CA2507265A1 - Inhalation device for producing a drug aerosol - Google Patents
Inhalation device for producing a drug aerosol Download PDFInfo
- Publication number
- CA2507265A1 CA2507265A1 CA002507265A CA2507265A CA2507265A1 CA 2507265 A1 CA2507265 A1 CA 2507265A1 CA 002507265 A CA002507265 A CA 002507265A CA 2507265 A CA2507265 A CA 2507265A CA 2507265 A1 CA2507265 A1 CA 2507265A1
- Authority
- CA
- Canada
- Prior art keywords
- drug
- chamber
- gas
- flow
- valve
- 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.)
- Abandoned
Links
- 229940079593 drug Drugs 0.000 title claims abstract description 67
- 239000003814 drug Substances 0.000 title claims abstract description 67
- 239000000443 aerosol Substances 0.000 title claims description 27
- 239000002245 particle Substances 0.000 claims abstract description 43
- 238000009833 condensation Methods 0.000 claims abstract description 34
- 230000005494 condensation Effects 0.000 claims abstract description 34
- 238000011144 upstream manufacturing Methods 0.000 claims abstract description 26
- BLUGYPPOFIHFJS-UUFHNPECSA-N (2s)-n-[(2s)-1-[[(3r,4s,5s)-3-methoxy-1-[(2s)-2-[(1r,2r)-1-methoxy-2-methyl-3-oxo-3-[[(1s)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino]propyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]-3-methyl-2-(methylamino)butanamid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 BLUGYPPOFIHFJS-UUFHNPECSA-N 0.000 claims abstract 4
- 208000007934 ACTH-independent macronodular adrenal hyperplasia Diseases 0.000 claims abstract 4
- 239000000758 substrate Substances 0.000 claims description 30
- 238000010438 heat treatment Methods 0.000 claims description 14
- 238000012377 drug delivery Methods 0.000 claims description 7
- 230000004044 response Effects 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 6
- 230000007423 decrease Effects 0.000 claims description 5
- 239000007789 gas Substances 0.000 description 21
- 230000008016 vaporization Effects 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000008021 deposition Effects 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000009834 vaporization Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 210000004072 lung Anatomy 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 238000011287 therapeutic dose Methods 0.000 description 4
- 230000004888 barrier function Effects 0.000 description 3
- 239000003990 capacitor Substances 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 239000007857 degradation product Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000004913 activation Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 230000033458 reproduction Effects 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 229920005570 flexible polymer Polymers 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002991 molded plastic Substances 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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
-
- 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
- A61M11/04—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised
- A61M11/041—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised using heaters
-
- 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
- A61M11/04—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised
- A61M11/041—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised using heaters
- A61M11/042—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised using heaters electrical
-
- 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
- A61M11/04—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised
- A61M11/041—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised using heaters
- A61M11/047—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised using heaters by exothermic chemical reaction
Abstract
A device for delivering a drug by inhalation is disclosed. The device includ es a body defining an interior flow-through chamber having upstream and downstream chamber openings, and a drug supply unit contained within the chamber for producing, upon actuation, a heated drug vapor in a condensation region of the chamber. Gas drawn through the chamber region at a selected ga s- flow rate is effective to form drug condensation particles from the drug vap or having a selected MMAD between 0.02 and 0.1 MMAD or between 1 and 3.5 gm. A gas-flow control valve disposed upstream of the unit functions to limit gas- flow rate through the condensation region to the selected gas-flow rate. An actuation switch in the device activates the drug-supply unit, such that the drug-supply unit can be controlled to produce vapor when the gas-flow rate through the chamber is at the selected flow rate.
Description
INHALATION DEVICE FOR PRODUCING A DRUG AEROSOL
Field of the Invention The present invention relates to an inhalation device for producing desired-size drug-aerosol particles for inhalation.
Background of the Invention Therapeutic compounds may be administered by a variety of routes, depending on the nature of the drug, the pharmacokinetic profile desired, patient convenience, and cost, among other factors. Among the most common routes of drug delivery are oral, intravenous (IV), intramuscular (IM) intraperitoneal (IP) subcutaneous, transdermal, transmucosal, and by inhalation to the patient's respiratory tract.
The inhalation route of drug administration offers several advantages for certain drugs, and in treating certain conditions. Since the drug administered passes quickly from the respiratory tract to the bloodstream, the drug may be active within a few minutes of delivery. This rapid drug effect is clearly advantageous for conditions like asthma, anaphylaxis, pain, and so forth where immediate relief is desired.
Further, the drug is more efficiently utilized by the patient, since the drug is taken up into the bloodstream without a first pass through the liver as is the case for oral drug delivery. Accordingly, the therapeutic dose of a drug administered by inhalation can be substantially less, e.g., one half that required for oral dosing.
Finally, since inhalation delivery is convenient, patient compliance can be expected to be high.
As is known, efficient aerosol delivery to the lungs requires that the particles have certain penetration and settling or diffusional characteristics. For larger particles, deposition in the deep lungs occurs by gravitational settling and requires particles to have an effective settling size, defined as mass median aerodynamic diameter (n~llVIAD), of between 1-3.5 ~.m. For smaller particles, deposition to the deep lung occurs by a diffusional process that requires having a particle size in the 10-100 nm, typically 20-100 nm range. Particle sizes that fall in the range between 10-100 nm and 1-3.5 N.m tend to have poor penetration and poor deposition. Therefore, an inhalation drug-delivery device for deep lung delivery should produce an aerosol having particles in one of these two size ranges.
Another important feature of an aerosol delivery device is control over total dose delivered, that is, the amount of aerosol generated should be predictable and repeatable from one dosing to another.
Other desirable features for an inhalation device are good product storageability, without significant loss of drug activity.
It would therefore be desirable to provide an aerosol inhalation device that provides these features in a simple, easily operated inhalation device.
Summary of the Invention The invention includes a device for delivering a drug by inhalation or by nasal administration, in an aerosol form composed of drug-particles having desired sizes, typically expressed as mass median aerodynamic diameter (MMAD) of the aerosol particles. The device includes a body defining an interior flow-through chamber having upstream and downstream chamber openings. A drug supply unit contained within the chamber is designed for producing, upon actuation, a heated drug vapor in a condensation region of the chamber adjacent the substrate and between the upstream and downstream chamber openings, such that gas drawn through the chamber region at a selected gas-flow rate is effective to condense drug vapor to form drug condensation particles having a selected MMAD particle size, for example, when used for deep-lung delivery, between 10-100 nm or between 1-3.5 pm. To this end, the device includes a gas-flow control valve disposed upstream of the drug-supply unit for limiting gas-flow rate through the condensation region to the selected gas-flow rate, for example, for limiting air flow through the chamber as air is drawn by the user's mouth into and through the chamber.
Also included is an actuation switch for actuating the drug-supply unit, such that the unit can be controlled to produce vapor when the gas-flow rate through the chamber is at the selected flow rate or within a selected flow-rate range.
The actuation switch may activate the drug-supply unit such that the unit is producing vapor when the selected air-flow rate is achieved; alternatively, the actuation switch may activate the drug-supply unit after the selected air-flow rate within the chamber is reached.
In one general embodiment, the gas-flow valve is designed to limit the rate of air flow through the chamber, as the user draws air through the chamber by mouth.
In a specific embodiment, the gas-flow valve includes an inlet port communicating with the chamber, and a deformable flap adapted to divert or restrict air flow away from the port increasingly, with increasing pressure drop across the valve. In another embodiment, the gas-flow valve includes the actuation switch, with valve movement in response to an air pressure differential across the valve acting to close the switch. In still another embodiment, the gas-flow valve includes an orifice designed to limit airflow rate into the chamber.
The device may also include a bypass valve communicating with the chamber downstream of the unit for offsetting the decrease in airflow produced by the gas-flow control valve, as the user draws air into the chamber.
The actuation switch may include a thermistor that is responsive to heat-dissipative effects of gas flow through the chamber. The device may further include a user-activated switch whose actuation is effective to heat the thermistor, prior to triggering of the drug-supply unit by the thermistor to initiate heating of the drug-supply unit.
The drug-supply unit may include a heat-conductive substrate having an outer surface, a film of drug formed on the substrate surface, and a heat source for heating the substrate to a temperature effective to vaporize said drug. The heat source, may be, for example, an electrical source for producing resistive heating of the substrate, or a chemical heat source for producing substrate heating by initiation of an exothermic reaction. Preferably, the drug delivery unit is effective to vaporize the film of drug, following actuation, within a period of less than 1 second, more preferably, within 0.5 seconds.
For producing condensation particles in the size range 1-3.5 ~,m MMAD, the chamber may have substantially smooth-surfaced walls, and the selected gas-flow rate may be in the range of 4-50 L/minute.
For producing condensation particles in the size range 20-100 nm MMAD, the chamber may provide gas-flow barriers for creating air turbulence within the condensation chamber. These barriers are typically placed within a few thousands of an inch from the substrate surface.
These and other objects and features of the invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying drawings.
Brief Descr~tion of the Drawings Fig. 1 is a simplified sectional view of an inhalation device constructed according to one embodiment of the invention;
Figs. 2A and 2B are plots of airflow rates through the device of the invention, showing airflow through primary and secondary flow regions, and the desired timing relationship between airflow level and vaporization of drug;
Fig. 3 is a perspective, partially exploded view of the device shown in Fig.
1;
Fig. 4A is a plot of aerosol condensation particle size (MMAD) as a function of airflow rate in the absence of internal turbulence for an airflow chamber having a cross-section area of 1 cm2, and at airflow rates between 5 and 30 liters/minute;
and Fig. 4B
shows the fraction of alveolar deposition of aerosol particles as a function of particle size;
Figs. SA-SF illustrate different types of gas-flow valves suitable for use in the device of the invention;
Figs. 6A-6C illustrate different types of actuation circuitry suitable for use in the device of the invention;
Figs. 7A-7E are photographic reproductions showing the development of aerosol particles in the device over a period of about 500 msec; and Figs. 8A-8C show alternative airflow control configurations in the device of the invention.
Detailed Description of the Invention Fig. 1 is a simplified cross-sectional view of an inhalation device 20 for delivering a drug by inhalation. The device includes a body 22 defining an interior flow-through chamber 24 having upstream and downstream chamber openings 26, 28, respectively. A
drug-supply unit 30 contained within the chamber is operable, upon actuation, to produce a heated drug vapor in a condensation region 32 of the chamber adjacent the substrate and between the upstream and downstream chamber openings. As will be detailed below, when gas is flowed across the surface of the drug-supply unit, with either laminar flow or with turbulence, at a selected velocity, the drug vapor condenses to form drug condensation particles having a selected NWAD particle size. As one of skill in the art would appreciate, the gas velocity through the chamber may be controlled by changing the volumetric gas-flow rate, cross-sectional area within the chamber, andlor the presence or absence of structures that produce turbulence within the chamber. For inhalation, two exemplary size ranges are between about 1 and 3.5 Eun, and within 0.02 and 0.1 pm.
The device includes a gas-flow control valve 34 disposed in or adjacent the upstream opening of the chamber for limiting gas-flow rate through the chamber's condensation region to a selected gas-flow rate. Typically, the gas flowed through the chamber is air drawn through the chamber by the user's mouth, that is, by the user drawing air through the upstream end of the device chamber. Various types of gas-flow valves suitable for use in the invention are described below with respect to Figs. SA-SF.
Also included in the device is an actuation switch, indicated generally at 36, for actuating the drug-supply unit. The switch allows the drug-supply unit to be controlled to produce vapor when the air-flow rate through the chamber's condensation region is at the selected flow rate. As will be seen, the switch is typically actuated by air flow through the chamber, such that as the user draws air through the chamber, vapor production is initiated when air flow through the condensation region reaches the selected air flow rate for producing desired-size condensation particles. Various types of activation switches suitable for use in the invention are described below with respect to Figs. 6A-6C.
In one general embodiment, the switch is constructed to activate the drug-supply unit prior to the gas-flow rate in the chamber reaching the selected rate. In this embodiment, the timing of actuation is such that the drug-supply unit begins its production of drug vapor at about the time or after the gas-flow through the chamber reaches its selected gas-flow flow rate. In another embodiment, the drug-supply unit is actuated when the gas-flow rate through the chamber reaches the selected flow rate. In yet another embodiment, the drug-supply unit is actuated at some selected time after the selected flow rate has been reached.
The condensation region in the device, where heated drug vapor is condensed to form desired-size aerosol particles, includes that portion of the chamber between the drug-supply unit and the interior wall of the chamber, and may include a portion of the chamber between the downstream end of the drug-supply unit and the downstream opening of the chamber. It is in this region where gas flow is controlled to a desired rate and thus velocity during aerosol formation.
As shown schematically in Fig. 1, drug-supply unit 30 in the device generally includes a heat-conductive substrate 38 having an outer surface 40, a film 42 of the drug to be administered formed on the substrate's outer surface, and a heat source 44 for heating the substrate to a temperature effective to vaporize the drug. In the embodiment illustrated, the substrate is a tapered cylindrical canister closed at its upstream end. A
preferred material for the substrate is stainless steel, which has been shown to be acceptable for drug stability.
The drug film includes the drug to be administered either in pure form, or mixed with suitable excipients. Exemplary drugs suitable for use include any drugs that can be vaporized at a temperature typically between 250°-560°C. The drug is preferably one that can be vaporized with little or no drug-degradation products. As has been reported in several co-owned applications, many classes of drugs can be successfully vaporized with little or no degradation, particularly where the drug coating has a selected film thickness between about 0.01 and 10 N.m. The amount of drug present is preferably sufficient to provide a therapeutic dose, although the device may also be used to Citrate a therapeutic dose by multiple dosing. The total area of the substrate on which the film is applied may be adjusted accordingly, so that the total amount of drug available for aerosol formation constitutes a therapeutic dose. Vaporization in typically less than 0.5 seconds is enabled by the thinness of the drug coating. Essentially, the thin nature of the drug coating exposes a large fraction of the heated compound to flowing air, resulting in almost the entire compound vaporizing and cooling in the air prior to thermal degradation. At film thicknesses used in the device, aerosol particles having less than 5%
degradation products are produced over a broad range of substrate peak temperatures.
The heat source for vaporizing the drug may be a resistive heating element, for example, the substrate itself, or resistive wires placed against the interior surface of the substrate. Alternatively, and as shown in Fig. 1, heat source 44 is a chemically reactive material which undergoes an exothermic reaction upon actuation, e.g., by a spark or heat element. In the particular embodiment shown, actuation is produced by a spark supplied to the upstream end of the chemical material, igniting an exothermic reaction that spreads in a downstream to upstream direction within the drug-supply unit, that is, in the direction opposite the flow of gas within the chamber during aerosol formation. An exemplary chemical material includes a mixture of Zr and Mo03, at a weight ratio of about 75%:25%. The mixture may contain binders, such as polyvinyl alcohol or nitrocellulose, and an initiator comprising additives such as boron and KC103, to control the reaction. In any case, and as mentioned above, the material should be formulated to produce complete heating over the substrate surface in a period of 2 sec or less, preferably in the range 10-500 msec.
An exemplary peak temperature of the surface of the drug-supply unit is 375°C.
The temperature can be modified by changes in the fuel formulation. Because high drug purities are obtained at temperatures higher than those needed for complete vaporization, there may be a large window within which emitted dose and aerosol purity are both high and consistent.
As noted above, actuation switch 36 in the device is designed for actuating the drug-supply unit in relation to airflow through the device chamber, such that the drug-supply unit produces drug vapor when the air flow rate through the chamber is sufficient for producing desired-size aerosol particles. In one general embodiment, described below with respect to Figs. 6A-6C, the switch is controlled by airflow through the chamber, such that the drug-supply unit is activated when (or just prior to, or after) the rate of airflow in the device reaches its desired rate. Alternatively, the switch may be user activated, allowing the user to initiate drug vapor formation as air is being drawn into the device. In the latter embodiment, the device may provide a signal, such as an audible tone, to the user, when the desired rate of airflow through the device is reached.
In the following discussion of gas-flow control through the device, it will be assumed that the gas being drawn through the device is air drawn in by the user's breath intake. However, it will be appreciated that the gas, or a portion therefore, might be supplied by a separate gas cartridge or source, such as a COZ or nitrogen gas source. An inert or non-oxidizing gas may be desirable, for example, in the vaporization of a drug that is labile to oxidative breakdown at elevated temperature, that is, during vaporization.
In this case, the "gas" breathed in by the user may be a combination of a pure gas supplied through the condensation region, and air drawn in by the user downstream of the condensation region, or may be just pure gas.
In the embodiment shown in Fig. 1, airflow between the upstream and downstream ends of the device is controlled by both gas-flow valve 34, which controls the flow of air into the upstream opening of the device, and hence through the condensation region of the chamber, and a bypass valve 46 located adjacent the downstream end of the device. The bypass valve cooperates with the gas-control valve to control the flow through the condensation region of the chamber as well as the total amount of air being drawn through the device.
In particular, and as seen in the air-flow plot in Fig. 2A, the total volumetric airflow through the device, indicated at I, is the sum of the volumetric airflow rate P
through valve 34, and the volumetric airflow rate B through the bypass valve.
Valve 34 acts to limit air drawn into the device to a preselected level P, e.g., 15 L/minute, corresponding to the selected air-flow rate for producing aerosol particles of a selected size. Once this selected airflow level is reached, additional air drawn into the device creates a pressure drop across valve 46 which then accommodates airflow through the valve into the downstream end of the device adjacent the user's mouth. Thus, the user senses a full breath being drawn in, with the two valves distributing the total airflow between desired airflow rate P and bypass airflow rate B.
Fig. 2A also indicates the timing of the heating for the drug-supply unit, wherein the time of heating is defined as the time during which sufficient heat is applies to the drug substance so as to cause rapid vaporization of the drug. As seen here, heating time, indicated by the hatched rectangle, is intended to occur within the period that the airflow P is at the desired airflow rate, for example, within the time period indicated at points a and b in the figure. It can be appreciated that if a user draws in more or less breath, the difference in airflow rate is accommodated by changes in B, with P remaining constant as long as I is greater than P.
Fig. 2B shows the same gas-distribution effect but plotted as a series of flow profiles over five different time periods during operation of the device. As seen here, the gas-flow rate through the condensation region in the device, indicated at P in the figure, remains relatively constant, while total gas-flow rate, indicated at I
increases over the first four time intervals, then decreases.
The linear velocity of airflow over the vaporizing drug affects the particle size of the aerosol particles produced by vapor condensation, with more rapid airflow diluting the vapor such that it condenses into smaller particles. In other words the particle size distribution of the aerosol is determined by the concentration of the compound vapor during condensation. This vapor concentration is, in turn, determined by the extent to which airflow over the surface of the heating substrate dilutes the evolved vapor. As shown in Figure 4A below, the particle size (MMAD) remains well within an acceptable range (1-3.5 microns) at airflow rates from 7 L/min to 28 L/min through the drug product.
To achieve smaller or larger particles, the gas velocity through the condensation region of the chamber may be altered by (i) modifying the gas-flow control valve to increase or decrease P, and/or (ii) modifying the cross-section of the chamber condensation region to increase or decrease linear gas velocity for a given volumetric flow rate.
Fig. 4B shows the fraction of alveolar deposition of aerosol particles as a function of particle size. As seen, maximum deposition into the lungs occurs in either of two size ranges: 1-3.5 pin or 20-100 nm. Therefore, where the device is employed for drug delivery by inhalation, the selected gas-flow rate in the device of a given geometry is such as to achieve aerosol particles sizes in one of these two size ranges. One skilled in the art will appreciate how changes in gas-flow velocity, to effect desired particle sizes, can be achieved by manipulating volumetric gas-flow rate, valve design and characteristics, cross-sectional area of the condensation region of the device, and, particularly where small particles are desired, placement of barriers within the chamber capable of producing turbulence that increases the dilution effect of gas flowing through the heated drug vapor.
Fig. 3 is an exploded view of device 20 illustrated in Fig. 1. Here the body of the device, indicated at 22, is formed of two molded plastic members 48, 50 which are sealed together conventionally. Bypass valves 46 are designed to be placed on either side of a downstream end region 52 of the device, when the two body members are sealed together.
Member 48 includes an air inlet 56 through which air is drawn into the device chamber adjacent the upstream end of the device 54.
The drug-supply unit, air-intake valve, and actuation switch in the device are all incorporated into a single assembly 58. The parts of the assembly that are visible are the coated substrate 38, gas control valve 34, battery housing 36 and a pull tab (user-activated switch) 60 which extends through an opening at the upstream end of the device body in the assembled device. An, outer flange 62 in the assembly is designed to fit in a groove 64 formed on the inner wall of each member, partitioning the chamber into upstream and downstream chamber sections 66, 68, respectively. The flange has openings, such as opening 70, formed on its opposite sides as shown, with each opening being gated by a gas-flow valve, such as valve 34, for regulating the rate of airflow across the valves.
Thus, when air is drawn into the device by the user, with the user's mouth on the upstream device end, air is drawn into the device through intake 56 and into section 66. Valve 34 then regulates airflow between the two chamber sections, as will be described below with reference to Figs. SA-SF, to limit airflow across the drug-supply device to the desired airflow rate P.
Turning to various gas-flow valve embodiments suitable for the invention, Fig.
SA
shows an umbrella valve 70. This valve is a low-durometer rubber member 71 that flexes out of the way to allow air to enter when the difference in pressure inside and outside of the airway (between the upstream and downstream chamber sections). This valve thus functions to "open" in response to an air pressure differential across the valve, and is constructed so that the valve limits airflow to the desired airflow rate in the device.
Fig. SB illustrates a reed valve 72 that includes two low-durometer rubber pieces 74 that are held together by a biasing member 76 (such as a spring). When the air-pressure across the two chamber sections reaches a selected differential, the two rubber pieces pull apart to create an opening for air to flow into the airway. Like valve 70, this valve thus functions to "open" in response to an air pressure differential across the valve, and is constructed so that the valve limits airflow to the desired airflow rate in the device.
Figs. SC and SD illustrate. a valve 80 that bends in response to a pressure differential across the chamber sections to let air into the airway.
Specifically, Fig. SC
illustrates this valve in an extended closed position that does not allow any air into the airway. One end portion of the valve is rigidly attached to a side of a valve opening 84, with the opposite side of the valve terminating against the side of an air-inlet opening 85.
When the difference in pressure between the inside and outside of the airway passes a threshold level, the valve 80 bends at its center, and rotates into the airway about the portion that stays rigidly attached to the airway, as shown in Fig. SD, creating the airway to create an orifice for air to flow through the valve opening.
In construction, the lower flexing layers at 86 are formed of flexible polymer plate material, while the upper short layers at 88 are formed of an inflexible polymer material.
Also as shown, the valve may include electrical contacts, such as contact 90, that are brought into a closed circuit configuration when the valve is moved to its open, deformed condition. Like the two valves above, valve 80 functions to "open" in response to an air pressure differential across the valve, and is constructed so that in the open condition, the valve limits airflow to the desired airflow rate in the device.
The electrical switch in the valve may serve as a switching member of the actuation switch, so that opening of the valve also acts to actuate the drug-supply unit.
The present invention contemplates a gas-control valve that includes an electrical switch that is moved from an open to closed condition, when the valve is moved to a condition that admits airflow at the selected desired rate.
Figs. SE and SF illustrate a valve 92 that moves from an open toward a partially closed condition as air is drawn into the device. The valve includes a curved screened opening 94 having a generally circular-arc cross section. A deformable valve flap 96 attached as shown at the top of the valve is designed to move toward opening 94 as the pressure differential across the valve increases, effectively closing a portion of the valve opening as the air differential increases. The deformability of the flap, in response to an air pressure differential across the valve, is such as to maintain the desired air flow rate P
through the valve substantially independent of the pressure differential across the valve.
The valve differs from those described above in that the valve is initially in an open condition, and moves progressively toward a closed condition as the pressure differential across the valve increases.
It will be appreciated that the bypass valve in the device may have the same general construction as one of the valves noted above, particular those valves that are designed to open when a pressure differential is applied across the valve. The gas-control and bypass valves are designed so that initial pressure differential across the valves, when the user begins drawing air into the device, is effective to first establish the desired flow rate P through the condensation region in the device. Once this flow rate is established, additional flow rate B applied by the user is effective to "open" the bypass valve to allow bypass airflow into the device. Since air is being drawn through the device along both airflow paths, the user is unaware of the bifurcation of airflow that occurs.
Exemplary actuation switches and associated circuitry suitable for use in the invention are illustrated in Figs. 6A-6C. Fig. 6A illustrates a circuit 100 having a trigger switch 98 that is connected between a voltage source 99 and microcontroller 102. The trigger switch may be a valve-actuated switch, as above, or a user activated switch that is activated during air intake. When the trigger switch opens, the microcontroller no longer receives the voltage from the voltage source. Accordingly, the microcontroller senses the trigger event, and starts to measure (e.g., starts a timer) the time that the trigger event lasts. If this trigger event lasts at least the threshold time period t~,, the microcontroller closes a second switch 104 for a pulsing time interval tp. This closing causes current flow from the voltage source to a resistor 106 that is effective to either heat the drug-substrate by resistive heating or to heat-initiate an exothermic reaction in the drug-supply unit, shown at 108.
Fig. 6B illustrates another circuit 110 that can be used for actuating the drug-supply unit, in accordance with the invention. This circuit is similar to circuit 100, except that it operates to pass a charge from a capacitor 112 to substrate 108. The capacitor is typically charged by voltage source 99. The microcontroller 102 closes the normally open switch 113 when it detects that switch 98 has remained open for a threshold time period. The closing of switch 113 transfers the charge from capacitor 112 to ground through the substrate. The transferred charge is used either to heat the substrate resistively, or to initiate an exothermic reaction in the drug-supply unit as above.
Another exemplary actuation switch is illustrated at 114 in Fig. 6C. This switch has a user-activated component which readies the switch for use shortly before use, e.g., an air-flow responsive component that activates the drug-supply unit when the desired air-flow rate is achieved. The user-activated component is a pull-tab switch 116 that is activated when the user pulls a tab (tab 60 in the device illustrated in Fig.
Field of the Invention The present invention relates to an inhalation device for producing desired-size drug-aerosol particles for inhalation.
Background of the Invention Therapeutic compounds may be administered by a variety of routes, depending on the nature of the drug, the pharmacokinetic profile desired, patient convenience, and cost, among other factors. Among the most common routes of drug delivery are oral, intravenous (IV), intramuscular (IM) intraperitoneal (IP) subcutaneous, transdermal, transmucosal, and by inhalation to the patient's respiratory tract.
The inhalation route of drug administration offers several advantages for certain drugs, and in treating certain conditions. Since the drug administered passes quickly from the respiratory tract to the bloodstream, the drug may be active within a few minutes of delivery. This rapid drug effect is clearly advantageous for conditions like asthma, anaphylaxis, pain, and so forth where immediate relief is desired.
Further, the drug is more efficiently utilized by the patient, since the drug is taken up into the bloodstream without a first pass through the liver as is the case for oral drug delivery. Accordingly, the therapeutic dose of a drug administered by inhalation can be substantially less, e.g., one half that required for oral dosing.
Finally, since inhalation delivery is convenient, patient compliance can be expected to be high.
As is known, efficient aerosol delivery to the lungs requires that the particles have certain penetration and settling or diffusional characteristics. For larger particles, deposition in the deep lungs occurs by gravitational settling and requires particles to have an effective settling size, defined as mass median aerodynamic diameter (n~llVIAD), of between 1-3.5 ~.m. For smaller particles, deposition to the deep lung occurs by a diffusional process that requires having a particle size in the 10-100 nm, typically 20-100 nm range. Particle sizes that fall in the range between 10-100 nm and 1-3.5 N.m tend to have poor penetration and poor deposition. Therefore, an inhalation drug-delivery device for deep lung delivery should produce an aerosol having particles in one of these two size ranges.
Another important feature of an aerosol delivery device is control over total dose delivered, that is, the amount of aerosol generated should be predictable and repeatable from one dosing to another.
Other desirable features for an inhalation device are good product storageability, without significant loss of drug activity.
It would therefore be desirable to provide an aerosol inhalation device that provides these features in a simple, easily operated inhalation device.
Summary of the Invention The invention includes a device for delivering a drug by inhalation or by nasal administration, in an aerosol form composed of drug-particles having desired sizes, typically expressed as mass median aerodynamic diameter (MMAD) of the aerosol particles. The device includes a body defining an interior flow-through chamber having upstream and downstream chamber openings. A drug supply unit contained within the chamber is designed for producing, upon actuation, a heated drug vapor in a condensation region of the chamber adjacent the substrate and between the upstream and downstream chamber openings, such that gas drawn through the chamber region at a selected gas-flow rate is effective to condense drug vapor to form drug condensation particles having a selected MMAD particle size, for example, when used for deep-lung delivery, between 10-100 nm or between 1-3.5 pm. To this end, the device includes a gas-flow control valve disposed upstream of the drug-supply unit for limiting gas-flow rate through the condensation region to the selected gas-flow rate, for example, for limiting air flow through the chamber as air is drawn by the user's mouth into and through the chamber.
Also included is an actuation switch for actuating the drug-supply unit, such that the unit can be controlled to produce vapor when the gas-flow rate through the chamber is at the selected flow rate or within a selected flow-rate range.
The actuation switch may activate the drug-supply unit such that the unit is producing vapor when the selected air-flow rate is achieved; alternatively, the actuation switch may activate the drug-supply unit after the selected air-flow rate within the chamber is reached.
In one general embodiment, the gas-flow valve is designed to limit the rate of air flow through the chamber, as the user draws air through the chamber by mouth.
In a specific embodiment, the gas-flow valve includes an inlet port communicating with the chamber, and a deformable flap adapted to divert or restrict air flow away from the port increasingly, with increasing pressure drop across the valve. In another embodiment, the gas-flow valve includes the actuation switch, with valve movement in response to an air pressure differential across the valve acting to close the switch. In still another embodiment, the gas-flow valve includes an orifice designed to limit airflow rate into the chamber.
The device may also include a bypass valve communicating with the chamber downstream of the unit for offsetting the decrease in airflow produced by the gas-flow control valve, as the user draws air into the chamber.
The actuation switch may include a thermistor that is responsive to heat-dissipative effects of gas flow through the chamber. The device may further include a user-activated switch whose actuation is effective to heat the thermistor, prior to triggering of the drug-supply unit by the thermistor to initiate heating of the drug-supply unit.
The drug-supply unit may include a heat-conductive substrate having an outer surface, a film of drug formed on the substrate surface, and a heat source for heating the substrate to a temperature effective to vaporize said drug. The heat source, may be, for example, an electrical source for producing resistive heating of the substrate, or a chemical heat source for producing substrate heating by initiation of an exothermic reaction. Preferably, the drug delivery unit is effective to vaporize the film of drug, following actuation, within a period of less than 1 second, more preferably, within 0.5 seconds.
For producing condensation particles in the size range 1-3.5 ~,m MMAD, the chamber may have substantially smooth-surfaced walls, and the selected gas-flow rate may be in the range of 4-50 L/minute.
For producing condensation particles in the size range 20-100 nm MMAD, the chamber may provide gas-flow barriers for creating air turbulence within the condensation chamber. These barriers are typically placed within a few thousands of an inch from the substrate surface.
These and other objects and features of the invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying drawings.
Brief Descr~tion of the Drawings Fig. 1 is a simplified sectional view of an inhalation device constructed according to one embodiment of the invention;
Figs. 2A and 2B are plots of airflow rates through the device of the invention, showing airflow through primary and secondary flow regions, and the desired timing relationship between airflow level and vaporization of drug;
Fig. 3 is a perspective, partially exploded view of the device shown in Fig.
1;
Fig. 4A is a plot of aerosol condensation particle size (MMAD) as a function of airflow rate in the absence of internal turbulence for an airflow chamber having a cross-section area of 1 cm2, and at airflow rates between 5 and 30 liters/minute;
and Fig. 4B
shows the fraction of alveolar deposition of aerosol particles as a function of particle size;
Figs. SA-SF illustrate different types of gas-flow valves suitable for use in the device of the invention;
Figs. 6A-6C illustrate different types of actuation circuitry suitable for use in the device of the invention;
Figs. 7A-7E are photographic reproductions showing the development of aerosol particles in the device over a period of about 500 msec; and Figs. 8A-8C show alternative airflow control configurations in the device of the invention.
Detailed Description of the Invention Fig. 1 is a simplified cross-sectional view of an inhalation device 20 for delivering a drug by inhalation. The device includes a body 22 defining an interior flow-through chamber 24 having upstream and downstream chamber openings 26, 28, respectively. A
drug-supply unit 30 contained within the chamber is operable, upon actuation, to produce a heated drug vapor in a condensation region 32 of the chamber adjacent the substrate and between the upstream and downstream chamber openings. As will be detailed below, when gas is flowed across the surface of the drug-supply unit, with either laminar flow or with turbulence, at a selected velocity, the drug vapor condenses to form drug condensation particles having a selected NWAD particle size. As one of skill in the art would appreciate, the gas velocity through the chamber may be controlled by changing the volumetric gas-flow rate, cross-sectional area within the chamber, andlor the presence or absence of structures that produce turbulence within the chamber. For inhalation, two exemplary size ranges are between about 1 and 3.5 Eun, and within 0.02 and 0.1 pm.
The device includes a gas-flow control valve 34 disposed in or adjacent the upstream opening of the chamber for limiting gas-flow rate through the chamber's condensation region to a selected gas-flow rate. Typically, the gas flowed through the chamber is air drawn through the chamber by the user's mouth, that is, by the user drawing air through the upstream end of the device chamber. Various types of gas-flow valves suitable for use in the invention are described below with respect to Figs. SA-SF.
Also included in the device is an actuation switch, indicated generally at 36, for actuating the drug-supply unit. The switch allows the drug-supply unit to be controlled to produce vapor when the air-flow rate through the chamber's condensation region is at the selected flow rate. As will be seen, the switch is typically actuated by air flow through the chamber, such that as the user draws air through the chamber, vapor production is initiated when air flow through the condensation region reaches the selected air flow rate for producing desired-size condensation particles. Various types of activation switches suitable for use in the invention are described below with respect to Figs. 6A-6C.
In one general embodiment, the switch is constructed to activate the drug-supply unit prior to the gas-flow rate in the chamber reaching the selected rate. In this embodiment, the timing of actuation is such that the drug-supply unit begins its production of drug vapor at about the time or after the gas-flow through the chamber reaches its selected gas-flow flow rate. In another embodiment, the drug-supply unit is actuated when the gas-flow rate through the chamber reaches the selected flow rate. In yet another embodiment, the drug-supply unit is actuated at some selected time after the selected flow rate has been reached.
The condensation region in the device, where heated drug vapor is condensed to form desired-size aerosol particles, includes that portion of the chamber between the drug-supply unit and the interior wall of the chamber, and may include a portion of the chamber between the downstream end of the drug-supply unit and the downstream opening of the chamber. It is in this region where gas flow is controlled to a desired rate and thus velocity during aerosol formation.
As shown schematically in Fig. 1, drug-supply unit 30 in the device generally includes a heat-conductive substrate 38 having an outer surface 40, a film 42 of the drug to be administered formed on the substrate's outer surface, and a heat source 44 for heating the substrate to a temperature effective to vaporize the drug. In the embodiment illustrated, the substrate is a tapered cylindrical canister closed at its upstream end. A
preferred material for the substrate is stainless steel, which has been shown to be acceptable for drug stability.
The drug film includes the drug to be administered either in pure form, or mixed with suitable excipients. Exemplary drugs suitable for use include any drugs that can be vaporized at a temperature typically between 250°-560°C. The drug is preferably one that can be vaporized with little or no drug-degradation products. As has been reported in several co-owned applications, many classes of drugs can be successfully vaporized with little or no degradation, particularly where the drug coating has a selected film thickness between about 0.01 and 10 N.m. The amount of drug present is preferably sufficient to provide a therapeutic dose, although the device may also be used to Citrate a therapeutic dose by multiple dosing. The total area of the substrate on which the film is applied may be adjusted accordingly, so that the total amount of drug available for aerosol formation constitutes a therapeutic dose. Vaporization in typically less than 0.5 seconds is enabled by the thinness of the drug coating. Essentially, the thin nature of the drug coating exposes a large fraction of the heated compound to flowing air, resulting in almost the entire compound vaporizing and cooling in the air prior to thermal degradation. At film thicknesses used in the device, aerosol particles having less than 5%
degradation products are produced over a broad range of substrate peak temperatures.
The heat source for vaporizing the drug may be a resistive heating element, for example, the substrate itself, or resistive wires placed against the interior surface of the substrate. Alternatively, and as shown in Fig. 1, heat source 44 is a chemically reactive material which undergoes an exothermic reaction upon actuation, e.g., by a spark or heat element. In the particular embodiment shown, actuation is produced by a spark supplied to the upstream end of the chemical material, igniting an exothermic reaction that spreads in a downstream to upstream direction within the drug-supply unit, that is, in the direction opposite the flow of gas within the chamber during aerosol formation. An exemplary chemical material includes a mixture of Zr and Mo03, at a weight ratio of about 75%:25%. The mixture may contain binders, such as polyvinyl alcohol or nitrocellulose, and an initiator comprising additives such as boron and KC103, to control the reaction. In any case, and as mentioned above, the material should be formulated to produce complete heating over the substrate surface in a period of 2 sec or less, preferably in the range 10-500 msec.
An exemplary peak temperature of the surface of the drug-supply unit is 375°C.
The temperature can be modified by changes in the fuel formulation. Because high drug purities are obtained at temperatures higher than those needed for complete vaporization, there may be a large window within which emitted dose and aerosol purity are both high and consistent.
As noted above, actuation switch 36 in the device is designed for actuating the drug-supply unit in relation to airflow through the device chamber, such that the drug-supply unit produces drug vapor when the air flow rate through the chamber is sufficient for producing desired-size aerosol particles. In one general embodiment, described below with respect to Figs. 6A-6C, the switch is controlled by airflow through the chamber, such that the drug-supply unit is activated when (or just prior to, or after) the rate of airflow in the device reaches its desired rate. Alternatively, the switch may be user activated, allowing the user to initiate drug vapor formation as air is being drawn into the device. In the latter embodiment, the device may provide a signal, such as an audible tone, to the user, when the desired rate of airflow through the device is reached.
In the following discussion of gas-flow control through the device, it will be assumed that the gas being drawn through the device is air drawn in by the user's breath intake. However, it will be appreciated that the gas, or a portion therefore, might be supplied by a separate gas cartridge or source, such as a COZ or nitrogen gas source. An inert or non-oxidizing gas may be desirable, for example, in the vaporization of a drug that is labile to oxidative breakdown at elevated temperature, that is, during vaporization.
In this case, the "gas" breathed in by the user may be a combination of a pure gas supplied through the condensation region, and air drawn in by the user downstream of the condensation region, or may be just pure gas.
In the embodiment shown in Fig. 1, airflow between the upstream and downstream ends of the device is controlled by both gas-flow valve 34, which controls the flow of air into the upstream opening of the device, and hence through the condensation region of the chamber, and a bypass valve 46 located adjacent the downstream end of the device. The bypass valve cooperates with the gas-control valve to control the flow through the condensation region of the chamber as well as the total amount of air being drawn through the device.
In particular, and as seen in the air-flow plot in Fig. 2A, the total volumetric airflow through the device, indicated at I, is the sum of the volumetric airflow rate P
through valve 34, and the volumetric airflow rate B through the bypass valve.
Valve 34 acts to limit air drawn into the device to a preselected level P, e.g., 15 L/minute, corresponding to the selected air-flow rate for producing aerosol particles of a selected size. Once this selected airflow level is reached, additional air drawn into the device creates a pressure drop across valve 46 which then accommodates airflow through the valve into the downstream end of the device adjacent the user's mouth. Thus, the user senses a full breath being drawn in, with the two valves distributing the total airflow between desired airflow rate P and bypass airflow rate B.
Fig. 2A also indicates the timing of the heating for the drug-supply unit, wherein the time of heating is defined as the time during which sufficient heat is applies to the drug substance so as to cause rapid vaporization of the drug. As seen here, heating time, indicated by the hatched rectangle, is intended to occur within the period that the airflow P is at the desired airflow rate, for example, within the time period indicated at points a and b in the figure. It can be appreciated that if a user draws in more or less breath, the difference in airflow rate is accommodated by changes in B, with P remaining constant as long as I is greater than P.
Fig. 2B shows the same gas-distribution effect but plotted as a series of flow profiles over five different time periods during operation of the device. As seen here, the gas-flow rate through the condensation region in the device, indicated at P in the figure, remains relatively constant, while total gas-flow rate, indicated at I
increases over the first four time intervals, then decreases.
The linear velocity of airflow over the vaporizing drug affects the particle size of the aerosol particles produced by vapor condensation, with more rapid airflow diluting the vapor such that it condenses into smaller particles. In other words the particle size distribution of the aerosol is determined by the concentration of the compound vapor during condensation. This vapor concentration is, in turn, determined by the extent to which airflow over the surface of the heating substrate dilutes the evolved vapor. As shown in Figure 4A below, the particle size (MMAD) remains well within an acceptable range (1-3.5 microns) at airflow rates from 7 L/min to 28 L/min through the drug product.
To achieve smaller or larger particles, the gas velocity through the condensation region of the chamber may be altered by (i) modifying the gas-flow control valve to increase or decrease P, and/or (ii) modifying the cross-section of the chamber condensation region to increase or decrease linear gas velocity for a given volumetric flow rate.
Fig. 4B shows the fraction of alveolar deposition of aerosol particles as a function of particle size. As seen, maximum deposition into the lungs occurs in either of two size ranges: 1-3.5 pin or 20-100 nm. Therefore, where the device is employed for drug delivery by inhalation, the selected gas-flow rate in the device of a given geometry is such as to achieve aerosol particles sizes in one of these two size ranges. One skilled in the art will appreciate how changes in gas-flow velocity, to effect desired particle sizes, can be achieved by manipulating volumetric gas-flow rate, valve design and characteristics, cross-sectional area of the condensation region of the device, and, particularly where small particles are desired, placement of barriers within the chamber capable of producing turbulence that increases the dilution effect of gas flowing through the heated drug vapor.
Fig. 3 is an exploded view of device 20 illustrated in Fig. 1. Here the body of the device, indicated at 22, is formed of two molded plastic members 48, 50 which are sealed together conventionally. Bypass valves 46 are designed to be placed on either side of a downstream end region 52 of the device, when the two body members are sealed together.
Member 48 includes an air inlet 56 through which air is drawn into the device chamber adjacent the upstream end of the device 54.
The drug-supply unit, air-intake valve, and actuation switch in the device are all incorporated into a single assembly 58. The parts of the assembly that are visible are the coated substrate 38, gas control valve 34, battery housing 36 and a pull tab (user-activated switch) 60 which extends through an opening at the upstream end of the device body in the assembled device. An, outer flange 62 in the assembly is designed to fit in a groove 64 formed on the inner wall of each member, partitioning the chamber into upstream and downstream chamber sections 66, 68, respectively. The flange has openings, such as opening 70, formed on its opposite sides as shown, with each opening being gated by a gas-flow valve, such as valve 34, for regulating the rate of airflow across the valves.
Thus, when air is drawn into the device by the user, with the user's mouth on the upstream device end, air is drawn into the device through intake 56 and into section 66. Valve 34 then regulates airflow between the two chamber sections, as will be described below with reference to Figs. SA-SF, to limit airflow across the drug-supply device to the desired airflow rate P.
Turning to various gas-flow valve embodiments suitable for the invention, Fig.
SA
shows an umbrella valve 70. This valve is a low-durometer rubber member 71 that flexes out of the way to allow air to enter when the difference in pressure inside and outside of the airway (between the upstream and downstream chamber sections). This valve thus functions to "open" in response to an air pressure differential across the valve, and is constructed so that the valve limits airflow to the desired airflow rate in the device.
Fig. SB illustrates a reed valve 72 that includes two low-durometer rubber pieces 74 that are held together by a biasing member 76 (such as a spring). When the air-pressure across the two chamber sections reaches a selected differential, the two rubber pieces pull apart to create an opening for air to flow into the airway. Like valve 70, this valve thus functions to "open" in response to an air pressure differential across the valve, and is constructed so that the valve limits airflow to the desired airflow rate in the device.
Figs. SC and SD illustrate. a valve 80 that bends in response to a pressure differential across the chamber sections to let air into the airway.
Specifically, Fig. SC
illustrates this valve in an extended closed position that does not allow any air into the airway. One end portion of the valve is rigidly attached to a side of a valve opening 84, with the opposite side of the valve terminating against the side of an air-inlet opening 85.
When the difference in pressure between the inside and outside of the airway passes a threshold level, the valve 80 bends at its center, and rotates into the airway about the portion that stays rigidly attached to the airway, as shown in Fig. SD, creating the airway to create an orifice for air to flow through the valve opening.
In construction, the lower flexing layers at 86 are formed of flexible polymer plate material, while the upper short layers at 88 are formed of an inflexible polymer material.
Also as shown, the valve may include electrical contacts, such as contact 90, that are brought into a closed circuit configuration when the valve is moved to its open, deformed condition. Like the two valves above, valve 80 functions to "open" in response to an air pressure differential across the valve, and is constructed so that in the open condition, the valve limits airflow to the desired airflow rate in the device.
The electrical switch in the valve may serve as a switching member of the actuation switch, so that opening of the valve also acts to actuate the drug-supply unit.
The present invention contemplates a gas-control valve that includes an electrical switch that is moved from an open to closed condition, when the valve is moved to a condition that admits airflow at the selected desired rate.
Figs. SE and SF illustrate a valve 92 that moves from an open toward a partially closed condition as air is drawn into the device. The valve includes a curved screened opening 94 having a generally circular-arc cross section. A deformable valve flap 96 attached as shown at the top of the valve is designed to move toward opening 94 as the pressure differential across the valve increases, effectively closing a portion of the valve opening as the air differential increases. The deformability of the flap, in response to an air pressure differential across the valve, is such as to maintain the desired air flow rate P
through the valve substantially independent of the pressure differential across the valve.
The valve differs from those described above in that the valve is initially in an open condition, and moves progressively toward a closed condition as the pressure differential across the valve increases.
It will be appreciated that the bypass valve in the device may have the same general construction as one of the valves noted above, particular those valves that are designed to open when a pressure differential is applied across the valve. The gas-control and bypass valves are designed so that initial pressure differential across the valves, when the user begins drawing air into the device, is effective to first establish the desired flow rate P through the condensation region in the device. Once this flow rate is established, additional flow rate B applied by the user is effective to "open" the bypass valve to allow bypass airflow into the device. Since air is being drawn through the device along both airflow paths, the user is unaware of the bifurcation of airflow that occurs.
Exemplary actuation switches and associated circuitry suitable for use in the invention are illustrated in Figs. 6A-6C. Fig. 6A illustrates a circuit 100 having a trigger switch 98 that is connected between a voltage source 99 and microcontroller 102. The trigger switch may be a valve-actuated switch, as above, or a user activated switch that is activated during air intake. When the trigger switch opens, the microcontroller no longer receives the voltage from the voltage source. Accordingly, the microcontroller senses the trigger event, and starts to measure (e.g., starts a timer) the time that the trigger event lasts. If this trigger event lasts at least the threshold time period t~,, the microcontroller closes a second switch 104 for a pulsing time interval tp. This closing causes current flow from the voltage source to a resistor 106 that is effective to either heat the drug-substrate by resistive heating or to heat-initiate an exothermic reaction in the drug-supply unit, shown at 108.
Fig. 6B illustrates another circuit 110 that can be used for actuating the drug-supply unit, in accordance with the invention. This circuit is similar to circuit 100, except that it operates to pass a charge from a capacitor 112 to substrate 108. The capacitor is typically charged by voltage source 99. The microcontroller 102 closes the normally open switch 113 when it detects that switch 98 has remained open for a threshold time period. The closing of switch 113 transfers the charge from capacitor 112 to ground through the substrate. The transferred charge is used either to heat the substrate resistively, or to initiate an exothermic reaction in the drug-supply unit as above.
Another exemplary actuation switch is illustrated at 114 in Fig. 6C. This switch has a user-activated component which readies the switch for use shortly before use, e.g., an air-flow responsive component that activates the drug-supply unit when the desired air-flow rate is achieved. The user-activated component is a pull-tab switch 116 that is activated when the user pulls a tab (tab 60 in the device illustrated in Fig.
3). When switch 116 is closed, voltage source 118 is connected to a thermistor 122 which is then heated to a temperature above ambient. The thermistor is connected to a voltage comparator 120, such as a Seiko S-8143 comparator available from Seiko. The comparator functions to measure the thermistor voltage output at a time shortly after the user switch is activated. When a user then begins to draw air across the thermistor, the airflow cause the thermistor to cool, generating a different voltage output (by the thermistor). When the difference in these voltages reaches a predetermined threshold, the comparator signals a solid-state switch 124 to close, producing current flow to drug-supply unit 108 from voltage source 118, and activation of the unit. The heating of the thermistor and comparator threshold are adjusted such that switch 124 is closed when the air flow rate through the device reaches a desired airflow rate.
The series of photographic reproductions in Figs. 7A-7D illustrate the time sequence of production of drug condensate during operation of the device of the invention. At time 0 (Fig. 7A) when the drug-supply unit is first actuated, air flow is established across the surface of the substrate, but no vapor has yet been formed. At 50 msec (Fig. 7B), some condensate formation can be observed downstream of the substrate.
The amount of condensate being formed increases up to about 200 msec, but is still being formed at 500 msec, although the majority of condensate has been formed in the first 500 msec.
Figs. 8A-8C illustrate alternative device embodiments for distributing airflow through the device during operation. In Fig. 8A, a device 126 includes an upstream opening 130 containing an airflow sensor 132, such as the thermistor described above, which is responsive to airflow through the opening. Air flow drawn into a central chamber 134 by the user through opening 130 is valued, to achieve a selected flow rate, by gas-flow control valves) 138. Excess airflow is diverted to the downstream end region of the chamber via a bypass channel 136 extending between the upstream and downstream ends of the device, and communicating with central chamber 134 through a valve 127. The orifice is so dimensioned that drawing air into the device creates an initial pressure differential across valve 138, so that airflow through the central chamber reaches the desired airflow rate, with excess air being diverted through the bypass orifice.
A device 142 shown in Fig. 8B has a similar airflow configuration, but differs from device 126 in having only a single valve 143 which functions to admit air into a central chamber 144 until a desired airflow rate is achieved, then divert excess air into a bypass channel 145 that communicates with the downstream end of the central chamber through an orifice as shown.
In the embodiment shown in Fig. 8C, and indicated at 146, air is drawn into the upstream end of the central chamber 148 through an upstream orifice 149, and is drawn into the downstream end of the chamber through a bypass orifice 150. The two orifices are dimensioned so that air drawn into the device by the user distributes at a predetermined ratio, corresponding roughly to the desired ratio of PB (see Fig. 2A) for a normal breath intake.
It will be appreciated from the above that the gas-control valve in the device, and/or the bypass valve may include a valve that has an active gas-control element, or may be an orifice dimensioned to admit gas at a desired gas-flow rate, under conditions of.
selected gas pressure differential.
From the forgoing, it can be appreciated how various objects and features of the invention have been met. For use in drug inhalation, the device reproducibly produces particles having selected MMAD sizes either in the 1-3.5 pm range, or in the 10-100nm range, achieved by controlling air flow rates through the device and the timing of airflow with respect to vapor production. Because of the rapid vapor production, and where necessary, because of the drug film thickness, the condensation particles are substantially pure, i.e., free of degradation products. The device is simple to operate, requiring little or no practice by the user to achieve desired aerosol delivery, and relatively simple in construction and operation.
Although the invention has been described with reference to particular embodiments, it will be appreciated that various changes and modifications may be made without departing from the invention.
The series of photographic reproductions in Figs. 7A-7D illustrate the time sequence of production of drug condensate during operation of the device of the invention. At time 0 (Fig. 7A) when the drug-supply unit is first actuated, air flow is established across the surface of the substrate, but no vapor has yet been formed. At 50 msec (Fig. 7B), some condensate formation can be observed downstream of the substrate.
The amount of condensate being formed increases up to about 200 msec, but is still being formed at 500 msec, although the majority of condensate has been formed in the first 500 msec.
Figs. 8A-8C illustrate alternative device embodiments for distributing airflow through the device during operation. In Fig. 8A, a device 126 includes an upstream opening 130 containing an airflow sensor 132, such as the thermistor described above, which is responsive to airflow through the opening. Air flow drawn into a central chamber 134 by the user through opening 130 is valued, to achieve a selected flow rate, by gas-flow control valves) 138. Excess airflow is diverted to the downstream end region of the chamber via a bypass channel 136 extending between the upstream and downstream ends of the device, and communicating with central chamber 134 through a valve 127. The orifice is so dimensioned that drawing air into the device creates an initial pressure differential across valve 138, so that airflow through the central chamber reaches the desired airflow rate, with excess air being diverted through the bypass orifice.
A device 142 shown in Fig. 8B has a similar airflow configuration, but differs from device 126 in having only a single valve 143 which functions to admit air into a central chamber 144 until a desired airflow rate is achieved, then divert excess air into a bypass channel 145 that communicates with the downstream end of the central chamber through an orifice as shown.
In the embodiment shown in Fig. 8C, and indicated at 146, air is drawn into the upstream end of the central chamber 148 through an upstream orifice 149, and is drawn into the downstream end of the chamber through a bypass orifice 150. The two orifices are dimensioned so that air drawn into the device by the user distributes at a predetermined ratio, corresponding roughly to the desired ratio of PB (see Fig. 2A) for a normal breath intake.
It will be appreciated from the above that the gas-control valve in the device, and/or the bypass valve may include a valve that has an active gas-control element, or may be an orifice dimensioned to admit gas at a desired gas-flow rate, under conditions of.
selected gas pressure differential.
From the forgoing, it can be appreciated how various objects and features of the invention have been met. For use in drug inhalation, the device reproducibly produces particles having selected MMAD sizes either in the 1-3.5 pm range, or in the 10-100nm range, achieved by controlling air flow rates through the device and the timing of airflow with respect to vapor production. Because of the rapid vapor production, and where necessary, because of the drug film thickness, the condensation particles are substantially pure, i.e., free of degradation products. The device is simple to operate, requiring little or no practice by the user to achieve desired aerosol delivery, and relatively simple in construction and operation.
Although the invention has been described with reference to particular embodiments, it will be appreciated that various changes and modifications may be made without departing from the invention.
Claims (15)
1. A device for delivering a drug by inhalation or nasally, comprising a) a body defining an interior flow-through chamber having upstream and downstream chamber openings, b) a drug supply unit contained within said chamber for producing, upon actuation, a heated drug vapor in a condensation region of the chamber adjacent the substrate and between the upstream and downstream chamber openings, wherein gas flowed through said chamber region at a selected gas-flow rate is effective to condense drug vapor produced by said unit to form drug condensation particles having a selected MMAD particle size, c) a gas-flow control valve disposed upstream of said unit for limiting gas-flow rate through said condensation region to said selected gas-flow rate, as gas is flowed through said chamber, and d) an actuation switch for actuating said unit, such that said unit produces vapor with the gas-flow rate through said chamber controlled to said selected flow rate.
2. The device of claim 1, for use in delivering a drug by inhalation, wherein said chamber is designed for substantially laminar air flow within said chamber the selected air-flow rate is in the range of 4-50 L/min and the condensation particles produced by condensation of drug vapor are in the range 1-3.5 µm MMAD.
3. The device of claim 1, for use in delivering a drug by inhalation, wherein the gas-flow control valve is designed to produce a selected gas-flow rate effective to produce aerosol particles in the 20-100 nm size range.
4. The device of claim 1, wherein said gas-flow valve is designed to limit the rate of air flow through said chamber, as the user draws air through the chamber by mouth.
5. The device of claim 4, wherein the gas-flow valve includes an inlet port communicating with said chamber, and a deformable flap adapted to divert air flow away from said port increasingly, with increasing pressure drop across the valve.
6. The device of claim 4, wherein said gas-flow valve includes said actuation switch, with valve movement in response to an air pressure differential across the valve acting to close said switch.
7. The device of claim 4, wherein said gas-flow valve includes an orifice designed to limit airflow rate into said chamber.
8. The device of claim 4, which further includes a bypass valve communicating with the chamber downstream of said unit for offsetting the decrease in airflow produced by said gas-flow control valve, as the user draws air into said chamber.
9. The device of claim 1, wherein the actuation switch includes a thermistor that is responsive to heat-dissipative effects of air flow through the chamber to activate said drug-supply unit.
10. The device of claim 9, which further includes a user-activated switch whose actuation is effective to heat said thermistor, prior to actuation by the thermistor of the drug-supply unit.
11. The device of claim 1, wherein said actuation switch is effective to activate said drug-supply unit prior to the selected gas-flow rate being reached, such that vapor is produced by said unit in said chamber when said selected gas-flow rate is reached.
12. The device of claim 1, wherein said actuation switch is effective to activate said drug-supply unit when the selected gas-flow rate is reached.
13 The device of claim 1, wherein said drug-supply unit includes i, a heat-conductive substrate having an outer surface, ii. a film of drug formed on said substrate surface, and iii. a heat source for heating the substrate to a temperature effective to vaporize said drug.
14. The device of claim 13 wherein said drug delivery unit is effective to vaporize the film of drug, following actuation, within a period of less than 1 second.
15. The device of claim 14, wherein said drug delivery unit is effective to vaporize the film of drug, following actuation, within a period of less than 0.5 second.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US42977602P | 2002-11-27 | 2002-11-27 | |
| US42958602P | 2002-11-27 | 2002-11-27 | |
| US60/429,586 | 2002-11-27 | ||
| US60/429,776 | 2002-11-27 | ||
| US10/442,385 | 2003-05-20 | ||
| US10/442,385 US7913688B2 (en) | 2002-11-27 | 2003-05-20 | Inhalation device for producing a drug aerosol |
| PCT/US2003/032803 WO2004050139A2 (en) | 2002-11-27 | 2003-10-16 | Inhalation device for producing a drug aerosol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2507265A1 true CA2507265A1 (en) | 2004-06-17 |
Family
ID=32329873
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002507265A Abandoned CA2507265A1 (en) | 2002-11-27 | 2003-10-16 | Inhalation device for producing a drug aerosol |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US7913688B2 (en) |
| EP (1) | EP1581281B1 (en) |
| JP (1) | JP2006507909A (en) |
| AU (1) | AU2003294231B9 (en) |
| CA (1) | CA2507265A1 (en) |
| ES (1) | ES2702606T3 (en) |
| MX (1) | MXPA05005628A (en) |
| NZ (1) | NZ540209A (en) |
| WO (1) | WO2004050139A2 (en) |
Families Citing this family (179)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9006175B2 (en) | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
| US6737043B2 (en) * | 2001-05-24 | 2004-05-18 | Alexza Molecula Delivery Corporation | Delivery of alprazolam, estazolam, midazolam or triazolam through an inhalation route |
| US7458374B2 (en) | 2002-05-13 | 2008-12-02 | Alexza Pharmaceuticals, Inc. | Method and apparatus for vaporizing a compound |
| US20070122353A1 (en) | 2001-05-24 | 2007-05-31 | Hale Ron L | Drug condensation aerosols and kits |
| US7766013B2 (en) * | 2001-06-05 | 2010-08-03 | Alexza Pharmaceuticals, Inc. | Aerosol generating method and device |
| US7645442B2 (en) | 2001-05-24 | 2010-01-12 | Alexza Pharmaceuticals, Inc. | Rapid-heating drug delivery article and method of use |
| US6737042B2 (en) * | 2001-05-24 | 2004-05-18 | Alexza Molecular Delivery Corporation | Delivery of drug esters through an inhalation route |
| US7078016B2 (en) * | 2001-11-21 | 2006-07-18 | Alexza Pharmaceuticals, Inc. | Delivery of caffeine through an inhalation route |
| WO2003080149A2 (en) | 2002-03-20 | 2003-10-02 | Mannkind Corporation | Inhalation apparatus |
| EP1503744A1 (en) * | 2002-05-13 | 2005-02-09 | Alexza Molecular Delivery Corporation | Delivery of drug amines through an inhalation route |
| US20060193788A1 (en) * | 2002-11-26 | 2006-08-31 | Hale Ron L | Acute treatment of headache with phenothiazine antipsychotics |
| NZ540208A (en) * | 2002-11-26 | 2007-09-28 | Alexza Pharmaceuticals Inc | Treatment of headache with antipsychotics delivered by inhalation |
| US7550133B2 (en) * | 2002-11-26 | 2009-06-23 | Alexza Pharmaceuticals, Inc. | Respiratory drug condensation aerosols and methods of making and using them |
| CN1717237A (en) * | 2002-11-26 | 2006-01-04 | 艾利斯达分子传输公司 | Use of loxapine and amoxapine for the manufacture of a medicament for the treatment of pain |
| US20040105818A1 (en) | 2002-11-26 | 2004-06-03 | Alexza Molecular Delivery Corporation | Diuretic aerosols and methods of making and using them |
| US7220597B2 (en) * | 2003-01-30 | 2007-05-22 | Zin Benedict L | Assay test device and method of making same |
| ATE520935T1 (en) * | 2003-05-21 | 2011-09-15 | Alexza Pharmaceuticals Inc | USE OF A SOLID FUEL LAYER, METHOD FOR PRODUCING SUCH A LAYER AND ASSOCIATED HEATING DEVICE |
| AU2004264344B2 (en) * | 2003-08-04 | 2011-02-17 | Alexza Pharmaceuticals, Inc. | Substrates for drug delivery device and methods of preparing and use |
| CN2719043Y (en) | 2004-04-14 | 2005-08-24 | 韩力 | Atomized electronic cigarette |
| US7402777B2 (en) | 2004-05-20 | 2008-07-22 | Alexza Pharmaceuticals, Inc. | Stable initiator compositions and igniters |
| US7540286B2 (en) | 2004-06-03 | 2009-06-02 | Alexza Pharmaceuticals, Inc. | Multiple dose condensation aerosol devices and methods of forming condensation aerosols |
| WO2006022715A1 (en) * | 2004-08-12 | 2006-03-02 | Alexza Pharmaceuticals, Inc. | Inhalation actuated percussive ignition system |
| AU2004322756B2 (en) * | 2004-08-12 | 2011-04-14 | Alexza Pharmaceuticals, Inc. | Aerosol drug delivery device incorporating percussively activated heat packages |
| JP4922934B2 (en) * | 2004-08-12 | 2012-04-25 | アレックザ ファーマシューティカルズ， インコーポレイテッド | Aerosol drug delivery device incorporating impact-activated heat package |
| JP5078014B2 (en) | 2004-08-20 | 2012-11-21 | マンカインド コーポレイション | Catalytic reaction of diketopiperazine synthesis. |
| HUE026797T2 (en) | 2004-08-23 | 2016-07-28 | Mannkind Corp | Diketopiperazine salts for drug delivery |
| BRPI0518437A2 (en) * | 2004-11-16 | 2008-11-18 | Brian Cran | lung treatment device and method |
| EP1848483B1 (en) * | 2005-02-02 | 2014-03-12 | Oglesby&Butler Research&Development Limited | A device for vaporising vaporisable matter |
| US9675109B2 (en) | 2005-07-19 | 2017-06-13 | J. T. International Sa | Method and system for vaporization of a substance |
| US10244793B2 (en) | 2005-07-19 | 2019-04-02 | Juul Labs, Inc. | Devices for vaporization of a substance |
| KR100857596B1 (en) * | 2005-08-23 | 2008-09-09 | 삼성전자주식회사 | Nano particle generator |
| KR20120060245A (en) | 2005-09-14 | 2012-06-11 | 맨카인드 코포레이션 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
| FR2891435B1 (en) * | 2005-09-23 | 2007-11-09 | Bull Sa Sa | HOLDING SYSTEM IN POSITION OF A THREE-PART ASSEMBLY PROVIDING A PREDETERMINAL COMPRESSION EFFORT ON THE INTERMEDIATE PART |
| US7494344B2 (en) * | 2005-12-29 | 2009-02-24 | Molex Incorporated | Heating element connector assembly with press-fit terminals |
| EP2497484A3 (en) | 2006-02-22 | 2012-11-07 | MannKind Corporation | A method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent |
| WO2008080170A1 (en) * | 2006-12-22 | 2008-07-03 | Alexza Pharmaceuticals, Inc. | Mixed drug aerosol compositiions |
| WO2008112661A2 (en) | 2007-03-09 | 2008-09-18 | Alexza Pharmaceuticals, Inc. | Heating unit for use in a drug delivery device |
| EP2121093B1 (en) | 2007-03-21 | 2016-11-02 | Resmed Paris SAS | Passive gas regulating valve for a respiratory system |
| US7631981B2 (en) * | 2007-10-15 | 2009-12-15 | Utah Medical Products, Inc. | Disposable medical-examination light |
| EP2534957B1 (en) | 2007-12-14 | 2015-05-27 | AeroDesigns, Inc | Delivering aerosolizable products |
| US8991402B2 (en) | 2007-12-18 | 2015-03-31 | Pax Labs, Inc. | Aerosol devices and methods for inhaling a substance and uses thereof |
| GB0802028D0 (en) † | 2008-02-05 | 2008-03-12 | Dunne Stephen T | Powder inhaler flow regulator |
| EP2242526A4 (en) | 2008-02-15 | 2014-06-18 | Timothy Sean Immel | Aerosol therapy device with high frequency delivery |
| EP2113178A1 (en) | 2008-04-30 | 2009-11-04 | Philip Morris Products S.A. | An electrically heated smoking system having a liquid storage portion |
| US8455784B2 (en) * | 2008-05-07 | 2013-06-04 | GM Global Technology Operations LLC | Method and system for welding workpieces |
| US8485180B2 (en) | 2008-06-13 | 2013-07-16 | Mannkind Corporation | Dry powder drug delivery system |
| EP3281663B8 (en) | 2008-06-13 | 2022-09-21 | MannKind Corporation | Breath powered dry powder inhaler for drug delivery |
| US9364619B2 (en) | 2008-06-20 | 2016-06-14 | Mannkind Corporation | Interactive apparatus and method for real-time profiling of inhalation efforts |
| TWI494123B (en) | 2008-08-11 | 2015-08-01 | Mannkind Corp | Use of ultrarapid acting insulin |
| US7834295B2 (en) | 2008-09-16 | 2010-11-16 | Alexza Pharmaceuticals, Inc. | Printable igniters |
| US20100065052A1 (en) * | 2008-09-16 | 2010-03-18 | Alexza Pharmaceuticals, Inc. | Heating Units |
| TWM352181U (en) * | 2008-09-19 | 2009-03-01 | Soa Technology Co Ltd | Cold cathode tube conductive device |
| US8314106B2 (en) | 2008-12-29 | 2012-11-20 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
| CA2754595C (en) | 2009-03-11 | 2017-06-27 | Mannkind Corporation | Apparatus, system and method for measuring resistance of an inhaler |
| US20100300433A1 (en) * | 2009-05-28 | 2010-12-02 | Alexza Pharmaceuticals, Inc. | Substrates for Enhancing Purity or Yield of Compounds Forming a Condensation Aerosol |
| WO2010144789A2 (en) | 2009-06-12 | 2010-12-16 | Mannkind Corporation | Diketopiperazine microparticles with defined specific surface areas |
| EP2319334A1 (en) * | 2009-10-27 | 2011-05-11 | Philip Morris Products S.A. | A smoking system having a liquid storage portion |
| CA2778698A1 (en) | 2009-11-03 | 2011-05-12 | Mannkind Corporation | An apparatus and method for simulating inhalation efforts |
| US8494351B1 (en) * | 2010-05-04 | 2013-07-23 | Cheryl A. Hayes | Decorative lighting with scent dispensers |
| AU2011271097B2 (en) | 2010-06-21 | 2014-11-27 | Mannkind Corporation | Dry powder drug delivery system and methods |
| US20120048963A1 (en) | 2010-08-26 | 2012-03-01 | Alexza Pharmaceuticals, Inc. | Heat Units Using a Solid Fuel Capable of Undergoing an Exothermic Metal Oxidation-Reduction Reaction Propagated without an Igniter |
| US11577035B2 (en) | 2010-09-22 | 2023-02-14 | Robert Irving Pratt, JR. | Therapeutic vaporizer |
| KR20130099112A (en) * | 2010-09-22 | 2013-09-05 | 클로버쉴드, 인크. | Therapeutic vaporizer |
| US20140158129A1 (en) | 2010-09-22 | 2014-06-12 | Clovershield, Inc. | Transversely-activated valve for a therapeutic vaporizer bag attachment system |
| PL2654864T3 (en) | 2010-12-22 | 2021-07-12 | Syqe Medical Ltd. | System for drug delivery |
| CN105667994B (en) | 2011-04-01 | 2018-04-06 | 曼金德公司 | Blister package for pharmaceutical kit |
| WO2012174472A1 (en) | 2011-06-17 | 2012-12-20 | Mannkind Corporation | High capacity diketopiperazine microparticles |
| US8528569B1 (en) | 2011-06-28 | 2013-09-10 | Kyle D. Newton | Electronic cigarette with liquid reservoir |
| EP2753200B1 (en) | 2011-09-06 | 2017-12-27 | British American Tobacco (Investments) Limited | Heating smokeable material |
| WO2013034456A1 (en) | 2011-09-06 | 2013-03-14 | British American Tobacco (Investments) Limited | Heating smokable material |
| GB201207054D0 (en) | 2011-09-06 | 2012-06-06 | British American Tobacco Co | Heating smokeable material |
| PL3354144T3 (en) | 2011-09-06 | 2021-06-14 | Nicoventures Trading Limited | Heating smokable material |
| UA110646C2 (en) | 2011-09-06 | 2016-01-25 | Брітіш Амерікан Тобакко (Інвестментс) Лімітед | Devices for the heating of smoking materials |
| KR20140095483A (en) | 2011-10-24 | 2014-08-01 | 맨카인드 코포레이션 | Methods and compositions for treating pain |
| WO2013111792A1 (en) * | 2012-01-24 | 2013-08-01 | 日本たばこ産業株式会社 | Non-combustion flavor inhalation apparatus |
| US9854839B2 (en) | 2012-01-31 | 2018-01-02 | Altria Client Services Llc | Electronic vaping device and method |
| US9532597B2 (en) | 2012-02-22 | 2017-01-03 | Altria Client Services Llc | Electronic smoking article |
| WO2013126777A2 (en) | 2012-02-22 | 2013-08-29 | Altria Client Services Inc. | Electronic smoking article and improved heater element |
| US10307562B2 (en) | 2012-04-13 | 2019-06-04 | Fresca Medical, Inc. | Auto-feedback valve for a sleep apnea device |
| US10206571B2 (en) | 2012-03-21 | 2019-02-19 | Fresca Medical, Inc. | Apparatus, systems, and methods for treating obstructive sleep apnea |
| GB201207039D0 (en) | 2012-04-23 | 2012-06-06 | British American Tobacco Co | Heating smokeable material |
| DK2872205T3 (en) | 2012-07-12 | 2017-02-27 | Mannkind Corp | DRY POWDER FORMAL ADMINISTRATION SYSTEM |
| US10517530B2 (en) | 2012-08-28 | 2019-12-31 | Juul Labs, Inc. | Methods and devices for delivering and monitoring of tobacco, nicotine, or other substances |
| WO2014066856A1 (en) | 2012-10-26 | 2014-05-01 | Mannkind Corporation | Inhalable influenza vaccine compositions and methods |
| EP2925395B1 (en) * | 2012-11-28 | 2019-03-06 | Fontem Holdings 1 B.V. | Device for generating a condensation aerosol from a liquid formulation |
| US10034988B2 (en) | 2012-11-28 | 2018-07-31 | Fontem Holdings I B.V. | Methods and devices for compound delivery |
| USD691765S1 (en) | 2013-01-14 | 2013-10-15 | Altria Client Services Inc. | Electronic smoking article |
| USD841231S1 (en) | 2013-01-14 | 2019-02-19 | Altria Client Services, Llc | Electronic vaping device mouthpiece |
| USD691766S1 (en) | 2013-01-14 | 2013-10-15 | Altria Client Services Inc. | Mouthpiece of a smoking article |
| USD849993S1 (en) | 2013-01-14 | 2019-05-28 | Altria Client Services | Electronic smoking article |
| USD695449S1 (en) | 2013-01-14 | 2013-12-10 | Altria Client Services Inc. | Electronic smoking article |
| USD752807S1 (en) | 2013-02-19 | 2016-03-29 | 1Ready, Llc | Therapeutic vaporizer |
| US10279934B2 (en) | 2013-03-15 | 2019-05-07 | Juul Labs, Inc. | Fillable vaporizer cartridge and method of filling |
| KR102499439B1 (en) | 2013-03-15 | 2023-02-13 | 맨카인드 코포레이션 | Microcrystalline diketopiperazine compositions and methods |
| WO2014182736A1 (en) | 2013-05-06 | 2014-11-13 | Ploom, Inc. | Nicotine salt formulations for aerosol devices and methods thereof |
| WO2014201432A1 (en) | 2013-06-14 | 2014-12-18 | Ploom, Inc. | Multiple heating elements with separate vaporizable materials in an electric vaporization device |
| CA3061122C (en) | 2013-07-11 | 2023-10-17 | Alexza Pharmaceuticals, Inc. | Nicotine salt with meta-salicylic acid |
| WO2015010092A1 (en) | 2013-07-18 | 2015-01-22 | Mannkind Corporation | Heat-stable dry powder pharmaceutical compositions and methods |
| JP2016530930A (en) | 2013-08-05 | 2016-10-06 | マンカインド コーポレイション | Ventilation device and method |
| US10194693B2 (en) * | 2013-09-20 | 2019-02-05 | Fontem Holdings 1 B.V. | Aerosol generating device |
| CN105592736B (en) * | 2013-09-30 | 2018-10-16 | 日本烟草产业株式会社 | Non-combustion-type fragrance extractor |
| US9820509B2 (en) | 2013-10-10 | 2017-11-21 | Kyle D. Newton | Electronic cigarette with encoded cartridge |
| BR302014001648S1 (en) | 2013-10-14 | 2015-06-09 | Altria Client Services Inc | Smoke Applied Configuration |
| KR102444219B1 (en) | 2013-10-29 | 2022-09-15 | 니코벤처스 트레이딩 리미티드 | Apparatus for heating smokable material |
| US10980273B2 (en) | 2013-11-12 | 2021-04-20 | VMR Products, LLC | Vaporizer, charger and methods of use |
| JP6877141B2 (en) | 2013-12-05 | 2021-05-26 | ジュール・ラブズ・インコーポレイテッドＪｕｕｌ Ｌａｂｓ， Ｉｎｃ． | Nicotine liquid formulation for aerosol devices and methods thereof |
| US10058129B2 (en) | 2013-12-23 | 2018-08-28 | Juul Labs, Inc. | Vaporization device systems and methods |
| USD825102S1 (en) | 2016-07-28 | 2018-08-07 | Juul Labs, Inc. | Vaporizer device with cartridge |
| US9549573B2 (en) | 2013-12-23 | 2017-01-24 | Pax Labs, Inc. | Vaporization device systems and methods |
| US10159282B2 (en) | 2013-12-23 | 2018-12-25 | Juul Labs, Inc. | Cartridge for use with a vaporizer device |
| DE202014011297U1 (en) | 2013-12-23 | 2019-02-13 | Juul Labs Uk Holdco Limited | Systems for an evaporation device |
| US10076139B2 (en) | 2013-12-23 | 2018-09-18 | Juul Labs, Inc. | Vaporizer apparatus |
| US20160366947A1 (en) | 2013-12-23 | 2016-12-22 | James Monsees | Vaporizer apparatus |
| USD842536S1 (en) | 2016-07-28 | 2019-03-05 | Juul Labs, Inc. | Vaporizer cartridge |
| TWI828016B (en) | 2014-02-06 | 2024-01-01 | 美商尤爾實驗室有限公司 | An electronic device for generating an inhalable vapor, a system, and a kit comprising the electronic device |
| US10709173B2 (en) | 2014-02-06 | 2020-07-14 | Juul Labs, Inc. | Vaporizer apparatus |
| US9380813B2 (en) | 2014-02-11 | 2016-07-05 | Timothy McCullough | Drug delivery system and method |
| US10821240B2 (en) | 2014-02-11 | 2020-11-03 | Vapor Cartridge Technology Llc | Methods and drug delivery devices using cannabis |
| US9220294B2 (en) | 2014-02-11 | 2015-12-29 | Timothy McCullough | Methods and devices using cannabis vapors |
| WO2015132174A1 (en) * | 2014-03-05 | 2015-09-11 | Takeda Gmbh | Device for providing a constant amount of aerosol |
| WO2015148905A1 (en) | 2014-03-28 | 2015-10-01 | Mannkind Corporation | Use of ultrarapid acting insulin |
| US11478021B2 (en) | 2014-05-16 | 2022-10-25 | Juul Labs, Inc. | Systems and methods for aerosolizing a vaporizable material |
| CN104114050B (en) * | 2014-05-30 | 2019-01-18 | 深圳麦克韦尔股份有限公司 | Electronic cigarette and its atomizer |
| PL3160552T3 (en) | 2014-06-30 | 2020-03-31 | Syqe Medical Ltd. | Drug dose cartridge for an inhaler device |
| PL3160553T3 (en) | 2014-06-30 | 2022-02-21 | Syqe Medical Ltd. | Device for vaporization and inhalation of isolated substances |
| US11298477B2 (en) | 2014-06-30 | 2022-04-12 | Syqe Medical Ltd. | Methods, devices and systems for pulmonary delivery of active agents |
| EP3160565B1 (en) | 2014-06-30 | 2021-08-18 | Syqe Medical Ltd. | Devices and systems for pulmonary delivery of active agents |
| CA3215815A1 (en) * | 2014-06-30 | 2016-01-07 | Syqe Medical Ltd. | Method and device for vaporization and inhalation of isolated substances |
| IL273507B1 (en) | 2014-06-30 | 2024-02-01 | Syqe Medical Ltd | Methods, devices and systems for pulmonary delivery of active agents |
| EP3160558B1 (en) * | 2014-06-30 | 2020-02-12 | Syqe Medical Ltd. | Flow regulating inhaler device |
| US10857313B2 (en) | 2014-07-01 | 2020-12-08 | Aerami Therapeutics, Inc. | Liquid nebulization systems and methods |
| US11273271B2 (en) * | 2014-07-01 | 2022-03-15 | Aerami Therapeutics, Inc. | Aerosolization system with flow restrictor and feedback device |
| US10471222B2 (en) | 2014-07-01 | 2019-11-12 | Dance Biopharm Inc. | Aerosolization system with flow restrictor and feedback device |
| EP3191162B1 (en) * | 2014-09-10 | 2022-02-23 | Fontem Holdings 1 B.V. | Methods and devices for modulating air flow in delivery devices |
| US10561806B2 (en) | 2014-10-02 | 2020-02-18 | Mannkind Corporation | Mouthpiece cover for an inhaler |
| KR102627987B1 (en) | 2014-12-05 | 2024-01-22 | 쥴 랩스, 인크. | Calibrated dose control |
| JP6431214B2 (en) | 2015-01-22 | 2018-11-28 | フォンテム ホールディングス １ ベー．ハー．Ｆｏｎｔｅｍ Ｈｏｌｄｉｎｇｓ １ Ｂ．Ｖ． | Electronic vaporizer |
| SI3268072T1 (en) | 2015-03-11 | 2024-03-29 | Alexza Pharmaceuticals, Inc. | Use of antistatic materials in the airway for thermal aerosol condensation process |
| GB201511349D0 (en) | 2015-06-29 | 2015-08-12 | Nicoventures Holdings Ltd | Electronic aerosol provision systems |
| GB2541719B (en) * | 2015-08-27 | 2019-06-12 | Nerudia Ltd | An inhaler |
| US20170055584A1 (en) | 2015-08-31 | 2017-03-02 | British American Tobacco (Investments) 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 |
| USD799691S1 (en) | 2015-09-03 | 2017-10-10 | 1Ready, Llc | Tray for a therapeutic vaporizer |
| EP3399972B1 (en) | 2016-01-06 | 2021-03-31 | Syqe Medical Ltd. | Low dose therapeutic treatment |
| WO2017139595A1 (en) | 2016-02-11 | 2017-08-17 | Pax Labs, Inc. | Fillable vaporizer cartridge and method of filling |
| EA039727B1 (en) | 2016-02-11 | 2022-03-04 | Джуул Лэбз, Инк. | Securely attaching cartridges for vaporizer devices |
| BR112018067606A2 (en) | 2016-02-25 | 2019-01-08 | Juul Labs Inc | vaporization device control methods and systems |
| US10433580B2 (en) | 2016-03-03 | 2019-10-08 | Altria Client Services Llc | Methods to add menthol, botanic materials, and/or non-botanic materials to a cartridge, and/or an electronic vaping device including the cartridge |
| US10455863B2 (en) | 2016-03-03 | 2019-10-29 | Altria Client Services Llc | Cartridge for electronic vaping device |
| US10368580B2 (en) | 2016-03-08 | 2019-08-06 | Altria Client Services Llc | Combined cartridge for electronic vaping device |
| US10405582B2 (en) | 2016-03-10 | 2019-09-10 | Pax Labs, Inc. | Vaporization device with lip sensing |
| US10258087B2 (en) | 2016-03-10 | 2019-04-16 | Altria Client Services Llc | E-vaping cartridge and device |
| US10368581B2 (en) | 2016-03-11 | 2019-08-06 | Altria Client Services Llc | Multiple dispersion generator e-vaping device |
| US10357060B2 (en) | 2016-03-11 | 2019-07-23 | Altria Client Services Llc | E-vaping device cartridge holder |
| GB201610220D0 (en) * | 2016-06-13 | 2016-07-27 | Nicoventures Holdings Ltd | Aerosol delivery device |
| CN109562235A (en) | 2016-06-16 | 2019-04-02 | 尤尔实验室有限公司 | On-demand portable counter flow evaporator |
| USD849996S1 (en) | 2016-06-16 | 2019-05-28 | Pax Labs, Inc. | Vaporizer cartridge |
| USD848057S1 (en) | 2016-06-23 | 2019-05-07 | Pax Labs, Inc. | Lid for a vaporizer |
| USD836541S1 (en) | 2016-06-23 | 2018-12-25 | Pax Labs, Inc. | Charging device |
| USD851830S1 (en) | 2016-06-23 | 2019-06-18 | Pax Labs, Inc. | Combined vaporizer tamp and pick tool |
| GB201612945D0 (en) | 2016-07-26 | 2016-09-07 | British American Tobacco Investments Ltd | Method of generating aerosol |
| US10306927B2 (en) * | 2016-07-28 | 2019-06-04 | Altria Client Services Llc | Venturi effect-driven formulation delivery in e-vaping devices |
| US10960163B2 (en) | 2016-09-02 | 2021-03-30 | Fresca Medical Inc. | Apparatus, systems, and methods for improved treatment of obstructive sleep apnea |
| US11660403B2 (en) | 2016-09-22 | 2023-05-30 | Juul Labs, Inc. | Leak-resistant vaporizer device |
| PT3551189T (en) | 2016-12-09 | 2024-01-22 | Alexza Pharmaceuticals Inc | Method of treating epilepsy |
| GB201707095D0 (en) * | 2017-05-04 | 2017-06-21 | 3M Innovative Properties Co | Inhaler flow control mechanism |
| USD887632S1 (en) | 2017-09-14 | 2020-06-16 | Pax Labs, Inc. | Vaporizer cartridge |
| US20190217027A1 (en) * | 2018-01-17 | 2019-07-18 | Indose Inc | Device for vaporized substance dosage metering based on an input dosage |
| GB201905425D0 (en) * | 2019-04-17 | 2019-05-29 | Nicoventures Trading Ltd | Electronic aerosol provision device |
| US11497249B2 (en) | 2019-09-16 | 2022-11-15 | Vapor Cartridge Technology Llc | Drug delivery system with stackable substrates |
| EP3794971A1 (en) * | 2019-09-20 | 2021-03-24 | Nerudia Limited | Smoking substitute apparatus |
| EP3794973A1 (en) * | 2019-09-20 | 2021-03-24 | Nerudia Limited | Smoking substitute apparatus |
| JP1715888S (en) | 2020-10-30 | 2022-05-25 | Smoking aerosol generator | |
| JP1714440S (en) | 2020-10-30 | 2022-05-10 | Smoking aerosol generator | |
| JP1714441S (en) | 2020-10-30 | 2022-05-10 | Smoking aerosol generator | |
| JP1714442S (en) | 2020-10-30 | 2022-05-10 | Smoking aerosol generator | |
| USD990765S1 (en) | 2020-10-30 | 2023-06-27 | Nicoventures Trading Limited | Aerosol generator |
| JP1714443S (en) | 2020-10-30 | 2022-05-10 | Smoking aerosol generator | |
| USD989384S1 (en) | 2021-04-30 | 2023-06-13 | Nicoventures Trading Limited | Aerosol generator |
Family Cites Families (451)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US1803334A (en) | 1931-05-05 | Ootthujp lehmann | ||
| US3080624A (en) | 1963-03-12 | weber iii | ||
| US1864980A (en) | 1932-06-28 | Vapobizeb | ||
| US2243669A (en) | 1941-05-27 | Electrical vaporizer | ||
| US1239634A (en) * | 1916-07-25 | 1917-09-11 | Frank J Stuart | Medical appliance. |
| US1535486A (en) | 1922-08-28 | 1925-04-28 | James W Lundy | Electric-lamp bulb |
| US2086140A (en) * | 1933-09-08 | 1937-07-06 | Silten Ernst | Automatic temperature regulated narcosis apparatus |
| US2084299A (en) * | 1934-12-15 | 1937-06-15 | Arthur G Borden | Medicament holder for nasal inhalers |
| US2230753A (en) | 1937-02-15 | 1941-02-04 | Bilhuber Corp E | Unsaturated ethylamine derivatives |
| US2230754A (en) | 1937-02-15 | 1941-02-04 | Bilhuber Corp E | Unsaturated ethylamine derivatives |
| GB502761A (en) | 1938-01-29 | 1939-03-24 | Christopher Engelbreth | Improvements in and relating to hand inhalation apparatus |
| US2309846A (en) * | 1941-03-06 | 1943-02-02 | Holm Einar Marius | Inhaler |
| FR921852A (en) | 1945-12-06 | 1947-05-21 | Diffuser of volatile products | |
| US2469656A (en) | 1946-04-19 | 1949-05-10 | Peter H Lienert | Vaporizer |
| US2714649A (en) | 1952-11-25 | 1955-08-02 | Lyle H Critzer | Vaporizer |
| US2761055A (en) | 1953-06-10 | 1956-08-28 | Malcome Van Ike | Lamp-heated vaporizer |
| US2741812A (en) | 1954-02-15 | 1956-04-17 | Tellier Andre | Perfume dispenser |
| US2902484A (en) | 1954-04-27 | 1959-09-01 | Rhone Poulenc Sa | Phenthiazine derivatives and processes for their preparation |
| US2887106A (en) | 1956-09-27 | 1959-05-19 | Robinson Joseph | Combined vaporizer and cover for medicament jar |
| US2898649A (en) | 1956-11-19 | 1959-08-11 | Elaine T Cassidy | Perfume diffuser |
| US3371085A (en) | 1959-12-10 | 1968-02-27 | Hoffmann La Roche | 5-aryl-3h-1,4-benzodiazepin-2(1h)-ones |
| US3043977A (en) | 1960-03-30 | 1962-07-10 | Puritron Corp | Device and method for producing negative ions |
| US3474101A (en) | 1960-09-05 | 1969-10-21 | Reckitt & Sons Ltd | Thebaine and oripavine derivatives |
| GB903866A (en) | 1961-05-09 | 1962-08-22 | Dausse Lab | Therapeutic preparations containing 7-substituted theophylline derivatives |
| NL284196A (en) | 1961-10-10 | |||
| US3299185A (en) | 1962-09-27 | 1967-01-17 | Ube Nitto Kasei Co | Dyeable polyolefin fibers containing a binary copolymer of styrene and acrylonitrile |
| US3169095A (en) | 1962-10-30 | 1965-02-09 | Rexall Drug Chemical | Self-propelling powder-dispensing compositions |
| NL289785A (en) | 1962-11-29 | |||
| GB1063512A (en) | 1962-11-30 | 1967-03-30 | Benger Lab Ltd | Aerosols |
| US3282729A (en) | 1963-02-27 | 1966-11-01 | Union Carbide Corp | Barrier coated thermoplastic olefin polymer substrates |
| US3200819A (en) | 1963-04-17 | 1965-08-17 | Herbert A Gilbert | Smokeless non-tobacco cigarette |
| NL298071A (en) | 1963-06-04 | |||
| IL26896A (en) | 1966-01-19 | 1970-11-30 | Endo Lab | 14-hydroxynormorphines and 14-hydroxynormorphinones |
| US3909463A (en) | 1968-11-29 | 1975-09-30 | Allied Chem | Grafted block copolymers of synthetic rubbers and polyolefins |
| US3987052A (en) | 1969-03-17 | 1976-10-19 | The Upjohn Company | 6-Phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines |
| US4008723A (en) | 1970-03-23 | 1977-02-22 | Imperial Chemical Industries Limited | Smoking mixture |
| US3831606A (en) | 1971-02-19 | 1974-08-27 | Alza Corp | Auto inhaler |
| US3847650A (en) | 1971-09-09 | 1974-11-12 | Airco Inc | Flashlamp with improved combustion foil and method of making same |
| US3749547A (en) | 1971-09-09 | 1973-07-31 | Airco Inc | Flashlamp with improved combustible foil |
| US4166087A (en) | 1971-11-22 | 1979-08-28 | Cline-Buckner, Inc. | Automatic intermittent vapor dispenser |
| US3701782A (en) | 1972-02-10 | 1972-10-31 | Upjohn Co | 1-carbolower alkoxy - 6 - phenyl-4h-s-triazolo(1,4)benzodiazepine compounds |
| US3763347A (en) | 1972-04-13 | 1973-10-02 | Ncr Co | Vaporous lamp |
| IE37524B1 (en) | 1972-04-20 | 1977-08-17 | Gallaher Ltd | Synthetic smoking product |
| US3864326A (en) | 1972-05-22 | 1975-02-04 | Robert S Babington | Spraying devices, in particular nebulizing devices |
| USRE30285E (en) | 1972-05-22 | 1980-05-27 | Spraying devices, in particular nebulizing devices | |
| GB1366041A (en) | 1972-07-21 | 1974-09-11 | Kodama Bros Co Ltd | Device for volatilizing insecticides and the like |
| US3842828A (en) * | 1972-09-08 | 1974-10-22 | Bird F M | Pediatric ventilator |
| US3773995A (en) | 1972-10-27 | 1973-11-20 | Westinghouse Electric Corp | Motor advanced spring charging pawl and ratchet mechanism with spring assist |
| US3949743A (en) | 1973-03-19 | 1976-04-13 | Schick Incorporated | Medicated vapor production method and apparatus |
| US3930796A (en) | 1973-09-13 | 1976-01-06 | Universal Oil Products Company | Catalytic fume control device |
| US3982095A (en) | 1973-10-04 | 1976-09-21 | Searle Cardio-Pulmonary Systems Inc. | Respiratory humidifier |
| US3971377A (en) | 1974-06-10 | 1976-07-27 | Alza Corporation | Medicament dispensing process for inhalation therapy |
| US3894040A (en) | 1974-09-16 | 1975-07-08 | American Home Prod | 2,5,6,7-Tetrahydro-3H-imidazo(1,2-D)(1,4)benzodiazepine-5,6-dicarboxylic acid esters |
| US4045156A (en) | 1974-12-23 | 1977-08-30 | Gte Sylvania Incorporated | Photoflash lamp |
| US4020379A (en) | 1975-10-02 | 1977-04-26 | Eg&G, Inc. | Bulb-shaped flashtube with metal envelope |
| US4104210A (en) | 1975-12-17 | 1978-08-01 | Monsanto Company | Thermoplastic compositions of high unsaturation diene rubber and polyolefin resin |
| US4121583A (en) | 1976-07-13 | 1978-10-24 | Wen Yuan Chen | Method and apparatus for alleviating asthma attacks |
| US4286604A (en) | 1976-10-05 | 1981-09-01 | Gallaher Limited | Smoking materials |
| US4079742A (en) | 1976-10-20 | 1978-03-21 | Philip Morris Incorporated | Process for the manufacture of synthetic smoking materials |
| US4160765A (en) | 1976-11-17 | 1979-07-10 | Smithkline Corporation | Method for 6-bromination of 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine compounds |
| US4141369A (en) | 1977-01-24 | 1979-02-27 | Burruss Robert P | Noncombustion system for the utilization of tobacco and other smoking materials |
| US4184099A (en) | 1977-04-27 | 1980-01-15 | International Flavors & Fragrances Inc. | Composition for slow release of volatile ingredients at _high temperature; and article comprising same |
| DE2752384A1 (en) | 1977-08-29 | 1979-03-15 | Simes | PHARMACEUTICAL PREPARATION BASED ON ANTY-RELEASE AGENTS AND INHIBITANTS OF BETA ADRENERGIC RECEPTORS |
| SE7812207L (en) | 1977-12-01 | 1979-06-02 | Welsh Nat School Med | APPARATUS, PROCEDURE AND MANUFACTURED PRODUCTS FOR USE IN THE ADMINISTRATION OF ANTIHISTAMINES |
| US4183912A (en) | 1978-01-16 | 1980-01-15 | American Home Products Corporation | Inhalation therapy for relieving bronchial spasm using quaternary salts of promethazine |
| JPS54120065A (en) | 1978-02-24 | 1979-09-18 | Osaka Takeshi | Stick for blind person |
| US4198200A (en) | 1978-05-18 | 1980-04-15 | Lord Corporation | Damage-preventive coatings |
| US4284089A (en) | 1978-10-02 | 1981-08-18 | Ray Jon P | Simulated smoking device |
| US4276243A (en) | 1978-12-08 | 1981-06-30 | Western Electric Company, Inc. | Vapor delivery control system and method |
| US4280629A (en) | 1979-01-08 | 1981-07-28 | Anchor Brush Company, Inc. | Container for nail polish or the like |
| US4229931A (en) | 1979-03-05 | 1980-10-28 | Deere & Company | Hydraulic height sensing system with cylinder by-pass |
| US4219031A (en) | 1979-03-05 | 1980-08-26 | Philip Morris Incorporated | Smoking product having core of fibrillar carbonized matter |
| IL59407A (en) | 1979-03-06 | 1983-12-30 | Sanofi Sa | Di-n-propylacetic acid diesters of glycerol,their preparation and pharmaceutical compositions containing them |
| US4654370A (en) | 1979-03-12 | 1987-03-31 | Abbott Laboratories | Glyceryl valproates |
| US4251525A (en) | 1979-05-25 | 1981-02-17 | Smithkline Corporation | 3-Allyl-7,8-dihydroxy-6-halo-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine derivatives |
| US4229447A (en) | 1979-06-04 | 1980-10-21 | American Home Products Corporation | Intraoral methods of using benzodiazepines |
| GB2064296B (en) | 1979-11-16 | 1983-06-22 | Imp Group Ltd | Cigarette or cigarette-like device which produces aerosol in smoke |
| EP0039369B1 (en) | 1980-05-02 | 1983-06-15 | Schering Corporation | Beclomethasone ester solvates, process for their preparation, and preparation of a formulation |
| US4391285A (en) | 1980-05-09 | 1983-07-05 | Philip Morris, Incorporated | Smoking article |
| US4347855A (en) | 1980-07-23 | 1982-09-07 | Philip Morris Incorporated | Method of making smoking articles |
| US4303083A (en) | 1980-10-10 | 1981-12-01 | Burruss Jr Robert P | Device for evaporation and inhalation of volatile compounds and medications |
| US4376767A (en) | 1981-01-02 | 1983-03-15 | Merck & Co., Inc. | Pyridylmethyl esters of selected bio-affecting carboxylic acids |
| US4346059A (en) | 1981-03-03 | 1982-08-24 | Donald Spector | Aroma-generating lamp structure |
| DE3116951C2 (en) | 1981-04-29 | 1984-12-20 | Drägerwerk AG, 2400 Lübeck | Device for adding liquid anesthetics to the breathing gas to be supplied to the patient |
| JPS5876038A (en) | 1981-10-28 | 1983-05-09 | 高森 正之 | Evaporation apparatus of insecticide or aromatic agent |
| GB2122903B (en) | 1982-06-22 | 1986-11-05 | Masayuki Takamori | Vaporizers for vaporisable substances and support media for substances usable therewith |
| DE3224849A1 (en) | 1982-07-02 | 1984-01-05 | Plantorgan Werk Heinrich G.E. Christensen, KG, 2903 Bad Zwischenahn | STEAM INHALER |
| US4556539A (en) | 1982-08-27 | 1985-12-03 | Donald Spector | Disc-playing aroma generator |
| US4508726A (en) | 1982-09-16 | 1985-04-02 | The Upjohn Company | Treatment of panic disorders with alprazolam |
| GB2147216B (en) | 1982-09-30 | 1987-03-04 | Dainippon Jochugiku Kk | Apparatus for heat-volatilizing medicinal agent |
| US4474191A (en) | 1982-09-30 | 1984-10-02 | Steiner Pierre G | Tar-free smoking devices |
| US4753758A (en) | 1983-05-19 | 1988-06-28 | Intertech Resources Inc. | Respiratory humidifier |
| US4523589A (en) * | 1983-06-29 | 1985-06-18 | Krauser Robert S | Method and apparatus for treating ailments |
| US5038769A (en) | 1983-06-29 | 1991-08-13 | Krauser Robert S | Method and apparatus for treating ailments |
| DE3326089A1 (en) | 1983-07-20 | 1985-02-07 | Gödecke AG, 1000 Berlin | INHALATION-INTENDED PHARMACEUTICAL FORM OF CALCIUM ANTAGONISTS |
| US4588721A (en) | 1983-09-12 | 1986-05-13 | The Upjohn Company | Treatment of negative symptoms of schizophrenia |
| ATE44470T1 (en) | 1983-11-08 | 1989-07-15 | Bunnell Life Systems Inc | HUMIDIFIER, ESPECIALLY FOR RESPIRATORY ASSISTANCE SYSTEMS. |
| GB8405190D0 (en) | 1984-02-28 | 1984-04-04 | British Petroleum Co Plc | Thermoplastic elastomer composition |
| US4627963A (en) | 1984-02-29 | 1986-12-09 | Lad Technology, Inc. | Heat activated dispenser and method of dispensing a vapor therefrom |
| US4683231A (en) | 1984-03-02 | 1987-07-28 | Research Foundation For Mental Hygiene, Inc. | Method of preventing withdrawal symptoms associated with the cessation or reduction of tobacco smoking |
| US4963367A (en) | 1984-04-27 | 1990-10-16 | Medaphore, Inc. | Drug delivery compositions and methods |
| US4647428A (en) | 1984-06-04 | 1987-03-03 | Gyulay Joseph M | Air freshener method |
| US4755508A (en) | 1984-06-26 | 1988-07-05 | Merck & Co., Inc. | Benzodiazepine analogs and use as antogonists of gastrin and cholecystokinin |
| US5042509A (en) | 1984-09-14 | 1991-08-27 | R. J. Reynolds Tobacco Company | Method for making aerosol generating cartridge |
| US5067499A (en) | 1984-09-14 | 1991-11-26 | R. J. Reynolds Tobacco Company | Smoking article |
| US4793365A (en) | 1984-09-14 | 1988-12-27 | R. J. Reynolds Tobacco Company | Smoking article |
| US5020548A (en) | 1985-08-26 | 1991-06-04 | R. J. Reynolds Tobacco Company | Smoking article with improved fuel element |
| US4854331A (en) | 1984-09-14 | 1989-08-08 | R. J. Reynolds Tobacco Company | Smoking article |
| US4647433A (en) | 1984-10-01 | 1987-03-03 | Donald Spector | Long-life aroma-generating capsule |
| CN1018329B (en) | 1984-12-21 | 1992-09-23 | 美国耳杰瑞诺兹烟草公司 | Carbon fuel element and method for mfg same |
| GB8501015D0 (en) | 1985-01-16 | 1985-02-20 | Riker Laboratories Inc | Drug |
| US5119834A (en) | 1985-04-15 | 1992-06-09 | R. J. Reynolds Tobacco Company | Smoking article with improved substrate |
| US4928714A (en) | 1985-04-15 | 1990-05-29 | R. J. Reynolds Tobacco Company | Smoking article with embedded substrate |
| JPS63500175A (en) | 1985-05-22 | 1988-01-21 | リポソ−ム テクノロジ−，インコ−ポレイテツド | Liposome inhalation method and inhalation system |
| US4800903A (en) | 1985-05-24 | 1989-01-31 | Ray Jon P | Nicotine dispenser with polymeric reservoir of nicotine |
| US4722334A (en) * | 1985-07-16 | 1988-02-02 | Transpirator Technologies, Inc. | Method and apparatus for pulmonary and cardiovascular conditioning of racehorses and competition animals |
| US4989619A (en) | 1985-08-26 | 1991-02-05 | R. J. Reynolds Tobacco Company | Smoking article with improved fuel element |
| US5105831A (en) | 1985-10-23 | 1992-04-21 | R. J. Reynolds Tobacco Company | Smoking article with conductive aerosol chamber |
| US5060666A (en) | 1985-10-28 | 1991-10-29 | R. J. Reynolds Tobacco Company | Smoking article with tobacco jacket |
| US5033483A (en) | 1985-10-28 | 1991-07-23 | R. J. Reynolds Tobacco Company | Smoking article with tobacco jacket |
| US4756318A (en) | 1985-10-28 | 1988-07-12 | R. J. Reynolds Tobacco Company | Smoking article with tobacco jacket |
| US4793366A (en) | 1985-11-12 | 1988-12-27 | Hill Ira D | Nicotine dispensing device and methods of making the same |
| JPS62204756A (en) | 1986-03-04 | 1987-09-09 | 大研医工株式会社 | Drug volatilizing method and apparatus |
| EP0259383B1 (en) | 1986-03-10 | 1991-01-23 | Kurt Dr. Burghart | Pharmaceutical preparation and process for preparing the same |
| US4708151A (en) | 1986-03-14 | 1987-11-24 | R. J. Reynolds Tobacco Company | Pipe with replaceable cartridge |
| US4765347A (en) | 1986-05-09 | 1988-08-23 | R. J. Reynolds Tobacco Company | Aerosol flavor delivery system |
| US4771795A (en) | 1986-05-15 | 1988-09-20 | R. J. Reynolds Tobacco Company | Smoking article with dual burn rate fuel element |
| US4917120A (en) | 1986-05-21 | 1990-04-17 | Advanced Tobacco Products, Inc. | Nicotine impact modification |
| US4774971A (en) | 1986-06-03 | 1988-10-04 | Vieten Michael J | Cigarette substitute |
| US4801411A (en) | 1986-06-05 | 1989-01-31 | Southwest Research Institute | Method and apparatus for producing monosize ceramic particles |
| US4735217A (en) | 1986-08-21 | 1988-04-05 | The Procter & Gamble Company | Dosing device to provide vaporized medicament to the lungs as a fine aerosol |
| US4858630A (en) | 1986-12-08 | 1989-08-22 | R. J. Reynolds Tobacco Company | Smoking article with improved aerosol forming substrate |
| IE873108L (en) | 1986-12-12 | 1988-06-12 | Huels Chemische Werke Ag | Impact modifying agent for use with smoking articles |
| US4734560A (en) | 1987-01-20 | 1988-03-29 | Medical Enterprises, Ltd. | Vaporizing unit |
| US4819665A (en) | 1987-01-23 | 1989-04-11 | R. J. Reynolds Tobacco Company | Aerosol delivery article |
| US4968885A (en) | 1987-03-06 | 1990-11-06 | Extrel Corporation | Method and apparatus for introduction of liquid effluent into mass spectrometer and other gas-phase or particle detectors |
| US4924883A (en) | 1987-03-06 | 1990-05-15 | R. J. Reynolds Tobacco Company | Smoking article |
| US4889850A (en) | 1987-05-11 | 1989-12-26 | Thornfeldt Carl R | Treatment of colic and teething |
| US5017575A (en) | 1987-06-09 | 1991-05-21 | Golwyn Daniel H | Treatment of immunologically based disorders, specifically Crohn's disease |
| GB8713645D0 (en) | 1987-06-11 | 1987-07-15 | Imp Tobacco Ltd | Smoking device |
| US5019122A (en) | 1987-08-21 | 1991-05-28 | R. J. Reynolds Tobacco Company | Smoking article with an enclosed heat conductive capsule containing an aerosol forming substance |
| US4935624A (en) | 1987-09-30 | 1990-06-19 | Cornell Research Foundation, Inc. | Thermal-assisted electrospray interface (TAESI) for LC/MS |
| US5072726A (en) | 1987-10-09 | 1991-12-17 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Vaporizer for inhalation anesthetics during high-frequency jet ventilation and associated method |
| US4911157A (en) | 1988-01-07 | 1990-03-27 | Pegasus Research Corporation | Self-regulating, heated nebulizer system |
| US4906417A (en) | 1988-02-08 | 1990-03-06 | Associated Mills Inc. | Humidifier |
| JPH01221313A (en) | 1988-02-29 | 1989-09-04 | Hayashi Teruaki | Sublimation-releasable medicine composition and releasing system thereof |
| US4853517A (en) | 1988-03-28 | 1989-08-01 | John G. Bowen | Vaporizing unit |
| DE3815221C2 (en) | 1988-05-04 | 1995-06-29 | Gradinger F Hermes Pharma | Use of a retinol and / or retinoic acid ester-containing pharmaceutical preparation for inhalation for acting on the mucous membranes of the tracheo-bronchial tract, including the lung alveoli |
| US5137034A (en) | 1988-05-16 | 1992-08-11 | R. J. Reynolds Tobacco Company | Smoking article with improved means for delivering flavorants |
| US4881556A (en) | 1988-06-06 | 1989-11-21 | R. J. Reynolds Tobacco Company | Low CO smoking article |
| US5264433A (en) | 1988-07-07 | 1993-11-23 | Fujisawa Pharmaceutical Co., Ltd. | Benzodiazepine derivatives |
| CH678151A5 (en) | 1988-07-13 | 1991-08-15 | Heinz Hermann Weick | Self-medication nasal dispenser |
| US5345951A (en) | 1988-07-22 | 1994-09-13 | Philip Morris Incorporated | Smoking article |
| US4852561A (en) | 1988-07-27 | 1989-08-01 | Sperry C R | Inhalation device |
| US4922901A (en) * | 1988-09-08 | 1990-05-08 | R. J. Reynolds Tobacco Company | Drug delivery articles utilizing electrical energy |
| US4947874A (en) * | 1988-09-08 | 1990-08-14 | R. J. Reynolds Tobacco Company | Smoking articles utilizing electrical energy |
| US4947875A (en) | 1988-09-08 | 1990-08-14 | R. J. Reynolds Tobacco Company | Flavor delivery articles utilizing electrical energy |
| EP0358114A3 (en) | 1988-09-08 | 1990-11-14 | R.J. Reynolds Tobacco Company | Aerosol delivery articles utilizing electrical energy |
| USRE36744E (en) | 1988-09-16 | 2000-06-20 | Ribogene, Inc. | Nasal administration of benzodiazepine hypnotics |
| US4950664A (en) | 1988-09-16 | 1990-08-21 | Rugby-Darby Group Companies, Inc. | Nasal administration of benzodiazepine hypnotics |
| US4963289A (en) | 1988-09-19 | 1990-10-16 | The United States Of America As Represented By The United States Department Of Energy | Method for producing monodisperse aerosols |
| US4917830A (en) | 1988-09-19 | 1990-04-17 | The United States Of America As Represented By The United States Department Of Energy | Monodisperse aerosol generator |
| US5511726A (en) | 1988-09-23 | 1996-04-30 | Battelle Memorial Institute | Nebulizer device |
| HU200105B (en) | 1988-10-04 | 1990-04-28 | Ferenc Inkovics | Electrically actuated inhaler of uniform medicine feeding |
| US4984158A (en) * | 1988-10-14 | 1991-01-08 | Hillsman Dean | Metered dose inhaler biofeedback training and evaluation system |
| US4917119A (en) * | 1988-11-30 | 1990-04-17 | R. J. Reynolds Tobacco Company | Drug delivery article |
| US4906476A (en) | 1988-12-14 | 1990-03-06 | Liposome Technology, Inc. | Novel liposome composition for sustained release of steroidal drugs in lungs |
| US4959380A (en) | 1988-12-19 | 1990-09-25 | Wilson Jordan E | Method of treating people to stop smoking and composition |
| US4881541A (en) | 1988-12-21 | 1989-11-21 | The Regents Of The University Of California | Vaporizer for an anesthetic having a vapor pressure about one atmosphere |
| US4892109A (en) | 1989-03-08 | 1990-01-09 | Brown & Williamson Tobacco Corporation | Simulated smoking article |
| DE3908161A1 (en) | 1989-03-13 | 1990-09-27 | Bat Cigarettenfab Gmbh | Smokable article |
| GB8909891D0 (en) | 1989-04-28 | 1989-06-14 | Riker Laboratories Inc | Device |
| EP0705614B1 (en) | 1989-04-28 | 2002-09-25 | Riker Laboratories, Inc. | Dry powder inhalation device |
| KR920700648A (en) | 1989-05-05 | 1992-08-10 | 오닐 크리스토퍼 | Increased fertility |
| US4941483A (en) | 1989-09-18 | 1990-07-17 | R. J. Reynolds Tobacco Company | Aerosol delivery article |
| US6313176B1 (en) | 1989-10-17 | 2001-11-06 | Everett J. Ellinwood, Jr. | Dosing method of administering deprenyl via intraoral administration or inhalation administration |
| US6048857A (en) | 1989-10-17 | 2000-04-11 | Ellinwood, Jr.; Everett H. | Dosing method of administering medicaments via inhalation administration |
| US5707644A (en) | 1989-11-04 | 1998-01-13 | Danbiosyst Uk Limited | Small particle compositions for intranasal drug delivery |
| US5408574A (en) | 1989-12-01 | 1995-04-18 | Philip Morris Incorporated | Flat ceramic heater having discrete heating zones |
| US5144962A (en) | 1989-12-01 | 1992-09-08 | Philip Morris Incorporated | Flavor-delivery article |
| US5224498A (en) * | 1989-12-01 | 1993-07-06 | Philip Morris Incorporated | Electrically-powered heating element |
| US5269327A (en) | 1989-12-01 | 1993-12-14 | Philip Morris Incorporated | Electrical smoking article |
| US5093894A (en) | 1989-12-01 | 1992-03-03 | Philip Morris Incorporated | Electrically-powered linear heating element |
| US5060671A (en) * | 1989-12-01 | 1991-10-29 | Philip Morris Incorporated | Flavor generating article |
| US5109180A (en) | 1989-12-14 | 1992-04-28 | Phillips Petroleum Company | Apparatus providing a shatter-resistant electric lamp |
| US5733572A (en) | 1989-12-22 | 1998-03-31 | Imarx Pharmaceutical Corp. | Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles |
| US5580575A (en) | 1989-12-22 | 1996-12-03 | Imarx Pharmaceutical Corp. | Therapeutic drug delivery systems |
| GB2239807A (en) | 1990-01-09 | 1991-07-17 | Boc Group Plc | Anaesthetic vaporiser |
| US5376386A (en) | 1990-01-24 | 1994-12-27 | British Technology Group Limited | Aerosol carriers |
| US5099861A (en) | 1990-02-27 | 1992-03-31 | R. J. Reynolds Tobacco Company | Aerosol delivery article |
| US5156170A (en) | 1990-02-27 | 1992-10-20 | R. J. Reynolds Tobacco Company | Cigarette |
| US5118494A (en) | 1990-03-23 | 1992-06-02 | Minnesota Mining And Manufacturing Company | Use of soluble fluorosurfactants for the preparation of metered-dose aerosol formulations |
| US5366770A (en) | 1990-04-17 | 1994-11-22 | Xingwu Wang | Aerosol-plasma deposition of films for electronic cells |
| US5229382A (en) | 1990-04-25 | 1993-07-20 | Lilly Industries Limited | 2-methyl-thieno-benzodiazepine |
| US5192548A (en) | 1990-04-30 | 1993-03-09 | Riker Laboratoires, Inc. | Device |
| MC2210A1 (en) | 1990-06-07 | 1992-11-26 | Wellcome Found | THERAPEUTIC HETEROCYCLIC COMPOUNDS, THEIR USE AND PROCESS FOR PREPARING THEM |
| US5167242A (en) | 1990-06-08 | 1992-12-01 | Kabi Pharmacia Aktiebolaq | Nicotine-impermeable container and method of fabricating the same |
| US5455043A (en) | 1990-06-13 | 1995-10-03 | Fischel-Ghodsian; Fariba | Device for controlled release of vaporous medications through nasal route |
| US5126123A (en) | 1990-06-28 | 1992-06-30 | Glaxo, Inc. | Aerosol drug formulations |
| EP0469797B2 (en) | 1990-08-02 | 2001-12-12 | Datex-Ohmeda Inc. | Anaesthetic vaporiser |
| US5060667A (en) | 1990-08-16 | 1991-10-29 | Brown & Williamson Tobacco Corporation | Smoking article |
| US5292499A (en) | 1990-09-11 | 1994-03-08 | University Of Wales College Of Cardiff | Method of preparing medical aerosol formulations including drug dissolved in reverse micelles |
| US5166202A (en) | 1990-09-19 | 1992-11-24 | Trustees Of The University Of Pennsylvania | Method for the treatment of panic disorder |
| NO904226D0 (en) * | 1990-09-28 | 1990-09-28 | Forsvarets Forsknings | MOISTURE DEVICES. |
| US5179966A (en) | 1990-11-19 | 1993-01-19 | Philip Morris Incorporated | Flavor generating article |
| US5095921A (en) | 1990-11-19 | 1992-03-17 | Philip Morris Incorporated | Flavor generating article |
| HU219778B (en) | 1990-12-21 | 2001-07-30 | Gyógyszerkutató Intézet Közös Vállalat | Process for producing n-acyl-2,3-benzodiazepine derivatives, their acid additional salts and pharmaceutical compositions containing them and a grop of the compounds and pharmaceutical compositions containing them |
| US5519019A (en) | 1990-12-21 | 1996-05-21 | Gyogyszerkutato Intezet | N-acyl-2,3-benzoidazepine derivatives, pharmaceutical compositions containing them and process for preparing same |
| FR2671487B1 (en) | 1991-01-14 | 1993-03-19 | Oreal | USE OF A GROWTH FACTOR IN A SLIMMING COMPOSITION. |
| DE69229070T2 (en) | 1991-02-09 | 1999-11-18 | B S D Bio Science Dev Snc Di O | Antireactive anti-asthmatic effects of acetylsalicylic acid by inhalation |
| US5226411A (en) | 1991-03-07 | 1993-07-13 | Walter Levine | Aerosol nebulizer heater |
| US5505214A (en) | 1991-03-11 | 1996-04-09 | Philip Morris Incorporated | Electrical smoking article and method for making same |
| US5249586A (en) * | 1991-03-11 | 1993-10-05 | Philip Morris Incorporated | Electrical smoking |
| US5479948A (en) | 1993-08-10 | 1996-01-02 | Philip Morris Incorporated | Electrical smoking article having continuous tobacco flavor web and flavor cassette therefor |
| US5186164A (en) | 1991-03-15 | 1993-02-16 | Puthalath Raghuprasad | Mist inhaler |
| US5993805A (en) | 1991-04-10 | 1999-11-30 | Quadrant Healthcare (Uk) Limited | Spray-dried microparticles and their use as therapeutic vehicles |
| US5817656A (en) | 1991-04-23 | 1998-10-06 | Eli Lilly And Company | Mental disorders |
| US5605897A (en) | 1991-04-23 | 1997-02-25 | Eli Lilly And Company | 2-methyl-thieno-benzodiazepine |
| US5627178A (en) | 1991-04-23 | 1997-05-06 | Lilly Industries Limited | 2-methyl-thieno-benzodiazepine |
| US5938117A (en) | 1991-04-24 | 1999-08-17 | Aerogen, Inc. | Methods and apparatus for dispensing liquids as an atomized spray |
| US5164740A (en) | 1991-04-24 | 1992-11-17 | Yehuda Ivri | High frequency printing mechanism |
| GB9109442D0 (en) | 1991-05-01 | 1991-06-26 | Volex Group Plc | Apparatus for emitting a chemical agent |
| US5160664A (en) | 1991-05-31 | 1992-11-03 | Msp Corporation | High output monodisperse aerosol generator |
| US5261424A (en) * | 1991-05-31 | 1993-11-16 | Philip Morris Incorporated | Control device for flavor-generating article |
| US5149538A (en) | 1991-06-14 | 1992-09-22 | Warner-Lambert Company | Misuse-resistive transdermal opioid dosage form |
| US5177071A (en) | 1991-06-17 | 1993-01-05 | Merck & Co., Inc. | 1,4-benzodiazepines with 6-membered heterocyclic rings to treat panic and anxiety disorder |
| CA2069687A1 (en) | 1991-06-28 | 1992-12-29 | Chandra Kumar Banerjee | Tobacco smoking article with electrochemical heat source |
| US5285798A (en) | 1991-06-28 | 1994-02-15 | R. J. Reynolds Tobacco Company | Tobacco smoking article with electrochemical heat source |
| US5457100A (en) | 1991-12-02 | 1995-10-10 | Daniel; David G. | Method for treatment of recurrent paroxysmal neuropsychiatric |
| US5363842A (en) * | 1991-12-20 | 1994-11-15 | Circadian, Inc. | Intelligent inhaler providing feedback to both patient and medical professional |
| GB9200047D0 (en) | 1992-01-03 | 1992-02-26 | Univ Alberta | Nicotine-containing nasal spray |
| US5229120A (en) | 1992-02-05 | 1993-07-20 | Devincent James F | Treatment for cocaine abuse |
| US5639441A (en) | 1992-03-06 | 1997-06-17 | Board Of Regents Of University Of Colorado | Methods for fine particle formation |
| DK64592D0 (en) | 1992-05-14 | 1992-05-14 | Carlbiotech Ltd As | PEPTIDES FOR THERAPEUTIC TREATMENT |
| US5391081A (en) | 1992-05-13 | 1995-02-21 | University Of Florida Research Foundation, Incorporated | Method and apparatus for simulating neuromuscular stimulation during medical surgery |
| US5584701A (en) | 1992-05-13 | 1996-12-17 | University Of Florida Research Foundation, Incorporated | Self regulating lung for simulated medical procedures |
| US5525329A (en) | 1992-05-21 | 1996-06-11 | The Johns Hopkins University | Inhibition of phosphodiesterase in olfactory mucosa |
| US5607691A (en) | 1992-06-12 | 1997-03-04 | Affymax Technologies N.V. | Compositions and methods for enhanced drug delivery |
| US5626871A (en) | 1992-06-12 | 1997-05-06 | Teijin Limited | Preparation for intratracheobronchial administration |
| US5622944A (en) | 1992-06-12 | 1997-04-22 | Affymax Technologies N.V. | Testosterone prodrugs for improved drug delivery |
| US5284133A (en) | 1992-07-23 | 1994-02-08 | Armstrong Pharmaceuticals, Inc. | Inhalation device with a dose-timer, an actuator mechanism, and patient compliance monitoring means |
| US5322075A (en) | 1992-09-10 | 1994-06-21 | Philip Morris Incorporated | Heater for an electric flavor-generating article |
| US5613505A (en) | 1992-09-11 | 1997-03-25 | Philip Morris Incorporated | Inductive heating systems for smoking articles |
| US5333106A (en) | 1992-10-09 | 1994-07-26 | Circadian, Inc. | Apparatus and visual display method for training in the power use of aerosol pharmaceutical inhalers |
| US5915378A (en) | 1993-01-29 | 1999-06-29 | Aradigm Corporation | Creating an aerosolized formulation of insulin |
| US5970973A (en) * | 1993-01-29 | 1999-10-26 | Aradigm Corporation | Method of delivering insulin lispro |
| US5743250A (en) | 1993-01-29 | 1998-04-28 | Aradigm Corporation | Insulin delivery enhanced by coached breathing |
| US5934272A (en) | 1993-01-29 | 1999-08-10 | Aradigm Corporation | Device and method of creating aerosolized mist of respiratory drug |
| US6098620A (en) | 1993-01-29 | 2000-08-08 | Aradigm Corporation | Device for aerosolizing narcotics |
| US5724957A (en) | 1993-01-29 | 1998-03-10 | Aradigm Corporation | Intrapulmonary delivery of narcotics |
| US5672581A (en) * | 1993-01-29 | 1997-09-30 | Aradigm Corporation | Method of administration of insulin |
| US6024090A (en) | 1993-01-29 | 2000-02-15 | Aradigm Corporation | Method of treating a diabetic patient by aerosolized administration of insulin lispro |
| US5558085A (en) | 1993-01-29 | 1996-09-24 | Aradigm Corporation | Intrapulmonary delivery of peptide drugs |
| US5694919A (en) | 1993-01-29 | 1997-12-09 | Aradigm Corporation | Lockout device for controlled release of drug from patient-activated dispenser |
| US5888477A (en) | 1993-01-29 | 1999-03-30 | Aradigm Corporation | Use of monomeric insulin as a means for improving the bioavailability of inhaled insulin |
| US5364838A (en) | 1993-01-29 | 1994-11-15 | Miris Medical Corporation | Method of administration of insulin |
| US5507277A (en) | 1993-01-29 | 1996-04-16 | Aradigm Corporation | Lockout device for controlled release of drug from patient-activateddispenser |
| US5372148A (en) * | 1993-02-24 | 1994-12-13 | Philip Morris Incorporated | Method and apparatus for controlling the supply of energy to a heating load in a smoking article |
| US5468936A (en) | 1993-03-23 | 1995-11-21 | Philip Morris Incorporated | Heater having a multiple-layer ceramic substrate and method of fabrication |
| GB9310412D0 (en) | 1993-05-20 | 1993-07-07 | Danbiosyst Uk | Nasal nicotine system |
| US5497763A (en) | 1993-05-21 | 1996-03-12 | Aradigm Corporation | Disposable package for intrapulmonary delivery of aerosolized formulations |
| CZ287275B6 (en) | 1993-06-03 | 2000-10-11 | Schrader Barthold Von | Inhalation apparatus |
| US5666977A (en) * | 1993-06-10 | 1997-09-16 | Philip Morris Incorporated | Electrical smoking article using liquid tobacco flavor medium delivery system |
| ES2171455T3 (en) * | 1993-06-29 | 2002-09-16 | Ponwell Entpr Ltd | DISPENSER. |
| US5388574A (en) * | 1993-07-29 | 1995-02-14 | Ingebrethsen; Bradley J. | Aerosol delivery article |
| DE4328243C1 (en) | 1993-08-19 | 1995-03-09 | Sven Mielordt | Smoke or inhalation device |
| US5456247A (en) | 1993-08-26 | 1995-10-10 | Iowa State University Research Foundation, Inc. | Method for delivering drugs soluble in a vaporization vehicle |
| US5462740A (en) | 1993-09-17 | 1995-10-31 | Athena Neurosciences, Inc. | Rectally-administered, epileptic-seizure-inhibiting composition |
| US5400969A (en) | 1993-09-20 | 1995-03-28 | Keene; Christopher M. | Liquid vaporizer and diffuser |
| SE9303574D0 (en) | 1993-11-01 | 1993-11-01 | Kabi Pharmacia Ab | Composition for drug delivery and method of manufacturing thereof |
| FI98270C (en) | 1993-11-29 | 1997-05-26 | Instrumentarium Oy | Method and apparatus for evaporation of anesthetic agent |
| MA23420A1 (en) | 1994-01-07 | 1995-10-01 | Smithkline Beecham Corp | BICYCLIC FIBRINOGEN ANTAGONISTS. |
| US6143746A (en) | 1994-01-21 | 2000-11-07 | Icos Corporation | Tetracyclic cyclic GMP-specific phosphodiesterase inhibitors, process of preparation and use |
| GB9401894D0 (en) | 1994-02-01 | 1994-03-30 | Rhone Poulenc Rorer Ltd | New compositions of matter |
| US5543434A (en) | 1994-02-25 | 1996-08-06 | Weg; Stuart L. | Nasal administration of ketamine to manage pain |
| US5522008A (en) | 1994-03-16 | 1996-05-28 | Bernard; Costello J. | Device for heating and vaporizing a vaporizable module |
| US5451408A (en) | 1994-03-23 | 1995-09-19 | Liposome Pain Management, Ltd. | Pain management with liposome-encapsulated analgesic drugs |
| AU1975895A (en) | 1994-03-30 | 1995-10-23 | Procter & Gamble Company, The | Combined skin moisturizing and cleansing bar composition |
| US6102036A (en) * | 1994-04-12 | 2000-08-15 | Smoke-Stop | Breath activated inhaler |
| WO1995031182A1 (en) | 1994-05-13 | 1995-11-23 | Aradigm Corporation | Narcotic containing aerosol formulation |
| US5457101A (en) | 1994-06-03 | 1995-10-10 | Eli Lilly And Company | Thieno[1,5]benzoidiazepine use |
| CA2152684A1 (en) | 1994-07-01 | 1996-01-02 | Richard Anthony Henry | Aerosol delivery of midazolam |
| DE4425255A1 (en) | 1994-07-16 | 1996-01-18 | Asta Medica Ag | Formulation for inhalation application |
| JPH10504825A (en) | 1994-08-22 | 1998-05-12 | スミスクライン・ビーチャム・コーポレイション | Bicyclic compound |
| US5456677A (en) | 1994-08-22 | 1995-10-10 | Spector; John E. | Method for oral spray administration of caffeine |
| US5522385A (en) * | 1994-09-27 | 1996-06-04 | Aradigm Corporation | Dynamic particle size control for aerosolized drug delivery |
| US5537507A (en) | 1994-09-28 | 1996-07-16 | Advanced Ceramics Corporation | Coated flash evaporator heater |
| AU3745795A (en) | 1994-10-14 | 1996-05-06 | Glaxo Wellcome S.P.A. | Use of CCK-B receptor antagonists for the treatment of sleepdisorders |
| US5767117A (en) | 1994-11-18 | 1998-06-16 | The General Hospital Corporation | Method for treating vascular headaches |
| US5540959A (en) | 1995-02-21 | 1996-07-30 | Howard J. Greenwald | Process for preparing a coated substrate |
| EP0810853B1 (en) | 1995-02-24 | 2004-08-25 | Elan Pharma International Limited | Aerosols containing nanoparticle dispersions |
| US5747001A (en) | 1995-02-24 | 1998-05-05 | Nanosystems, L.L.C. | Aerosols containing beclomethazone nanoparticle dispersions |
| DE19507410C2 (en) | 1995-03-03 | 1997-05-22 | Gsf Forschungszentrum Umwelt | Method and device for producing aerosols |
| US5565148A (en) | 1995-03-16 | 1996-10-15 | Minnesota Mining And Manufacturing Company | Device for selectively providing a multiplicity of aromas |
| US5823180A (en) * | 1995-04-03 | 1998-10-20 | The General Hospital Corporation | Methods for treating pulmonary vasoconstriction and asthma |
| US6014970A (en) | 1998-06-11 | 2000-01-18 | Aerogen, Inc. | Methods and apparatus for storing chemical compounds in a portable inhaler |
| US5758637A (en) | 1995-08-31 | 1998-06-02 | Aerogen, Inc. | Liquid dispensing apparatus and methods |
| US5586550A (en) | 1995-08-31 | 1996-12-24 | Fluid Propulsion Technologies, Inc. | Apparatus and methods for the delivery of therapeutic liquids to the respiratory system |
| US5612053A (en) | 1995-04-07 | 1997-03-18 | Edward Mendell Co., Inc. | Controlled release insufflation carrier for medicaments |
| NZ306280A (en) | 1995-04-14 | 1999-07-29 | Glaxo Wellcome Inc | Metered dose inhaler for salmeterol |
| BR9604976A (en) | 1995-04-14 | 1998-06-09 | Glaxo Wellcome Inc | Metered dose inhaler metered dose inhaler system and use |
| EP0820414B1 (en) | 1995-04-14 | 2004-02-04 | SmithKline Beecham Corporation | Metered dose inhaler for beclomethasone dipropionate |
| US5725756A (en) | 1995-04-18 | 1998-03-10 | Center For Research, Inc. | In situ mitigation of coke buildup in porous catalysts with supercritical reaction media |
| US5690809A (en) | 1995-04-18 | 1997-11-25 | Center For Research, Inc. | In situ mitigation of coke buildup in porous catalysts by pretreatment of hydrocarbon feed to reduce peroxides and oxygen impurities |
| US5776928A (en) | 1995-04-21 | 1998-07-07 | Eli Lilly And Company | Method for treating dyskinesias with olanzapine |
| FR2733594B1 (en) | 1995-04-28 | 1997-06-06 | France Etat | DEVICE FOR THE SAMPLING OF GASEOUS SUBSTANCES, LIQUIDS, AEROSOLS OR EVEN OF POWDERY MATERIALS, FOR THEIR IN SITU ANALYSIS |
| US5809997A (en) * | 1995-05-18 | 1998-09-22 | Medtrac Technologies, Inc. | Electronic medication chronolog device |
| US5874481A (en) | 1995-06-07 | 1999-02-23 | Alliance Pharmaceutical Corp. | Fluorochemical solutions for the delivery of lipophilic pharmaceutical agents |
| US6672304B1 (en) * | 1995-06-08 | 2004-01-06 | Innovative Devices, Llc | Inhalation actuated device for use with metered dose inhalers (MDIs) |
| GB9512708D0 (en) | 1995-06-22 | 1995-08-23 | Reckitt & Colman Inc | Improvements in or relating to organic compounds |
| US6245347B1 (en) | 1995-07-28 | 2001-06-12 | Zars, Inc. | Methods and apparatus for improved administration of pharmaceutically active compounds |
| US6209538B1 (en) | 1995-08-02 | 2001-04-03 | Robert A. Casper | Dry powder medicament inhalator having an inhalation-activated flow diverting means for triggering delivery of medicament |
| US5591409A (en) | 1995-08-15 | 1997-01-07 | Watkins; Carl J. | Providing aromas |
| SE9503141D0 (en) | 1995-09-12 | 1995-09-12 | Siemens Elema Ab | Anesthesia apparatus |
| US5649554A (en) | 1995-10-16 | 1997-07-22 | Philip Morris Incorporated | Electrical lighter with a rotatable tobacco supply |
| US6013050A (en) | 1995-10-20 | 2000-01-11 | Powderject Research Limited | Particle delivery |
| US5564442A (en) | 1995-11-22 | 1996-10-15 | Angus Collingwood MacDonald | Battery powered nicotine vaporizer |
| US6041777A (en) | 1995-12-01 | 2000-03-28 | Alliance Pharmaceutical Corp. | Methods and apparatus for closed-circuit ventilation therapy |
| DK0870497T3 (en) | 1995-12-14 | 2004-05-24 | Taisho Pharmaceutical Co Ltd | aerosol |
| SE9504580L (en) | 1995-12-21 | 1997-06-22 | Siemens Elema Ab | Procedure for gasification of an anesthetic fluid and a carburetor |
| US5829436A (en) | 1996-02-05 | 1998-11-03 | Aradigm Corporation | Ventilation imaging using a fine particle aerosol generator |
| AUPN814496A0 (en) | 1996-02-19 | 1996-03-14 | Monash University | Dermal penetration enhancer |
| GB9604329D0 (en) | 1996-02-29 | 1996-05-01 | Ici Plc | Electrostatic spraying |
| US5833891A (en) | 1996-10-09 | 1998-11-10 | The University Of Kansas | Methods for a particle precipitation and coating using near-critical and supercritical antisolvents |
| JPH11505547A (en) | 1996-03-13 | 1999-05-21 | エール ユニバーシティ | Smoking cessation treatment with naltrexone and related compounds |
| US5944012A (en) | 1996-03-25 | 1999-08-31 | Pera; Ivo E. | Method for dispensing antioxidant vitamins by inhalation background of the invention |
| US5875776A (en) | 1996-04-09 | 1999-03-02 | Vivorx Pharmaceuticals, Inc. | Dry powder inhaler |
| GB2312848B (en) * | 1996-04-26 | 1999-11-17 | Bespak Plc | Controlled flow inhalers |
| AU724503B2 (en) * | 1996-04-29 | 2000-09-21 | Dura Pharmaceuticals, Inc. | Methods of dry powder inhalation |
| US5743251A (en) | 1996-05-15 | 1998-04-28 | Philip Morris Incorporated | Aerosol and a method and apparatus for generating an aerosol |
| US5855913A (en) | 1997-01-16 | 1999-01-05 | Massachusetts Instite Of Technology | Particles incorporating surfactants for pulmonary drug delivery |
| US5874064A (en) | 1996-05-24 | 1999-02-23 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
| US5985309A (en) | 1996-05-24 | 1999-11-16 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
| US5929093A (en) | 1996-06-13 | 1999-07-27 | Mayo Foundation For Medical Education And Research | Bifunctional acetylcholinesterase reactivators |
| DE69719719T2 (en) | 1996-06-17 | 2004-03-25 | Japan Tobacco Inc. | FLAVORING ITEMS AND FLAVORING DEVICE |
| GB9613015D0 (en) | 1996-06-21 | 1996-08-28 | Reckitt & Colman Inc | Device |
| US6089857A (en) | 1996-06-21 | 2000-07-18 | Japan Tobacco, Inc. | Heater for generating flavor and flavor generation appliance |
| US6004516A (en) | 1996-08-06 | 1999-12-21 | Illinois Institute Of Technology | Apparatus for generating odor upon electronic signal demand |
| US6325475B1 (en) | 1996-09-06 | 2001-12-04 | Microfab Technologies Inc. | Devices for presenting airborne materials to the nose |
| PT951280E (en) | 1996-10-03 | 2004-05-31 | Hermes Biosciences Inc | HYDROPHILIC MICROPARTICLES AND METHODS FOR THEIR PREPARATION |
| US5934289A (en) * | 1996-10-22 | 1999-08-10 | Philip Morris Incorporated | Electronic smoking system |
| US5906202A (en) | 1996-11-21 | 1999-05-25 | Aradigm Corporation | Device and method for directing aerosolized mist to a specific area of the respiratory tract |
| US6694975B2 (en) | 1996-11-21 | 2004-02-24 | Aradigm Corporation | Temperature controlling device for aerosol drug delivery |
| US6131570A (en) | 1998-06-30 | 2000-10-17 | Aradigm Corporation | Temperature controlling device for aerosol drug delivery |
| US5878752A (en) | 1996-11-25 | 1999-03-09 | Philip Morris Incorporated | Method and apparatus for using, cleaning, and maintaining electrical heat sources and lighters useful in smoking systems and other apparatuses |
| US5744469A (en) | 1996-11-26 | 1998-04-28 | Eli Lilly And Company | Method for treating dermatitis |
| CA2222830C (en) | 1996-12-02 | 2004-03-30 | Fisher & Paykel Limited | Humidifier sleep apnea treatment apparatus |
| ES2178817T3 (en) | 1997-02-05 | 2003-01-01 | Jago Res Ag | AEROSOL MEDICINAL FORMULATIONS. |
| US6126919A (en) | 1997-02-07 | 2000-10-03 | 3M Innovative Properties Company | Biocompatible compounds for pharmaceutical drug delivery systems |
| US6051257A (en) | 1997-02-24 | 2000-04-18 | Superior Micropowders, Llc | Powder batch of pharmaceutically-active particles and methods for making same |
| US5769621A (en) | 1997-05-23 | 1998-06-23 | The Regents Of The University Of California | Laser ablation based fuel ignition |
| US5907075A (en) | 1997-06-11 | 1999-05-25 | The University Of Kansas | Solid acid supercritical alkylation reactions using carbon dioxide and/or other co-solvents |
| US5906811A (en) | 1997-06-27 | 1999-05-25 | Thione International, Inc. | Intra-oral antioxidant preparations |
| US5928520A (en) | 1997-07-16 | 1999-07-27 | Abanaki Corporation | Method and apparatus for extracting ground water contaiminants |
| KR100289448B1 (en) | 1997-07-23 | 2001-05-02 | 미즈노 마사루 | Flavor generator |
| US6090212A (en) | 1997-08-15 | 2000-07-18 | Micro C Technologies, Inc. | Substrate platform for a semiconductor substrate during rapid high temperature processing and method of supporting a substrate |
| US5855564A (en) | 1997-08-20 | 1999-01-05 | Aradigm Corporation | Aerosol extrusion mechanism |
| US6250301B1 (en) | 1997-08-28 | 2001-06-26 | Hortal Harm B.V. | Vaporizer for inhalation and method for extraction of active ingredients from a crude natural product or other matrix |
| US6138683A (en) | 1997-09-19 | 2000-10-31 | Thione International, Inc. | Smokeless tobacco products containing antioxidants |
| US6390453B1 (en) | 1997-10-22 | 2002-05-21 | Microfab Technologies, Inc. | Method and apparatus for delivery of fragrances and vapors to the nose |
| US6403597B1 (en) | 1997-10-28 | 2002-06-11 | Vivus, Inc. | Administration of phosphodiesterase inhibitors for the treatment of premature ejaculation |
| US6044777A (en) | 1998-02-09 | 2000-04-04 | Walsh; Michael J. | Composite metal safe and method of making |
| US6158431A (en) | 1998-02-13 | 2000-12-12 | Tsi Incorporated | Portable systems and methods for delivery of therapeutic material to the pulmonary system |
| US5996589A (en) | 1998-03-03 | 1999-12-07 | Brown & Williamson Tobacco Corporation | Aerosol-delivery smoking article |
| CA2322805C (en) | 1998-03-05 | 2005-09-13 | Nippon Shinyaku Co., Ltd. | Fat emulsions for inhalational administration |
| RU2219924C2 (en) | 1998-04-14 | 2003-12-27 | Дзе Дженерал Хоспитал Корпорейшн | Method for treatment of neuropsychiatric disorders |
| US6095153A (en) | 1998-06-19 | 2000-08-01 | Kessler; Stephen B. | Vaporization of volatile materials |
| TWI223598B (en) | 1998-06-22 | 2004-11-11 | Pfizer Ireland Pharmaceuticals | An intranasal pharmaceutical composition for the treatment of male erectile dysfunction or female sexual disorders, an intranasal delivery system or device and sildenafil mesylate |
| US6241969B1 (en) | 1998-06-26 | 2001-06-05 | Elan Corporation Plc | Aqueous compositions containing corticosteroids for nasal and pulmonary delivery |
| US6090403A (en) | 1998-08-17 | 2000-07-18 | Lectec Corporation | Inhalation therapy decongestant with foraminous carrier |
| US6234167B1 (en) * | 1998-10-14 | 2001-05-22 | Chrysalis Technologies, Incorporated | Aerosol generator and methods of making and using an aerosol generator |
| US6509005B1 (en) | 1998-10-27 | 2003-01-21 | Virginia Commonwealth University | Δ9 Tetrahydrocannabinol (Δ9 THC) solution metered dose inhaler |
| US6255334B1 (en) | 1998-10-30 | 2001-07-03 | Pfizer Inc | 5HT 1 receptor agonists and metoclopramide for the treatment of migraine |
| DE19854007C2 (en) | 1998-11-12 | 2001-05-17 | Reemtsma H F & Ph | Inhalable aerosol delivery system |
| US6113795A (en) | 1998-11-17 | 2000-09-05 | The University Of Kansas | Process and apparatus for size selective separation of micro- and nano-particles |
| JP3506618B2 (en) | 1998-11-18 | 2004-03-15 | ウシオ電機株式会社 | Incandescent light bulb for yellow light emission |
| US6376550B1 (en) | 1999-02-09 | 2002-04-23 | Asta Medica Ag | Pharmaceutical compositions containing tramadol for migraine |
| US6591839B2 (en) | 1999-02-17 | 2003-07-15 | Dieter Meyer | Filter material for reducing harmful substances in tobacco smoke |
| US6053176A (en) * | 1999-02-23 | 2000-04-25 | Philip Morris Incorporated | Heater and method for efficiently generating an aerosol from an indexing substrate |
| US6309986B1 (en) | 1999-05-07 | 2001-10-30 | S. C. Johnson & Son, Inc. | Mat for dispensing volatile materials |
| US20020061281A1 (en) | 1999-07-06 | 2002-05-23 | Osbakken Robert S. | Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis |
| NZ517575A (en) | 1999-09-30 | 2004-04-30 | Neurogen Corp | Certain alkylene diamine-substituted heterocycles |
| DE10001035A1 (en) | 2000-01-13 | 2001-07-26 | Bayer Ag | Active ingredient chip with integrated heating element |
| CN100341483C (en) | 2000-02-28 | 2007-10-10 | 维克丘拉有限公司 | Improvements in or relating to delivery of oral drugs |
| US6443151B1 (en) * | 2000-03-08 | 2002-09-03 | Aradigm Corporation | Fluid velocity-sensitive trigger mechanism |
| BR0109685B1 (en) | 2000-03-23 | 2013-07-23 | electric smoking system and method for cigarette smoking for electric smoking system | |
| US6632047B2 (en) | 2000-04-14 | 2003-10-14 | Board Of Regents, The University Of Texas System | Heater element for use in an in situ thermal desorption soil remediation system |
| JP2001299916A (en) | 2000-04-18 | 2001-10-30 | Kao Corp | Mask-shaped inhalator |
| MY136453A (en) | 2000-04-27 | 2008-10-31 | Philip Morris Usa Inc | "improved method and apparatus for generating an aerosol" |
| WO2001093846A2 (en) | 2000-05-23 | 2001-12-13 | The Trustees Of Columbia University In The City Of New York | Method for treating respiratory disorders associated with pulmonary elastic fiber injury comprising the use of clycosaminoglycans |
| FR2812545B1 (en) | 2000-08-03 | 2003-03-28 | Air Liquide Sante Int | INHALABLE DRUG AEROSOL FOR TREATMENT OR PREVENTION OF SWEETNESS |
| US6514482B1 (en) | 2000-09-19 | 2003-02-04 | Advanced Inhalation Research, Inc. | Pulmonary delivery in treating disorders of the central nervous system |
| US6613308B2 (en) | 2000-09-19 | 2003-09-02 | Advanced Inhalation Research, Inc. | Pulmonary delivery in treating disorders of the central nervous system |
| AU2002246500A1 (en) | 2000-10-27 | 2002-07-30 | Emlin Biosciences | Thermal vaporizing device for drug delivery |
| US20030121906A1 (en) | 2000-11-29 | 2003-07-03 | Abbott Richard C. | Resistive heaters and uses thereof |
| US6701921B2 (en) * | 2000-12-22 | 2004-03-09 | Chrysalis Technologies Incorporated | Aerosol generator having heater in multilayered composite and method of use thereof |
| US6501052B2 (en) | 2000-12-22 | 2002-12-31 | Chrysalis Technologies Incorporated | Aerosol generator having multiple heating zones and methods of use thereof |
| US6799572B2 (en) | 2000-12-22 | 2004-10-05 | Chrysalis Technologies Incorporated | Disposable aerosol generator system and methods for administering the aerosol |
| US6681998B2 (en) | 2000-12-22 | 2004-01-27 | Chrysalis Technologies Incorporated | Aerosol generator having inductive heater and method of use thereof |
| US6491233B2 (en) | 2000-12-22 | 2002-12-10 | Chrysalis Technologies Incorporated | Vapor driven aerosol generator and method of use thereof |
| US6443152B1 (en) | 2001-01-12 | 2002-09-03 | Becton Dickinson And Company | Medicament respiratory delivery device |
| US6680668B2 (en) | 2001-01-19 | 2004-01-20 | Vishay Intertechnology, Inc. | Fast heat rise resistor using resistive foil |
| WO2002074247A2 (en) | 2001-03-19 | 2002-09-26 | Praecis Pharmaceuticals Incorporated | Pharmaceutical formulations for sustained release |
| US20030004142A1 (en) | 2001-04-18 | 2003-01-02 | Prior Christopher P. | Use of NSAIDs for prevention and treatment of cellular abnormalities of the lung or bronchial pathway |
| US20070122353A1 (en) | 2001-05-24 | 2007-05-31 | Hale Ron L | Drug condensation aerosols and kits |
| US7458374B2 (en) | 2002-05-13 | 2008-12-02 | Alexza Pharmaceuticals, Inc. | Method and apparatus for vaporizing a compound |
| WO2002094244A2 (en) | 2001-05-24 | 2002-11-28 | Alexza Molecular Delivery Corporation | Delivery of benzodiazepines through an inhalation route |
| US7766013B2 (en) | 2001-06-05 | 2010-08-03 | Alexza Pharmaceuticals, Inc. | Aerosol generating method and device |
| US6759029B2 (en) | 2001-05-24 | 2004-07-06 | Alexza Molecular Delivery Corporation | Delivery of rizatriptan and zolmitriptan through an inhalation route |
| US7585493B2 (en) | 2001-05-24 | 2009-09-08 | Alexza Pharmaceuticals, Inc. | Thin-film drug delivery article and method of use |
| US7078016B2 (en) | 2001-11-21 | 2006-07-18 | Alexza Pharmaceuticals, Inc. | Delivery of caffeine through an inhalation route |
| US7645442B2 (en) | 2001-05-24 | 2010-01-12 | Alexza Pharmaceuticals, Inc. | Rapid-heating drug delivery article and method of use |
| US6737042B2 (en) | 2001-05-24 | 2004-05-18 | Alexza Molecular Delivery Corporation | Delivery of drug esters through an inhalation route |
| US7090830B2 (en) | 2001-05-24 | 2006-08-15 | Alexza Pharmaceuticals, Inc. | Drug condensation aerosols and kits |
| US7498019B2 (en) | 2001-05-24 | 2009-03-03 | Alexza Pharmaceuticals, Inc. | Delivery of compounds for the treatment of headache through an inhalation route |
| US20030118512A1 (en) | 2001-10-30 | 2003-06-26 | Shen William W. | Volatilization of a drug from an inclusion complex |
| US6805853B2 (en) | 2001-11-09 | 2004-10-19 | Alexza Molecular Delivery Corporation | Delivery of diazepam through an inhalation route |
| US6737043B2 (en) | 2001-05-24 | 2004-05-18 | Alexza Molecula Delivery Corporation | Delivery of alprazolam, estazolam, midazolam or triazolam through an inhalation route |
| EP2495004B1 (en) | 2001-07-31 | 2014-04-16 | Philip Morris Products S.a.s. | Method and apparatus for generating a volatilized material |
| US6568390B2 (en) | 2001-09-21 | 2003-05-27 | Chrysalis Technologies Incorporated | Dual capillary fluid vaporizing device |
| US6648950B2 (en) | 2001-10-15 | 2003-11-18 | Hewlett-Packard Development Company, L.P. | Electro-thermal odor-releasing inks and methods for releasing odors from the same |
| US6779520B2 (en) * | 2001-10-30 | 2004-08-24 | Iep Pharmaceutical Devices Inc. | Breath actuated dry powder inhaler |
| WO2003045484A2 (en) | 2001-11-21 | 2003-06-05 | Alexza Molecular Delivery Corporation | Open-celled substrates for drug delivery |
| US20030106551A1 (en) | 2001-12-06 | 2003-06-12 | Sprinkel F. Murphy | Resistive heater formed inside a fluid passage of a fluid vaporizing device |
| US6681769B2 (en) | 2001-12-06 | 2004-01-27 | Crysalis Technologies Incorporated | Aerosol generator having a multiple path heater arrangement and method of use thereof |
| CN1176075C (en) | 2001-12-07 | 2004-11-17 | 北京燕山石油化工公司研究院 | Pyrrole derivative preparation method |
| AU2002361742A1 (en) | 2001-12-18 | 2003-06-30 | Alexza Molecular Delivery Corporation | Parental analgesic formulations comprising fentanyl and a cannabinoid receptor agonist |
| US6701922B2 (en) * | 2001-12-20 | 2004-03-09 | Chrysalis Technologies Incorporated | Mouthpiece entrainment airflow control for aerosol generators |
| US6772756B2 (en) * | 2002-02-09 | 2004-08-10 | Advanced Inhalation Revolutions Inc. | Method and system for vaporization of a substance |
| US6961515B2 (en) | 2002-02-15 | 2005-11-01 | Dekko Technologies, Inc. | PTC heater with flexible printed circuit board |
| US6728478B2 (en) | 2002-02-21 | 2004-04-27 | Dekko Heating Technologies, Inc. | Heated chemical delivery system |
| EP1503744A1 (en) | 2002-05-13 | 2005-02-09 | Alexza Molecular Delivery Corporation | Delivery of drug amines through an inhalation route |
| US20060193788A1 (en) | 2002-11-26 | 2006-08-31 | Hale Ron L | Acute treatment of headache with phenothiazine antipsychotics |
| US6909840B2 (en) | 2002-06-06 | 2005-06-21 | S. C. Johnson & Son, Inc. | Localized surface volatilization |
| CA2497845C (en) | 2002-09-06 | 2012-08-14 | Chrysalis Technologies Incorporated | Liquid aerosol formulations and aerosol generating devices and methods for generating aerosols |
| US6772757B2 (en) * | 2002-10-25 | 2004-08-10 | Chrysalis Technologies Incorporated | Concentric controlled temperature profile fluid vaporizing device |
| CN1717237A (en) | 2002-11-26 | 2006-01-04 | 艾利斯达分子传输公司 | Use of loxapine and amoxapine for the manufacture of a medicament for the treatment of pain |
| US7550133B2 (en) | 2002-11-26 | 2009-06-23 | Alexza Pharmaceuticals, Inc. | Respiratory drug condensation aerosols and methods of making and using them |
| NZ540208A (en) | 2002-11-26 | 2007-09-28 | Alexza Pharmaceuticals Inc | Treatment of headache with antipsychotics delivered by inhalation |
| US20040105818A1 (en) | 2002-11-26 | 2004-06-03 | Alexza Molecular Delivery Corporation | Diuretic aerosols and methods of making and using them |
| ATE520935T1 (en) | 2003-05-21 | 2011-09-15 | Alexza Pharmaceuticals Inc | USE OF A SOLID FUEL LAYER, METHOD FOR PRODUCING SUCH A LAYER AND ASSOCIATED HEATING DEVICE |
| US20050037506A1 (en) | 2003-08-04 | 2005-02-17 | Alexza Molecular Delivery Corporation | Methods of determining film thicknesses for an aerosol delivery article |
| AU2004264344B2 (en) | 2003-08-04 | 2011-02-17 | Alexza Pharmaceuticals, Inc. | Substrates for drug delivery device and methods of preparing and use |
| EP1703932A1 (en) | 2003-12-15 | 2006-09-27 | Alexza Molecular Delivery Corporation | Treatment of breakthrough pain by drug aerosol inhalation |
| WO2005059804A2 (en) | 2003-12-16 | 2005-06-30 | Alexza Pharmaceuticals, Inc. | Methods for monitoring severity of panic attacks and other rapidly evolving medical events in real-time |
| US7402777B2 (en) | 2004-05-20 | 2008-07-22 | Alexza Pharmaceuticals, Inc. | Stable initiator compositions and igniters |
| US7540286B2 (en) | 2004-06-03 | 2009-06-02 | Alexza Pharmaceuticals, Inc. | Multiple dose condensation aerosol devices and methods of forming condensation aerosols |
| AU2004322756B2 (en) | 2004-08-12 | 2011-04-14 | Alexza Pharmaceuticals, Inc. | Aerosol drug delivery device incorporating percussively activated heat packages |
| US20060032496A1 (en) | 2004-08-12 | 2006-02-16 | Alexza Molecular Delivery Corporation | Inhalation actuated percussive ignition system |
| US20060120962A1 (en) | 2004-10-12 | 2006-06-08 | Rabinowitz Joshua D | Cardiac safe, rapid medication delivery |
| WO2008112661A2 (en) | 2007-03-09 | 2008-09-18 | Alexza Pharmaceuticals, Inc. | Heating unit for use in a drug delivery device |
-
2003
- 2003-05-20 US US10/442,385 patent/US7913688B2/en not_active Expired - Fee Related
- 2003-10-16 JP JP2004570754A patent/JP2006507909A/en active Pending
- 2003-10-16 EP EP03789712.1A patent/EP1581281B1/en not_active Expired - Lifetime
- 2003-10-16 WO PCT/US2003/032803 patent/WO2004050139A2/en active Application Filing
- 2003-10-16 NZ NZ540209A patent/NZ540209A/en unknown
- 2003-10-16 MX MXPA05005628A patent/MXPA05005628A/en active IP Right Grant
- 2003-10-16 CA CA002507265A patent/CA2507265A1/en not_active Abandoned
- 2003-10-16 ES ES03789712T patent/ES2702606T3/en not_active Expired - Lifetime
- 2003-10-16 AU AU2003294231A patent/AU2003294231B9/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| EP1581281B1 (en) | 2018-09-26 |
| ES2702606T3 (en) | 2019-03-04 |
| WO2004050139A2 (en) | 2004-06-17 |
| NZ540209A (en) | 2006-11-30 |
| US20040099266A1 (en) | 2004-05-27 |
| US7913688B2 (en) | 2011-03-29 |
| EP1581281A2 (en) | 2005-10-05 |
| MXPA05005628A (en) | 2005-08-16 |
| WO2004050139A3 (en) | 2005-09-15 |
| AU2003294231B9 (en) | 2009-10-22 |
| EP1581281A4 (en) | 2007-06-27 |
| AU2003294231B2 (en) | 2009-09-10 |
| AU2003294231A1 (en) | 2004-06-23 |
| JP2006507909A (en) | 2006-03-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7913688B2 (en) | Inhalation device for producing a drug aerosol | |
| US10543324B2 (en) | Inhaler with a pinch clamp | |
| CA2497871C (en) | Aerosol generating devices and methods for generating aerosols having controlled particle sizes | |
| US20070023043A1 (en) | Actuator for a metered dose inhaler | |
| CA2854037C (en) | Multiple dose condensation aerosol devices and uses thereof | |
| US5437271A (en) | Deagglomerators for dry powder inhalers | |
| US10112019B2 (en) | Dry powder inhaler | |
| US7748385B2 (en) | Valved holding chamber for use with an aerosol medication delivery system | |
| SK78297A3 (en) | An inhalation device, a method of dispersing a pharmaceutically active substance and a method of administering a dose of a pharmaceutically active substance | |
| EP1627655A2 (en) | Apparatus for delivering aerosolized medication | |
| US20030136404A1 (en) | Mouthpiece entrainment airflow control for aerosol generators | |
| AU777488B2 (en) | Method and apparatus for delivering aerosolized medication |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |
Effective date: 20130619 |