.
  • the liposomes used can be, for example, large multilamellar vesicles (MLV), produced inter alia by homogenization with and without high pressure, or small unilamellar vesicles (SUV), produced inter alia by sonication.
  • Nanoparticulate powder aerosol consists, for example, of active substance crystals or of active substance-loaded polymer particles.
  • the liposomes or nanoparticles can be surface-modified, for example with polyethylene glycol, plasma- or surfactant-associated proteins or with antibody fragments.
  • the invention can be used to treat all known respiratory diseases loaded with the corresponding active ingredient. All conventional medicinal substances and genetic material are to be regarded as active substances.
  • Liposomal powder aerosol without active ingredient can be used for substitution therapy for pulmonary surfactant, for example in the treatment of respiratory distress syndrome in the newborn or shock lung.
  • the liposomal and nanoparticulate powder aerosols are produced by atomizing the liposomes or the nanoparticle dispersion together with compressed air via a two-component nozzle in a cylinder (as described above).
  • the average aerosol particle size can be adjusted by varying the dispersion concentration and the primary drop spectrum, for example via the nebulizing pressure.
  • the diameter can be set according to the desired requirements in the application in the test animal or on humans.
  • the inhaled drug can be quantitatively reproduced, deposited homogeneously and with high efficiency.
  • Particles in the size range between 3 and 5 ⁇ m are optimal for this.
  • Particle sizes of approx. 1 ⁇ m result when using a nebulization pressure of 3 bar and a dispersion concentration of 0.5%.
  • the mean particle size can be shifted towards larger values.
  • the invention provides a method by which the inhaled drug can be quantitatively reproduced and deposited homogeneously.
  • liposomal powder aerosol with the following composition has been successfully produced: 1. Hydrogenated soy phosphatidylcholine and cholesterol in a molar ratio of 1: 0.25 SUV's manufactured with ultrasound
  • Average particle size of the liposomes 121 nm
  • Average particle size of the aerosol 1.02 ⁇ m
  • Average particle size of the liposomes 1.5 ⁇ m
  • Average particle size of the aerosol 1.03 ⁇ m
  • Average particle size of the aerosol 0.7 ⁇ m
  • Average particle size of the aerosol 0.6 ⁇ m

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Anesthesiology (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Otolaryngology (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un inhalateur à air comprimé qui permet d'administrer au niveau pulmonaire un aérosol constitué d'une poudre de liposomes contenant un principe actif ou non chargée. Son objectif est de proposer un inhalateur qui permette notamment d'administrer au niveau pulmonaire, sans obliger à des manoeuvres respiratoires forcées et au site d'action désiré, des liposomes porteurs d'un principe actif en une quantité suffisante et sans pertes. A cet effet, ledit inhalateur comprend un réservoir (20) pouvant contenir une dispersion aqueuse de liposomes, à l'intérieur duquel les liposomes contenant le principe actif sont dispersés dans l'eau. Le réservoir est relié, par l'intermédiaire d'un dispositif doseur (19) de liquide, à une tubulure de pulvérisation (1) et à une unité de séchage (17), telle qu'une chambre de vaporisation, qui sèche les liposomes par pulvérisation. Un dispositif de sortie (18), tel qu'un embout buccal, est raccordé à ladite unité de séchage. La tubulure de pulvérisation (1) comporte des orifices d'alimentation séparés (14, 16) pour l'air comprimé et pour la dispersion de liposomes (fig. 1). L'invention concerne également une poudre pour aérosol constituée de liposomes ou de nanoparticules.
EP00912355A 1999-02-03 2000-02-03 Inhalateur a air comprime pour administration intra-pulmonaire d'aerosols a base de poudres de liposomes, et poudres pour aerosols correspondantes Withdrawn EP1148905A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE19905285 1999-02-03
DE19905285 1999-02-03
DE19954107 1999-11-02
DE19954107 1999-11-02
PCT/DE2000/000337 WO2000045878A2 (fr) 1999-02-03 2000-02-03 Inhalateur a air comprime pour administration intra-pulmonaire d'aerosols a base de poudres de liposomes, et poudres pour aerosols correspondantes

Publications (1)

Publication Number Publication Date
EP1148905A2 true EP1148905A2 (fr) 2001-10-31

Family

ID=26051750

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00912355A Withdrawn EP1148905A2 (fr) 1999-02-03 2000-02-03 Inhalateur a air comprime pour administration intra-pulmonaire d'aerosols a base de poudres de liposomes, et poudres pour aerosols correspondantes

Country Status (12)

Country Link
EP (1) EP1148905A2 (fr)
JP (1) JP2002538855A (fr)
KR (1) KR20010101991A (fr)
CN (1) CN1338956A (fr)
AU (1) AU3416400A (fr)
CA (1) CA2361807A1 (fr)
DE (1) DE10004860A1 (fr)
HU (1) HUP0105445A2 (fr)
PL (1) PL349885A1 (fr)
RU (1) RU2001124354A (fr)
SK (1) SK10942001A3 (fr)
WO (1) WO2000045878A2 (fr)

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US10036574B2 (en) 2013-06-28 2018-07-31 British American Tobacco (Investments) Limited Devices comprising a heat source material and activation chambers for the same
US10542777B2 (en) 2014-06-27 2020-01-28 British American Tobacco (Investments) Limited Apparatus for heating or cooling a material contained therein
US11064725B2 (en) 2015-08-31 2021-07-20 British American Tobacco (Investments) Limited Material for use with apparatus for heating smokable material
US11241042B2 (en) 2012-09-25 2022-02-08 Nicoventures Trading Limited Heating smokeable material
US11452313B2 (en) 2015-10-30 2022-09-27 Nicoventures Trading Limited Apparatus for heating smokable material
US11659863B2 (en) 2015-08-31 2023-05-30 Nicoventures Trading Limited Article for use with apparatus for heating smokable material
US11672279B2 (en) 2011-09-06 2023-06-13 Nicoventures Trading Limited Heating smokeable material
US11825870B2 (en) 2015-10-30 2023-11-28 Nicoventures Trading Limited Article for use with apparatus for heating smokable material
US11924930B2 (en) 2015-08-31 2024-03-05 Nicoventures Trading Limited Article for use with apparatus for heating smokable material

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BRPI0509348A (pt) 2004-04-21 2007-09-11 Innovata Biomed Ltd inalador
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WO2010098430A1 (fr) * 2009-02-26 2010-09-02 日本エー・シー・ピー株式会社 Inhalateur de brume gazeuse
JP5368661B1 (ja) * 2011-11-04 2013-12-18 正一 中村 ガスミスト吸入器
KR101373981B1 (ko) * 2012-07-24 2014-03-12 한국화학연구원 약물 흡입 장치
KR101313993B1 (ko) * 2012-07-24 2013-10-01 한국화학연구원 약물 흡입 장치
GB201415381D0 (en) * 2014-08-29 2014-10-15 Algipharma As Inhalable powder formulations of alginate oligomers
AU2016402362B2 (en) * 2016-04-15 2022-03-17 Kaer Biotherapeutics Corporation Aerosolizing nozzle and method of operating such aerosolizing nozzle
GB201817868D0 (en) * 2018-11-01 2018-12-19 Nicoventures Trading Ltd Aerosolised formulation
CN111514418B (zh) * 2019-06-12 2022-01-14 中南大学湘雅二医院 一种自吸式经鼻粉末材料给送装置

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11672279B2 (en) 2011-09-06 2023-06-13 Nicoventures Trading Limited Heating smokeable material
US12041968B2 (en) 2011-09-06 2024-07-23 Nicoventures Trading Limited Heating smokeable material
US11241042B2 (en) 2012-09-25 2022-02-08 Nicoventures Trading Limited Heating smokeable material
US10036574B2 (en) 2013-06-28 2018-07-31 British American Tobacco (Investments) Limited Devices comprising a heat source material and activation chambers for the same
US10542777B2 (en) 2014-06-27 2020-01-28 British American Tobacco (Investments) Limited Apparatus for heating or cooling a material contained therein
US11064725B2 (en) 2015-08-31 2021-07-20 British American Tobacco (Investments) Limited Material for use with apparatus for heating smokable material
US11659863B2 (en) 2015-08-31 2023-05-30 Nicoventures Trading Limited Article for use with apparatus for heating smokable material
US11924930B2 (en) 2015-08-31 2024-03-05 Nicoventures Trading Limited Article for use with apparatus for heating smokable material
US11452313B2 (en) 2015-10-30 2022-09-27 Nicoventures Trading Limited Apparatus for heating smokable material
US11825870B2 (en) 2015-10-30 2023-11-28 Nicoventures Trading Limited Article for use with apparatus for heating smokable material
US12016393B2 (en) 2015-10-30 2024-06-25 Nicoventures Trading Limited Apparatus for heating smokable material

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JP2002538855A (ja) 2002-11-19
CN1338956A (zh) 2002-03-06
HUP0105445A2 (en) 2002-06-29
DE10004860A1 (de) 2000-10-05
WO2000045878A2 (fr) 2000-08-10
WO2000045878A3 (fr) 2000-09-28
SK10942001A3 (sk) 2002-05-09
RU2001124354A (ru) 2003-06-20
AU3416400A (en) 2000-08-25
CA2361807A1 (fr) 2000-08-10
PL349885A1 (en) 2002-09-23
KR20010101991A (ko) 2001-11-15

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