US20030051728A1 - Method and device for delivering a physiologically active compound - Google Patents

Method and device for delivering a physiologically active compound Download PDF

Info

Publication number
US20030051728A1
US20030051728A1 US10057198 US5719801A US2003051728A1 US 20030051728 A1 US20030051728 A1 US 20030051728A1 US 10057198 US10057198 US 10057198 US 5719801 A US5719801 A US 5719801A US 2003051728 A1 US2003051728 A1 US 2003051728A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
compound
method
gas
device
heating
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
Application number
US10057198
Inventor
Peter Lloyd
Martin Wensley
Daniel Mufson
Craig Hodges
Daniel Rogers
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alexza Pharmaceuticals Inc
Original Assignee
Alexza Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M11/00Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/04Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised
    • A61M11/041Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised using heaters
    • A61M11/042Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised using heaters electrical
    • A61M11/044Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised using heaters electrical with electrodes immersed in the liquid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4468Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/007Pulmonary tract; Aromatherapy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/007Pulmonary tract; Aromatherapy
    • A61K9/0073Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M11/00Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/001Particle size control
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M11/00Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/02Sprayers or atomisers specially adapted for therapeutic purposes operated by air or other gas pressure applied to the liquid or other product to be sprayed or atomised
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M15/00Inhalators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M15/00Inhalators
    • A61M15/0028Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M16/00Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/10Preparation of respiratory gases or vapours
    • A61M16/1075Preparation of respiratory gases or vapours by influencing the temperature
    • A61M16/109Preparation of respiratory gases or vapours by influencing the temperature the humidifying liquid or the beneficial agent
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B05SPRAYING OR ATOMISING IN GENERAL; APPLYING LIQUIDS OR OTHER FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05BSPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B17/00Apparatus for spraying or atomising liquids or other fluent materials, not covered by the preceding groups
    • B05B17/04Apparatus for spraying or atomising liquids or other fluent materials, not covered by the preceding groups operating with special methods
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B05SPRAYING OR ATOMISING IN GENERAL; APPLYING LIQUIDS OR OTHER FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05BSPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/16Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas incorporating means for heating or cooling the material to be sprayed
    • B05B7/1686Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas incorporating means for heating or cooling the material to be sprayed involving vaporisation of the material to be sprayed or of an atomising-fluid-generating product
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M16/00Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/0003Accessories therefor, e.g. sensors, vibrators, negative pressure
    • A61M2016/003Accessories therefor, e.g. sensors, vibrators, negative pressure with a flowmeter
    • A61M2016/0033Accessories therefor, e.g. sensors, vibrators, negative pressure with a flowmeter electrical
    • A61M2016/0039Accessories therefor, e.g. sensors, vibrators, negative pressure with a flowmeter electrical in the inspiratory circuit
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/36General characteristics of the apparatus related to heating or cooling
    • A61M2205/3606General characteristics of the apparatus related to heating or cooling cooled
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/36General characteristics of the apparatus related to heating or cooling
    • A61M2205/3653General characteristics of the apparatus related to heating or cooling by Joule effect, i.e. electric resistance
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/36General characteristics of the apparatus related to heating or cooling
    • A61M2205/368General characteristics of the apparatus related to heating or cooling by electromagnetic radiation, e.g. IR waves
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/50General characteristics of the apparatus with microprocessors or computers

Abstract

A method and device are provided to generate an aerosol having a desired particle sizes, i.e., from molecular to about 10 microns, which can be used to effectively deliver a physiologically active compound to organs and tissues such as the lung, eye, mucosa and skin. The aerosol is formed through vaporization of the compound while simultaneously mixing the resulting vapor with air or other gas. The purity of the compound is maintained meet FDA requirements by closely controlling its degradant levels during vaporization.

Description

  • This application claims the benefit of prior U.S. provisional application Serial No. 60/296,225 filed Jun. 5, 2001.[0001]
  • FIELD OF THE INVENTION
  • This invention relates to a method and a device for volatilizing a physiologically active compound and administering the volatilized compound in the form of an aerosol to a patient. [0002]
  • BACKGROUND OF THE INVENTION
  • An aerosol is defined as an assembly of liquid or solid particles suspended in a gaseous medium. (See Aerosol Measurement, Willeke and Baron, Wiley-lnterscience 1993.) It is known that aerosols of appropriate particle size, can be used to deliver drugs to organs and tissues such as the lung and mucosa. (See Gonda, I., “Particle Deposition in the Human Respiratory Tract,” [0003] The Lung: Scientific Foundations, 2nd ed., Crystal, West, et al. editors, Lippincott-Raven Publishers, 1997).
  • A problem in generating an aerosol is maintaining the purity of a compound being administered into the lung, as an aerosol. This is a critical issue that must be addressed before inhalation delivery of a compound to humans will be acceptable to regulatory agencies, physicians and patients. Any compound administered to humans must meet strict purity requirements regulated by government agencies and industry. For example, the United States Food and Drug Administration mandates purity requirements for pharmaceutical materials sold in the United States to protect the health of consumers of those products. Purity requirements are often material specific. Maximum impurity or degradant levels are specified at the time of manufacture of compounds as well as at the time of their consumption or administration. Any aerosolization device or process that will be utilized for pharmaceutical applications, therefore, must deliver materials meeting purity requirements. Mechanisms of chemical degradation that might occur during vaporization and aerosolization, the processes relevant to this invention, are discussed below. [0004]
  • Currently approved products for inhalation administration of physiologically acting compounds can be divided into several categories: dry powder inhalers, nebulizers, and pressurized metered dose inhalers. The desired particle size of these methods and devices usually are in the fine aerosol region (1-3 micron) and not in the ultra fine region (10-100 nm). A large percentage of these devices fall short of the type of partical size control desirable for reproducible and efficient delivery of compounds to the lung. Additionally current devices focus on the fine aerosol region because to date a practice device that can reproducibly generate an ultra fine aerosol has not been commercially available for drug delivery to the lung. [0005]
  • There are many types of dry powder inhalers (DPI's) on the market with some common problems. The first problem is the manufacturing of the dry powder. For a dry powder inhalation system it is necessary to mill the drug until it falls into the desirable particle range. Some mills used for micronization are known to produce heat, which can cause degradation of the drug, and tend to shed metallic particles as contaminants. Following milling it is often necessary to mix the drug with a carrier to impart flowability. The micronized drug and the drug-excipient mix must be maintained in a dry atmosphere lest moisture cause agglomeration of the drug into larger particles. Additionally it is well known that many dry powders grow as they are delivered to the patient's airways due to the high levels of moisture present in the lung. Thus, this approach requires scrupulous attention during milling, blending, powder flow, filling and even administration to assure that the patient receives the proper particle size distribution. [0006]
  • Nebulizers generate an aerosol from a liquid, some by breakup of a liquid jet and some by ultrasonic vibration of the liquid with or without a nozzle. All liquid aerosol devices must overcome the problems associated with formulation of the compound into a stable liquid state. Liquid formulations must be prepared and stored under aseptic or sterile conditions since they can harbor microorganisms. This necessitates the use of preservatives or unit dose packaging. Additionally solvents, detergents and other agents are used to stabilize the drug formulation. The FDA is increasingly concerned about airway hypersensitivity from these agents. [0007]
  • Pressurized metered dose inhalers, or pMDI's, are an additional class of aerosol dispensing devices. PMDI's package the compound in a canister under pressure with a solvent and propellant mixture, usually chlorofluorocarbons (CFC's, which are being phased out due to environmental concerns), or hydroflouroalkanes (HFA's). Upon being dispensed a jet of the mixture is ejected through a valve and nozzle and the propellant “flashes off” leaving an aerosol of the compound. With pMDI's particle size is hard to control and has poor reproducibility leading to uneven and unpredictable bioavailability. pMDIs are inefficient because a portion of the dose is lost on the walls of the actuator, and due to the high speed ejection of the aerosol from the nozzle, much of the drug impacts ballistically on the tongue, mouth and throat and never gets to the lung. [0008]
  • Another method suggested in the prior art to generate aerosols is to volatilize the drug and administer the vapor to a patient. (See Rosen, PCT Publication No. 94/09842, published May 11, 1994.) However, the teaching of Rosen is not a viable solution to the problem because it yields (1) a large quantity of degradation products, and (2) too much variability in particle size distribution (PSD) to insure reproducible and predictable bioavailability. [0009]
  • Predicting the reactions that result in a compound's degradation, and anticipating the energies necessary to activate those reactions are typically very difficult. Reactions may involve only the parent compound or may involve other chemicals such as oxygen in air and materials in the surfaces to which the compound may be exposed. Reactions may be single step or multiple steps, leading to the potential of many degradation products. Activation energies of these reactions depend on molecular structures, energy transfer mechanisms, transitory configurations of the reacting molecular complexes, and the effects of neighboring molecules. Frequently, on the practical macroscopic scale, a drug dose may suffer from many degradation reactions in progress at the same time. Because of this complex potential for degradation, drug substances are often stored at or below room temperature. International health authorities recommend that the stability of a drug be evaluated under exaggerated (stress) conditions to determine the mechanism of degradation and the degradant structures. (See Guidance for Industry: Stability testing of drug substances and products; FDA CDER May 27, 1998). For these tests, 50° C. is recognized as a stress temperature. [0010]
  • The present invention overcomes the foregoing disadvantages and problems, making it possible to produce pure aerosols of degradable compounds wherein the particle size is stable and selectable. [0011]
  • SUMMARY OF THE INVENTION
  • Embodiments of the present invention are directed to a method and a device for generating and delivering an aerosol formed through vaporization of a compound with real or potential physiological activity. [0012]
  • A physiologically active compound with real or potential physiological activity is defined here as a chemical compound or mixture of compounds that alters affects, treats, cures, prevents or diagnoses a disease after it is administered to the mammalian body. The compound with real or potential physiological activity will be referred to hereafter as the compound or as the drug. Examples would include medicinal drugs, or “pro-drugs” (substances converted into drugs within the body), that would be administered for the treatment, cure, or diagnosis of diseases. [0013]
  • The method of the present invention for generating an aerosol comprises the steps: [0014]
  • (a) heating the physiologically active compound to a temperature that results in an acceptably low level of decomposition, while [0015]
  • (b) simultaneously passing a gas across the surface of the compound to achieve a desired rate of vaporization. [0016]
  • A desired particle size is typically from molecular to about 10 microns in diameter. Aerosols having “ultra fine” (0.01 to 0.1 micron) and “fine” (1 to 3 micron) particle sizes are known to provide efficient and effective systemic delivery through the lung. Current literature suggests that the middle size range of particles, between ultra fine and fine, i.e., between 0.1 and 1 micron in size, are too small to settle onto the lung wall and too massive to diffuse to the wall in a timely manner. Thus, a significant number of such particles are removed from the lung by exhalation, and thus are not involved in treating disease (see Gonda). [0017]
  • This method creates a mixture of vapor and gas for administration to the patient. For the purposes of controlling particle size the terms “air”, “mixing gas”, “dilution gas” and “carrier gas” are interchangeable. [0018]
  • Various alternatives to generate the desired aerosol in accordance with the method of the present invention are summarized here: [0019]
  • 1. Simultaneous vaporization of the compound and mixing with a gas. [0020]
  • 2. Simultaneous vaporization of the compound and mixing with a portion of a volume of a gas followed by additional mixing with the balance of the volume. [0021]
  • 3. Rapid vaporization of the compound with simultaneous mixing with a gas. [0022]
  • 4. Simultaneous vaporization of the compound with rapid mixing with a gas.[0023]
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • Further features and advantages will become apparent from the following description of various embodiments of the invention, as illustrated in the accompanying drawings in which: [0024]
  • FIG. 1 is a schematic diagram of the overall system for conducting experiments using a laboratory device of the present invention; [0025]
  • FIG. 2 is a top, right end and front perspective view of the actual laboratory device depicted in FIG. 1; [0026]
  • FIG. 3 is a partial cross-sectional and partial schematic side view of the device shown in FIG. 2; [0027]
  • FIG. 4 is a partial cross-sectional and partial schematic end view of the device shown in FIG. 2; [0028]
  • FIG. 5 is a partial cross-sectional and partial schematic top view of the device shown in FIG. 2; [0029]
  • FIG. 6 is a schematic cross-sectional side view of an alternate embodiment of the device of the present invention using an annunciating device; [0030]
  • FIG. 7 is a top, left end and front perspective views of the removable sub-assembly containing the compound and a movable slide of the device shown in FIG. 2 showing the sub-assembly being mounted within the slide; [0031]
  • FIG. 8 is a schematic view of the heating element of the embodiment shown in FIG. 2 showing the electric drive circuit; [0032]
  • FIG. 9 is a schematic side view of a second embodiment of the present invention using a venturi tube; [0033]
  • FIG. 10 is a schematic side view of third embodiment of the present invention using a thin-walled tube coated with the compound; [0034]
  • FIG. 11 is a schematic side end view of the embodiment shown in FIG. 10; [0035]
  • FIG. 12 is a schematic side end view of the embodiment shown in FIG. 10 showing an inductive heating system generating an alternating magnetic field; [0036]
  • FIG. 13 is a schematic side view of an alternate embodiment of that shown in FIG. 10 using a flow restrictor within the thin-walled tube coated with the compound; [0037]
  • FIG. 14 is a schematic side view of a fourth embodiment of the present invention using a pressurized gas to flow over the compound; [0038]
  • FIG. 15 is a schematic end view of the embodiment shown in FIG. 14; [0039]
  • FIG. 16 is a schematic side view of a fifth embodiment using a re-circulation of a gas over the compound's surface; [0040]
  • FIG. 17 is a schematic side view of a sixth embodiment of the present invention using a tube containing particles coated with the compound; [0041]
  • FIG. 18 is a schematic side view of the embodiment shown in FIG. 17 using a heating system to heat the gas passing over the coated particles; [0042]
  • FIG. 19 is a schematic side view of a seventh embodiment of the present invention referred to herein as the “oven device”; [0043]
  • FIG. 20 is a schematic side view of an eighth embodiment of the present invention using gradient heating; [0044]
  • FIG. 21 is a schematic side view of a ninth embodiment of the present invention using a fine mesh screen coated with the compound; [0045]
  • FIG. 22 is a top, right end and front perspective view of the embodiment shown in FIG. 21; [0046]
  • FIG. 23 is a plot of the rate of aggregation of smaller particles into larger ones; [0047]
  • FIG. 24 is a plot of the coagulation coefficient (K) versus particle size of the compound; [0048]
  • FIG. 25 is a plot of vapor pressure of various compounds, e.g., diphenyl ether, hexadecane, geranyl formate and caproic acid, versus temperature; [0049]
  • FIG. 26 is a plot of blood levels for both the IV dose and the inhalation dose administered to various dogs during the experiments using the system shown in FIG. 1; [0050]
  • FIG. 27 is a plot of calculated and experimental mass median diameter (MMD) versus compound mass in the range of 10 to 310 μg; [0051]
  • FIG. 28 is a plot of calculated and experimental MMD versus compound mass in the range of 10 to 310 μg; and [0052]
  • FIG. 29 is a plot of the theoretical size (diameter) of an aerosol as a function of the ratio of the vaporized compound to volume of the mixing gas.[0053]
  • DETAILED DESCRIPTION
  • In the method and device of the present invention, compounds with real or potential physiological activity can be volatilized without medicinally significant degradation and the resulting vapors controlled to form aerosols with particle sizes useful for the administration of the compound to a patient. [0054]
  • In the preferred embodiments of the present invention, compounds are volatilized into vapors avoiding medicinally-significant degradation and thus maintaining acceptable compound purity by the steps of (1) heating the physiologically active compound to a temperature for a limited time and (2) under the conditions of step (1), simultaneously passing a gas across the surface of the compound. [0055]
  • As described previously in the BACKGROUND OF THE INVENTION section, it is often difficult to predict the susceptibility to, and the mechanisms and conditions of chemical degradation for a compound of pharmaceutical potential. As a rule, therefore, such compounds are typically protected from temperatures above room temperature. However, vaporization is slow at low temperatures as evidenced by the rapid decline in the equilibrium vapor pressure as a compound's temperature decreases below its boiling point. The plot in FIG. 25 of the vapor pressures for a number of compounds shows that a small decrease in temperature below the boiling point results in a large drop in vapor pressure. At temperatures roughly 200° C. below the compound's boiling point, the vapor pressure is between 25 and 50 mm of Hg. A vapor pressure of 50 mm Hg implies that the ratio of the volumes of the compound vapor to the atmospheric gases above the liquid compound is 50/760. [0056]
  • In view of the foregoing, vaporization has not previously been viewed as a reasonable mechanism for the delivery of most pharmaceutical compounds. In fact, it is common practice to create a form of a medicinal compound that is chemically and physically stable at room temperature to deter vaporization. This can be accomplished by creating a salt, which has a higher melting point and boiling point than the parent molecule. [0057]
  • The present invention, however, makes vaporization a practical delivery method in part, by utilizing a flow of gas across the surface of the compound, to create a dynamic situation in which a compound's vapor molecules are swept away from its surface, driving the chemical equilibrium process towards further vaporization. For many compounds, this method creates a practical rate of vaporization with only moderate heating. Thus, 1 mg of nicotine, (boiling point of 247° C./745 mm), for example, was observed to vaporize around 130° C. in less than 2 seconds with a laboratory device of the present invention described in detail in the EXAMPLES below. Similarly, fentanyl, which decomposes rapidly at 300° C. before reaching its boiling point, was vaporized in quantities up to 2 mg at temperatures around 190° C. Vaporization can therefore be accomplished with the embodiments of this invention at practical rates, i.e., in the range of about 0.5 to about 2 mg/second, and at temperatures much below the compounds' boiling points. The ability to vaporize at these reduced temperatures provides a means to lower rates of degradation reactions in many compounds. [0058]
  • However, even these lower temperatures noted above could lead to significant decomposition for some compounds, so the ability of the present invention to also limit the time during which the compound is exposed to an elevated temperature is also critical. Limiting the exposure time of a compound to temperature is accomplished by rapid heating of a thin film of a deposited compound followed by immediate cooling of the compound vapors as they enter a carrier gas stream. In the preferred embodiments, the compound is moved quickly through a heating/mixing zone to facilitate a rapid temperature rise on the order of 2,000° C./second. Compounds thus reach vaporization temperatures in ten's of milliseconds. Under these conditions, compound molecules quickly escape as vapors from thin layers of deposited compound, and move into a cool carrier gas stream that flows across the surface of the compound. The vapor molecules, thus quickly created, lose their thermal energy when they collide with molecules of the cooler carrier gas. [0059]
  • The method of the present invention, which uses rapid heating to reach vaporization temperatures of compounds, and after vaporization, rapid cooling of the vapor, has been shown to be significant in reducing decomposition, one of the obstacles to generating the desired aerosol. Lipophilic substance # 87, for example, decomposed by more than 90% when heated at 425° C. for 5 minutes, but only 20% when the temperature was lowered to 350° C. Decomposition was lowered further to about 12% when the time was decreased to 30 seconds, and to less than 2% when the time was decreased to 10-50 milliseconds. Similarly, 100% of a fentanyl sample decomposed when heated to 200° C. for 30 seconds, but decreased to 15-30% decomposition when fentanyl was heated to 280° C. for 10 milliseconds. When fentanyl was vaporized using the laboratory device, which minimized the vaporization temperature and limited the exposure time to that temperature, no medicinally significant decomposition (<0.1%) was observed. [0060]
  • After a compound has been vaporized, the method of this invention also overcomes the second obstacle to generating the desired aerosol by controlling the generated compound vapors so that an aerosol is formed that (1) is comprised of particles within a desired size range and (2) these particles are sufficiently stable so they will retain their sizes within that range during the time necessary to administer the aerosol to a patient. Particle size is usually expressed as the equivalent diameter of a spherical particle with the same physical behavior. The range of particle sizes in an aerosol is most often described by its mass median diameter (MMD) or mass median aerodynamic diameter (MMAD), and its geometric standard deviation (GSD). As the size of the particles is changed, the site of deposition within the lung can be changed. This can allow targeting of the site of deposition of the compound in the lung and airways. [0061]
  • The method of the present invention forms an aerosol with particles of a desired size range and stability by applying the principle that particle growth can be predicted from the number concentration of the particles in a given volume. In high concentrations, particles frequently collide and adhere to each other. Such a collision and adhesion event (aggregation) creates one particle from two smaller ones. In a population of particles in an aerosol, these events lead to an increase in mean particle size and a decrease in number concentration. The frequency of collisions among particles then decreases, since there are fewer particles available and because the remaining larger particles move more slowly. As a consequence, the rate of particle size growth slows. (See “Aerosol Technology” W. C. Hinds, second edition 1999, Wiley, N.Y.) The term “stable particle size” can be applied in a practical sense when particle size growth has slowed sufficiently to ensure the purpose of the application. For the purposes of drug delivery by inhalation, a stable particle would be one that exists in the ultra fine or fine size range for the 1 to 3 seconds required for a typical inhalation. [0062]
  • In accordance with the present invention, a particle of the ultra fine or fine size range is produced that is stable for several seconds. Also in accordance with the present invention, a predetermined amount of compound in its vapor-state can be mixed into a predetermined volume of a carrier gas in a ratio to give particles of a desired size as the number concentration of the aerosol itself becomes stable. As detailed below, a stable number concentration is approximately 10[0063] 9 particles/cc.
  • The method of the present invention forms the aerosol with particles of a desired size range and stability by controlling the rate of vaporization, the rate of introduction of a carrier gas, and the mixing of the vapors and the carrier gas, thereby manipulating the parameters that govern the physical processes of a compound's condensation and particle aggregation. [0064]
  • Controlling the ratio of the vaporized compound to the volume of mixing air can be done by a number of methods including: (a) measuring the quantity and regulating the flow rate of the mixing air; and/or (b) regulating the vaporization rate of the compound, e.g. changing the energy transferred to the compound during the heating process or changing the amount of compound introduced into a heating region. As the size of the particles is changed, the site of deposition within the lung can be changed. This can allow targeting of the site of deposition of the compound in the lung and airways. [0065]
  • A desired particle size is achieved by mixing a compound in its vapor-state into a volume of a carrier gas, in a ratio such that when the number concentration of the mixture reaches approximately 10[0066] 9 particles/ml, a “stable” particle size is present. The amount of compound and the volume of gas are each predetermined to achieve this ratio.
  • FIG. 23 shows the time in seconds it takes for the number concentration of an aerosol to aggregate to half of its original value as a function of the particle concentration. It is a plot of theoretical data calculated from a mathematical model, (See Hinds). For example, a 1.0 mg vaporized dose of a compound with a molecular weight of 200 that is mixed into 1 liter of air will have approximately 3×10[0067] 18 molecules (particles) in the liter. This results in a number concentration of 3×1015/cc. Extrapolating from FIG. 23, one can see that the time required for the number of particles to halve in this example is less than 10 microseconds. This demonstrates that to insure uniform mixing of the vaporized compound, the mixing must happen in a very short time. Even if the compound is allowed to aggregate in size (for example to 12 nm in diameter), the number concentration is still 1×1012 particles/cc, and the time required for the number of particles to halve is still about 1 millisecond. FIG. 23 also shows that when the number concentration of the mixture reaches approximately 109 particles/cc, the particle sized will be “stable” for the purpose of drug delivery by inhalation.
  • FIG. 23 is for an aerosol having a Coagulation Coefficient (K) of 5×10[0068] −16 meters3/second. This K value corresponds to a particle size of 200 nm. As the particle size changes, so can its K value. Table 1 below gives the K values for various particle sizes. As K increases, the time required for the aerosol to aggregate from a particular particle size to a larger particle size is reduced. As can be seen from Table 1 and FIG. 24, when the particle is in the ultra fine region, as defined in the BACKGROUND OF THE INVENTION section, the effect of a changing K value tends to accelerate the coagulation process towards 100 nm in size. In calculating the stability of an aerosol's particle size, the size of the particle affects its stability. Smaller particles in this region will tend to aggregate faster than the larger sized particles. Therefore, the stability of particle size in the ultra fine range is not linear with dose size. In the fine particle size range, K remains fairly constant. Thus, the stability of particle size can be calculated from the dose size alone and consideration of particle size on the aggregation procession is unnecessary.
    TABLE 1
    Coagulation Coefficient (×e−15
    Particle size (diameter in nm) meters3/second)
      1 3.11
      5 6.93
      10 9.48
      20 11.50
      50 9.92
     100 7.17
     200 5.09
     500 3.76
     1000 3.35
     2000 3.15
     5000 3.04
    10000 3.00
  • In creating an aerosol of a particular particle size, the ratio of mass of vaporized compound to the volume of the mixing gas is the controlling condition. By changing this ratio, the particle size can be manipulated (see FIG. 29). However, not all compounds and not all gases, with the same ratio will result in the same particle size distribution (PSD). Other factors must be known to be able to accurately predict the resultant particle size. A compound's density, polarity, and temperature are examples of some of these factors. Additionally, whetheer the compound is hydrophilic or hydrophobic will affect the eventual particle size, because this factor affects an aerosol's tendency to grow by taking on water from the surrounding environment. [0069]
  • In order to simplify the approach used to predict the resulting particle size, the following assumptions were made: [0070]
  • 1. The compound is non polar (or has a weak polarity). [0071]
  • 2. The compound is hydrophobic or hydrophilic with a mixing gas that is dry. [0072]
  • 3. The resultant aerosol is at or close to standard temperature and pressure. [0073]
  • 4. The coagulation coefficient is constant over the particle size range and therefore the number concentration that predicts the stability of the particle size is constant. [0074]
  • Consequently, the following variables are taken into consideration in predicting the resulting particle size: [0075]
  • 1. The amount (in grams) of compound vaporized. [0076]
  • 2. The volume of gas (in cc's) that the vaporized compound is mixed into. [0077]
  • 3. The “stable” number concentration in number of particles/cc. [0078]
  • 4. The GSD of the aerosol. [0079]
  • Predicting the particle size would be a simple matter for a given number concentration and amount of the compound, if the GSD is 1. With a GSD of 1, all of the particle sizes are the same size and therefore the calculation of particle size becomes a matter of dividing a compound's mass into the number of particles given by the number concentration and from there calculating the particle size diameter using the density of the compound. [0080]
  • The problem becomes different though if the GSD is other than 1. As an aerosol changes from a GSD of 1 to a GSD of 1.35, the mass median diameter (MMD) will increase. MMD is the point of equilibrium where an equal mass of material exists in smaller diameter particles as exists in larger diameter particles. Since total mass is not changing as the GSD changes, and since there are large and small particles, the MMD must become larger as the GSD increases because the mass of a particle goes up as the cube of its diameter. Therefore larger particles, in effect, carry more weight so the MMD becomes larger to “balance” out the masses. [0081]
  • To determine the effect of a changing GSD, one can start with the formula for the mass per unit volume of an aerosol given a known MMD, GSD, density, and number concentration. The formula is from Finlay's “[0082] The Mechanics of Inhaled Pharmaceutical Aerosols” (2001, Academic press). Formula 2.39 states that the mass per unit volume of an aerosol is:
  • M=(ρNπ/6) (MMD)3exp[−9/2(1 g)2]
  • Where: [0083]
  • ρ=density in gm/cc [0084]
  • N=Number concentration in particles/cc [0085]
  • MMD=mass median diameter (in cm) [0086]
  • σ[0087] g=the GSD
  • M=the mass per unit volume of the aerosol in gms/cc [0088]
  • If the change in the MMD is considered as an aerosol changes from one GSD to another, while the density, number concentration, and the mass remain unchanged the following equality can be set up: [0089]
  • ρNπ/6(MMD 1)3exp[−9/2(1 g1)2 ]=ρNπ/6(MMD 2)3exp[−9/2(1 g2)2]
  • simplifying: [0090]
  • (MMD 1)3exp[−9/2(1 g1)2]=(MMD 2)3exp[−9/2(1 g2)2]
  • Or [0091]
  • (MMD 1)3/(MMD 2)3=exp[−9/2(1 g2)2]/exp[−9/2(1 g1)2]
  • If one sets the GSD of case 1 to 1.0 then: [0092]
  • exp[−9/2(1 g1)2=1
  • And therefore: [0093]
  • (MMD 1 /MMD 2)3=exp[−9/2)1 g2)2]
  • Or: [0094]
  • MMD 1 /MMD 2=exp[−3/2(1 g2)2]
  • It is advantageous to calculate the change in the MMD as the GSD changes. Solving for MMD[0095] 2 as a function of MMD1 and the new GSD2 yields:
  • MMD 2 =MMD 1/exp[−3/2(1 g2)2] for a σg1=1
  • To calculate MMD[0096] 1, divide the compound's mass into the number of particles and then, calculate its diameter using the density of the compound.
  • MMD[0097] 1=(6C/ρNVπ) for an aerosol with a GSD of 1
  • Where: [0098]
  • C=the mass of the compound in gm's [0099]
  • ρ=Density in gm/cc (as before) [0100]
  • N=Number concentration in particles/cc (as before) [0101]
  • V=volume of the mixing gas in cc [0102]
  • Insertion of MMD[0103] 1 into the above equation leads to:
  • MMD[0104] 2=(6C/ρNVπ)[exp[−3/2(1nσg2)2], measured in centimeters.
  • A resultant MMD can be calculated from the number concentration, the mass of the compound, the compound density, the volume of the mixing gas, and the GSD of the aerosol. [0105]
  • In all of the embodiments of the present invention, an aerosol of the desired particle size range is created by controlling the volume of air (or other gas) within which the compound is allowed to aggregate. For creating ultra fine particles, a large ratio of mixing gas to compound vapor is used. In producing fine particles, it is necessary to reduce the volume of the initial mixing gas, which leads to an increase in the concentration of the compound, which in turn results in a greater particle size growth before a desired number concentration is reached and aggregation slows. When a stable particle size is reached in a smaller total volume, the mixture is then injected into the balance of the air. As referred to in some of the embodiments, this initial mixing stage can be, if needed, accomplished in the presence of an inert gas to reduce decomposition resulting from oxidation. [0106]
  • It is important to recognize that an aerosol with a particle size of 100 nm will occupy a volume 8,000 times as large as an aerosol with a particle size of 2 microns with the same number concentration and with the same total dose. Because the present method will require vastly different volumes of mixing air depending on the particle size desired for different compounds and amounts to be delivered, the various embodiments of the present invention are of different physical sizes and geometries. [0107]
  • The required vaporization rate is different depending on the particle size one wishes to create. If the particle size is in the ultra fine region, then the compound, once vaporized, must be mixed, in most cases, into the largest possible volume of air. This volume of air is determined from lung physiology and can be assumed to have a reasonable upper limit of 2 liters. If the volume of air is limited to below 2 liters (e.g. 500 cc, unless the dose is exceedingly small, i.e., less that 50 μg, too large a particle will result and optimum lung deposition will not be possible. [0108]
  • In the ultra fine range, doses of 1-2 mg are possible. If this dose is mixed into 2 liters of air, which will be inhaled in 1-2 seconds, the required, desired vaporization rate is in the range of about 0.5 to about 2 mg/second. A reasonable vaporization rate for ultra fine aerosols is about 1 mg/second for the embodiments of this invention. [0109]
  • In the fine particle size region, there is no need for as large a volume of air as possible. Until the establishment of the correct number concentration that makes a stable aerosol, a large volume of air is undesirable. Rapid mixing of the vaporized compound into air needs to happen at the time of vaporization to minimize decomposition. As a result, the volume of mixing air and not the entire volume of air used to deliver the drug to the lung is of chief concern. [0110]
  • The first embodiment of the present invention is shown in FIG. 1 and is the basic device through which the principles cited above have been demonstrated in the laboratory. This device is described in detail in the EXAMPLES. [0111]
  • In the second embodiment of the present invention shown in FIG. 9, the use of a reduced airway cross section increases the speed of the air across the compound's surface to about 10 meters/second. If complete mixing is to happen within 1 millisecond then the distance the gas and vaporized mixture must travel to achieve complete mixing must be no longer than 10 millimeters. However, it is more desirable for complete mixing to happen before the compound has aggregated to a larger size, so a desirable mixing distance is about 1 millimeter or less. [0112]
  • In the third embodiment of the present invention shown in FIGS. [0113] 10-13, an ultra fine aerosol is generated by allowing air to sweep over a thin film of the compound during the heating process. This allows the compound to become vaporized at a lower temperature due to the lowering of the partial pressure of the compound near the surface of the film.
  • The fourth embodiment shown in FIGS. [0114] 14-15 is directed to placing the compound on a slide that moves within an airway along the direction of air travel and simultaneously passing a pressurized gas over the compound as it is vaporized. Upon vaporization the compound is free to move down the airway and to the patient.
  • In the fifth embodiment shown in FIG. 16, a volume of gas is re-circulated over the surface of the heated compound to aid in its vaporization. The resulting aerosol is then combined with additional gas to rapidly cool the mixture before delivery to a patient. [0115]
  • In the sixth embodiment shown in FIGS. [0116] 17-18, gas is passed into a first tube and over discrete substrate particles having a large surface area to mass ratio and coated with the compound. The particles are heated as shown in FIG. 17 to vaporize the compound or the gas is heated and the heated gas vaporizes the compound as shown in FIG. 18. The gaseous mixture from the first tube is combined with the gas passing through second tube to rapidly cool the mixture before administering to a patient.
  • In the seventh embodiment shown in FIG. 19, the compound is introduced into the gas as a pure vapor. This involves vaporizing the compound in an oven or other container and then injecting the gaseous mixture into an air or other gas stream through one or more mixing nozzles. [0117]
  • The eighth embodiment shown in FIG. 20 is a thermal gradient device that is similar to the preferred embodiment used in the laboratory experiments. This device also has a moving heating zone without any moving parts, accomplished by establishing a heat gradient that transverses from one end of the device to the other over time. As the heating zone moves, exposed portions of the compound are sequentially heated and vaporized. In this manner the vaporized compound can be introduced into a gas stream over time. [0118]
  • The ninth embodiment shown in FIGS. [0119] 21-22 is the screen device and is preferred for generating a fine aerosol. In this embodiment, air is channeled through a fine mesh screen upon which the drug to be administered to the patient has been deposited.
  • The embodiments above can create aerosols without significant drug decomposition. This is accomplished while maintaining a required vaporization rate for particle size control by employing a short duration heating cycle. An airflow over the surface of the compound is established such that when the compound is heated and reaches the temperature where vaporization is first possible, the resulting compound vapors will immediately cool in the air. In the preferred embodiments, this is accomplished by extending the increased velocity and mixing region over an area that is larger than the heating zone region. As a result, precise control of temperature is not necessary since the compound vaporizes the instant its vaporization temperature is reached. Additionally because mixing is also present at the point of vaporization, cooling is accomplished quickly upon vaporization. [0120]
  • Application of the present invention to human inhalation drug delivery must accommodate constraints of the human body and breathing physiology. Many studies of particle deposition in the lung have been conducted in the fields of public health, environmental toxicology and radiation safety. Most of the models and the in vivo data collected from those studies, relate to the exposure of people to aerosols homogeneously distributed in the air that they breathe, where the subject does nothing actively to minimize or maximize particle deposition in the lung. The International Commission On Radiological Protection (ICRP) models are examples of this. (See James A C, Stahlhofen W, Rudolph G, Egan M J, Nixon W, Gehr P, Briant J K, [0121] The respiratory tract deposition model proposed by the ICRP Task Group, Radiation Protection Dosimetry, 1991; vol. 38: pgs.157-168).
  • However, in the field of aerosol drug delivery, a patient is directed to breathe in a way that maximizes deposition of the drug in the lung. This kind of breathing usually involves a full exhalation, followed by a deep inhalation sometimes at a prescribed inhalation flow rate range, e.g., about 10 to about 150 liters/minute, followed by a breath hold of several seconds. In addition, ideally, the aerosol is not uniformly distributed in the air being inhaled, but is loaded into the early part of the breath as a bolus of aerosol, followed by a volume of clean air so that the aerosol is drawn into the alveoli and flushed out of the conductive airways, bronchi and trachea by the volume of clean air that follows. A typical deep adult human breath has a volume of about 2 to 5 liters. In order to ensure consistent delivery in the whole population of adult patients, delivery of the drug bolus should be completed in the first 1-1½ liters or so of inhaled air. [0122]
  • As a result of the constraints placed on the various embodiments of the present invention due to their application in human inhalation drug delivery, a compound must be vaporized in a minimum amount of time, preferably no greater than 1 to 2 seconds. As discussed earlier, it is also advantageous, to keep the temperature of vaporization at a minimum. In order for a compound to be vaporized in 2 seconds or less and for the temperature to be kept at a minimum, rapid air movement, in the range of about 10 to about 120 liters/minute, needs to flow across the surface of the compound. [0123]
  • The following parameters are imposed in carrying out the best mode of the present invention, due to human lung physiology, the physics of particle growth, and the physical chemistry of the desirable compounds: [0124]
  • (1) The compound needs to be vaporized over approximately 1 to 2 seconds for creation of particles in the ultra fine range. [0125]
  • (2) The compound needs to be raised to the vaporization temperature as rapidly as possible. [0126]
  • (3) The compound, once vaporized, needs to be cooled as quickly as possible. [0127]
  • (4) The compound needs to be raised to the maximum temperature for a minimum duration of time to minimize decomposition. [0128]
  • (5) The air or other gas needs to be moved rapidly across the surface of the compound to achieve the maximum rate of vaporization. [0129]
  • (6) The heating of the air or other gas should be kept to a minimum, i.e., an increase of temperature of no greater than about 15° C. above ambient. [0130]
  • (7) The compound needs to be mixed into the air or other gas at a consistent rate to have a consistent and repeatable particle size. [0131]
  • (8) As the gas speed increases across the compound being vaporized, the cross sectional area through the device needs to decrease. Additionally as the surface area of the compound increases the heating of the gas increases. [0132]
  • The parameters of the design for one of the preferred embodiments shown in FIGS. [0133] 2-5, 7 and 8 are the result of meeting and balancing the competing requirements listed above. One especially important requirement for an ultra fine aerosol is that a compound, while needing to be vaporized within at least a 1-second period, also needs to have each portion of the compound exposed to a heat-up period that is as brief as possible. In this embodiment, the compound is deposited onto a foil substrate and an alternating magnetic field is swept along a foil substrate heating the substrate such that the compound is vaporized sequentially over no more than about a one second period of time. Because of the sweeping action of the magnetic field, each segment of the compound has a heat-up time that is much less than one second.
  • In the embodiment noted directly above, the compound is laid down on a thin metallic foil. In one of the examples set forth below, stainless steel (alloy of 302, 304, or 316) was used in which the surface was treated to produce a rough texture. Other foil materials can be used, but it is important that the surface and texture of the material is such that it is “wetted” by the compound when the compound is in its liquid phase, otherwise it is possible for the liquid compound to “ball” up which would defeat the design of the device and significantly change the volatilizing parameters. If the liquid compound “balls” up, the compound can be blown into and picked up by the airflow without ever vaporizing. This leads to delivery of a particle size that is uncontrolled and undesirable. [0134]
  • Stainless steel has advantages over materials like aluminum because it has a lower thermal conductivity value, without an appreciable increase in thermal mass. Low thermal conductivity is helpful because heat generated by the process needs to remain in the immediate area of interest. [0135]
  • Exemplary compounds that can be vaporized in accordance with the present invention include cannabinoid extracts from cannabis, THC, ketorolac, fentanyl, morphine, testosterone, ibuprofen, codeine, nicotine, Vitamin A, Vitamin E acetate, Vitamin E, nitroglycerin, pilocarpine, mescaline, testosterone enanthate, menthol, phencaramide, methsuximide, eptastigmine, promethazine, procaine, retinol, lidocaine, trimeprazine, isosorbide dinitrate, timolol, methyprylon, etamiphyllin, propoxyphene, salmetrol, vitamin E succinate, methadone, oxprenolol, isoproterenol bitartrate, etaqualone, Vitamin D3, ethambutol, ritodrine, omoconazole, cocaine, lomustine, ketamine, ketoprofen, cilazaprol, propranolol, sufentanil, metaproterenol, pentoxapylline, captopril, loxapine, cyproheptidine, carvediol, trihexylphenadine, alprostadil, melatonin, testosterone proprionate, valproic acid, acebutolol, terbutaline, diazepam, topiramate, pentobarbital, alfentanil HCl, papaverine, nicergoline, fluconazole, zafirlukast, testosterone acetate, droperidol, atenolol, metoclopramide, enalapril, albuterol, ketotifen, isoproterenol, amiodarone HCl, zileuton, midazolam, oxycodone, cilostazol, propofol, nabilone, gabapentin, famotidine, lorezepam, naltrexone, acetaminophen, sumatriptan, bitolterol, nifedipine, phenobarbital, phentolamine, 13-cis retinoic acid, droprenilamine HCl, amlodipine, caffeine, zopiclone, tramadol HCl, pirbuterol, naloxone, meperidine HCl, trimethobenzamide, nalmefene, scopolamine, sildenafil, carbamazepine, procaterol HCl, methysergide, glutathione, olanzapine, zolpidem, levorphanol, buspirone and mixtures thereof. [0136]
  • The present invention has unique advantages as a means of delivering drugs by inhalation to the human body. The FDA has expressed concern about airway hypersensitivity due to inhalation products (See G. Poochikian and C. M. Bertha, “Inhalation drug product excipients controls: significance and pitfalls” presented at RDD VII, 2000). The method and device of the present invention are capable of delivering pure drug vapor to the lung without the simultaneous delivery of formulation ingredients, which oftentimes comprise a significant portion of the mass delivered to the patient when other drug delivery methods and devices are utilized. Formulation ingredients often include propellants such as chlorofluorohydrocarbons, solvents such as ethanol, detergents such as Polysorbate 80, preservatives such as benzalkonium chloride or carrier particles such as lactose. The present invention has the advantage of not introducing such excipient molecules into the delicate tissues of the lungs. The ability to deliver pure drug is especially advantageous for drugs that must be administered chronically. This invention allows for the administration of water insoluble drugs to a mammal without the need for excipients or injection. This can be advantageous in treating diseases of the eye, mucosa, skin and broken-skin. [0137]
  • Another advantage comes from the ability of the present invention to produce an ultra fine aerosol. Approximately 50,000 times as many particles exist within a volume of ultra fine aerosol as exists in the same mass of a fine aerosol. Since each particle deposits on the membrane of the lung, a correspondingly greater number of deposition sites are created in the lungs and at each site less material has to be dissolved and transported into the blood stream. This may be important for improving the rate of absorption and thus the bioavailabilty of compounds, e.g., lipophilic compounds, and large molecules such as proteins, peptides and DNA. It is suspected that a portion of some drugs that have a slow absorption rate from the peripheral airways are assimilated by macrophages before they can be absorbed, leading to a low bioavailability despite efficient deposition. Increasing absorption rate through deposition of ultra fine particles would thus be advantageous. [0138]
  • EXAMPLES
  • The following examples further illustrate the method and various embodiments of the present invention. These examples are for illustrative purposes and are not meant to limit the scope of the claims in any way. [0139]
  • Example 1
  • In this example, the laboratory embodiment of the device of this invention, referred to as Absorption/Distribution/Metabolism/Excretion (ADME) device [0140] 1, was designed to deliver an experimental dose of fentanyl between 20 μg and 500 μg, in a range of ultra fine particle sizes, in about 800 cc of air to a 10 kg dog. The lung volume of each dog under experimentation was approximately 600-700 cc and the device was designed to deliver the compound to the lung in the first half of the inhalation. Because of the value of these parameters, ADME device 1 can be considered a ¼ scale device for administering a dose to a human. It is believed that scaling the device to work for human subjects involves mainly increasing the airflow through the device.
  • In this embodiment, representing one of the preferred embodiments of the present invention, the two main obstacles, decomposition and particle size control, as noted above, were addressed by moving a substrate that had the compound deposited on it into a heating/vaporization/mixing zone. The substrate material, which had been chosen in part for its electrical and thermal properties, was moved into an alternating magnetic field, which also coincided with a region of restricted cross-sectional area and mixing geometry. The alternating magnetic field induced an electrical current in the substrate and because of the substrate's electrical resistance resulted in a rapid temperature rise, which in turn vaporized the compound. The temperature rise occurred in a region where, because of the restriction of the cross- sectional area of the air channel, there was an increase in the air speed across the surface of the compound. The increased airflow acted to “sweep” away any compound vapors above the film of compound, which in turn lowered the partial pressure of the compound and increased the rate of vaporization. [0141]
  • Additionally, the temperature rise was also in a region where the geometry of the passage had been designed to promote rapid mixing of the vaporized compound into the air. This rapid mixing helped overcome the two noted obstacles in two ways. First, because of the rapid mixing there was a more uniform distribution of the compound into the air. This gave rise to a small distribution of particle sizes, which in turn insured a consistent and small particle size. Second, because rapid mixing occurred, the vaporized compound was rapidly cooled by exchange of its kinetic energy with kinetic energy of the cooler carrier air; which reduced decomposition. [0142]
  • The time frame of the introduction of the compound into the heating/vaporization/mixing zone was designed to vaporize the compound into a volume of air that was suitable for both the volume required by lung anatomy (600-700 cc) for the dog and the volume needed to control the ratio of the compound to the air, and thereby to control particle size. In other words, some of the functional limits for this device were defined by lung capacity as well as the requirements for dilution of the aerosol. Lung capacity limits the total amount of drug that can be suspended in the inhaled air at a given concentration. [0143]
  • The ADME device [0144] 1 as shown in FIG. 1 is operably connected to flow meter 4. In this example a TSI 4100 flow meter was used as the flow measuring equipment. The readings from flow meter 4 were fed to the electronics within chassis 8 shown in FIG. 2. It is noted that flow meter 4 is shown in FIG. 1 within a dotted line to indicate housing 10. For a practical device used to administer a drug to human patients, a flow meter will be included within a handheld housing. Device controller 20 includes Chembook model # N30W laptop computer having actuator switch 22 (FIG. 3) and National Instruments I/O Board (model #SC2345) that interfaces with computer 20 to control ADME device 1 and to control the recording of all data collected during the experiments. A software program to carry out these functions was developed using National Instruments' Labview software program. Connection between device 1 and the I/O board was accomplished with a DB25 cable (not shown). A standard “off the shelf” Condor F15-15-A+ power supply (not shown) delivered power to device 1. Inhalation controller 30 was used to control the rate and volume of inhalation through device 1 into the anesthetized dog through an endotracheal tube 34. Controller 30 had a programmable breath hold delay, at the end of which, exhaust valve 40 in exhaust line 42 opened and the dog was allowed to exhale. Filter 50 in line 42 measured the amount of exhaust and its composition to monitor any exhaled drug. The source air through inlet line 54, inlet valve 58, flow meter 4 and inlet orifice 59 was from a compressed air cylinder (not shown).
  • Now referring to FIGS. [0145] 3-5 and 7, the dose of compound 60 was deposited onto thin, stainless steel foil 64 so that the thickness of compound 60 was less than 10 microns. In most cases, compound 60 was deposited by making a solution of the compound with an organic solvent. This mixture was then applied to the foil substrate with an automated pump system. The size of the entire foil 64 was 0.7 by 2.9 inches and the area in which compound 60 was deposited was 0.35 by 1.6 inches.
  • Stainless steel (alloy of 302 or 304) foil [0146] 64 having a thickness of 0.004 inches was used for foil 64. Other foil materials can be used but stainless steel has an advantage over other materials like aluminum in that it has a much lower thermal conductivity value, while not appreciably increasing the thermal mass. A low thermal conductivity is helpful because the heat generated in foil 64 should stay in the area of interest, i.e. the heating/vaporization zone 70. Foil 64 needs to have a constant cross section, because without it the electrical currents induced by the heater will not be uniform.
  • Foil [0147] 64 was held in frame 68, made so that the trailing edge of foil 64 had no lip on movable slide 78 and so compound 60, once mixed with the air, was free to travel downstream as seen in FIG. 7. Frame 68 was made of a non-conductive material to withstand moderate heat (200° C.) and to be non-chemically reactive with the compound. The material for frame 68 was Delrin AF, a copolymer of acetal and Teflon.
  • Sub-assembly [0148] 80 shown in FIG. 7 consists of frame 68 having foil 64 mounted therein and with compound 60 deposited on foil 64. Sub-assembly 80 was secured within movable slide 84 by setting each of the downstream ends of frame 68 that were tapered to abut against small rods 86 protruding from each downstream end of slide 78, as shown in FIG. 7. Slide 78 was driven by stepper motor 88 that moved sub-assembly 80 containing compound 60 along the axis of device 1. This, in turn, moved stainless steel foil 64 through an alternating magnetic field. It is preferable for the magnetic field to be confined within heating/vaporization zone 70 as in this laboratory embodiment. Ferrite 90 was used to direct the magnetic field and was placed approximately 0.05 inches below foil 64. In this laboratory embodiment designed to achieve the optimum results, heated area 70 was approximately 0.15 by 0.4 inches, with the smaller dimension along the direction of travel from left to right, i.e. from the upstream to the downstream ends of device 1, and the large dimension across the direction of travel, i.e., the width of device 1.
  • Stainless steel foil [0149] 64 functions as both a substrate for the drug to be delivered to the subject and the heating element for the vaporization of the drug. Heating element 64 was heated primarily by eddy currents induced by an alternating magnetic field. The alternating magnetic field was produced in ferrite toroid 90 with slit 94, which was wrapped with coil 98 of copper magnet wire. For this preferred embodiment, a ferrite toroid from the Fair-Rite Company was used. The slit was 0.10 inch wide. When an alternating current was passed through coil 98, an alternating magnetic field was produced in ferrite 90. A magnetic field filled the gap formed by slit 94 and magnetic field fringe lines 100 extended out from the toroid. The magnetic field line fringes intersected stainless steel heating element 64. When using a ferrite core, the alternating frequency of the field was limited to below 1 MHz. In this laboratory device, a frequency between 100 and 300 kHz was used. As alternating magnetic field lines 100 pass through foil 64, an alternating electric field was induced following Faraday's Law of Induction. The electric field caused eddy currents in the foil according to Ohm's law. The current moving through the intrinsic resistance of the foil generated the heat.
  • It is important to consider skin depth when inductively heating thin foils. If skin depth is much greater that the thickness of the foil, the magnetic field will pass through the foil and induce little heating. For a given frequency and material, the skin depth of a magnetic field can be determined using Formula #3 below: [0150] δ = 2 ɛ 0 c 2 σω
    Figure US20030051728A1-20030320-M00001
  • (Ref. The Feynman Lectures on Physics, vol. 2, pg. 32-11 Addison Wesley 1964) [0151]
  • Where: [0152]
  • ε[0153] o is the permittivity of free space (8.85×10−12 farad/meter)
  • c is the speed of light (3×10[0154] 8 meters/second)
  • σ is the conductivity of the foil (1.38×10[0155] 6 1/ohm-meters for stainless steel)
  • ω is the frequency of the alternating magnetic field in radians/second. [0156]
  • The thicker the stainless steel foil used, the better the coupling of the magnetic field into the foil. However, more energy is needed to achieve a given temperature rise. Therefore, for a practical implementation of the device described above, a number of factors must be considered. First, the very thin foils that require less energy to raise them to a given temperature are less able to absorb the magnetic field due to the skin effect. Second, the ferrite is limited in its ability to conduct magnetic flux. The ferrite has both a saturation limit and internal power loses due to magnetic hysteresis. Foil thickness, ferrite material properties and geometry and operating frequency must be traded off to optimize the transfer of energy from the magnetic components to the foil. [0157]
  • The location and geometry of the eddy currents are also important since they determine where foil [0158] 64 will be heated. Since magnetic field fringe lines 100 pass through foil 64 twice, once leaving ferrite toroid 90 and once returning, two rings of current were produced, and in opposite directions. One of the rings was formed around magnetic field lines 100 that leave toroid 90 and the other ring formed around magnetic field lines 100 that return to the toroid. The rings of current overlapped directly over the center of slit 94. Since they were in opposite directions, they sum together. The greatest heating effect was produced over the center of slit 94.
  • Slide [0159] 84 and its contents, were housed in airway 102 made up of upper airway section 104 and lower airway 108 shown in FIG. 3. Upper airway section 104 was removable and allowed the insertion of movable slide 84 and then sub-assembly 80 of frame 78 and foil 64 with compound 60 on it and the removal of sub-assembly 80 after the dose had been administered. Lower airway section 108 was mounted on top of chassis 8 that housed the electronics, magnetic field generator 110, stepper motor 88 and position sensors (not shown). Mounted in upper airway section 104 was upstream passage 120 and inlet orifice 59 that coupled upper airway section 104 to flow meter 4. The readings from the flow meter 4 were fed to the electronics housed in chassis 8. Additionally, at the downstream end of airway passage 102 was outlet 124 connected to mouthpiece 126. Under test conditions, air was pulled through the mouthpiece 126 through airway tube 102 and inlet orifice 59. During administration of compound 60 to the dog, when joined to the system, air was forced through flow meter 4, inlet line 54, airway tube 102, and outlet 124 into the dog.
  • Additionally, a pyrometer at the end of TC2 line [0160] 130 was located within airway 102 and was used to measure the temperature of foil 64. Because of the specific geometry of ADME device 1, the temperature reading of foil 64 was taken after heating zone 70. Calibration of the thermal decay between heating zone 70 and the measurement area was required. Temperature data was collected and used for quality control and verification and not to control any heating parameters. A second temperature sensor was located at the end of TC 1 line 132 in outlet 124 and was used to monitor the temperature of the air delivered to the dog.
  • In a preferred embodiment of the experimental device, removable airway section [0161] 140 contained a restricted cross-sectional area along with specific mixing geometry mounted in upper airway section 104. In this preferred embodiment, airway 140 lowered the roof of upper airway section 104 to within 0.04 inch of foil 64. Additionally, airway section 140 contained 31 steel rods (not shown) 0.05 inches in diameter. These rods were oriented perpendicular to the foil and extended from the “roof”, i.e., the top of upper airway section 104, to within 0.004 inches of the foil. The rods that were placed in a staggered pattern had sharp squared off ends, which caused turbulence as the air was draw around them. Rapid, highly turbulent movement of mixing air resulted, which assured complete mixing of the vapor with the air passing through the device.
  • FIG. 9 schematically represents device [0162] 150, the second embodiment of the present invention, in which the cross-sectional area was also restricted along the gas/vapor mixing area. In this embodiment, venturi tube 152 within housing 10 having inlet 154, outlet 156 and throat 158 between inlet 154 and outlet 156 was used to restrict the gas flow through venturi tube 152. Controller 160 was designed to control the flow of air passing through valve 164 based on readings from the thermocouple 168 of the temperature of the air as a result of heater 166.
  • Airway section [0163] 140 was located directly over heating zone 70 and created a heating/vaporization/mixing zone. Prior to commencing aerosol generation, slide 78 was in the downstream position. Slide 78, with its contents, was then drawn upstream into this heating/vaporization/mixing zone 70 as energy was applied to foil 64 through the inductive heater system described in detail below.
  • The device of the present invention can be equipped with an annunciating device. One of the many functions for the annunciating device is to alert the operator of the device that the compound is not being vaporized or is being improperly vaporized. The annunciating device can also be used to alert the operator that the gas flow rate is outside a desired range. Annunciating device [0164] 170 with on-off switch 174 is schematically represented in FIG. 6 for use with hand held device 180. During the use of device 180 in which the patient's inhalation rate controls the airflow rate, a signal from annunciating device 170 would alert the patient to adjust the inhalation rate to the desired range. In this case, controller 160 would be connected to annunciating device 170 to send the necessary signal that the flow rate was not within the desired range.
  • The induction drive circuit [0165] 190 shown in FIG. 8 was used to drive the induction-heating element of ADME device 1. The purpose of circuit 190 was to produce an alternating current in drive coil 98 wrapped around ferrite core 90. Circuit 190 consisted of two P-channel transistors 200 and two N-channel MOSFET transistors 202 arranged in a bridge configuration. MOSFET transistors 200 and 202 connected to clock pulse generator 219 were turned on and off in pairs by D-type flip-flop 208 through MOSFET transistor drive circuit 210. D-type flip-flop 208 was wired in such a way as to cause the Q output of the flip-flop to alternately change state with the rising edge of the clock generation signal. One pair of MOSFET transistors 200 was connected to the Q output on D-type flip-flop 208 and the other pair, 202, is connected to the Q-not output of flip-flop 208. When Q was high (5 Volts), a low impedance connection was made between the D.C. power supply (not shown) and the series combination of drive coil 98 and the capacitor through the pair of MOSFET transistors 200 controlled by the Q output. When D-type flip-flop 208 changed state and Q-not was high, the low impedance connection from the power supply to the series combination drive coil 98 and capacitor 220 was reversed. Since flip-flop 208 changes state on the rising edge of the clock generation signal, two flip-flop changes are required for one complete drive cycle of the induction-heating element. The clock generation signal was set at twice the resonant frequency of the series combination of drive coil 90 and capacitor 220. The clock signal frequency can be manually or automatically set.
  • The following was the sequence of events that took place during each operation: [0166]
  • 1. At the beginning of the run, the operator triggered inhalation controller [0167] 30 to start monitoring data from pressure transducer 240 and input flow meter 4.
  • 2. Controller [0168] 30 signaled controller 20 to start ADME device 1 and to begin collecting data from the two temperature sensors and flow meter 4.
  • 3. After a pre-programmed delay, device [0169] 1 initiated the generation of the aerosol. (Note: there was a delay of about 0.4 seconds between the start of the controller 30 and the start of aerosol generation.)
  • 4. After an independent preprogrammed delay (from original trigger signal), controller [0170] 30 opened input valve 58 to start forced inhalation to a dog under experimentation.
  • 5. Device [0171] 1 completed the aerosol generation during the inhalation.
  • 6. Controller [0172] 30 monitored flow meter 4 and pressure transducer 240 throughout the inhalation and closed off flow at input valve 58 when a pre-specified volume or pressure was met. (Note: the pre-specified pressure is a safety feature to prevent injury to the subject animal. Termination of the breath at the pre-specified volume is the desirable occurrence of the experiment.)
  • 7. After a breath hold delay (5 seconds), exhaust valve [0173] 40 was opened and the dog was allowed to exhale.
  • 8. Exhaled aerosol was trapped on exhaust filter [0174] 40 for later analysis. Controller 30 recorded values for the following: volume dispensed, terminal pressure, duration of air pulse, and average flow rate. Controller 20 continuously recorded at millisecond resolution, input flow rate, exhaust flow rate, foil temperature, mouthpiece temperature, slide position, heater on/off time, and other internal diagnostic electrical parameters.
  • In Vivo Results of the ADME Device [0175] 1 Embodiment
  • Three weight-matched female beagle dogs received fentanyl at a 100 μg intravenous bolus dose. The same dogs received fentanyl UF for Inhalation (100 μg aerosolized and administered as two successive activations of an ADME device [0176] 1, containing approximately 50 μg of fentanyl base) at a particle size of 80 nm (MMAD). The aerosol was administered to anesthetized dogs via the system schematically represented in FIG. 1, with a target delivered volume of 600-700 ml air, followed by a 5 second breath hold. After dosing, plasma samples for pharmacokinetic analysis were obtained at various time points from 2 min to 24 hr. Fentanyl remaining in the dosing and administration apparatus 1 was recovered and measured. Fentanyl concentrations were measured by using a validated GC method, with a limit of detection of 0.2 ng/ml.
  • Plasma pharmacokinetics from this example was compared to intravenous (IV) fentanyl (100 μg) in the same dogs. Inhalation of fentanyl resulted in rapid absorption (Cmax, maximum concentration in plasma, 11.6 ng/ml and Tmax, maximum time, 2 min.) and high bioavailability (84%). The time course of inhaled fentanyl was nearly identical to that of IV fentanyl. Thus, fentanyl UF for inhalation had an exposure profile that was similar to that of an IV injection. [0177]
  • The use of fentanyl to demonstrate the utility of the preferred embodiment is significant for several reasons. First, the liver extensively metabolizes fentanyl. Thus, an oral dosage form of fentanyl would tend to be less effective because the drug must be absorbed from the gastrointestinal tract and then delivered to the liver. Either an IV dose or an inhalation dose of fentanyl travels directly from its site of entry, a vein in the case of an IV or to the lung in the case of the present invention, to the brain, its primary site of action, before it passes through the liver. The administration of fentanyl to patients is currently provided in several dosage forms: intravenous, transdermal and transmucosal. The latter consists of a matrix of fentanyl citrate on a stick (Actiq® oral transmucosal fentanyl citrate). The product literature provided for Actiq indicate that 25% of the dose is absorbed from the buccal mucosa while the remaining 75% is swallowed with the saliva and is then slowly absorbed from the gastrointestinal tract. About ⅓ of this amount (25% of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available. Thus, a significant advantage of the delivery system of the present invention is that it provides a means for rapid absorption of drugs such as fentanyl into the blood system for delivery directly to the brain, without the use of needles or excipients and without being exposed to a first pass metabolism in the gastrointestinal tract or liver. [0178]
  • Standard non-compartmental pharmacokinetic methods were used to calculate pharmacokinetic parameters for each animal. The maximum concentration in plasma (Cmax) and the maximum time it occurred (Tmax) were determined by examination of the data. The area under the plasma concentration vs. time curve (AUC) was determined. The bioavailability (F) of inhaled fentanyl was determined as: [0179]
  • F=(DIV/DINHAL)*(AUCTNHAL/AUCIV)
  • Where D was the dose and AUC was the AUC determined to the last measurable time point. [0180]
  • FIG. 26 plots the data obtained on the blood levels, by dog, for both the IV doses and the inhalation doses using device [0181] 1 as described above under Example 1.
  • The fentanyl aerosol was rapidly absorbed, with the same Tmax (2 min, the earliest time point) observed for both routes of administration. The maximum plasma concentration of fentanyl aerosol (11.6±1.9 ng/ml) was nearly two-thirds that of IV fentanyl (17.6±3.6 ng/ml). Plasma concentrations fell below the assay limit of quantitation by 6-8 hr after IV administration and by 3-4 hr after aerosol inhalation. Bioavailability calculations were based on the AUC's observed to the last measurable time point for the inhalation administration. Bioavailability for the inhalation study was 84% based on the nominal (uncorrected) fentanyl dose. [0182]
  • The mean plasma elimination half-life was similar after IV (75.4 min) and inhalation dose. Distribution phase half-lives (3-4 min) were also similar after both routes of administration. The inter-animal variability of pharmacokinetic parameters after the inhalation dose was low, with relative standard deviations (RSD<25%) lower than those observed for IV administration. [0183]
  • In Vitro Results: ADME Device [0184] 1 Embodiment
  • Table 2 below summarizes the data collected from use of ADME device [0185] 1 for in vitro testing of fentanyl. Particle size was measured with a Moudi cascade impactor.
    TABLE 2
    Compound Mass Mixing air volume
    (ug) (cc) MMAD (nm) GSD
     20 400 71 1.9
     25 400 72-78 1.7-1.8
     50 400 77-88 1.7-185
    100 400 100-105 1.4-1.8
    200 400 103-123 1.6-1.9
    300 400 140-160 1.8-2.1
  • FIG. 27 compares the MAD calculated value for a GSD equal to 1.35 and 1.60 to actual data on MAD summarized in Table 2 for ADME device. The distinction between MMAD (Mass Mean Aerodynamic Diameter; the diameter of a particle of unit density material that exhibits the same aerodynamic behavior as the measured aerosol) and MMD (Mass Mean Diameter; the diameter of a unit density particle) is ignored since the density of fentanyl is very close to 1 gm/cc. The calculated values for MMD are discussed above in section A of the DETAILED DESCRIPTION. [0186]
  • The curves of FIG. 27 demonstrate a good correlation between the theoretical model based on the equations set forth earlier and actual data. Note that the theoretical prediction for small particles is less than the actual data. The reason, as stated earlier, is that when particle size becomes less than 80 nm the coagulation coefficient gets larger. As this happens a stable number concentration is reached at a lower number. If the calculation of MMD is redone with a number concentration of 0.5×10[0187] 9/cc instead of 1.0×109/cc, as used above, the curves shown in FIG. 28 result. As can be seen, the actual data fits the calculated data much better for the small particle sizes.
  • Example 2
  • In this example, ADME device [0188] 1 was slightly modified and the flow rate changed, as discussed below, to make a fine aerosol in the 1 to 3 micron particle size range.
  • Airway section [0189] 140 was removed and the air channel heating/vaporization zone 70 was changed. An airway insert (not shown) had a “roof” that was 0.25 inches above the foil. There were no mixing rods as rapid mixing was not desirable in this example. Because of these two device changes, there was much less mixing with the air, thus the vapor/aerosol cloud was mixed with less air and produced a larger particle size aerosol.
  • The airflow rate was reduced from 15 liters/minute in Example 1 to 1 liter/minute in this example. Again, this allowed the vapor to be mixed with much less air, resulting in the larger particle size aerosol. [0190]
  • Some operational problems with high compound loading on foil [0191] 64 in ADME device 1 were encountered. The compound tested, dioctyl phthalate (DOP), was an oil and during the aerosolization process, a substantial quantity was blown downwind and not aerosolized. Three additional design alternatives were made to address this issue, involving changes to the substrate surface that the compound was deposited on. In the three alternatives, the substrate was made to “hold” the compound through the use of texture. They were:
  • a. Texturing the foil. [0192]
  • b. Adding a stainless steel screen on top of the foil. [0193]
  • c. Replacing the foil with a fine stainless steel screen [0194]
  • The results from this example are set forth below in Table 3 below: [0195]
    TABLE 3
    Substrate Type MMAD, microns GSD Emitted Dose, ug
    Textured foil 1.49 microns 1.9  97
    Textured foil 2.70 microns  1.95 824
    Fine screen alone 1.59 microns 1.8 441
    Fine screen alone 1.66 microns 1.8 530
    Screen on Foil 2.42 microns 2.2 482
  • As shown above, a fine particle size can be made with ADME device [0196] 1 merely by changing the ratio of the compound to the mixing air.
  • Example 3
  • In this example, device [0197] 300, the third embodiment of the present invention, is described in which a gas stream is passed into thin walled tube 302 having a coating 310 of compound 60 on the inside of the tube as shown in FIGS. 10-11. The flow rate of the gas stream is controlled by valve 314. This is another example that allows for rapid heat-up using resistive heating system 320 while controlling the flow direction of the vaporized compound. After activating heating system 320 with actuator 330, current is passed along tube 302 in the heating/vaporization zone 340 as the carrier gas, e.g., air, N2 and the like, is passed through tube 302 and mixes with the resulting vapor. Another advantage of thin walled tube device 300 is that if drug is splattered from the interior wall of the tube before it can be vaporized, the drug will impact the other side of the hot tube where it would be vaporized. FIG. 12 shows an alternative heating system to resistive heating system 320 used in connection the third embodiment shown in FIGS. 10-11. In this case, inductive heating system 350 consists of a plurality of ferrites 360 for conducting the magnetic flux to vaporize drug 310.
  • FIG. 13 shows the alternate to the third embodiment in which flow restrictor [0198] 370 is mounted within thin-walled tube 302 by means of support 374 within a housing (not shown) to increase the flow of mixing gas across the surface of a compound.
  • Example 4
  • In this example, device [0199] 400, the fourth embodiment of the present invention shown in FIGS. 14-15, is described. A thin layer of compound 60 is deposited onto flat substrate 402 in a shape that has a high aspect ratio with the long direction of the deposition in the direction of airflow through airway tube 404 in housing 10. Substrate 60 is held in a frame that is then mounted in a slide in the manner described in Example 1 above. The slide is able to travel within an airway along the direction of air travel. A motor (not shown) drives the slide. Heater 406 is positioned so that it can heat substrate 402 and thereby compound 60. Heater 406 is connected to actuator 410. Chamber 420 is filled with a gas and has outlet 430 connected to passageway 440. Airflow is regulated through passageway 440 by valve 442 that is controlled by a controller (not shown). Passageway 440 is connected to nozzle 448 that is positioned above compound 60 deposited on substrate 402. Chamber 440 has a means to compress the gas within it. In the embodiment, this is accomplished by the use of movable piston 450 driven by a motor (not shown). Alternatively, the chamber can be compressed by a lever articulated by the user.
  • Upon actuation of device [0200] 400, valve 442 is opened, simultaneously with heater 406 being activated, and the slide and thereby compound 60 is moved under nozzle 448. Gas from chamber 420 is directed onto the compound's surface as the compound is raised in temperature. Upon vaporization, compound 30 is free to move down airway tube 404 to the patient.
  • Example 5
  • In this example, device [0201] 500, the fifth embodiment of the present invention is described in which the problem of the presence of oxygen during the heat-up period is also solved. Compound 60 is placed in an inert atmosphere or under a vacuum in container 502 within housing 10 and is heated by resistance heater 504 upon being activated by actuator 508 as shown in FIG. 15. Once compound 60 has become vaporized it can then be ejected through outlet passage 510 into the air stream passing through tube 520.
  • FIG. 16 shows an alternative to the embodiment shown in FIG. 15 in which fan [0202] 530 re-circulates the inert atmosphere over the surface of compound 60. The inert gas from a compressed gas cylinder (not shown) enters through inlet 540 and one-way valve 550 and exits through outlet passage 510 into tube 520 as in the above example.
  • Example 6
  • In this example, device [0203] 600, the sixth embodiment of the present invention is described in which compound 60 is deposited onto a substrate in the form of discrete particles 602, e.g., aluminum oxide (alumina), silica, coated silica, carbon, graphite, diatomaceous earth, and other packing materials commonly used in gas chromatography. The coated particles are placed within first tube 604 sandwiched between filters 604 and 608 and are heated by resistance heater 610 upon being activated by actuator 620 as shown in FIG. 17. The resulting vapor from tube 604 is combined with the air or other gas passing through second tube 625.
  • FIG. 18 shows an alternative to the embodiment shown in FIG. 17 in which resistance heater [0204] 630 heats the air prior to passing through first tube 604 and over discrete particles 602.
  • Example 7
  • If the decomposition of the compound is primarily caused by the presence of oxygen and not heat, and if the partial pressure of the compound is sufficient to produce the vaporization necessary at a temperature that does not produce decomposition, then an additional method of vaporization is possible. In device [0205] 700, the seventh embodiment of the present invention, compound 60 is deposited into chamber 710 and is heated by resistance heater 715 upon being activated by actuator 720 as shown in FIG. 19. Upon heating, some of compound 60 will vaporize and then become ejected from chamber 710 by moving an inert gas entering housing 10 through inert gas inlet 725 and valve 728 and passing across the surface of compound 60. The mixture of inert gas and vaporized compound passes through passage 730 and is then mixed with a gas passing through tube 735.
  • In Vitro Test Results for Example 7 [0206]
  • A tank is partially filled with DOP and placed inside an oven (not shown) having an inlet and an outlet. DOP was used as the test compound. The tank was purged with helium prior to heating the tank and its contents to a temperature of 350° C. Helium was pumped through the tank and used to carry the DOP vapor out of the outlet. The gaseous mixture of helium and vaporized compound [0207] 60 was introduced into different size mixing tubes through a nozzle. Each of the tubes had air moving through them at 14 liters/minute. The nozzle was perpendicular to the flow direction. After this gaseous mixture was mixed with the air, the resulting aerosol was introduced into a parallel flow diffusion battery for particle size analysis. Results are set forth in Table 4 below.
    TABLE 4
    Mixing tube size (ID) MMAD GSD
    4.8 mm 65 nm 1.3
    14 mm 516 nm 3.3
  • As can be seen above, as the tube diameter became larger so did the particle size. Additionally, as the diameter became larger, the GSD also became larger. As the tube becomes larger, it is believed that the vaporized gas is introduced into a smaller segment of the mixing gas because the gas is being introduced as a point source leading to uneven mixing, which results in a large GSD, as discussed under the DETAILED DESCRIPTION heading above. [0208]
  • Example 8
  • In this example, progressive heating is used during which multiple sections of a substrate are heated sequentially. The compound is deposited uniformly on the substrate. In order to subject the compound to rapid heat up, while at the same time not vaporizing the compound all at once, a movable heating zone is used. Compared to the entire surface area that the compound is laid down on, a relatively small heating area is generated in this example and moved, or “swept out” over the compound deposition area. A number of specific means for accomplishing this are described below. [0209]
  • 1. Moving Heater Relative To Substrate [0210]
  • A variety of heating methods can be used to heat the substrate upon which a compound has been deposited. A small zone in the substrate can be heated or only a segment of the substrate or portion of the compound can be directly heated. In the preferred embodiment described in Example 1 above, an inductive heater heating method was utilized, which heated a zone in the foil substrate. Regardless of the heating method, as long as only a small zone of the compound and/or the substrate is heated, it is possible to move the heater relative to the substrate/compound. In the preferred embodiment, an inductive heating zone was induced in a conductive substrate that was in direct contact with the compound. The substrate was moved relative to this magnetic field, causing the compound to be locally vaporized. [0211]
  • 2. Thermal Gradient [0212]
  • An alternative device for producing a moving heating zone was accomplished by device [0213] 800, the eighth embodiment of the present invention as shown in FIG. 20. Device 800 is referred as the gradient heating device. In device 800, thermally conductive substrate 802 was heated by resistance heater 810 at the upstream end of tube 820, and the thermal energy was allowed to travel along substrate 802. This produced, when observed in a particular location, a heat up rate that was determined from the characteristics of the thermally conductive substrate. By varying the material and its cross sectional area, it was possible to control the rate of heat up.
  • The source of the thermal energy can originate from a variety of other heating methods. A simple resistive heater [0214] 810 is shown. This resistive heater was embedded in substrate 802 at one end. However, it could be embedded into both ends, or in a variety of positions along the substrate and still allow the temperature gradient to move along the carrier and/or substrate shown in FIG. 20.
  • To demonstrate effectiveness of a thermal gradient device, a 4-inch long piece of aluminum was fitted with a 150-watt cartridge heater at one end. The heater was powered with a variac AC power transformer. The thickness of the aluminum was designed to ensure that heat would transverse from one end of the aluminum to the other in approximately 30 seconds. [0215]
  • On the topside of the aluminum, an indentation was machined to hold the compound and to hold one of two top covers. The indentation for the compound was approximately 3.5 inches long and 0.4 inches wide. The indentation was 0.025 inches deep, and was filled with 1 mg of DOP. [0216]
  • The first top consisted of a sheet of flat glass placed 0.04 inches above the heated surface, creating an airway. At the exit end an outlet was fitted allowing the air to be drawn into an analytical measurement device. Air was made to flow through the airway at a rate of 15 liters/minute. [0217]
  • In the second configuration, the top was replaced with a half cylinder made of glass. This increased the cross sectional area of the airway by an order of magnitude. [0218]
  • Particle size was measured with both configurations and shown to be affected by the cross sectional area of the airway. [0219]
  • Results from the thermal gradient test are set forth in Table 5 below: [0220]
    TABLE 5
    Cover size and
    cross section MMAD GSD
    Small 92 nm 1.4
    Big 650 nm unknown
  • As shown above, the results confirm that as the cross section becomes larger, so does the particle size. [0221]
  • 3. Discrete Heating Zones [0222]
  • A third method established a set of heated zones, energized sequentially. The zones could be produced from any of the heating devices including a resistive heater as disclosed in Rosen, PCT Publication No. 94/09842, published May 11, 1994, the relevant portions of which are incorporated herein by reference. For example, a substrate could have three (3) sections A, B, C. where section A is first heated until the compound have been vaporized followed by the section B, and then C. [0223]
  • 4. Inductive Heater, Vary Field To Heat Different Zones [0224]
  • A fourth method involved heating a zone in a substrate with an inductive heater, and then by manipulating the magnetic field, causing the induced current in the substrate to move along the substrate. This was accomplished by a number of methods. One method was to use a ferrite with a saturation value such that, by increasing the electrical field internal to the ferrite, the resultant magnetic field leaves the confines of the ferrite and enters a different area of the substrate. [0225]
  • Another method involved constructing a ferrite with a shape that can be changed, such as opening up an air gap, and thereby changing the shape of the magnetic field. [0226]
  • 5. The Use Of Radiative Heating [0227]
  • An additional method involved incrementally heating a substrate through the focusing and/or de-focusing of all forms of photon energy, especially in the visible and IR spectrum. [0228]
  • Example 9
  • The ninth embodiment of the present invention is shown in FIGS. [0229] 21-22 as screen device 900. In device 900, air was channeled through a fine mesh metal screen 902 that had the drug deposited thereon. Rapid heating and/or rapid cooling, as stated above, can preclude decomposition. This example involves rapidly mixing a compound, once it has vaporized, into air. A thin (0.01 to 10 micron) layer of compound can be deposited onto fine mesh screen 902, e.g., 200 and 400 mesh screens were used in this example. Screen 902 was positioned across airway passage 910. In this preferred embodiment for producing fine aerosols, airway passage 910 was constructed from 18 mm diameter glass tubing. However, the passage can be made in any shape with a comparable cross-sectional area and out of any suitable material. The screen size, mesh, and the amount of compound were chosen in this example so that a gas could pass through the screen without interference once the compound had been deposited on it.
  • The two sides of the screen were electrically connected to charged capacitor [0230] 920 through silicon-controlled rectifier (SCR) 922 to make a circuit. The charge of the capacitor was calculated and set at a value such that, when actuator 930 closed SCR 922, the energy from capacitor 920 was converted to a desired temperature rise in screen 902. Because the internal resistance of the screen was low, i.e., between 0.01 and 0.2 ohms, the discharge rate (the RC time constant) of the capacitor was rapid, and on the order of a few milliseconds, i.e. less than 20 milliseconds, preferably in the range of about 2 to about 10 milliseconds. Upon discharge of capacitor 902 and the subsequent heating of screen 902, the deposited compound was rapidly vaporized. Because air moved through screen 902, the vaporized compound rapidly mixed with air and cooled.
  • The compound was deposited onto the fine stainless steel screen, e.g., 200 mesh, made from 316 stainless steel, having measurements of 2.54 cm.×2.54 cm. The current from the capacitor was passed between one edge and another. It was not necessary to heat the screen to temperatures comparable to the thin foil in Example 1, because the compound vaporized at a lower temperature due to the rapid air movement. Rapid air movement allowed the compound to vaporize at a lower vapor pressure, since airflow constantly removed compound vapors from the surface as soon as they were formed. Thus, the compound vaporized at a lower temperature without decomposition. [0231]
  • Deposition of the compound onto the screen was accomplished by mixing the compound with an organic solvent until the compound dissolved. The resulting solution was then applied to the fine stainless steel screen [0232] 902 and the solvent was allowed to evaporate. The screen was then inserted into holder 940 that electrically connected two sides of screen 902 to the power circuit described above.
  • A 10,000 mF capacitor was discharged while the gas was passing through screen [0233] 902. The rapid heat up of the screen resulted in a rapid vaporization of the compound into the gas. Thus the resulting vaporized compound was mixed into a small volume of the gas. Because the ratio of the mass of the compound to the volume of the mixing gas was large, a fine (1-3 micron diameter) particle aerosol was made.
  • One of ordinary skill in the art can combine the foregoing embodiments or make various other embodiments and aspects of the method and device of the present invention to adapt them to specific usages and conditions. As such, these changes and modifications are properly, equitably, and intended to be, within the full range of equivalents of the following claims. [0234]

Claims (83)

    What is claimed is:
  1. 1. A method for delivering a physiologically active compound to a patient comprising the steps of:
    (a) heating the physiologically active compound to a temperature and for a duration that results in an acceptably low level of decomposition;
    (b) simultaneously passing a gas across the surface of said compound to achieve a desired rate of vaporization; and
    (c) administering the resulting aerosol to a patient.
  2. 2. The method of claim 1 wherein said gas is air.
  3. 3. The method of claim 2 wherein said air is at ambient temperature.
  4. 4. The method of claim 2 wherein air is passed across said surface at a rapid rate.
  5. 5. The method of claim 4 wherein the rapid rate does not result in a large rise in the air temperature.
  6. 6. The method of claim 4 wherein the rapid rate does not result in said compound being blown downstream with the air without being first vaporized.
  7. 7. The method of claim 2 wherein the vaporized compound is rapidly mixed into the air to cool and preclude additional decomposition of said compound.
  8. 8. The method of claim 7 wherein the resulting mixture of said vaporized compound and air is further mixed into an additional air stream to further cool and preclude additional decomposition of said compound.
  9. 9. The method of claim 4 wherein the rapid rate of air passing across said surface is caused by inhalation through the device by the patient.
  10. 10. The method of claim 2 wherein the air passing across said surface is generated by mechanical means.
  11. 11. The method of claim 1 wherein said compound is moved into a region of rapid gas movement and heated so that the said compound vaporizes at the lowest possible temperature.
  12. 12. The method of claim 1 wherein said compound is selected from the group consisting of cannabinoid extracts from cannabis, THC, ketorolac, fentanyl, morphine, testosterone, ibuprofen, nicotine, Vitamin A, Vitamin E acetate, Vitamin E, nitroglycerin, pilocarpine, mescaline, testosterone enanthate, menthol, phencaramide, methsuximide, eptastigmine, promethazine, procaine, retinol, lidocaine, trimeprazine, isosorbide dinitrate, timolol, methyprylon, etamiphyllin, propoxyphene, salmetrol, vitamin E succinate, methadone, oxprenolol, isoproterenol bitartrate, etaqualone, Vitamin D3, ethambutol, ritodrine, omoconazole, cocaine, lomustine, ketamine, ketoprofen, cilazaprol, propranolol, sufentanil, metaproterenol, pentoxapylline, captopril, loxapine, cyproheptidine, carvediol, trihexylphenadine, alprostadil, melatonin, testosterone proprionate, valproic acid, acebutolol, terbutaline, diazepam, topiramate, pentobarbital, alfentanil HCl, papaverine, nicergoline, fluconazole, zafirlukast, codeine, testosterone acetate, droperidol, atenolol, metoclopramide, enalapril, albuterol, ketotifen, isoproterenol, amiodarone HCl, zileuton, midazolam, oxycodone, cilostazol, propofol, nabilone, ketorolac, gabapentin, famotidine, lorezepam, naltrexone, acetaminophen, sumatriptan, bitolterol, nifedipine, phenobarbital, phentolamine, 13-cis retinoic acid, droprenilamine HCl, amlodipine, caffeine, zopiclone, tramadol HCl, pirbuterol, naloxone, meperidine HCl, trimethobenzamide, nalmefene, scopolamine, sildenafil, carbamazepine, procaterol HCl, methysergide, glutathione, olanzapine, zolpidem, levorphanol, buspirone and mixtures thereof.
  13. 13. The method of claim 12 wherein said gas is air.
  14. 14. The method of claim 5 wherein said compound is contained in a heating-vaporization-mixing zone having a sufficiently restricted cross-sectional area to increase the rate of air passing across said compound and to achieve the desired rate of vaporization.
  15. 15. The method of claim 14 wherein the mixing zone is designed to rapidly cool the vaporized compound.
  16. 16. The method of claim 1 wherein said compound is heated with photon energy.
  17. 17. The method of claim 1 wherein said compound is heated with resistive heaters.
  18. 18. The method of claim 1 wherein said compound is heated by inductive means.
  19. 19. A method for delivering a physiologically active compound to a patient comprising the steps of:
    (a) heating the physiologically active compound to a temperature and for a duration that results in an acceptably low level of decomposition;
    (b) simultaneously passing a gas across the surface of said compound, said compound being contained in a heating-vaporization-mixing zone having a sufficiently restricted cross-sectional area to increase the rate of gas passing across said compound and to achieve a desired rate of vaporization;
    (c) rapidly mixing the vaporized compound into the gas to cool and preclude additional decomposition of said compound; and
    (d) administering the resulting aerosol to a patient.
  20. 20. The method of claim 19 wherein said gas is air.
  21. 21. The method of claim 20 wherein said air is at ambient temperature.
  22. 22. The method of claim 19 wherein the rapid rate of air passing across said surface is caused by the inhalation of the patient.
  23. 23. The method of claim 22 wherein the rapid rate does not result in a pressure drop across the restricted cross-sectional area of greater than about 10 inches of water.
  24. 24. A method for delivering a physiologically active compound to a patient comprising the steps of:
    (a) depositing the physiologically active compound onto a substrate;
    (b) feeding the substrate into a heating-vaporization-mixing zone while insuring a high level of vaporization by simultaneously passing a gas across the surface of said compound thereby insuring vaporization at the lowest possible temperature and shortest duration to achieve an acceptable level of decomposition;
    (c) mixing the vaporized compound into the gas to rapidly cool and minimize decomposition of said compound; and
    (d) administering the resulting aerosol to a patient.
  25. 25. The method of claim 24 wherein said heating-vaporization-mixing zone has a sufficiently restricted cross-sectional area to increase the rate of gas passing across said compound and to achieve the highest possible rate of vaporization.
  26. 26. The method of claim 24 wherein said gas is air.
  27. 27. The method of claim 26 wherein said air is at ambient temperature.
  28. 28. The method of claim 26 wherein the rapid rate of air passing across said surface is caused by inhalation though the device by the patient.
  29. 29. The method of claim 24 wherein said compound is heated with photon energy.
  30. 30. The method of claim 24 wherein said compound is heated with resistive heaters.
  31. 31. The method of claim 24 wherein said compound is heated by inductive means.
  32. 32. The method of claim 31 wherein said substrate is a metallic foil.
  33. 33. The method of claim 32 wherein said substrate is a stainless steel foil.
  34. 34. The method of claim 33 wherein said compound is deposited onto said stainless steel foil at a thickness of no greater than about 10 microns.
  35. 35. A method for delivering a physiologically active compound to a patient comprising the steps of:
    (a) depositing the physiologically active compound onto a substrate;
    (b) rapidly heating all of said compound to result in an acceptably low level of decomposition;
    (c) simultaneously passing a gas across the surface of said compound to insure:
    (i) a high level of vaporization of at least a portion of said compound, and
    (ii) rapid cooling of the vaporized compound to result in an acceptably low level of decomposition; and
    (d) administering the resulting aerosol to a patient.
  36. 36. The method of claim 35 wherein all of the compound is heated at the same rate.
  37. 37. The method of claim 35 wherein the compound is heated to the point of vaporization between 1 and 10 milliseconds.
  38. 38. The method of claim 35 wherein the compound is heated to the point of vaporization between about 10 and about 100 milliseconds.
  39. 39. The method of claim 35 wherein the compound in deposited onto a substrate having a surface area up to one meter square.
  40. 40. The method of claim 39 wherein the substrate is porous and allows for the passing of the gas through the substrate.
  41. 41. The method of claim 40 wherein the substrate is constructed and positioned in the gas stream so that said compound is vaporized into a small volume of gas.
  42. 42. The method of claim 35 wherein the compound is heated by heating the substrate on which the compound is deposited.
  43. 43. The method of claim 42 wherein the substrate is heated by making the substrate from an electrically conductive material and passing an electrical current though the substrate.
  44. 44. The method of claim 35 wherein the portion of the compound that is vaporized is all vaporized at close to the same rate.
  45. 45. The method of claim 42 wherein the substrate is made of an electrically conductive material and is heated inductively.
  46. 46. The method of claim 35 wherein the gas is passed across the entire surface of the substrate.
  47. 47. The method of claim 35 wherein the gas is passed across a portion of the surface of the substrate.
  48. 48. A device for delivering a physiologically active compound to a patient comprising:
    (a) a housing having an outlet;
    (b) a heating system for heating the physiologically active compound to a temperature and for a duration that results in an acceptably low level of decomposition while simultaneously passing a gas across the surface of said compound;
    (c) a venturi tube having a throat containing said compound within said housing and connected to the outlet, said throat having a sufficiently restricted cross-sectional area to result in a desired high level of vaporization of said compound by increasing in the rate of the gas passing through said throat and across the surface of said compound; and
    (d) an actuator operably coupled to said heater system and capable of activating said heater system.
  49. 49. The device of claim 48 wherein the compound is placed on a flat surface that is mechanically moved into said throat.
  50. 50. The device of claim 48 wherein said venturi tube has an inlet passage connected to said throat and an outlet passage connecting said throat with said outlet.
  51. 51. The device of claim 48 wherein the rate of gas does not result in a pressure drop across the venturi tube of greater than about 10 inches of water.
  52. 52. The device of claim 48 wherein the entire compound is vaporized in less than 2 seconds.
  53. 53. The device of claim 48 wherein any particular portion of the compound experiences a temperature heat up time to the point of vaporization in less than 0.1 second.
  54. 54. The device of claim 50 wherein air is the gas that enters the inlet passage and passes through said throat, said outlet passage and said outlet.
  55. 55. The device of claim 48 wherein said actuator is activated by the inhalation of the patient and drawing air through said throat.
  56. 56. The device of claim 48 wherein said actuator is manually activated by the patient.
  57. 57. The device of claim 48 wherein said heater means for heating is an inductive heater generating an alternating magnetic field.
  58. 58. The device of claim 57 wherein the frequency of said magnetic field is maintained at less than 1 MHz.
  59. 59. The device of claim 57 wherein the frequency of said magnetic field is maintained between about 100 and about 300 kHz.
  60. 60. A device for delivering a physiologically active compound to a patient comprising:
    (a) a housing having an outlet;
    (b) a heating system for heating said compound to a temperature that results in an acceptably low level of decomposition while simultaneously passing a gas across the surface of said compound;
    (c) a heating-vaporization-mixing zone containing said compound within said housing and connected to the outlet;
    (d) a chamber of compressed gas having a valve and connected to said heating-vaporization-mixing zone for directing a stream of gas at said compound and across the compound's surface to result in a desired high level of vaporization of said compound by increasing the rate of the gas passing across the surface of said compound; and
    (e) an actuator operably coupled to and capable of activating said heater system.
  61. 61. The device of claim 60 wherein a tube within said housing having an inlet passage connected to said heating-vaporization-mixing zone and an outlet passage connected to said outlet.
  62. 62. The device of claim 61 wherein air is the gas that is in said chamber and enters said inlet passage and passes through said heating-vaporization-mixing zone, said outlet passage and said outlet.
  63. 63. The device of claim 60 wherein said actuator is activated by the inhalation of the patient.
  64. 64. The device of claim 60 wherein said actuator is manually activated by the patient.
  65. 65. The device of claim 60 wherein said actuator is activated by the inhalation of the patient.
  66. 66. A device for delivering a physiologically active compound to a patient comprising:
    (a) a housing having an outlet;
    (b) a first tube within said housing through which a first gas stream is passed, having a filter at each end and containing a plurality of particles, each particle having a large surface area to mass ratio and a coating of a physiologically active compound;
    (c) a heating system for heating said compound to a temperature that results in an acceptably low level of decomposition while simultaneously passing the first gas stream through said first tube and over the surface of the coated particles;
    (d) a second tube connected to said outlet through which a second gas stream is passed and combined with a mixture of the vaporized compound and the first gas stream from said first tube; and
    (e) an actuator operably coupled to and capable of activating said heater system.
  67. 67. The device of claim 66 wherein the particles are selected from the group consisting of aluminum oxide, silica, coated silica, carbon, graphite, diatomaceous earth, and mixtures thereof.
  68. 68. The device of claim 66 wherein the compound is heated by heating the gas in the first tube and then passing the heated gas over the compound.
  69. 69. A device for delivering a physiologically active compound to a patient comprising:
    (a) a housing having an outlet;
    (b) a venturi tube within said housing and having a throat containing said compound coated on its interior surface and connected to the outlet, said throat having a sufficiently restricted cross-sectional area to result in a desired high level of vaporization of said compound and an increase in the rate of the gas passing through said throat and across the surface of said compound;
    (c) a heating system for heating said compound to a temperature by discharging electrical energy through said tube that results in an acceptably low level of decomposition while simultaneously passing a gas across the surface of said compound; and
    (d) an actuator operably coupled to said heater means for activating said heater system.
  70. 70. The device of claim 69 wherein the rate of gas does not result in a pressure drop across the venturi tube of greater than about 10 inches of water.
  71. 71. A device for delivering a physiologically active compound to a patient comprising:
    (a) depositing a physiologically active compound onto an electrically conductive mesh or screen carrier;
    (b) rapidly heating the carrier by passing a high current across the carrier to vaporize at least a portion of the compound, while simultaneously passing a gas through the screen thereby mixing the resulting vapor with the gas; and
    (c) administering the resulting mixture to a patient.
  72. 72. The device of claim 71 wherein the carrier is a single layer of stainless steel mesh.
  73. 73. The device of claim 71 wherein the carrier is made of multiple layers of material.
  74. 74. The device of claim 73 wherein the stainless steel mesh is a fine mesh
  75. 75. The device of claim 74 wherein the stainless steel mesh is in the range of about 100 to about 400 mesh.
  76. 76. The device of claim 71 wherein the high current in step (b) is supplied by the discharging of a capacitor.
  77. 77. The device of claim 71 wherein the current supplied is for less than about 20 milliseconds.
  78. 78. The device of claim 71 wherein the current supplied is from between about 2 and about 10 milliseconds.
  79. 79. The device of claim 71 wherein the substrate is heated inductively instead of directly passing the current though the substrate.
  80. 80. The method for generating an aerosol comprising the steps of:
    (a) heating the physiologically active compound to a temperature and for a duration that results in an acceptably low level of decomposition;
    (b) simultaneously passing a gas across the surface of said compound to achieve a desired rate of vaporization; and
    (c) administering the resulting aerosol to an organ or tissue of a patient.
  81. 81. The method of claim 80 wherein the aerosol is administered to the eye.
  82. 82. The method of claim 80 wherein the aerosol is administered to the skin.
  83. 83. The method of claim 80 wherein the aerosol is administered to the mucosa.
US10057198 2001-06-05 2001-10-26 Method and device for delivering a physiologically active compound Abandoned US20030051728A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US29622501 true 2001-06-05 2001-06-05
US10057198 US20030051728A1 (en) 2001-06-05 2001-10-26 Method and device for delivering a physiologically active compound
US10057197 US7766013B2 (en) 2001-06-05 2001-10-26 Aerosol generating method and device

Applications Claiming Priority (45)

Application Number Priority Date Filing Date Title
US10057198 US20030051728A1 (en) 2001-06-05 2001-10-26 Method and device for delivering a physiologically active compound
US10057197 US7766013B2 (en) 2001-06-05 2001-10-26 Aerosol generating method and device
PCT/US2002/018608 WO2002098390A3 (en) 2001-06-05 2002-05-13 Delivery of aerosols containing small particles through an inhalation route
PCT/US2002/015425 WO2002098389A8 (en) 2001-06-05 2002-05-13 Method of forming an aerosol for inhalation delivery
JP2003501430A JP2004532881A (en) 2001-06-05 2002-05-13 Delivery of microparticles containing aerosols via any inhalation route
EP20020739262 EP1392381B9 (en) 2001-06-05 2002-05-13 An aerosol forming device for use in inhalation therapy
CA 2447210 CA2447210C (en) 2001-06-05 2002-05-13 Delivery of aerosols containing small particles through an inhalation route
CA 2646756 CA2646756C (en) 2001-06-05 2002-05-13 Method of forming an aerosol for inhalation delivery
JP2003501429A JP4510438B2 (en) 2001-06-05 2002-05-13 Aerosol formation method for use in inhalation therapy
US10146088 US7537009B2 (en) 2001-06-05 2002-05-13 Method of forming an aerosol for inhalation delivery
CN 02811406 CN1304067C (en) 2001-06-05 2002-05-13 Aerosol forming device for use in inhalation therapy
CA 2447081 CA2447081C (en) 2001-06-05 2002-05-13 An aerosol forming device for use in inhalation therapy
DE2002639604 DE60239604D1 (en) 2001-06-05 2002-05-13 Atomizer for use in inhalation therapy
EP20020739267 EP1392242B1 (en) 2001-06-05 2002-05-13 Method of forming an aerosol for inhalation delivery
CA 2447354 CA2447354C (en) 2001-06-05 2002-05-13 Method of forming an aerosol for inhalation delivery
JP2003501533A JP4912566B2 (en) 2001-06-05 2002-05-13 Aerosol forming device for use in inhalation therapy
DE2002636430 DE60236430D1 (en) 2001-06-05 2002-05-13 Ation
US10146515 US6682716B2 (en) 2001-06-05 2002-05-13 Delivery of aerosols containing small particles through an inhalation route
PCT/US2002/015363 WO2002098496A1 (en) 2001-06-05 2002-05-13 An aerosol forming device for use in inhalation therapy
CN 02811407 CN100496458C (en) 2001-06-05 2002-05-13 Method of forming aerosol for inhalation delivery
ES02739267T ES2343678T3 (en) 2001-06-05 2002-05-13 Method of forming an aerosol for inhalation administration.
US10146080 US7942147B2 (en) 2001-06-05 2002-05-13 Aerosol forming device for use in inhalation therapy
EP20020742015 EP1392263A2 (en) 2001-06-05 2002-05-13 Delivery of aerosols containing small particles through an inhalation route
US10633877 US7585493B2 (en) 2001-05-24 2003-08-04 Thin-film drug delivery article and method of use
US10633876 US7645442B2 (en) 2001-05-24 2003-08-04 Rapid-heating drug delivery article and method of use
US10696959 US20040096402A1 (en) 2001-06-05 2003-10-30 Delivery of aerosols containing small particles through an inhalation route
US10718982 US7090830B2 (en) 2001-05-24 2003-11-20 Drug condensation aerosols and kits
US11504419 US20070122353A1 (en) 2001-05-24 2006-08-15 Drug condensation aerosols and kits
US11687466 US20080038363A1 (en) 2001-05-24 2007-03-16 Aerosol delivery system and uses thereof
US11744799 US20070286816A1 (en) 2001-05-24 2007-05-04 Drug and excipient aerosol compositions
US12117737 US8235037B2 (en) 2001-05-24 2008-05-08 Drug condensation aerosols and kits
US12471070 US8074644B2 (en) 2001-06-05 2009-05-22 Method of forming an aerosol for inhalation delivery
JP2009259070A JP2010057950A (en) 2001-06-05 2009-11-12 Aerosol forming device for use in inhalation therapy
US12847584 US9308208B2 (en) 2001-06-05 2010-07-30 Aerosol generating method and device
US13078606 US20110240013A1 (en) 2001-06-05 2011-04-01 Method of forming an aerosol for inhalation delivery
US13078600 US20110240022A1 (en) 2001-06-05 2011-04-01 Aerosol forming device for use in inhalation therapy
US13078516 US20110244020A1 (en) 2001-05-24 2011-04-01 Drug condensation aerosols and kits
US13569006 US9211382B2 (en) 2001-05-24 2012-08-07 Drug condensation aerosols and kits
US13851577 US8955512B2 (en) 2001-06-05 2013-03-27 Method of forming an aerosol for inhalation delivery
US14077015 US9439907B2 (en) 2001-06-05 2013-11-11 Method of forming an aerosol for inhalation delivery
US14078679 US9440034B2 (en) 2001-05-24 2013-11-13 Drug condensation aerosols and kits
US14078577 US9687487B2 (en) 2001-06-05 2013-11-13 Aerosol forming device for use in inhalation therapy
US14624311 US20150157635A1 (en) 2001-06-05 2015-02-17 Method Of Forming An Aerosol For Inhalation Delivery
US15262954 US20160374937A1 (en) 2001-05-24 2016-09-12 Drug Condensation Aerosols And Kits
US15633508 US20170281884A1 (en) 2001-06-05 2017-06-26 Aerosol Forming Device For Use In Inhalation Therapy

Related Parent Applications (4)

Application Number Title Priority Date Filing Date
US10057197 Continuation-In-Part US7766013B2 (en) 2001-06-05 2001-10-26 Aerosol generating method and device
US10057197 Continuation US7766013B2 (en) 2001-06-05 2001-10-26 Aerosol generating method and device
US10146080 Continuation-In-Part US7942147B2 (en) 2001-06-05 2002-05-13 Aerosol forming device for use in inhalation therapy
US10633876 Continuation-In-Part US7645442B2 (en) 2001-05-24 2003-08-04 Rapid-heating drug delivery article and method of use

Related Child Applications (8)

Application Number Title Priority Date Filing Date
US10057197 Continuation-In-Part US7766013B2 (en) 2001-06-05 2001-10-26 Aerosol generating method and device
US10146088 Continuation-In-Part US7537009B2 (en) 2001-06-05 2002-05-13 Method of forming an aerosol for inhalation delivery
US10146080 Continuation-In-Part US7942147B2 (en) 2001-06-05 2002-05-13 Aerosol forming device for use in inhalation therapy
US10146515 Continuation-In-Part US6682716B2 (en) 2001-06-05 2002-05-13 Delivery of aerosols containing small particles through an inhalation route
US10633876 Continuation-In-Part US7645442B2 (en) 2001-05-24 2003-08-04 Rapid-heating drug delivery article and method of use
US10633877 Continuation-In-Part US7585493B2 (en) 2001-05-24 2003-08-04 Thin-film drug delivery article and method of use
US10718982 Continuation-In-Part US7090830B2 (en) 2001-05-24 2003-11-20 Drug condensation aerosols and kits
US11687466 Continuation-In-Part US20080038363A1 (en) 2001-05-24 2007-03-16 Aerosol delivery system and uses thereof

Publications (1)

Publication Number Publication Date
US20030051728A1 true true US20030051728A1 (en) 2003-03-20

Family

ID=27369190

Family Applications (15)

Application Number Title Priority Date Filing Date
US10057198 Abandoned US20030051728A1 (en) 2001-06-05 2001-10-26 Method and device for delivering a physiologically active compound
US10057197 Active 2023-11-26 US7766013B2 (en) 2001-06-05 2001-10-26 Aerosol generating method and device
US10146080 Active US7942147B2 (en) 2001-06-05 2002-05-13 Aerosol forming device for use in inhalation therapy
US10146088 Active 2024-10-28 US7537009B2 (en) 2001-06-05 2002-05-13 Method of forming an aerosol for inhalation delivery
US10146515 Expired - Fee Related US6682716B2 (en) 2001-06-05 2002-05-13 Delivery of aerosols containing small particles through an inhalation route
US10696959 Abandoned US20040096402A1 (en) 2001-06-05 2003-10-30 Delivery of aerosols containing small particles through an inhalation route
US12471070 Active 2022-07-25 US8074644B2 (en) 2001-06-05 2009-05-22 Method of forming an aerosol for inhalation delivery
US12847584 Active US9308208B2 (en) 2001-06-05 2010-07-30 Aerosol generating method and device
US13078606 Abandoned US20110240013A1 (en) 2001-06-05 2011-04-01 Method of forming an aerosol for inhalation delivery
US13078600 Abandoned US20110240022A1 (en) 2001-06-05 2011-04-01 Aerosol forming device for use in inhalation therapy
US13851577 Active US8955512B2 (en) 2001-06-05 2013-03-27 Method of forming an aerosol for inhalation delivery
US14077015 Active US9439907B2 (en) 2001-06-05 2013-11-11 Method of forming an aerosol for inhalation delivery
US14078577 Active US9687487B2 (en) 2001-06-05 2013-11-13 Aerosol forming device for use in inhalation therapy
US14624311 Abandoned US20150157635A1 (en) 2001-06-05 2015-02-17 Method Of Forming An Aerosol For Inhalation Delivery
US15633508 Pending US20170281884A1 (en) 2001-06-05 2017-06-26 Aerosol Forming Device For Use In Inhalation Therapy

Family Applications After (14)

Application Number Title Priority Date Filing Date
US10057197 Active 2023-11-26 US7766013B2 (en) 2001-06-05 2001-10-26 Aerosol generating method and device
US10146080 Active US7942147B2 (en) 2001-06-05 2002-05-13 Aerosol forming device for use in inhalation therapy
US10146088 Active 2024-10-28 US7537009B2 (en) 2001-06-05 2002-05-13 Method of forming an aerosol for inhalation delivery
US10146515 Expired - Fee Related US6682716B2 (en) 2001-06-05 2002-05-13 Delivery of aerosols containing small particles through an inhalation route
US10696959 Abandoned US20040096402A1 (en) 2001-06-05 2003-10-30 Delivery of aerosols containing small particles through an inhalation route
US12471070 Active 2022-07-25 US8074644B2 (en) 2001-06-05 2009-05-22 Method of forming an aerosol for inhalation delivery
US12847584 Active US9308208B2 (en) 2001-06-05 2010-07-30 Aerosol generating method and device
US13078606 Abandoned US20110240013A1 (en) 2001-06-05 2011-04-01 Method of forming an aerosol for inhalation delivery
US13078600 Abandoned US20110240022A1 (en) 2001-06-05 2011-04-01 Aerosol forming device for use in inhalation therapy
US13851577 Active US8955512B2 (en) 2001-06-05 2013-03-27 Method of forming an aerosol for inhalation delivery
US14077015 Active US9439907B2 (en) 2001-06-05 2013-11-11 Method of forming an aerosol for inhalation delivery
US14078577 Active US9687487B2 (en) 2001-06-05 2013-11-13 Aerosol forming device for use in inhalation therapy
US14624311 Abandoned US20150157635A1 (en) 2001-06-05 2015-02-17 Method Of Forming An Aerosol For Inhalation Delivery
US15633508 Pending US20170281884A1 (en) 2001-06-05 2017-06-26 Aerosol Forming Device For Use In Inhalation Therapy

Country Status (8)

Country Link
US (15) US20030051728A1 (en)
EP (3) EP1392242B1 (en)
JP (4) JP2004532881A (en)
CN (2) CN1304067C (en)
CA (4) CA2646756C (en)
DE (2) DE60236430D1 (en)
ES (1) ES2343678T3 (en)
WO (3) WO2002098496A1 (en)

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030062042A1 (en) * 2001-06-05 2003-04-03 Wensley Martin J. Aerosol generating method and device
US20030209240A1 (en) * 2002-05-13 2003-11-13 Hale Ron L. Method and apparatus for vaporizing a compound
US20040009128A1 (en) * 2002-05-13 2004-01-15 Rabinowitz Joshua D Delivery of drug amines through an inhalation route
US20040102434A1 (en) * 2002-11-26 2004-05-27 Alexza Molecular Delivery Corporation Method for treating pain with loxapine and amoxapine
US20040105819A1 (en) * 2002-11-26 2004-06-03 Alexza Molecular Delivery Corporation Respiratory drug condensation aerosols and methods of making and using them
WO2004096118A2 (en) 2003-04-29 2004-11-11 Neurim Pharmaceuticals (1991) Ltd. Composition for improving cognition and memory
US20040234916A1 (en) * 2003-05-21 2004-11-25 Alexza Molecular Delivery Corporation Optically ignited or electrically ignited self-contained heating unit and drug-supply unit employing same
US20050034723A1 (en) * 2003-08-04 2005-02-17 Bryson Bennett Substrates for drug delivery device and methods of preparing and use
WO2005053444A1 (en) * 2003-12-05 2005-06-16 Lts Lohmann Therapie-Systeme Ag Inhaler for basic pharmaceutical agents and method for production thereof
US20060153779A1 (en) * 2001-05-24 2006-07-13 Alexza Pharmaceuticals, Inc. Delivery of stimulants through an inhalation route
US20060233718A1 (en) * 2001-05-24 2006-10-19 Alexza Pharmaceuticals, Inc. Delivery of alprazolam, estazolam, midazolam or triazolam through an inhalation route
US20060251810A1 (en) * 2005-05-03 2006-11-09 Eastman Kodak Company Metering material to promote rapid vaporization
US20060257328A1 (en) * 2001-11-21 2006-11-16 Alexza Pharmaceuticals, Inc. Delivery of caffeine through an inhalation route
US20070070612A1 (en) * 2005-09-23 2007-03-29 Bull, S.A.S. System for maintaining an assembly of three parts in position that exerts a predetermined compressive force on the itermediate part
US20070155255A1 (en) * 2005-12-29 2007-07-05 Charles Galauner Heating element connector assembly with press-fit terminals
US20080299048A1 (en) * 2006-12-22 2008-12-04 Alexza Pharmaceuticals, Inc. Mixed drug aerosol compositions
US20080311176A1 (en) * 2001-05-24 2008-12-18 Alexza Pharmaceuticals, Inc. Drug Condensation Aerosols And Kits
US20090062254A1 (en) * 2002-11-26 2009-03-05 Alexza Pharmaceuticals, Inc. Acute Treatment of Headache with Phenothiazine Antipsychotics
US7513781B2 (en) 2006-12-27 2009-04-07 Molex Incorporated Heating element connector assembly with insert molded strips
US20090107495A1 (en) * 2005-07-21 2009-04-30 National Institute For Materials Science Device for inhalation of medicine
US7645442B2 (en) 2001-05-24 2010-01-12 Alexza Pharmaceuticals, Inc. Rapid-heating drug delivery article and method of use
US20100055048A1 (en) * 2002-05-20 2010-03-04 Alexza Pharmaceuticals, Inc. Acute treatment of headache with phenothiazine antipsychotics
US20100065052A1 (en) * 2008-09-16 2010-03-18 Alexza Pharmaceuticals, Inc. Heating Units
US20100068154A1 (en) * 2008-09-16 2010-03-18 Alexza Pharmaceuticals, Inc. Printable Igniters
US20100300433A1 (en) * 2009-05-28 2010-12-02 Alexza Pharmaceuticals, Inc. Substrates for Enhancing Purity or Yield of Compounds Forming a Condensation Aerosol
US7913688B2 (en) 2002-11-27 2011-03-29 Alexza Pharmaceuticals, Inc. Inhalation device for producing a drug aerosol
US7923662B2 (en) 2004-05-20 2011-04-12 Alexza Pharmaceuticals, Inc. Stable initiator compositions and igniters
US7981401B2 (en) 2002-11-26 2011-07-19 Alexza Pharmaceuticals, Inc. Diuretic aerosols and methods of making and using them
US8333197B2 (en) 2004-06-03 2012-12-18 Alexza Pharmaceuticals, Inc. Multiple dose condensation aerosol devices and methods of forming condensation aerosols
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
WO2014085719A1 (en) * 2012-11-28 2014-06-05 E-Nicotine Technology, Inc. Methods and devices for compound delivery
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US9119846B2 (en) 2003-04-29 2015-09-01 Neurim Pharmaceuticals (1991) Ltd. Method and composition for enhancing cognition in alzheimer's patients
US9724341B2 (en) 2013-07-11 2017-08-08 Alexza Pharmaceuticals, Inc. Nicotine salt with meta-salicylic acid
US10034988B2 (en) 2012-11-28 2018-07-31 Fontem Holdings I B.V. Methods and devices for compound delivery

Families Citing this family (107)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6962904B1 (en) * 1998-03-13 2005-11-08 Connective Tissue Imagineering Elastin peptide analogs and uses thereof
US7090830B2 (en) * 2001-05-24 2006-08-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US6759029B2 (en) 2001-05-24 2004-07-06 Alexza Molecular Delivery Corporation Delivery of rizatriptan and zolmitriptan through an inhalation route
US7498019B2 (en) 2001-05-24 2009-03-03 Alexza Pharmaceuticals, Inc. Delivery of compounds for the treatment of headache through an inhalation route
GB2381450B (en) * 2001-10-31 2006-05-31 Gw Pharma Ltd Compositions for administration of natural or synthetic cannabinoids by vaporisation
WO2003041693A1 (en) 2001-11-09 2003-05-22 Alexza Molecular Delivery Corporation Delivery of diazepam through an inhalation route
WO2003043574A3 (en) * 2001-11-19 2004-03-04 Becton Dickinson Co Pharmaceutical compositions in particulate form
GB2384184B (en) * 2002-01-10 2005-01-12 Aea Technology Plc Cannabis aerosol
JP2006516963A (en) * 2003-02-04 2006-07-13 クリサリス テクノロジーズ インコーポレイテッドChrysalis Technologies Incorporated Aerosol formulations and buspirone, buprenorphine, triazolam, aerosol delivery of cyclobenzaprine and zolpidem
CN1938027A (en) * 2003-02-28 2007-03-28 德莱克斯疗法公司 Opioid delivery system
CN1780605A (en) * 2003-02-28 2006-05-31 迪莱克斯治疗技术公司 Opioid drug delivery system
US7648982B2 (en) * 2003-02-28 2010-01-19 Ym Biosciences Inc. Opioid delivery system
US7648981B2 (en) * 2003-02-28 2010-01-19 Ym Biosciences Inc. Opioid delivery system
CN100381083C (en) 2003-04-29 2008-04-16 力 韩 Electronic nonflammable spraying cigarette
US20050042177A1 (en) * 2003-07-23 2005-02-24 Elan Pharma International Ltd. Novel compositions of sildenafil free base
WO2005014090A1 (en) * 2003-08-04 2005-02-17 Alexza Pharmaceuticals, Inc. Methods of determining film thicknesses for an aerosol delivery article
US7252050B2 (en) * 2003-09-04 2007-08-07 Maury Dean Cole Substance inhalation system
WO2005037949A3 (en) * 2003-10-07 2006-01-12 Chrysalis Tech Inc Aerosol formulations of butalbital, lorazepam, ipratropium, baclofen, morphine and scopolamine
CN2719043Y (en) 2004-04-14 2005-08-24 韩力 Atomized electronic cigarette
CA2567840C (en) 2004-06-03 2014-08-19 Alexza Pharmaceuticals, Inc. Multiple dose condensation aerosol devices and methods of forming condensation aerosols
US20100006092A1 (en) * 2004-08-12 2010-01-14 Alexza Pharmaceuticals, Inc. Aerosol Drug Delivery Device Incorporating Percussively Activated Heat Packages
KR20070118069A (en) * 2004-12-09 2007-12-13 인시스 테라퓨틱스, 인코포레이티드 Room-temperature stable dronabinol formulations
FR2880279A1 (en) * 2005-01-05 2006-07-07 Cvb Sarl Sarl A multi-odor diffusion
CA2600011C (en) * 2005-02-23 2015-11-10 Teva Pharmaceutical Industries Ltd. Rasagiline formulations of improved content uniformity
US20070083677A1 (en) 2005-05-18 2007-04-12 Nektar Therapeutics Valves, devices, and methods for endobronchial therapy
EP1733753A1 (en) * 2005-06-14 2006-12-20 RIZK, Nelly Kamel An apparatus containing a composition
US7884136B2 (en) 2005-06-27 2011-02-08 Biovail Laboratories International S.R.L. Modified-release formulations of a bupropion salt
WO2007024812A1 (en) * 2005-08-23 2007-03-01 Aerogen, Inc. Self-sealing t-piece and valved t-piece
US7900625B2 (en) * 2005-08-26 2011-03-08 North Carolina State University Inhaler system for targeted maximum drug-aerosol delivery
JP2009507925A (en) * 2005-09-13 2009-02-26 エラン ファーマ インターナショナル リミテッド Nanoparticles tadalafil formulation
US8865743B2 (en) 2006-01-06 2014-10-21 Acelrx Pharmaceuticals, Inc. Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain
US8252329B2 (en) 2007-01-05 2012-08-28 Acelrx Pharmaceuticals, Inc. Bioadhesive drug formulations for oral transmucosal delivery
US8535714B2 (en) 2006-01-06 2013-09-17 Acelrx Pharmaceuticals, Inc. Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain
US9066847B2 (en) 2007-01-05 2015-06-30 Aceirx Pharmaceuticals, Inc. Storage and dispensing devices for administration of oral transmucosal dosage forms
US8357114B2 (en) 2006-01-06 2013-01-22 Acelrx Pharmaceuticals, Inc. Drug dispensing device with flexible push rod
US8202535B2 (en) 2006-01-06 2012-06-19 Acelrx Pharmaceuticals, Inc. Small-volume oral transmucosal dosage forms
US8252328B2 (en) * 2006-01-06 2012-08-28 Acelrx Pharmaceuticals, Inc. Bioadhesive drug formulations for oral transmucosal delivery
US9289583B2 (en) * 2006-01-06 2016-03-22 Acelrx Pharmaceuticals, Inc. Methods for administering small volume oral transmucosal dosage forms using a dispensing device
US8753308B2 (en) 2006-01-06 2014-06-17 Acelrx Pharmaceuticals, Inc. Methods for administering small volume oral transmucosal dosage forms using a dispensing device
US20070260491A1 (en) * 2006-05-08 2007-11-08 Pamela Palmer System for delivery and monitoring of administration of controlled substances
US20070286818A1 (en) * 2006-06-07 2007-12-13 Wyeth Treating cystic fibrosis with antibiotics via an aerosol drug
WO2007145868A1 (en) * 2006-06-07 2007-12-21 Wyeth Treating cystic fibrosis with antibiotics via an aerosol drug
ES2402584T3 (en) * 2006-06-09 2013-05-06 Philip Morris Products S.A. Capillary aerosol generator indirectly heated
US20070299687A1 (en) * 2006-06-23 2007-12-27 Pamela Palmer Inpatient system for patient-controlled delivery of oral transmucosal medications dosed as needed
EP2046290A4 (en) * 2006-08-04 2011-08-17 Insys Therapeutics Inc Aqueous dronabinol formulations
US20090054333A1 (en) * 2006-10-17 2009-02-26 Antonio Giordano Peptide inhibitors of cyclin-dependent kinase activity and uses thereof
JP2010512333A (en) * 2006-12-07 2010-04-22 ヘルシン ヘルスケア ソシエテ アノニム Crystal of palonosetron hydrochloride and amorphous forms
EP1964564A1 (en) * 2007-04-19 2008-09-03 LAB International SRL Breakthrough Pain Management
JP2010535774A (en) * 2007-08-06 2010-11-25 インシス セラピューティクス インコーポレイテッド Oral cannabinoid Liquid formulations and methods of treatment
JP5632284B2 (en) * 2007-08-07 2014-11-26 エーセルアールエックス ファーマシューティカルズ, インコーポレイテッド Compositions and methods for sedation and analgesia during treatment using the oral transmucosal dosage form
US8551534B2 (en) 2007-10-10 2013-10-08 Parion Sciences, Inc. Inhaled hypertonic saline delivered by a heated nasal cannula
CA2709071C (en) 2007-12-14 2016-11-15 Labogroup S.A.S. Delivering aerosolizable food products
EP2564857B1 (en) 2008-03-06 2017-05-03 Anacor Pharmaceuticals, Inc. Boron-containing small molecules as anti-inflammatory agents
WO2009143572A1 (en) * 2008-05-27 2009-12-03 The University Of Melbourne Methods of treating mammals with eustachian tube dysfunctions
WO2010033220A3 (en) * 2008-09-19 2010-06-03 Nektar Therapeutics Modified therapeutics peptides, methods of their preparation and use
EP2341942A1 (en) * 2008-09-19 2011-07-13 Nektar Therapeutics Polymer conjugates of therapeutic peptides
US8945592B2 (en) 2008-11-21 2015-02-03 Acelrx Pharmaceuticals, Inc. Sufentanil solid dosage forms comprising oxygen scavengers and methods of using the same
WO2010065547A1 (en) * 2008-12-01 2010-06-10 Map Pharmaceuticals, Inc. Inhalation delivery methods and devices
US8555875B2 (en) * 2008-12-23 2013-10-15 Map Pharmaceuticals, Inc. Inhalation devices and related methods for administration of sedative hypnotic compounds
US8548623B2 (en) 2009-03-18 2013-10-01 Acelrx Pharmaceuticals, Inc. Storage and dispensing devices for administration of oral transmucosal dosage forms
CN201445686U (en) * 2009-06-19 2010-05-05 李文博 High-frequency induction atomizing device
US8488952B2 (en) * 2009-06-22 2013-07-16 Magic-Flight General Manufacturing, Inc. Aromatic vaporizer
US9180263B2 (en) * 2009-07-01 2015-11-10 Microdose Therapeutx, Inc. Laboratory animal pulmonary dosing device
EP2453864B1 (en) * 2009-07-17 2016-09-14 Nektar Therapeutics Systems and methods for driving sealed nebulizers
US9149605B2 (en) 2009-07-28 2015-10-06 Clement Kleinstreuer Methods and devices for targeted injection of microspheres
US20110091544A1 (en) * 2009-10-16 2011-04-21 Acelrx Pharmaceuticals, Inc. Compositions and Methods for Mild Sedation, Anxiolysis and Analgesia in the Procedural Setting
WO2011094450A1 (en) 2010-01-27 2011-08-04 Anacor Pharmaceuticals, Inc Boron-containing small molecules
US9078985B2 (en) 2010-03-08 2015-07-14 Stc.Unm Dry powder nebulizer
CN102009012B (en) * 2010-03-31 2012-10-24 范维林 Liquid atomized aerosol generating device with temperature control
KR20140093598A (en) 2010-09-07 2014-07-28 아나코르 파마슈티칼스 인코포레이티드 Boron-containing small molecules
US8945605B2 (en) * 2011-06-07 2015-02-03 Parion Sciences, Inc. Aerosol delivery systems, compositions and methods
US8778383B2 (en) 2011-06-07 2014-07-15 Parion Sciences, Inc. Methods of treatment
CN103732280B (en) * 2011-08-19 2016-01-06 日本烟草产业株式会社 Aerosol aspirator
US9854839B2 (en) 2012-01-31 2018-01-02 Altria Client Services Llc Electronic vaping device and method
WO2014113734A3 (en) * 2013-01-18 2014-11-27 Tonix Pharmaceuticals Inc. Isometheptene isomer
CA2882405A1 (en) 2013-03-15 2014-09-18 Trudell Medical International Ventilator circuit, adapter for use in ventilator circuit and methods for the use thereof
EP3073846A2 (en) 2013-05-22 2016-10-05 Njoy, Inc. Compositions, devices, and methods for nicotine aerosol delivery
WO2016004409A1 (en) * 2014-07-03 2016-01-07 Luxena Pharmaceuticals, Inc. Novel aerosol formulations of ondansetron and uses thereof
CN104274426A (en) 2013-07-03 2015-01-14 陆克塞纳医药公司 Novel aerosol formulations of ondansetron and uses thereof
US10010692B2 (en) * 2013-07-08 2018-07-03 Virginia Commonwealth University Systems, devices, and methods for changing therapeutic aerosol size and improving efficiency of ventilation and aerosol drug delivery
USD788697S1 (en) 2014-03-04 2017-06-06 VMR Products, LLC Battery portion for a vaporizer
USD763502S1 (en) 2014-03-04 2016-08-09 Vmr Products Llc Cartomizer for a vaporizer
US10039321B2 (en) 2013-11-12 2018-08-07 Vmr Products Llc Vaporizer
EP3068244A4 (en) 2013-11-15 2017-07-05 VMR Products, LLC Vaporizer with cover sleeve
EP3082816A1 (en) 2013-12-20 2016-10-26 Antiop, Inc. Intranasal naloxone compositions and methods of making and using same
CN104740737A (en) * 2013-12-26 2015-07-01 北京谊安医疗系统股份有限公司 Anesthesia machine and heating device of absorption loop of anesthesia machine
US9380813B2 (en) 2014-02-11 2016-07-05 Timothy McCullough Drug delivery system and method
US9220294B2 (en) 2014-02-11 2015-12-29 Timothy McCullough Methods and devices using cannabis vapors
USD752278S1 (en) 2014-03-07 2016-03-22 VMR Products, LLC Battery portion of a vaporizer
USD752280S1 (en) 2014-03-07 2016-03-22 VMR Products, LLC Cartomizer for a vaporizer
USD749505S1 (en) 2014-03-07 2016-02-16 VMR Products, LLC Charger for a vaporizer
CN104940224A (en) 2014-03-25 2015-09-30 林信涌 Inhalation-type pharmaceutical composition for treatment of parkinson's disease and preparation method thereof
USD804090S1 (en) 2014-04-08 2017-11-28 VMR Products, LLC Vaporizer with indicators
CA2940797A1 (en) * 2014-05-21 2015-11-26 Philip Morris Products S.A. Aerosol-generating article with multi-material susceptor
WO2016001924A3 (en) 2014-06-30 2016-03-24 Syqe Medical Ltd. Methods, devices and systems for pulmonary delivery of active agents
CN104122179B (en) * 2014-08-05 2017-03-22 云南中烟工业有限责任公司 An electronic method for evaluating the amount of smoke cigarette
USD750320S1 (en) 2014-08-05 2016-02-23 VMR Products, LLC Vaporizer
US20160227838A1 (en) * 2015-02-02 2016-08-11 David M. Johnson Personal Electronic Vaporizer
WO2017100369A1 (en) * 2015-12-07 2017-06-15 Ebbu, LLC Printable cannabinoid and terpene compositions
US9943388B2 (en) 2015-06-30 2018-04-17 Maury D. Cole Substance inhalation system and method
US10034857B2 (en) 2015-07-02 2018-07-31 Civitas Therapeutics, Inc. Triptan powders for pulmonary delivery
US20170038184A1 (en) * 2015-08-06 2017-02-09 Charles E. Ankner Formulation delivery system
WO2017153827A1 (en) * 2016-03-07 2017-09-14 Wallbrooke Investments Ltd. Inductive heating apparatus and related method
US20170280772A1 (en) * 2016-03-31 2017-10-05 Rui Nuno BATISTA Vaporizing assembly comprising sheet heating element and liquid delivery device for an aerosol generating system
WO2017167647A1 (en) * 2016-03-31 2017-10-05 Philip Morris Products S.A. Vaporizing assembly comprising sheet heating element and liquid delivery device for an aerosol generating system
WO2017168174A1 (en) 2016-04-02 2017-10-05 N4 Pharma Uk Limited New pharmaceutical forms of sildenafil
US9867815B1 (en) 2017-02-07 2018-01-16 Genus Lifesciences Inc. Pharmaceutical compositions and methods of using the same

Citations (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1535486A (en) * 1922-08-28 1925-04-28 James W Lundy Electric-lamp bulb
US1803334A (en) * 1931-05-05 Ootthujp lehmann
US1864980A (en) * 1932-06-28 Vapobizeb
US2243669A (en) * 1941-05-27 Electrical vaporizer
US2309846A (en) * 1941-03-06 1943-02-02 Holm Einar Marius Inhaler
US2469656A (en) * 1946-04-19 1949-05-10 Peter H Lienert Vaporizer
US2887106A (en) * 1956-09-27 1959-05-19 Robinson Joseph Combined vaporizer and cover for medicament jar
US3080624A (en) * 1963-03-12 weber iii
US3164600A (en) * 1961-10-10 1965-01-05 Res Lab Dr C Janssen N V 1-aralkyl-4-(n-aryl-carbonyl amino)-piperidines and related compounds
US3169095A (en) * 1962-10-30 1965-02-09 Rexall Drug Chemical Self-propelling powder-dispensing compositions
US3433791A (en) * 1960-09-05 1969-03-18 Reckitt & Sons Ltd Endoethano nor oripavines and nor thebaines
US3560607A (en) * 1962-11-30 1971-02-02 Fisons Pharmaceuticals Ltd Aerosol formulations of finely divided solid medicaments with anionic surface-active agents
US3930796A (en) * 1973-09-13 1976-01-06 Universal Oil Products Company Catalytic fume control device
US3949743A (en) * 1973-03-19 1976-04-13 Schick Incorporated Medicated vapor production method and apparatus
US4020379A (en) * 1975-10-02 1977-04-26 Eg&G, Inc. Bulb-shaped flashtube with metal envelope
US4183912A (en) * 1978-01-16 1980-01-15 American Home Products Corporation Inhalation therapy for relieving bronchial spasm using quaternary salts of promethazine
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
US4276243A (en) * 1978-12-08 1981-06-30 Western Electric Company, Inc. Vapor delivery control system and method
US4588721A (en) * 1983-09-12 1986-05-13 The Upjohn Company Treatment of negative symptoms of schizophrenia
US4647433A (en) * 1984-10-01 1987-03-03 Donald Spector Long-life aroma-generating capsule
US4647428A (en) * 1984-06-04 1987-03-03 Gyulay Joseph M Air freshener method
US4722334A (en) * 1985-07-16 1988-02-02 Transpirator Technologies, Inc. Method and apparatus for pulmonary and cardiovascular conditioning of racehorses and competition animals
US4735358A (en) * 1986-03-04 1988-04-05 Daiken Iko Kabushiki Kaisha Method and apparatus of vaporizing active substances
US4892109A (en) * 1989-03-08 1990-01-09 Brown & Williamson Tobacco Corporation Simulated smoking article
US4911157A (en) * 1988-01-07 1990-03-27 Pegasus Research Corporation Self-regulating, heated nebulizer system
US4924883A (en) * 1987-03-06 1990-05-15 R. J. Reynolds Tobacco Company Smoking article
US4935624A (en) * 1987-09-30 1990-06-19 Cornell Research Foundation, Inc. Thermal-assisted electrospray interface (TAESI) for LC/MS
US4984158A (en) * 1988-10-14 1991-01-08 Hillsman Dean Metered dose inhaler biofeedback training and evaluation system
US5017575A (en) * 1987-06-09 1991-05-21 Golwyn Daniel H Treatment of immunologically based disorders, specifically Crohn's disease
US5093894A (en) * 1989-12-01 1992-03-03 Philip Morris Incorporated Electrically-powered linear heating element
US5095921A (en) * 1990-11-19 1992-03-17 Philip Morris Incorporated Flavor generating article
US5109180A (en) * 1989-12-14 1992-04-28 Phillips Petroleum Company Apparatus providing a shatter-resistant electric lamp
US5112598A (en) * 1988-05-04 1992-05-12 Hermes Fabrik Pharmazeutischer Preparate Franz Gradinger Gmbh & Co. Kg Vitamin a aerosol-inhalate preparations
US5126123A (en) * 1990-06-28 1992-06-30 Glaxo, Inc. Aerosol drug formulations
US5179966A (en) * 1990-11-19 1993-01-19 Philip Morris Incorporated Flavor generating article
US5186164A (en) * 1991-03-15 1993-02-16 Puthalath Raghuprasad Mist inhaler
US5285798A (en) * 1991-06-28 1994-02-15 R. J. Reynolds Tobacco Company Tobacco smoking article with electrochemical heat source
US5322075A (en) * 1992-09-10 1994-06-21 Philip Morris Incorporated Heater for an electric flavor-generating article
US5400969A (en) * 1993-09-20 1995-03-28 Keene; Christopher M. Liquid vaporizer and diffuser
US5402517A (en) * 1991-05-01 1995-03-28 Reckitt & Colman Products Limited Apparatus for emitting a volatile chemical agent by heating and means for adjusting a spacing between a heater and the chemical agent to regulate the rate of vaporization
US5408574A (en) * 1989-12-01 1995-04-18 Philip Morris Incorporated Flat ceramic heater having discrete heating zones
US5479948A (en) * 1993-08-10 1996-01-02 Philip Morris Incorporated Electrical smoking article having continuous tobacco flavor web and flavor cassette therefor
US5505214A (en) * 1991-03-11 1996-04-09 Philip Morris Incorporated Electrical smoking article and method for making same
US5591409A (en) * 1995-08-15 1997-01-07 Watkins; Carl J. Providing aromas
US5592934A (en) * 1990-08-02 1997-01-14 The Boc Group Plc Anaesthetic vaporizer
US5593792A (en) * 1991-06-28 1997-01-14 R. J. Reynolds Tobacco Company Electrochemical heat source
US5605146A (en) * 1993-11-29 1997-02-25 Instrumentarium Oy Method and an arrangement in connection with vaporizing an anaesthetic
US5613505A (en) * 1992-09-11 1997-03-25 Philip Morris Incorporated Inductive heating systems for smoking articles
US5738865A (en) * 1995-04-07 1998-04-14 Edward Mendell Co., Inc. Controlled release insufflation carrier for medicaments
US5743251A (en) * 1996-05-15 1998-04-28 Philip Morris Incorporated Aerosol and a method and apparatus for generating an aerosol
US5767117A (en) * 1994-11-18 1998-06-16 The General Hospital Corporation Method for treating vascular headaches
US5769621A (en) * 1997-05-23 1998-06-23 The Regents Of The University Of California Laser ablation based fuel ignition
US5874841A (en) * 1997-07-28 1999-02-23 Philips Electronics North America Corporation Sample-and-hold circuit for a switched-mode power supply
US5874481A (en) * 1995-06-07 1999-02-23 Alliance Pharmaceutical Corp. Fluorochemical solutions for the delivery of lipophilic pharmaceutical agents
US5894841A (en) * 1993-06-29 1999-04-20 Ponwell Enterprises Limited Dispenser
US5904900A (en) * 1995-04-28 1999-05-18 Etat Francais As Represented By Le Delegue General Pour L'armement Device for sampling gaseous substances, liquids, aerosols or even powdered materials for in situ analysis
US6041777A (en) * 1995-12-01 2000-03-28 Alliance Pharmaceutical Corp. Methods and apparatus for closed-circuit ventilation therapy
US6050260A (en) * 1996-12-02 2000-04-18 Fisher & Paykel Limited Humidifier sleep apnea treatment apparatus
US6051566A (en) * 1991-02-09 2000-04-18 B.S.D. Bio Science Development Snc Di Omini C. & Zuccari G. Anti-reactive anti-asthmatic activity of non-steroidal anti-inflammatory drugs by inhalation
US6053176A (en) * 1999-02-23 2000-04-25 Philip Morris Incorporated Heater and method for efficiently generating an aerosol from an indexing substrate
US6178969B1 (en) * 1998-03-03 2001-01-30 Brown & Williamson Tobacco Corporation Aerosol delivery smoking article
US6241969B1 (en) * 1998-06-26 2001-06-05 Elan Corporation Plc Aqueous compositions containing corticosteroids for nasal and pulmonary delivery
US20020031480A1 (en) * 1998-10-27 2002-03-14 Joanne Peart Delta9 tetrahydrocannabinol (Delta9 THC) solution metered dose inhalers and methods of use
US20020037828A1 (en) * 1997-10-28 2002-03-28 Wilson Leland F. Administration of phosphodiesterase inhibitors for the treatment of premature ejaculation
US6376550B1 (en) * 1999-02-09 2002-04-23 Asta Medica Ag Pharmaceutical compositions containing tramadol for migraine
US20020058009A1 (en) * 2000-09-19 2002-05-16 Advanced Inhalation Research, Inc. Pulmonary delivery in treating disorders of the central nervous system
US6390453B1 (en) * 1997-10-22 2002-05-21 Microfab Technologies, Inc. Method and apparatus for delivery of fragrances and vapors to the nose
US20020061281A1 (en) * 1999-07-06 2002-05-23 Osbakken Robert S. Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis
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
US6506762B1 (en) * 1999-09-30 2003-01-14 Neurogen Corporation Certain alkylene diamine-substituted heterocycles
US6514482B1 (en) * 2000-09-19 2003-02-04 Advanced Inhalation Research, Inc. Pulmonary delivery in treating disorders of the central nervous system
US6516796B1 (en) * 1998-10-14 2003-02-11 Chrysalis Technologies Incorporated Aerosol generator and methods of making and using an aerosol generator
US20030033055A1 (en) * 2001-07-31 2003-02-13 Mcrae Douglas D. Method and apparatus for generating a volatilized liquid
US20030049025A1 (en) * 2000-01-13 2003-03-13 Hermann Neumann Chip that comprises an active agent and an integrated heating element
US6561186B2 (en) * 1995-08-02 2003-05-13 Innovative Devices Dry powder medicament inhalator having an inhalation-activated flow diverting means for triggering delivery of medicament
US6568390B2 (en) * 2001-09-21 2003-05-27 Chrysalis Technologies Incorporated Dual capillary fluid vaporizing device
US6671945B2 (en) * 2001-01-19 2004-01-06 Vishay Intertechnology, Inc. Method for making a resistor using resistive foil
US20040009128A1 (en) * 2002-05-13 2004-01-15 Rabinowitz Joshua D Delivery of drug amines through an inhalation route
US6681998B2 (en) * 2000-12-22 2004-01-27 Chrysalis Technologies Incorporated Aerosol generator having inductive heater and method of use thereof
US6681769B2 (en) * 2001-12-06 2004-01-27 Crysalis Technologies Incorporated Aerosol generator having a multiple path heater arrangement and method of use thereof
US20040016427A1 (en) * 2000-04-27 2004-01-29 Byron Peter R. Method and apparatus for generating an aerosol
US6688313B2 (en) * 2000-03-23 2004-02-10 Philip Morris Incorporated Electrical smoking system and method
US6694975B2 (en) * 1996-11-21 2004-02-24 Aradigm Corporation Temperature controlling device for aerosol drug delivery
US20040035409A1 (en) * 2002-06-06 2004-02-26 Harwig Jeffrey L. Localized surface volatilization
US6701922B2 (en) * 2001-12-20 2004-03-09 Chrysalis Technologies Incorporated Mouthpiece entrainment airflow control for aerosol generators
US6701921B2 (en) * 2000-12-22 2004-03-09 Chrysalis Technologies Incorporated Aerosol generator having heater in multilayered composite and method of use thereof
US20040055504A1 (en) * 2001-10-15 2004-03-25 Lee Brian Craig Electro-thermal odor-releasing inks and methods for releasing odors from the same
US6728478B2 (en) * 2002-02-21 2004-04-27 Dekko Heating Technologies, Inc. Heated chemical delivery system
US20040081624A1 (en) * 2002-09-06 2004-04-29 Chrysalis Technologies Incorporated Liquid aerosol formulations and aerosol generating devices and methods for generating aerosols
US6737042B2 (en) * 2001-05-24 2004-05-18 Alexza Molecular Delivery Corporation Delivery of drug esters through an inhalation route
US20040099266A1 (en) * 2002-11-27 2004-05-27 Stephen Cross Inhalation device for producing a drug aerosol
US20070028916A1 (en) * 2001-05-24 2007-02-08 Hale Ron L Rapid-heating drug delivery article and method of use
US20070031340A1 (en) * 2001-05-24 2007-02-08 Hale Ron L Thin-film drug delivery article and method of use

Family Cites Families (456)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1239634A (en) 1916-07-25 1917-09-11 Frank J Stuart Medical appliance.
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
FR921852A (en) 1945-12-06 1947-05-21 Diffuser volatiles
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
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
GB903866A (en) 1961-05-09 1962-08-22 Dausse Lab Therapeutic preparations containing 7-substituted theophylline derivatives
US3299185A (en) 1962-09-27 1967-01-17 Ube Nitto Kasei Co Dyeable polyolefin fibers containing a binary copolymer of styrene and acrylonitrile
BE629985A (en) 1962-11-29
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
GB1119270A (en) 1966-01-19 1968-07-10 Endo Lab 14-hydroxy dihydronormorphine derivatives and their preparation
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
US3863347A (en) * 1970-04-13 1975-02-04 Philip Michael Banner Navigation device
US3773955A (en) 1970-08-03 1973-11-20 Bristol Myers Co Analgetic compositions
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
US3943941A (en) 1972-04-20 1976-03-16 Gallaher Limited 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
US3773995A (en) 1972-10-27 1973-11-20 Westinghouse Electric Corp Motor advanced spring charging pawl and ratchet mechanism with spring assist
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
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
DE2752384A1 (en) 1977-08-29 1979-03-15 Simes A pharmaceutical preparation based beklemmungsloesender agents and inhibitors of beta-adrenergic receptors
DE2851543A1 (en) 1977-12-01 1979-06-07 Welsh Nat School Med Inhalationspraeparat
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
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
US4423071A (en) 1979-03-06 1983-12-27 Sanofi Polyol derivatives, processes for preparing the same and their uses in therapeutics
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 Draegerwerk Ag, 2400 Luebeck, De
JPS5876038A (en) 1981-10-28 1983-05-09 Masayuki Takamori 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 Christensen Plantorgan Werk Dampfinhaliergeraet
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
US4474191A (en) 1982-09-30 1984-10-02 Steiner Pierre G Tar-free smoking devices
US4693868A (en) 1982-09-30 1987-09-15 Dainihon Jochugiku Co., Ltd. Thermal fumigator for drugs
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 Goedecke Ag For inhalation dosage form in particular of calcium antagonists
EP0133795B1 (en) 1983-08-01 1989-01-18 THE McLEAN HOSPITAL CORPORATION Gaba esters and gaba analogue esters
DE3478900D1 (en) 1983-11-08 1989-08-17 Bunnell Life Systems Inc Humidifier, particularly for pulmonary assistance systems
FI68988C (en) * 1984-01-04 1985-12-10 Rauma Repola Oy Flissikt vars siktkorg delats i tvao korgsektorer
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
DE3414640C2 (en) * 1984-04-18 1992-02-06 Kaiser Gmbh & Co Kg, 8580 Bayreuth, De
US4963367A (en) 1984-04-27 1990-10-16 Medaphore, Inc. Drug delivery compositions and methods
US4755508A (en) 1984-06-26 1988-07-05 Merck & Co., Inc. Benzodiazepine analogs and use as antogonists of gastrin and cholecystokinin
US5067499A (en) 1984-09-14 1991-11-26 R. J. Reynolds Tobacco Company Smoking article
US5042509A (en) 1984-09-14 1991-08-27 R. J. Reynolds Tobacco Company Method for making aerosol generating cartridge
US4793365A (en) 1984-09-14 1988-12-27 R. J. Reynolds Tobacco Company Smoking article
US4854331A (en) 1984-09-14 1989-08-08 R. J. Reynolds Tobacco Company Smoking article
CN1024996C (en) 1984-12-21 1994-06-15 美国J·R瑞诺兹烟草公司 Smoking article
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
US5192528A (en) * 1985-05-22 1993-03-09 Liposome Technology, Inc. Corticosteroid inhalation treatment method
EP0223831B1 (en) 1985-05-22 1992-07-15 Liposome Technology, Inc. Liposome inhalation method and system
US4800903A (en) 1985-05-24 1989-01-31 Ray Jon P Nicotine dispenser with polymeric reservoir of nicotine
US4989619A (en) 1985-08-26 1991-02-05 R. J. Reynolds Tobacco Company Smoking article with improved fuel element
US5020548A (en) 1985-08-26 1991-06-04 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
US4756318A (en) 1985-10-28 1988-07-12 R. J. Reynolds Tobacco Company Smoking article with tobacco jacket
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
US4793366A (en) 1985-11-12 1988-12-27 Hill Ira D Nicotine dispensing device and methods of making the same
DE3767615D1 (en) 1986-03-10 1991-02-28 Kurt Burghart Pharmaceutical and process for its production.
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
EP0270944A3 (en) 1986-12-12 1989-03-15 R.J. Reynolds Tobacco Company 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
WO1988008304A1 (en) 1987-04-23 1988-11-03 Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. Pharmaceutical composition
US4889850A (en) 1987-05-11 1989-12-26 Thornfeldt Carl R Treatment of colic and teething
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
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
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
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
US4955945A (en) 1988-07-13 1990-09-11 Weick Heinz Hermann Dispenser for the vaporization of active substances to be inhaled
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
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
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
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
US4917119A (en) 1988-11-30 1990-04-17 R. J. Reynolds Tobacco Company Drug delivery article
US5049389A (en) 1988-12-14 1991-09-17 Liposome Technology, Inc. Novel liposome composition for the treatment of interstitial lung diseases
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
GB8900267D0 (en) 1989-01-06 1989-03-08 Riker Laboratories Inc Narcotic analgesic formulations and apparatus containing same
DE3908161C2 (en) 1989-03-13 1992-09-03 B.A.T. Cigarettenfabriken Gmbh, 2000 Hamburg, De
WO1990013327A1 (en) 1989-04-28 1990-11-15 Riker Laboratories, Inc. Dry powder inhalation device
GB8909891D0 (en) 1989-04-28 1989-06-14 Riker Laboratories Inc Device
DE69027992D1 (en) 1989-05-05 1996-09-05 North Sydney Area Health Serv Increasing fertility
US4941483A (en) 1989-09-18 1990-07-17 R. J. Reynolds Tobacco Company Aerosol delivery article
US6048857A (en) 1989-10-17 2000-04-11 Ellinwood, Jr.; Everett H. Dosing method of administering medicaments via inhalation administration
US6313176B1 (en) 1989-10-17 2001-11-06 Everett J. Ellinwood, Jr. Dosing method of administering deprenyl via intraoral administration or inhalation administration
US5707644A (en) 1989-11-04 1998-01-13 Danbiosyst Uk Limited Small particle compositions for intranasal drug delivery
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
US5144962A (en) 1989-12-01 1992-09-08 Philip Morris Incorporated Flavor-delivery article
US5060671A (en) 1989-12-01 1991-10-29 Philip Morris Incorporated Flavor generating article
EP0504263B1 (en) 1989-12-05 1997-08-13 Ramsey Foundation Neurologic agents for nasal administration to the brain
US5580575A (en) 1989-12-22 1996-12-03 Imarx Pharmaceutical Corp. Therapeutic drug delivery systems
US5733572A (en) 1989-12-22 1998-03-31 Imarx Pharmaceutical Corp. Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles
GB9000042D0 (en) * 1990-01-03 1990-03-07 Ralph John F Decorative wall covering applied to steel radiators
GB9000421D0 (en) * 1990-01-09 1990-03-07 Boc Group Plc Improvements in anaesthetic vaporisers
US5376386A (en) 1990-01-24 1994-12-27 British Technology Group Limited Aerosol carriers
US5156170A (en) 1990-02-27 1992-10-20 R. J. Reynolds Tobacco Company Cigarette
US5099861A (en) 1990-02-27 1992-03-31 R. J. Reynolds Tobacco Company Aerosol delivery article
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
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
US5229382A (en) 1990-04-25 1993-07-20 Lilly Industries Limited 2-methyl-thieno-benzodiazepine
US5817656A (en) 1991-04-23 1998-10-06 Eli Lilly And Company Mental disorders
US5192548A (en) 1990-04-30 1993-03-09 Riker Laboratoires, Inc. Device
RU2160736C2 (en) 1990-06-07 2000-12-20 Зенека Лимитед Indole derivatives and physiologically acceptable salts and solvates thereof, methods of preparing thereof, drug for treatment or prophylaxes of clinical states for which administration of 5-ht1-like receptor agonist, and method of preparing thereof
EP0569356B1 (en) 1990-06-08 1997-08-27 Pharmacia &amp; Upjohn Aktiebolag Use of a smoking composition
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
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
US5255674A (en) 1990-09-28 1993-10-26 Forsvarets Forskningsinstitutt Portable heating and humidifying device
US5175152A (en) 1990-09-28 1992-12-29 Singh Nikhilesh N Composition containing ephedrine base and alkyl salicylate for the delivery of ephedrine base in vapor form
CA2057504C (en) 1990-12-21 2002-02-12 Ferenc Andrasi Process for preparing new n-acyl-2,3-benzodiazepine derivatives, their acid addition salts and pharmaceutical compositions containing the same
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.
US5404871A (en) 1991-03-05 1995-04-11 Aradigm Delivery of aerosol medications for inspiration
DE69430303T2 (en) 1991-03-05 2002-11-28 Aradigm Corp A method and apparatus for correcting a zero signal of a pressure sensor for a flow meter
US5394866A (en) 1991-03-05 1995-03-07 Aradigm Corporation Automatic aerosol medication delivery system and methods
US5226411A (en) 1991-03-07 1993-07-13 Walter Levine Aerosol nebulizer heater
US5249586A (en) 1991-03-11 1993-10-05 Philip Morris Incorporated Electrical smoking
US5993805A (en) 1991-04-10 1999-11-30 Quadrant Healthcare (Uk) Limited Spray-dried microparticles and their use as therapeutic vehicles
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
GB9109021D0 (en) 1991-04-26 1991-06-12 Boc Group Plc Dosing pump
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
US5184133A (en) * 1991-11-26 1993-02-02 Texas Instruments Incorporated ISAR imaging radar system
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
US5584701A (en) 1992-05-13 1996-12-17 University Of Florida Research Foundation, Incorporated Self regulating lung for simulated medical procedures
US5391081A (en) 1992-05-13 1995-02-21 University Of Florida Research Foundation, Incorporated Method and apparatus for simulating neuromuscular stimulation during medical surgery
DK64592D0 (en) 1992-05-14 1992-05-14 Carlbiotech Ltd As Peptides for therapeutic treatment
US5525329A (en) 1992-05-21 1996-06-11 The Johns Hopkins University Inhibition of phosphodiesterase in olfactory mucosa
US5622944A (en) 1992-06-12 1997-04-22 Affymax Technologies N.V. Testosterone prodrugs for improved drug delivery
US5607691A (en) 1992-06-12 1997-03-04 Affymax Technologies N.V. Compositions and methods for enhanced drug delivery
CA2115444C (en) 1992-06-12 2000-10-03 Yuji Makino Preparation for intratracheobronchial administration
US6258341B1 (en) 1995-04-14 2001-07-10 Inhale Therapeutic Systems, Inc. Stable glassy state powder formulations
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
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
WO1994009842A1 (en) 1992-10-28 1994-05-11 Rosen Charles A Method and devices for delivering drugs by inhalation
US6024090A (en) 1993-01-29 2000-02-15 Aradigm Corporation Method of treating a diabetic patient by aerosolized administration of insulin lispro
US5672581A (en) 1993-01-29 1997-09-30 Aradigm Corporation Method of administration of insulin
US5694919A (en) 1993-01-29 1997-12-09 Aradigm Corporation Lockout device for controlled release of drug from patient-activated dispenser
US5915378A (en) 1993-01-29 1999-06-29 Aradigm Corporation Creating an aerosolized formulation of insulin
US5743250A (en) 1993-01-29 1998-04-28 Aradigm Corporation Insulin delivery enhanced by coached breathing
US5507277A (en) 1993-01-29 1996-04-16 Aradigm Corporation Lockout device for controlled release of drug from patient-activateddispenser
US5558085A (en) 1993-01-29 1996-09-24 Aradigm Corporation Intrapulmonary delivery of peptide drugs
US5934272A (en) 1993-01-29 1999-08-10 Aradigm Corporation Device and method of creating aerosolized mist of respiratory drug
US5364838A (en) 1993-01-29 1994-11-15 Miris Medical Corporation Method of administration of insulin
US6098620A (en) 1993-01-29 2000-08-08 Aradigm Corporation Device for aerosolizing narcotics
US5888477A (en) 1993-01-29 1999-03-30 Aradigm Corporation Use of monomeric insulin as a means for improving the bioavailability of inhaled insulin
US5724957A (en) 1993-01-29 1998-03-10 Aradigm Corporation Intrapulmonary delivery of narcotics
US5970973A (en) 1993-01-29 1999-10-26 Aradigm Corporation Method of delivering insulin lispro
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
CN1082365A (en) 1993-05-25 1994-02-23 潘昆年 Nutrient health cigarette
US5666977A (en) 1993-06-10 1997-09-16 Philip Morris Incorporated Electrical smoking article using liquid tobacco flavor medium delivery system
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 inhaler
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
DE69427832T2 (en) 1993-11-01 2001-11-22 Pharmacia Ab Drug delivery preparation containing nicotine or a derivative thereof and starch microspheres, and process for its manufacture
DE69530571D1 (en) 1994-01-07 2003-06-05 Smithkline Beecham Corp bicyclic fibrinogen
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
CN1082365C (en) 1994-03-30 2002-04-10 普罗克特和甘保尔公司 Combined skin moisturizing and cleaning bar compsn.
US6102036A (en) 1994-04-12 2000-08-15 Smoke-Stop Breath activated inhaler
DE69523301T2 (en) 1994-05-13 2002-07-04 Aradigm Corp A narcotic aerosol formulation containing
US5457101A (en) 1994-06-03 1995-10-10 Eli Lilly And Company Thieno[1,5]benzoidiazepine use
WO1996000070A1 (en) 1994-06-23 1996-01-04 The Procter & Gamble Company Treatment of nicotine craving and/or smoking withdrawal symptoms with an oral composition containing nicotine and caffeine or xanthine
WO1996000071A1 (en) 1994-06-23 1996-01-04 The Procter & Gamble Company Treatment of nicotine craving and/or smoking withdrawal symptoms with a liquid nasal composition containing nicotine and caffeine or xanthine
WO1996000069A1 (en) 1994-06-23 1996-01-04 The Procter & Gamble Company Treatment of nicotine craving and/or smoking withdrawal symptoms with a solid or semi-solid composition containing nicotine and caffeine or xanthine, especially for nasal administration
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
US5456677A (en) 1994-08-22 1995-10-10 Spector; John E. Method for oral spray administration of caffeine
EP0777657A4 (en) 1994-08-22 1997-07-16
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
WO1996010663A1 (en) 1994-09-30 1996-04-11 M & J Fibretech A/S A plant and a process for dry-producing a web-formed product
WO1996011689A1 (en) 1994-10-14 1996-04-25 Glaxo Wellcome Spa Use of cck-b receptor antagonists for the treatment of sleep disorders
US6013050A (en) 1995-10-20 2000-01-11 Powderject Research Limited Particle delivery
EP1177807A3 (en) 1994-10-28 2003-10-22 Aradigm Corporation Device and method of creating aerosolized mist of respiratory drug
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 apparatus for the production of aerosols
US5565148A (en) 1995-03-16 1996-10-15 Minnesota Mining And Manufacturing Company Device for selectively providing a multiplicity of aromas
EP0817655B1 (en) 1995-03-31 2004-05-19 Aradigm Corporation Intrapulmonary delivery of hematopoietic drug
DE69622166D1 (en) 1995-04-14 2002-08-08 Smithkline Beecham Corp Metered dose inhaler for albuterol
WO1996032345A1 (en) 1995-04-14 1996-10-17 Glaxo Wellcome Inc. Metered dose inhaler for beclomethasone dipropionate
DE69630111T2 (en) 1995-04-14 2004-07-22 Smithkline Beecham Corp. Metered dose inhaler for salmeterol
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
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
US5776928A (en) 1995-04-21 1998-07-07 Eli Lilly And Company Method for treating dyskinesias with olanzapine
US5809997A (en) 1995-05-18 1998-09-22 Medtrac Technologies, Inc. Electronic medication chronolog device
DE19519056A1 (en) 1995-05-24 1997-01-16 Klinge Co Chem Pharm Fab Use of antidepressants for the treatment of asthma and / or respiratory diseases by inhalatory application
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
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
EP0761249B1 (en) 1995-09-12 2003-10-01 Siemens-Elema AB Anaesthetic apparatus
US5649554A (en) 1995-10-16 1997-07-22 Philip Morris Incorporated Electrical lighter with a rotatable tobacco supply
WO1997016181A1 (en) 1995-11-03 1997-05-09 University Of Kentucky Method for the intranasal administration of l-dopa prodrugs
US6017963A (en) 1995-11-14 2000-01-25 Euro-Celtique, S.A. Formulation for intranasal administration
US5564442A (en) 1995-11-22 1996-10-15 Angus Collingwood MacDonald Battery powered nicotine vaporizer
US6133327A (en) 1995-12-14 2000-10-17 Taisho Pharmaceutical Co., Ltd. Aerosol preparation
DE19648269B4 (en) 1995-12-21 2005-02-24 Maquet Critical Care Ab A method for gasifying a liquid anesthetic and a carburetor
WO1997023221A1 (en) 1995-12-21 1997-07-03 Eli Lilly And Company Method for treating dermatitis
EP0955885A4 (en) 1996-02-05 1999-12-22
US5829436A (en) 1996-02-05 1998-11-03 Aradigm Corporation Ventilation imaging using a fine particle aerosol generator
DE19606107C1 (en) * 1996-02-19 1997-02-13 Martin Umwelt & Energietech Grate, especially for waste incinerators
CA2244089C (en) 1996-02-19 2009-06-02 Monash University Dermal penetration enhancers and drug delivery systems involving same
GB9604329D0 (en) 1996-02-29 1996-05-01 Ici Plc Electrostatic spraying
JP3986086B2 (en) 1996-03-01 2007-10-03 ザ ユニバーシティ オブ カンザス Particles precipitated methods and coating methods using a near-critical and supercritical antisolvent
EP0828489A4 (en) 1996-03-13 2001-04-04 Univ Yale Smoking cessation treatments using naltrexone and related compounds
GB9606188D0 (en) 1996-03-23 1996-05-29 Danbiosyst Uk Pollysaccharide microspheres for the pulmonary delivery of drugs
US5944012A (en) 1996-03-25 1999-08-31 Pera; Ivo E. Method for dispensing antioxidant vitamins by inhalation background of the invention
GB9606677D0 (en) 1996-03-29 1996-06-05 Glaxo Wellcome Inc Process and device
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
CA2252814A1 (en) 1996-04-29 1997-11-06 Dura Pharmaceuticals, Inc. Methods of dry powder inhalation
US5985309A (en) 1996-05-24 1999-11-16 Massachusetts Institute Of Technology Preparation of particles for inhalation
US5874064A (en) 1996-05-24 1999-02-23 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug delivery
US5929093A (en) 1996-06-13 1999-07-27 Mayo Foundation For Medical Education And Research Bifunctional acetylcholinesterase reactivators
EP0845220B1 (en) * 1996-06-17 2003-09-03 Japan Tobacco Inc. Flavor producing article
DE69719719D1 (en) 1996-06-17 2003-04-17 Japan Tobacco Inc Aroma-producing articles and flavor generation 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
WO1997049690A1 (en) 1996-06-27 1997-12-31 Merck & Co., Inc. A method for treating meniere's disease
CA2259418A1 (en) 1996-07-11 1998-01-22 Farmarc Nederland B.V. Pharmaceutical composition containing acid addition salt of basic drug
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
DK0951280T3 (en) 1996-10-03 2004-05-17 Hermes Biosciences Inc Hydrophilic microparticles and methods for their preparation
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
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
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
WO1998029110A3 (en) 1996-12-30 1999-04-15 Battelle Memorial Institute Formulation and method for treating neoplasms by inhalation
US5855913A (en) 1997-01-16 1999-01-05 Massachusetts Instite Of Technology Particles incorporating surfactants for pulmonary drug delivery
EP0954282B1 (en) 1997-01-16 2005-01-19 Massachusetts Institute Of Technology Preparation of particles for inhalation
EP1014943B1 (en) 1997-02-05 2002-06-19 Jago Research Ag Medical aerosol 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
US6192882B1 (en) 1997-02-24 2001-02-27 Aradigm Corporation Formulation and devices for monitoring the efficacy of the delivery of aerosols
US5829435A (en) 1997-02-24 1998-11-03 Aradigm Corporation Prefilter for prevention of clogging of a nozzle in the generation of an aerosol and prevention of administration of undesirable particles
US5837713A (en) 1997-02-26 1998-11-17 Mayo Foundation For Medical Education And Research Treatment of eosinophil-associated pathologies by administration of topical anesthetics and glucocorticoids
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
DE69804385T2 (en) 1997-07-23 2002-11-07 Japan Tobacco Inc Aroma-producing device
WO1999004797A1 (en) 1997-07-24 1999-02-04 EGIS Gyógyszergyár Rt. Use of 2,3-benzodiazepine derivatives for the preparation of pharmaceutical compositions to treat diseases connected with the endogenous opioid system
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
CN1176075A (en) 1997-08-29 1998-03-18 宋国合 Combustion-less innoxious cigarette and its preparation
US6138683A (en) 1997-09-19 2000-10-31 Thione International, Inc. Smokeless tobacco products containing antioxidants
DE69813853T3 (en) 1997-09-29 2011-05-12 Novartis Ag Perforated microparticles and their use
DE19881732D2 (en) 1997-11-12 2000-08-24 Bayer Ag 2-phenyl-substituted imidazotriazinones as inhibitors Phoshodiesterase
CN1293663A (en) 1998-01-27 2001-05-02 美国氰胺公司 2,3,4,5-tetrahydro-1H-[1,4] benzodiazepine-3-hydroxamix acids as matrix metal-protease
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
DE69927139T2 (en) 1998-03-05 2006-06-14 Zivena Inc pulmonary dosing
KR20010041623A (en) 1998-03-05 2001-05-25 니뽄 신야쿠 가부시키가이샤 Fat emulsions for inhalational administration
WO1999052519A3 (en) 1998-04-14 1999-12-02 Gen Hospital Corp Methods for treating neuropsychiatric disorders
WO1999055362A1 (en) * 1998-04-29 1999-11-04 Genentech, Inc. Spray dried formulations of igf-i
GB9810559D0 (en) 1998-05-15 1998-07-15 Bradford Particle Design Ltd Method and apparatus for particle formation
US6060212A (en) * 1998-06-11 2000-05-09 Clariant Finance (Bvi) Limited 193 nm positive-working photoresist composition
US6014970A (en) 1998-06-11 2000-01-18 Aerogen, Inc. Methods and apparatus for storing chemical compounds in a portable inhaler
WO1999064094A1 (en) 1998-06-12 1999-12-16 Aradigm Corporation Methods of delivering aerosolized polynucleotides to the respiratory tract
US6095153A (en) 1998-06-19 2000-08-01 Kessler; Stephen B. Vaporization of volatile materials
ES2221733T3 (en) 1998-06-22 2005-01-01 Pfizer Ireland Pharmaceuticals Intranasal formulations to treat sexual disorders.
WO2000000215A1 (en) 1998-06-29 2000-01-06 Inhale Therapeutic Systems, Inc. Particulate delivery systems and methods of use
US6131570A (en) 1998-06-30 2000-10-17 Aradigm Corporation Temperature controlling device for aerosol drug delivery
GB9814172D0 (en) 1998-06-30 1998-08-26 Andaris Ltd Formulation for inhalation
US6090403A (en) 1998-08-17 2000-07-18 Lectec Corporation Inhalation therapy decongestant with foraminous carrier
WO2000019991A1 (en) 1998-10-02 2000-04-13 Battelle Memorial Institute Inhalation chemotherapy for prevention and treatment of metastatic tumors in the lung
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 System for providing an inhalable aerosol
US7521068B2 (en) 1998-11-12 2009-04-21 Elan Pharma International Ltd. Dry powder aerosols of nanoparticulate drugs
JP2002529393A (en) 1998-11-12 2002-09-10 フランク ジー. ピルキーウィッツ, Inhalation system
DE19854012C2 (en) 1998-11-12 2001-05-10 Reemtsma H F & Ph System for providing an inhalable aerosol
EP1283036B1 (en) 1998-11-13 2008-01-02 Jagotec AG Multidosis dry powder inhaler with powder reservoir
WO2000029167A1 (en) 1998-11-16 2000-05-25 Aradigm Corporation Method of fabricating porous membrane with unique pore structure for aerosolized delivery of drugs
US6070575A (en) 1998-11-16 2000-06-06 Aradigm Corporation Aerosol-forming porous membrane with certain pore structure
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 bulb yellow light radiation
WO2000035417A1 (en) 1998-12-11 2000-06-22 Pharmachemie B.V. Pharmaceutical preparation for inhalation of an opioid
EP1313426A2 (en) 1998-12-24 2003-05-28 Bristol-Myers Squibb Pharma Company Succinoylamino benzodiazepines as inhibitors of a-beta protein production
DE69901284D1 (en) 1999-01-27 2002-05-23 Idea Ag Transnasal transport or vaccination with hochadaptierbaren carriers
CA2356267A1 (en) 1999-01-27 2000-08-03 Wyeth Holdings Corporation 2,3,4,5-tetrahydro-1h-¬1,4|benzodiazepine-3-hydroxamic acid as matrix metalloproteinase inhibitors
WO2000047203A9 (en) 1999-02-12 2001-09-07 Mqs Inc Formulation and system for intra-oral delivery of pharmaceutical agents
US6591839B2 (en) 1999-02-17 2003-07-15 Dieter Meyer Filter material for reducing harmful substances in tobacco smoke
WO2000051491A1 (en) 1999-03-05 2000-09-08 Battelle Memorial Institute Method for safely and effectively administering a drug by inhalation
JP2002543092A (en) 1999-04-27 2002-12-17 イーライ・リリー・アンド・カンパニー Pulmonary administration for insulin crystals
CA2372150C (en) 1999-04-30 2011-08-30 The Regents Of The University Of Michigan Therapeutic applications of pro-apoptotic benzodiazepines
CA2370853C (en) 1999-05-03 2007-07-10 Battelle Memorial Institute Compositions for aerosolization and inhalation
US6428769B1 (en) 1999-05-04 2002-08-06 Aradigm Corporation Acute testosterone administration
US6309986B1 (en) 1999-05-07 2001-10-30 S. C. Johnson & Son, Inc. Mat for dispensing volatile materials
DK1180020T4 (en) 1999-05-27 2009-10-05 Acusphere Inc Poröse Drug and processes for the preparation thereof
WO2000076673A1 (en) 1999-06-11 2000-12-21 Aradigm Corporation Method for producing an aerosol
WO2001095903A1 (en) 2000-06-15 2001-12-20 Respiratorius Ab 5-ht3 receptor antagonists for treatment of disorders involving airway constriction
JP4999245B2 (en) 1999-07-16 2012-08-15 アラディグム コーポレイション System in order to achieve a non smoking
CA2381425A1 (en) 1999-08-24 2001-03-01 Cellgate, Inc. Enhancing drug delivery across and into epithelial tissues using oligo arginine moieties
JP2003508502A (en) 1999-09-07 2003-03-04 コンジュケム,インコーポレーテッド Methods and compositions for the production of long-lived anti-tumor agent
JP2003509142A (en) 1999-09-15 2003-03-11 アラダイム コーポレーション Vacuum aerosol Kaana structure
CA2386974C (en) 1999-10-15 2009-10-13 Geo Adam Benzodiazepine derivatives for use in acute or chronic neurological disorders
ES2254164T3 (en) 1999-10-29 2006-06-16 Nektar Therapeutics Dry powder compositions with improved dispersibility.
WO2001041732A1 (en) 1999-12-06 2001-06-14 Gore Stanley L Compositions and methods for intranasal delivery of active agents to the brain
DE19961300A1 (en) 1999-12-18 2001-06-21 Asta Medica Ag Storage system for drugs in powder form and therefore equipped inhaler
ES2305057T3 (en) 2000-02-28 2008-11-01 Pharmakodex Limited Device for oral drug delivery.
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
WO2001093846A3 (en) 2000-05-23 2002-05-23 Exhale Therapeutics Inc Method for treating respiratory disorders associated with pulmonary elastic fiber injury comprising the use of clycosaminoglycans
GB0015981D0 (en) 2000-06-29 2000-08-23 Glaxo Group Ltd Novel process for preparing crystalline particles
FR2812545B1 (en) 2000-08-03 2003-03-28 Air Liquide Sante Int Aerosol inhalable medicated in the treatment or prevention of sweetness
US20020117175A1 (en) 2000-10-27 2002-08-29 Kottayil S. George Thermal vaporizing device for drug delivery
US20030121906A1 (en) 2000-11-29 2003-07-03 Abbott Richard C. Resistive heaters and uses thereof
US6799572B2 (en) 2000-12-22 2004-10-05 Chrysalis Technologies Incorporated Disposable aerosol generator system and methods for administering the aerosol
US6491233B2 (en) 2000-12-22 2002-12-10 Chrysalis Technologies Incorporated Vapor driven aerosol generator 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
US6443152B1 (en) 2001-01-12 2002-09-03 Becton Dickinson And Company Medicament respiratory delivery device
FI20010115A0 (en) 2001-01-18 2001-01-18 Orion Corp Process for the preparation of nanoparticles
WO2002074247A8 (en) 2001-03-19 2003-01-03 Praecis Pharm Inc Pharmaceutical formulations for sustained release
US20030023638A1 (en) * 2001-05-02 2003-01-30 Weight Christopher F. Method and apparatus for processing content
WO2002094234A1 (en) 2001-05-24 2002-11-28 Alexza Molecular Delivery Corporation Delivery of opioids through an inhalation route
US7498019B2 (en) 2001-05-24 2009-03-03 Alexza Pharmaceuticals, Inc. Delivery of compounds for the treatment of headache through an inhalation route
US6759029B2 (en) * 2001-05-24 2004-07-06 Alexza Molecular Delivery Corporation Delivery of rizatriptan and zolmitriptan through an inhalation route
US20080038363A1 (en) * 2001-05-24 2008-02-14 Zaffaroni Alejandro C Aerosol delivery system and uses thereof
CA2641760A1 (en) * 2001-05-24 2002-11-28 Alexza Pharmaceuticals, Inc. Delivery of alprazolam, estazolam, midazolam or triazolam through an inhalation route
US7090830B2 (en) * 2001-05-24 2006-08-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US20070122353A1 (en) 2001-05-24 2007-05-31 Hale Ron L Drug condensation aerosols and kits
WO2002094244A3 (en) 2001-05-24 2003-01-16 Alexza Molecular Delivery Corp Delivery of benzodiazepines through an inhalation route
US20030051728A1 (en) 2001-06-05 2003-03-20 Lloyd Peter M. Method and device for delivering a physiologically active compound
US20030118512A1 (en) 2001-10-30 2003-06-26 Shen William W. Volatilization of a drug from an inclusion complex
US6779520B2 (en) 2001-10-30 2004-08-24 Iep Pharmaceutical Devices Inc. Breath actuated dry powder inhaler
GB0126150D0 (en) 2001-10-31 2002-01-02 Gw Pharma Ltd A device method and resistive element for vaporising a substance
WO2003041693A1 (en) * 2001-11-09 2003-05-22 Alexza Molecular Delivery Corporation Delivery of diazepam through an inhalation route
CA2462576A1 (en) 2001-11-21 2003-06-03 Alexza Molecular Delivery Corporation Open-celled substrates for drug delivery
US7078016B2 (en) 2001-11-21 2006-07-18 Alexza Pharmaceuticals, Inc. Delivery of caffeine through an inhalation route
US20030106551A1 (en) 2001-12-06 2003-06-12 Sprinkel F. Murphy Resistive heater formed inside a fluid passage of a fluid vaporizing device
CN1176075C (en) 2001-12-07 2004-11-17 北京燕山石油化工公司研究院 Pyrrole derivatives preparation method
US20030138508A1 (en) 2001-12-18 2003-07-24 Novack Gary D. Method for administering an analgesic
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
US7458374B2 (en) 2002-05-13 2008-12-02 Alexza Pharmaceuticals, Inc. Method and apparatus for vaporizing a compound
US7074806B2 (en) * 2002-06-06 2006-07-11 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US6772757B2 (en) 2002-10-25 2004-08-10 Chrysalis Technologies Incorporated Concentric controlled temperature profile fluid vaporizing device
US7550133B2 (en) 2002-11-26 2009-06-23 Alexza Pharmaceuticals, Inc. Respiratory drug condensation aerosols and methods of making and using them
US20060193788A1 (en) 2002-11-26 2006-08-31 Hale Ron L Acute treatment of headache with phenothiazine antipsychotics
WO2004047841A1 (en) 2002-11-26 2004-06-10 Alexza Molecular Delivery Corporation Treatment of headache with antipsychotics delivered by inhalation
DK1567164T3 (en) 2002-11-26 2009-05-18 Alexza Pharmaceuticals Inc Use of Loxapine 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
EP1625333A1 (en) 2003-05-21 2006-02-15 Alexza Pharmaceuticals, Inc. Self-contained heating unit and drug-supply unit employing same
WO2005014090A1 (en) * 2003-08-04 2005-02-17 Alexza Pharmaceuticals, Inc. Methods of determining film thicknesses for an aerosol delivery article
CA2534566A1 (en) 2003-08-04 2005-02-24 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
US20050131739A1 (en) 2003-12-16 2005-06-16 Alexza Molecular Delivery Corporation 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
CA2576961A1 (en) * 2004-08-12 2006-03-02 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
US20100006092A1 (en) * 2004-08-12 2010-01-14 Alexza Pharmaceuticals, Inc. Aerosol Drug Delivery Device Incorporating Percussively Activated Heat Packages
WO2006044421A3 (en) 2004-10-12 2006-08-03 Alexza Pharmaceuticals Inc Cardiac safe, rapid medication delivery
US7494344B2 (en) 2005-12-29 2009-02-24 Molex Incorporated Heating element connector assembly with press-fit terminals
US20080299048A1 (en) 2006-12-22 2008-12-04 Alexza Pharmaceuticals, Inc. Mixed drug aerosol compositions
US7513781B2 (en) 2006-12-27 2009-04-07 Molex Incorporated Heating element connector assembly with insert molded strips
US20080216828A1 (en) 2007-03-09 2008-09-11 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
WO2008134668A3 (en) 2007-04-27 2009-04-16 Alexza Pharmaceuticals Inc Heat-labile prodrugs
US20090180968A1 (en) 2008-01-11 2009-07-16 Alexza Pharmaceuticals, Inc. Metal Coordination Complexes Of Volatile Drugs
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
US20100068155A1 (en) 2008-09-16 2010-03-18 Alexza Pharmaceuticals, Inc. Reactant Formulations and Methods for Controlled Heating
US20100300433A1 (en) 2009-05-28 2010-12-02 Alexza Pharmaceuticals, Inc. Substrates for Enhancing Purity or Yield of Compounds Forming a Condensation Aerosol
US20100181387A1 (en) 2009-12-01 2010-07-22 Zaffaroni Alejandro C Aerosol delivery system and uses thereof
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

Patent Citations (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3080624A (en) * 1963-03-12 weber iii
US1803334A (en) * 1931-05-05 Ootthujp lehmann
US1864980A (en) * 1932-06-28 Vapobizeb
US2243669A (en) * 1941-05-27 Electrical vaporizer
US1535486A (en) * 1922-08-28 1925-04-28 James W Lundy Electric-lamp bulb
US2309846A (en) * 1941-03-06 1943-02-02 Holm Einar Marius Inhaler
US2469656A (en) * 1946-04-19 1949-05-10 Peter H Lienert Vaporizer
US2887106A (en) * 1956-09-27 1959-05-19 Robinson Joseph Combined vaporizer and cover for medicament jar
US3433791A (en) * 1960-09-05 1969-03-18 Reckitt & Sons Ltd Endoethano nor oripavines and nor thebaines
US3164600A (en) * 1961-10-10 1965-01-05 Res Lab Dr C Janssen N V 1-aralkyl-4-(n-aryl-carbonyl amino)-piperidines and related compounds
US3169095A (en) * 1962-10-30 1965-02-09 Rexall Drug Chemical Self-propelling powder-dispensing compositions
US3560607A (en) * 1962-11-30 1971-02-02 Fisons Pharmaceuticals Ltd Aerosol formulations of finely divided solid medicaments with anionic surface-active agents
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
US4020379A (en) * 1975-10-02 1977-04-26 Eg&G, Inc. Bulb-shaped flashtube with metal envelope
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
US4183912A (en) * 1978-01-16 1980-01-15 American Home Products Corporation Inhalation therapy for relieving bronchial spasm using quaternary salts of promethazine
US4276243A (en) * 1978-12-08 1981-06-30 Western Electric Company, Inc. Vapor delivery control system and method
US4588721A (en) * 1983-09-12 1986-05-13 The Upjohn Company Treatment of negative symptoms of schizophrenia
US4647428A (en) * 1984-06-04 1987-03-03 Gyulay Joseph M Air freshener method
US4647433A (en) * 1984-10-01 1987-03-03 Donald Spector Long-life aroma-generating capsule
US4722334A (en) * 1985-07-16 1988-02-02 Transpirator Technologies, Inc. Method and apparatus for pulmonary and cardiovascular conditioning of racehorses and competition animals
US4735358A (en) * 1986-03-04 1988-04-05 Daiken Iko Kabushiki Kaisha Method and apparatus of vaporizing active substances
US4924883A (en) * 1987-03-06 1990-05-15 R. J. Reynolds Tobacco Company Smoking article
US5017575A (en) * 1987-06-09 1991-05-21 Golwyn Daniel H Treatment of immunologically based disorders, specifically Crohn's disease
US4935624A (en) * 1987-09-30 1990-06-19 Cornell Research Foundation, Inc. Thermal-assisted electrospray interface (TAESI) for LC/MS
US4911157A (en) * 1988-01-07 1990-03-27 Pegasus Research Corporation Self-regulating, heated nebulizer system
US5112598A (en) * 1988-05-04 1992-05-12 Hermes Fabrik Pharmazeutischer Preparate Franz Gradinger Gmbh & Co. Kg Vitamin a aerosol-inhalate preparations
US4984158A (en) * 1988-10-14 1991-01-08 Hillsman Dean Metered dose inhaler biofeedback training and evaluation system
US4892109A (en) * 1989-03-08 1990-01-09 Brown & Williamson Tobacco Corporation Simulated smoking article
US5093894A (en) * 1989-12-01 1992-03-03 Philip Morris Incorporated Electrically-powered linear heating element
US5408574A (en) * 1989-12-01 1995-04-18 Philip Morris Incorporated Flat ceramic heater having discrete heating zones
US5109180A (en) * 1989-12-14 1992-04-28 Phillips Petroleum Company Apparatus providing a shatter-resistant electric lamp
US5126123A (en) * 1990-06-28 1992-06-30 Glaxo, Inc. Aerosol drug formulations
US5592934A (en) * 1990-08-02 1997-01-14 The Boc Group Plc Anaesthetic vaporizer
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
US6051566A (en) * 1991-02-09 2000-04-18 B.S.D. Bio Science Development Snc Di Omini C. & Zuccari G. Anti-reactive anti-asthmatic activity of non-steroidal anti-inflammatory drugs by inhalation
US5613504A (en) * 1991-03-11 1997-03-25 Philip Morris Incorporated Flavor generating article and method for making same
US5865185A (en) * 1991-03-11 1999-02-02 Philip Morris Incorporated Flavor generating article
US5505214A (en) * 1991-03-11 1996-04-09 Philip Morris Incorporated Electrical smoking article and method for making same
US5186164A (en) * 1991-03-15 1993-02-16 Puthalath Raghuprasad Mist inhaler
US5402517A (en) * 1991-05-01 1995-03-28 Reckitt & Colman Products Limited Apparatus for emitting a volatile chemical agent by heating and means for adjusting a spacing between a heater and the chemical agent to regulate the rate of vaporization
US5285798A (en) * 1991-06-28 1994-02-15 R. J. Reynolds Tobacco Company Tobacco smoking article with electrochemical heat source
US5593792A (en) * 1991-06-28 1997-01-14 R. J. Reynolds Tobacco Company Electrochemical heat source
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
US5894841A (en) * 1993-06-29 1999-04-20 Ponwell Enterprises Limited Dispenser
US5479948A (en) * 1993-08-10 1996-01-02 Philip Morris Incorporated Electrical smoking article having continuous tobacco flavor web and flavor cassette therefor
US5400969A (en) * 1993-09-20 1995-03-28 Keene; Christopher M. Liquid vaporizer and diffuser
US5605146A (en) * 1993-11-29 1997-02-25 Instrumentarium Oy Method and an arrangement in connection with vaporizing an anaesthetic
US5767117A (en) * 1994-11-18 1998-06-16 The General Hospital Corporation Method for treating vascular headaches
US5738865A (en) * 1995-04-07 1998-04-14 Edward Mendell Co., Inc. Controlled release insufflation carrier for medicaments
US5904900A (en) * 1995-04-28 1999-05-18 Etat Francais As Represented By Le Delegue General Pour L'armement Device for sampling gaseous substances, liquids, aerosols or even powdered materials for in situ analysis
US5874481A (en) * 1995-06-07 1999-02-23 Alliance Pharmaceutical Corp. Fluorochemical solutions for the delivery of lipophilic pharmaceutical agents
US6561186B2 (en) * 1995-08-02 2003-05-13 Innovative Devices 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
US6041777A (en) * 1995-12-01 2000-03-28 Alliance Pharmaceutical Corp. Methods and apparatus for closed-circuit ventilation therapy
US5743251A (en) * 1996-05-15 1998-04-28 Philip Morris Incorporated Aerosol and a method and apparatus for generating an aerosol
US6694975B2 (en) * 1996-11-21 2004-02-24 Aradigm Corporation Temperature controlling device for aerosol drug delivery
US6050260A (en) * 1996-12-02 2000-04-18 Fisher & Paykel Limited Humidifier sleep apnea treatment apparatus
US5769621A (en) * 1997-05-23 1998-06-23 The Regents Of The University Of California Laser ablation based fuel ignition
US5874841A (en) * 1997-07-28 1999-02-23 Philips Electronics North America Corporation Sample-and-hold circuit for a switched-mode power supply
US6390453B1 (en) * 1997-10-22 2002-05-21 Microfab Technologies, Inc. Method and apparatus for delivery of fragrances and vapors to the nose
US20020037828A1 (en) * 1997-10-28 2002-03-28 Wilson Leland F. Administration of phosphodiesterase inhibitors for the treatment of premature ejaculation
US6178969B1 (en) * 1998-03-03 2001-01-30 Brown & Williamson Tobacco Corporation Aerosol delivery smoking article
US6241969B1 (en) * 1998-06-26 2001-06-05 Elan Corporation Plc Aqueous compositions containing corticosteroids for nasal and pulmonary delivery
US6557552B1 (en) * 1998-10-14 2003-05-06 Chrysalis Technologies Incorporated Aerosol generator and methods of making and using an aerosol generator
US6516796B1 (en) * 1998-10-14 2003-02-11 Chrysalis Technologies Incorporated Aerosol generator and methods of making and using an aerosol generator
US20020031480A1 (en) * 1998-10-27 2002-03-14 Joanne Peart Delta9 tetrahydrocannabinol (Delta9 THC) solution metered dose inhalers and methods of use
US6376550B1 (en) * 1999-02-09 2002-04-23 Asta Medica Ag Pharmaceutical compositions containing tramadol for migraine
US6053176A (en) * 1999-02-23 2000-04-25 Philip Morris Incorporated Heater and method for efficiently generating an aerosol from an indexing substrate
US20020061281A1 (en) * 1999-07-06 2002-05-23 Osbakken Robert S. Aerosolized anti-infectives, anti-inflammatories, and decongestants for the treatment of sinusitis
US6506762B1 (en) * 1999-09-30 2003-01-14 Neurogen Corporation Certain alkylene diamine-substituted heterocycles
US20030049025A1 (en) * 2000-01-13 2003-03-13 Hermann Neumann Chip that comprises an active agent and an integrated heating element
US6688313B2 (en) * 2000-03-23 2004-02-10 Philip Morris Incorporated Electrical smoking system and method
US20040016427A1 (en) * 2000-04-27 2004-01-29 Byron Peter R. Method and apparatus for generating an aerosol
US6514482B1 (en) * 2000-09-19 2003-02-04 Advanced Inhalation Research, Inc. Pulmonary delivery in treating disorders of the central nervous system
US20020058009A1 (en) * 2000-09-19 2002-05-16 Advanced Inhalation Research, Inc. Pulmonary delivery in treating disorders of the central nervous system
US6681998B2 (en) * 2000-12-22 2004-01-27 Chrysalis Technologies Incorporated Aerosol generator having inductive heater and method of use thereof
US6701921B2 (en) * 2000-12-22 2004-03-09 Chrysalis Technologies Incorporated Aerosol generator having heater in multilayered composite and method of use thereof
US6671945B2 (en) * 2001-01-19 2004-01-06 Vishay Intertechnology, Inc. Method for making a resistor using resistive foil
US6680668B2 (en) * 2001-01-19 2004-01-20 Vishay Intertechnology, Inc. Fast heat rise resistor using resistive foil
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
US6737042B2 (en) * 2001-05-24 2004-05-18 Alexza Molecular Delivery Corporation Delivery of drug esters through an inhalation route
US20070014737A1 (en) * 2001-05-24 2007-01-18 Alexza Pharmaceuticals, Inc. Delivery of muscle relaxants through an inhalation route
US20070028916A1 (en) * 2001-05-24 2007-02-08 Hale Ron L Rapid-heating drug delivery article and method of use
US20070031340A1 (en) * 2001-05-24 2007-02-08 Hale Ron L Thin-film drug delivery article and method of use
US20030033055A1 (en) * 2001-07-31 2003-02-13 Mcrae Douglas D. Method and apparatus for generating a volatilized liquid
US6715487B2 (en) * 2001-09-21 2004-04-06 Chrysalis Technologies Incorporated Dual capillary fluid vaporizing device
US6568390B2 (en) * 2001-09-21 2003-05-27 Chrysalis Technologies Incorporated Dual capillary fluid vaporizing device
US20040055504A1 (en) * 2001-10-15 2004-03-25 Lee Brian Craig Electro-thermal odor-releasing inks and methods for releasing odors from the same
US6681769B2 (en) * 2001-12-06 2004-01-27 Crysalis Technologies Incorporated Aerosol generator having a multiple path heater arrangement and method of use thereof
US6701922B2 (en) * 2001-12-20 2004-03-09 Chrysalis Technologies Incorporated Mouthpiece entrainment airflow control for aerosol generators
US6728478B2 (en) * 2002-02-21 2004-04-27 Dekko Heating Technologies, Inc. Heated chemical delivery system
US20040009128A1 (en) * 2002-05-13 2004-01-15 Rabinowitz Joshua D Delivery of drug amines through an inhalation route
US20040035409A1 (en) * 2002-06-06 2004-02-26 Harwig Jeffrey L. Localized surface volatilization
US20040081624A1 (en) * 2002-09-06 2004-04-29 Chrysalis Technologies Incorporated Liquid aerosol formulations and aerosol generating devices and methods for generating aerosols
US20040099266A1 (en) * 2002-11-27 2004-05-27 Stephen Cross Inhalation device for producing a drug aerosol

Cited By (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060257329A1 (en) * 2001-05-24 2006-11-16 Alexza Pharmaceuticals, Inc. Delivery of drug esters through an inhalation route
US7988952B2 (en) 2001-05-24 2011-08-02 Alexza Pharmaceuticals, Inc. Delivery of drug esters through an inhalation route
US20080311176A1 (en) * 2001-05-24 2008-12-18 Alexza Pharmaceuticals, Inc. Drug Condensation Aerosols And Kits
US20090246147A1 (en) * 2001-05-24 2009-10-01 Alexza Pharmaceuticals, Inc. Delivery Of Antipsychotics Through An Inhalation Route
US9211382B2 (en) 2001-05-24 2015-12-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US20060153779A1 (en) * 2001-05-24 2006-07-13 Alexza Pharmaceuticals, Inc. Delivery of stimulants through an inhalation route
US20070014737A1 (en) * 2001-05-24 2007-01-18 Alexza Pharmaceuticals, Inc. Delivery of muscle relaxants through an inhalation route
US9440034B2 (en) 2001-05-24 2016-09-13 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US20060286043A1 (en) * 2001-05-24 2006-12-21 Alexza Pharmaceuticals, Inc. Delivery of antihistamines through an inhalation route
US20060269487A1 (en) * 2001-05-24 2006-11-30 Alexza Pharmaceuticals, Inc. Delivery of nonsteroidal antiinflammatory drugs through an inhalation route
US7645442B2 (en) 2001-05-24 2010-01-12 Alexza Pharmaceuticals, Inc. Rapid-heating drug delivery article and method of use
US20060216243A1 (en) * 2001-05-24 2006-09-28 Alexza Pharmaceuticals, Inc. Delivery of Beta-Blockers Through An Inhalation Route
US20060216244A1 (en) * 2001-05-24 2006-09-28 Alexza Pharmaceuticals, Inc. Delivery of compounds for the treatment of parkinson's through an inhalation route
US8173107B2 (en) 2001-05-24 2012-05-08 Alexza Pharmaceuticals, Inc. Delivery of antipsychotics through an inhalation route
US20060233718A1 (en) * 2001-05-24 2006-10-19 Alexza Pharmaceuticals, Inc. Delivery of alprazolam, estazolam, midazolam or triazolam through an inhalation route
US20060239936A1 (en) * 2001-05-24 2006-10-26 Alexza Pharmaceuticals, Inc. Delivery of anti-migraine compounds through an inhalation route
US20060246012A1 (en) * 2001-05-24 2006-11-02 Alexza Pharmaceuticals, Inc. Delivery of physiologically active compounds through an inhalation route
US20060251588A1 (en) * 2001-05-24 2006-11-09 Alexza Pharmaceuticals, Inc. Delivery of erectile dysfunction drugs through an inhalation route
US20060280692A1 (en) * 2001-05-24 2006-12-14 Alexza Pharmaceuticals, Inc. Delivery of antipsychotics through an inhalation route
US20060251587A1 (en) * 2001-05-24 2006-11-09 Alexza Pharmaceuticals, Inc. Delivery of analgesics through an inhalation route
US8235037B2 (en) 2001-05-24 2012-08-07 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US20070178052A1 (en) * 2001-05-24 2007-08-02 Alexza Pharmaceuticals, Inc. Delivery of opioids through an inhalation route
US20030062042A1 (en) * 2001-06-05 2003-04-03 Wensley Martin J. Aerosol generating method and device
US9308208B2 (en) 2001-06-05 2016-04-12 Alexza Pharmaceuticals, Inc. Aerosol generating method and device
US9439907B2 (en) 2001-06-05 2016-09-13 Alexza Pharmaceutical, Inc. Method of forming an aerosol for inhalation delivery
US9687487B2 (en) 2001-06-05 2017-06-27 Alexza Pharmaceuticals, Inc. Aerosol forming device for use in inhalation therapy
US8074644B2 (en) 2001-06-05 2011-12-13 Alexza Pharmaceuticals, Inc. Method of forming an aerosol for inhalation delivery
US7766013B2 (en) 2001-06-05 2010-08-03 Alexza Pharmaceuticals, Inc. Aerosol generating method and device
US8955512B2 (en) 2001-06-05 2015-02-17 Alexza Pharmaceuticals, Inc. Method of forming an aerosol for inhalation delivery
US7942147B2 (en) 2001-06-05 2011-05-17 Alexza Pharmaceuticals, Inc. Aerosol forming device for use in inhalation therapy
US20060257328A1 (en) * 2001-11-21 2006-11-16 Alexza Pharmaceuticals, Inc. Delivery of caffeine through an inhalation route
US20040009128A1 (en) * 2002-05-13 2004-01-15 Rabinowitz Joshua D Delivery of drug amines through an inhalation route
US8003080B2 (en) 2002-05-13 2011-08-23 Alexza Pharmaceuticals, Inc. Delivery of drug amines through an inhalation route
US20030209240A1 (en) * 2002-05-13 2003-11-13 Hale Ron L. Method and apparatus for vaporizing a compound
US7987846B2 (en) 2002-05-13 2011-08-02 Alexza Pharmaceuticals, Inc. Method and apparatus for vaporizing a compound
US20100055048A1 (en) * 2002-05-20 2010-03-04 Alexza Pharmaceuticals, Inc. Acute treatment of headache with phenothiazine antipsychotics
US20040102434A1 (en) * 2002-11-26 2004-05-27 Alexza Molecular Delivery Corporation Method for treating pain with loxapine and amoxapine
US7981401B2 (en) 2002-11-26 2011-07-19 Alexza Pharmaceuticals, Inc. Diuretic aerosols and methods of making and using them
US20090062254A1 (en) * 2002-11-26 2009-03-05 Alexza Pharmaceuticals, Inc. Acute Treatment of Headache with Phenothiazine Antipsychotics
US8288372B2 (en) 2002-11-26 2012-10-16 Alexza Pharmaceuticals, Inc. Method for treating headache with loxapine
US20040105819A1 (en) * 2002-11-26 2004-06-03 Alexza Molecular Delivery Corporation Respiratory drug condensation aerosols and methods of making and using them
US8506935B2 (en) 2002-11-26 2013-08-13 Alexza Pharmaceuticals, Inc. Respiratory drug condensation aerosols and methods of making and using them
US20090258075A1 (en) * 2002-11-26 2009-10-15 Alexza Pharmaceuticals, Inc. Respiratory Drug Condensation Aerosols and Methods of Making and Using Them
US7913688B2 (en) 2002-11-27 2011-03-29 Alexza Pharmaceuticals, Inc. Inhalation device for producing a drug aerosol
WO2004096118A2 (en) 2003-04-29 2004-11-11 Neurim Pharmaceuticals (1991) Ltd. Composition for improving cognition and memory
US20060229340A1 (en) * 2003-04-29 2006-10-12 Neurim Pharmaceuticals (1991) Ltd. Composition for improving cognition and memory
US8859593B2 (en) 2003-04-29 2014-10-14 Neurim Pharmaceuticals (1991) Ltd. Composition for improving cognition and memory
US9119846B2 (en) 2003-04-29 2015-09-01 Neurim Pharmaceuticals (1991) Ltd. Method and composition for enhancing cognition in alzheimer's patients
US8387612B2 (en) 2003-05-21 2013-03-05 Alexza Pharmaceuticals, Inc. Self-contained heating unit and drug-supply unit employing same
US20040234916A1 (en) * 2003-05-21 2004-11-25 Alexza Molecular Delivery Corporation Optically ignited or electrically ignited self-contained heating unit and drug-supply unit employing same
US20050079166A1 (en) * 2003-05-21 2005-04-14 Alexza Molecular Delivery Corporation Self-contained heating unit and drug-supply unit employing same
US9370629B2 (en) 2003-05-21 2016-06-21 Alexza Pharmaceuticals, Inc. Self-contained heating unit and drug-supply unit employing same
US8991387B2 (en) 2003-05-21 2015-03-31 Alexza Pharmaceuticals, Inc. Self-contained heating unit and drug-supply unit employing same
US20050034723A1 (en) * 2003-08-04 2005-02-17 Bryson Bennett Substrates for drug delivery device and methods of preparing and use
US20140072605A1 (en) * 2003-08-04 2014-03-13 Alexza Pharmaceuticals, Inc. Substrates for Drug Delivery Device and Methods of Preparing and Use
WO2005053444A1 (en) * 2003-12-05 2005-06-16 Lts Lohmann Therapie-Systeme Ag Inhaler for basic pharmaceutical agents and method for production thereof
US7923662B2 (en) 2004-05-20 2011-04-12 Alexza Pharmaceuticals, Inc. Stable initiator compositions and igniters
US8333197B2 (en) 2004-06-03 2012-12-18 Alexza Pharmaceuticals, Inc. Multiple dose condensation aerosol devices and methods of forming condensation aerosols
US20060251810A1 (en) * 2005-05-03 2006-11-09 Eastman Kodak Company Metering material to promote rapid vaporization
US7213347B2 (en) * 2005-05-03 2007-05-08 Eastman Kodak Company Metering material to promote rapid vaporization
US20090107495A1 (en) * 2005-07-21 2009-04-30 National Institute For Materials Science Device for inhalation of medicine
US20070070612A1 (en) * 2005-09-23 2007-03-29 Bull, S.A.S. System for maintaining an assembly of three parts in position that exerts a predetermined compressive force on the itermediate part
US20070155255A1 (en) * 2005-12-29 2007-07-05 Charles Galauner Heating element connector assembly with press-fit terminals
US7494344B2 (en) 2005-12-29 2009-02-24 Molex Incorporated Heating element connector assembly with press-fit terminals
US20080299048A1 (en) * 2006-12-22 2008-12-04 Alexza Pharmaceuticals, Inc. Mixed drug aerosol compositions
US7513781B2 (en) 2006-12-27 2009-04-07 Molex Incorporated Heating element connector assembly with insert molded strips
US7834295B2 (en) 2008-09-16 2010-11-16 Alexza Pharmaceuticals, Inc. Printable igniters
US20100068154A1 (en) * 2008-09-16 2010-03-18 Alexza Pharmaceuticals, Inc. Printable Igniters
US20100065052A1 (en) * 2008-09-16 2010-03-18 Alexza Pharmaceuticals, Inc. Heating Units
US20100300433A1 (en) * 2009-05-28 2010-12-02 Alexza Pharmaceuticals, Inc. Substrates for Enhancing Purity or Yield of Compounds Forming a Condensation Aerosol
US10034988B2 (en) 2012-11-28 2018-07-31 Fontem Holdings I B.V. Methods and devices for compound delivery
WO2014085719A1 (en) * 2012-11-28 2014-06-05 E-Nicotine Technology, Inc. Methods and devices for compound delivery
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
US8889190B2 (en) 2013-03-13 2014-11-18 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US9555005B2 (en) 2013-03-15 2017-01-31 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US9724341B2 (en) 2013-07-11 2017-08-08 Alexza Pharmaceuticals, Inc. Nicotine salt with meta-salicylic acid

Also Published As

Publication number Publication date Type
US20130276779A1 (en) 2013-10-24 application
JP4912566B2 (en) 2012-04-11 grant
US20030015197A1 (en) 2003-01-23 application
CA2447081A1 (en) 2002-12-12 application
EP1392381A1 (en) 2004-03-03 application
EP1392381B1 (en) 2011-03-30 grant
CA2447210A1 (en) 2002-12-12 application
CA2447081C (en) 2010-02-23 grant
CA2447354C (en) 2008-12-02 grant
EP1392242A1 (en) 2004-03-03 application
CN1514719A (en) 2004-07-21 application
CA2447354A1 (en) 2002-12-12 application
US20100294268A1 (en) 2010-11-25 application
WO2002098390A2 (en) 2002-12-12 application
DE60236430D1 (en) 2010-07-01 grant
US20110240022A1 (en) 2011-10-06 application
JP2004532881A (en) 2004-10-28 application
US9687487B2 (en) 2017-06-27 grant
US8074644B2 (en) 2011-12-13 grant
ES2343678T3 (en) 2010-08-06 grant
US20030035776A1 (en) 2003-02-20 application
CA2447210C (en) 2007-09-11 grant
US7766013B2 (en) 2010-08-03 grant
US20140066618A1 (en) 2014-03-06 application
US20090229600A1 (en) 2009-09-17 application
EP1392263A2 (en) 2004-03-03 application
US7537009B2 (en) 2009-05-26 grant
US8955512B2 (en) 2015-02-17 grant
US20150157635A1 (en) 2015-06-11 application
DE60239604D1 (en) 2011-05-12 grant
WO2002098389A1 (en) 2002-12-12 application
CA2646756A1 (en) 2002-12-12 application
JP2004529724A (en) 2004-09-30 application
US20040096402A1 (en) 2004-05-20 application
JP2010057950A (en) 2010-03-18 application
JP4510438B2 (en) 2010-07-21 grant
WO2002098390A3 (en) 2003-02-20 application
CN1512900A (en) 2004-07-14 application
US6682716B2 (en) 2004-01-27 grant
WO2002098496A1 (en) 2002-12-12 application
US20110240013A1 (en) 2011-10-06 application
WO2002098389A8 (en) 2006-10-12 application
US20030015196A1 (en) 2003-01-23 application
US7942147B2 (en) 2011-05-17 grant
US9439907B2 (en) 2016-09-13 grant
JP2005503846A (en) 2005-02-10 application
EP1392381B9 (en) 2011-09-14 grant
CN100496458C (en) 2009-06-10 grant
US9308208B2 (en) 2016-04-12 grant
EP1392242B1 (en) 2010-05-19 grant
CN1304067C (en) 2007-03-14 grant
US20140060532A1 (en) 2014-03-06 application
US20030062042A1 (en) 2003-04-03 application
CA2646756C (en) 2010-10-26 grant
US20170281884A1 (en) 2017-10-05 application

Similar Documents

Publication Publication Date Title
Newman Aerosol deposition considerations in inhalation therapy
Everard et al. Drug delivery from jet nebulisers.
Hochrainer et al. Comparison of the aerosol velocity and spray duration of Respimat® Soft Mist™ inhaler and pressurized metered dose inhalers
US6167880B1 (en) Inhaled insulin dosage control delivery enhanced by controlling total inhaled volume
US6098620A (en) Device for aerosolizing narcotics
US6003512A (en) Dust gun-aerosol generator and generation
US5915378A (en) Creating an aerosolized formulation of insulin
Labiris et al. Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications
Newman et al. Deposition of pressurised aerosols in the human respiratory tract.
US6557552B1 (en) Aerosol generator and methods of making and using an aerosol generator
Clark Medical aerosol inhalers: past, present, and future
Timsina et al. Drug delivery to the respiratory tract using dry powder inhalers
Scheuch et al. Clinical perspectives on pulmonary systemic and macromolecular delivery
US6360743B1 (en) System for dispensing pharmaceutical active compounds
US20140014106A1 (en) Dry powder drug delivery system and methods
US6408854B1 (en) Insulin delivery enhanced by coached breathing
US20110000482A1 (en) Laboratory animal pulmonary dosing device
US6250300B1 (en) System for dispensing pharmaceutically active compounds
US5970973A (en) Method of delivering insulin lispro
Geller et al. Development of an inhaled dry-powder formulation of tobramycin using PulmoSphere™ technology
Rehman et al. Optimisation of powders for pulmonary delivery using supercritical fluid technology
US5873358A (en) Method of maintaining a diabetic patient&#39;s blood glucose level in a desired range
US6567686B2 (en) Method for improving lung delivery of pharmaceutical aerosols
FAARC Metered-dose inhalers, dry powder inhalers, and transitions
Fink et al. Reconciling in vitro and in vivo measurements of aerosol delivery from a metered-dose inhaler during mechanical ventilation and defining efficiency-enhancing factors

Legal Events

Date Code Title Description
AS Assignment

Owner name: ALEXZA MOLECULAR DELIVERY CORPORATION, CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LLOYD, PETER M.;WENSLEY, MARTIN J.;MUFSON, DANIEL;AND OTHERS;REEL/FRAME:013285/0525;SIGNING DATES FROM 20020828 TO 20020905

AS Assignment

Owner name: ALEXZA PHARMACEUTICALS, INC., CALIFORNIA

Free format text: CHANGE OF NAME;ASSIGNOR:ALEXZA MOLECULAR DELIVERY CORPORATION;REEL/FRAME:016926/0674

Effective date: 20050720