US 6,776,978 B2Grant
Delivery of opioids through an inhalation route
Issue Date:2004-08-17
•28 Claims
•1 Drawing Sheets
Abstract
The present invention relates to the delivery of opioids through an inhalation route. Specifically, it relates to aerosols containing opioids that are used in inhalation therapy. In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of an opioid. In a method aspect of the present invention, an opioid is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of an opioid, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. In a kit aspect of the present invention, a kit for delivering an opioid through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of an opioid; and, b) a device that forms an opioid aerosol from the composition, for inhalation by the mammal.
Metadata
Assignee
- Alexza Molecular Delivery Corporation
Inventors
- Joshua D. Rabinowitz
- Alejandro C. Zaffaroni
Application Information
Application Number:US 10/153,839
Filing Date:2002-05-21
Priority Date:2001-05-24
Art Unit:7
Classifications
IPC:
A61K 912A61K 914
Field of Search:
424 45424450424 464247801282001412820024514 54514220
Patent Drawings (1 sheets)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0002] This application claims priority to U.S. provisional application Ser. No. 60/294,203 entitled “Thermal Vapor Delivery of Drugs,” filed May 24, 2001, Rabinowitz and Zaffaroni, the entire disclosure of which is hereby incorporated by reference. This application further claims priority to U.S. provisional application Ser. No. 60/317,479 entitled “Aerosol Drug Delivery,” filed Sep. 5, 2001, Rabinowitz and Zaffaroni, the entire disclosure of which is hereby incorporated by reference.
FIELD OF THE INVENTION
[0003] The present invention relates to the delivery of opioids through an inhalation route. Specifically, it relates to aerosols containing opioids that are used in inhalation therapy.
BACKGROUND OF THE INVENTION
[0004] There are a number of currently marketed opioid compositions. The compositions contain at least one active ingredient that provides for observed therapeutic effects. Among the active ingredients given in such opioid compositions are morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, and sufentanil.
[0005] It is desirable to provide a new route of administration for the opioids that rapidly produces peak plasma concentrations of the compounds. The provision of such a route is an object of the present invention.
SUMMARY OF THE INVENTION
[0006] The present invention relates to the delivery of opioids through an inhalation route. Specifically, it relates to aerosols containing oploids that are used in inhalation therapy.
[0007] In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of an opioid. Preferably, the particles comprise at least 10 percent by weight of an opioid. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent by weight of an opioid.
[0008] Typically, the opioid is not morphine or heroin.
[0009] Typically, the aerosol has a mass of at least 1 μg. Preferably, the aerosol has a mass of at least 10 μg. More preferably, the aerosol has a mass of at least 20 μg.
[0010] Typically, the particles comprise less than 10 percent by weight of opioid degradation products. Preferably, the particles comprise less than 5 percent by weight of opioid degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of opioid degradation products.
[0011] Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
[0012] Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.
[0013] Typically, the aerosol has an inhalable aerosol particle density greater than 106particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107particles/mL or 108particles/mL.
[0014] Typically, the aerosol particles have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
[0015] Typically, the aerosol is formed by heating a composition containing an opioid to form a vapor and subsequently allowing the vapor to condense into an aerosol.
[0016] In another composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil. Preferably, the particles comprise at least 10 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil.
[0017] Typically, the aerosol has a mass of at least 1 μg. Preferably, the aerosol has a mass of at least 10 μg. More preferably, the aerosol has a mass of at least 20 μg.
[0018] Typically, the particles comprise less than 10 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil degradation products. Preferably, the particles comprise less than 5 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil degradation products.
[0019] Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
[0020] Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.
[0021] Typically, where the aerosol comprises morphine, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 25 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 7.5 mg/L and 22.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 20 mg/L.
[0022] Typically, where the aerosol comprises codeine, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 25 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 7.5 mg/L and 22.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 20 mg/L.
[0023] Typically, where the aerosol comprises naltrexone, the aerosol has an inhalable aerosol drug mass density of between 15 mg/L and 35 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 17.5 mg/L and 32.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 30 mg/L.
[0024] Typically, where the aerosol comprises buprenorphine, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 1 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.15 mg/L and 0.8 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 0.6 mg/L.
[0025] Typically, where the aerosol comprises fentanyl, the aerosol has an inhalable aerosol drug mass density of between 0.01 mg/L and 0.8 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.02 mg/L and 0.6 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.3 mg/L and 0.4 mg/L.
[0026] Typically, where the aerosol comprises nalbuphine, the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 30 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 27.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 25 mg/L.
[0027] Typically, where the aerosol comprises naloxone, the aerosol has an inhalable aerosol drug mass density of between 0.05 mg/L and 3.5 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 3 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 2.5 mg/L.
[0028] Typically, where the aerosol comprises butorphanol, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 3 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.15 mg/L and 2.75 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 2.5 mg/L.
[0029] Typically, where the aerosol comprises hydromorphone, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 10 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 7.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.4 mg/L and 5 mg/L.
[0030] Typically, where the aerosol comprises oxycodone, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 10 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.75 mg/L and 0.8 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 0.6 mg/L.
[0031] Typically, where the aerosol comprises meperidine, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 100 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 7.5 mg/L and 80 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 60 mg/L.
[0032] Typically, where the aerosol comprises methadone, the aerosol has an inhalable aerosol drug mass density of between 0.25 mg/L and 20 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 17.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.75 mg/L and 15 mg/L.
[0033] Typically, where the aerosol comprises pentazocine, the aerosol has an inhalable aerosol drug mass density of between 3 mg/L and 50 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 45 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 40 mg/L.
[0034] Typically, the aerosol has an inhalable aerosol particle density greater than 106particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107particles/mL or 108particles/mL.
[0035] Typically, the aerosol particles have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
[0036] Typically, the aerosol is formed by heating a composition containing morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil to form a vapor and subsequently allowing the vapor to condense into an aerosol.
[0037] In a method aspect of the present invention, an opioid is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of an opioid, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. Preferably, the composition comprises at least 10 percent by weight of an opioid. More preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of an opioid.
[0038] Typically, the opioid is not morphine or heroin.
[0039] Typically, the particles comprise at least 5 percent by weight of an opioid. Preferably, the particles comprise at least 10 percent by weight of an opioid. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of an opioid.
[0040] Typically, the aerosol has a mass of at least 1 μg. Preferably, the aerosol has a mass of at least 10 μg. More preferably, the aerosol has a mass of at least 20 μg.
[0041] Typically, the particles comprise less than 10 percent by weight of opioid degradation products. Preferably, the particles comprise less than 5 percent by weight of opioid degradation products. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of opioid degradation products.
[0042] Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
[0043] Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.
[0044] Typically, the particles of the delivered condensation aerosol have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
[0045] Typically, the delivered aerosol has an inhalable aerosol particle density greater than 106particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107particles/mL or 108particles/mL.
[0046] Typically, the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 108particles per second. Preferably, the aerosol is formed at a rate greater than 109inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 1010inhalable particles per second.
[0047] Typically, the delivered condensation aerosol is formed at a rate greater than 0.5 mg/second. Preferably, the aerosol is formed at a rate greater than 0.75 mg/second. More preferably, the aerosol is formed at a rate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.
[0048] Typically, the delivered condensation aerosol results in a peak plasma concentration of an opioid in the mammal in less than 1 h. Preferably, the peak plasma concentration is reached in less than 0.5 h. More preferably, the peak plasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).
[0049] In another method aspect of the present invention, one of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. Preferably, the composition comprises at least 10 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil. More preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil.
[0050] Typically, the particles comprise at least 5 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil. Preferably, the particles comprise at least 10 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil.
[0051] Typically, the aerosol has a mass of at least 1 μg. Preferably, the aerosol has a mass of at least 10 μg. More preferably, the aerosol has a mass of at least 20 μg.
[0052] Typically, the particles comprise less than 10 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil degradation products. Preferably, the particles comprise less than 5 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil degradation products. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil degradation products.
[0053] Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
[0054] Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.
[0055] Typically, the particles of the delivered condensation aerosol have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
[0056] Typically, where the aerosol comprises morphine, the delivered aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 25 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 7.5 mg/L and 22.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 20 mg/L.
[0057] Typically, where the aerosol comprises codeine, the delivered aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 25 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 7.5 mg/L and 22.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 20 mg/L.
[0058] Typically, where the aerosol comprises naltrexone, the delivered aerosol has an inhalable aerosol drug mass density of between 15 mg/L and 35 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 17.5 mg/L and 32.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 30 mg/L.
[0059] Typically, where the aerosol comprises buprenorphine, the delivered aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 1 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.15 mg/L and 0.8 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 0.6 mg/L.
[0060] Typically, where the aerosol comprises fentanyl, the delivered aerosol has an inhalable aerosol drug mass density of between 0.01 mg/L and 0.8 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.02 mg/L and 0.6 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.3 mg/L and 0.4 mg/L.
[0061] Typically, where the aerosol comprises nalbuphine, the delivered aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 30 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 27.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 25 mg/L.
[0062] Typically, where the aerosol comprises naloxone, the delivered aerosol has an inhalable aerosol drug mass density of between 0.05 mg/L and 3.5 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 3 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 2.5 mg/L.
[0063] Typically, where the aerosol comprises butorphanol, the delivered aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 3 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.15 mg/L and 2.75 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 2.5 mg/L.
[0064] Typically, where the aerosol comprises hydromorphone, the delivered aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 10 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 7.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.4 mg/L and 5 mg/L.
[0065] Typically, where the aerosol comprises oxycodone, the delivered aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 10 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.75 mg/L and 0.8 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 0.6 mg/L.
[0066] Typically, where the aerosol comprises meperidine, the delivered aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 100 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 7.5 mg/L and 80 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 60 mg/L.
[0067] Typically, where the aerosol comprises methadone, the delivered aerosol has an inhalable aerosol drug mass density of between 0.25 mg/L and 20 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 17.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.75 mg/L and 15 mg/L.
[0068] Typically, where the aerosol comprises pentazocine, the delivered aerosol has an inhalable aerosol drug mass density of between 3 mg/L and 50 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 45 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 40 mg/L.
[0069] Typically, the delivered aerosol has an inhalable aerosol particle density greater than 106particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107particles/mL or 108particles/mL.
[0070] Typically, the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 108particles per second. Preferably, the aerosol is formed at a rate greater than 109inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 1010inhalable particles per second.
[0071] Typically, the delivered condensation aerosol is formed at a rate greater than 0.5 mg/second. Preferably, the aerosol is formed at a rate greater than 0.75 mg/second. More preferably, the aerosol is formed at a rate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.
[0072] Typically, where the condensation aerosol comprises morphine, between 5 mg and 25 mg of morphine are delivered to the mammal in a single inspiration. Preferably, between 7.5 mg and 22.5 mg of morphine are delivered to the mammal in a single inspiration. More preferably, between 10 mg and 20 mg of morphine are delivered in a single inspiration.
[0073] Typically, where the condensation aerosol comprises codeine, between 5 mg and 25 mg of codeine are delivered to the mammal in a single inspiration. Preferably, between 7.5 mg and 22.5 mg of codeine are delivered to the mammal in a single inspiration. More preferably, between 10 mg and 20 mg of codeine are delivered in a single inspiration.
[0074] Typically, where the condensation aerosol comprises naltrexone, between 15 mg and 35 mg of naltrexone are delivered to the mammal in a single inspiration. Preferably, between 17.5 mg and 32.5 mg of naltrexone are delivered to the mammal in a single inspiration. More preferably, between 20 mg and 30 mg of naltrexone are delivered in a single inspiration.
[0075] Typically, where the condensation aerosol comprises buprenorphine, between 0.1 mg and 1 mg of buprenorphine are delivered to the mammal in a single inspiration. Preferably, between 0.15 mg and 0.8 mg of buprenorphine are delivered to the mammal in a single inspiration. More preferably, between 0.2 mg and 0.6 mg of naltrexone are delivered in a single inspiration.
[0076] Typically, where the condensation aerosol comprises fentanyl, between 0.01 mg and 0.8 mg of fentanyl are delivered to the mammal in a single inspiration. Preferably, between 0.02 mg and 0.6 mg of fentanyl are delivered to the mammal in a single inspiration. More preferably, between 0.03 mg and 0.4 mg of fentanyl are delivered in a single inspiration.
[0077] Typically, where the condensation aerosol comprises nalbuphine, between 1 mg and 30 mg of nalbuphine are delivered to the mammal in a single inspiration. Preferably, between 2 mg and 27.5 mg of nalbuphine are delivered to the mammal in a single inspiration. More preferably, between 3 mg and 25 mg of nalbuphine are delivered in a single inspiration.
[0078] Typically, where the condensation aerosol comprises naloxone, between 0.05 mg and 3.5 mg of naloxone are delivered to the mammal in a single inspiration. Preferably, between 0.1 mg and 3 mg of naloxone are delivered to the mammal in a single inspiration. More preferably, between 0.2 mg and 2.5 mg of naloxone are delivered in a single inspiration.
[0079] Typically, where the condensation aerosol comprises butorphanol, between 0.1 mg and 3 mg of butorphanol are delivered to the mammal in a single inspiration. Preferably, between 0.15 mg and 2.75 mg of butorphanol are delivered to the mammal in a single inspiration. More preferably, between 0.2 mg and 2.5 mg of butorphanol are delivered in a single inspiration.
[0080] Typically, where the condensation aerosol comprises hydromorphone, between 0.1 mg and 10 mg of hydromorphone are delivered to the mammal in a single inspiration. Preferably, between 0.2 mg and 7.5 mg of hydromorphone are delivered to the mammal in a single inspiration. More preferably, between 0.4 mg and 5 mg of hydromorphone are delivered in a single inspiration.
[0081] Typically, where the condensation aerosol comprises oxycodone, between 0.5 mg and 10 mg of oxycodone are delivered to the mammal in a single inspiration. Preferably, between 0.75 mg and 8 mg of oxycodone are delivered to the mammal in a single inspiration. More preferably, between 1 mg and 6 mg of oxycodonel are delivered in a single inspiration.
[0082] Typically, where the condensation aerosol comprises meperidine, between 5 mg and 100 mg of meperidine are delivered to the mammal in a single inspiration. Preferably, between 7.5 mg and 80 mg of meperidine are delivered to the mammal in a single inspiration. More preferably, between 10 mg and 60 mg of meperidine are delivered in a single inspiration.
[0083] Typically, where the condensation aerosol comprises methadone, between 0.25 mg and 20 mg of methadone are delivered to the mammal in a single inspiration. Preferably, between 0.5 mg and 17.5 mg of methadone are delivered to the mammal in a single inspiration. More preferably, between 0.75 mg and 15 mg of methadone are delivered in a single inspiration.
[0084] Typically, where the condensation aerosol comprises pentazocine, between 3 mg and 50 mg of pentazocine are delivered to the mammal in a single inspiration. Preferably, between 4 mg and 45 mg of pentazocine are delivered to the mammal in a single inspiration. More preferably, between 5 mg and 40 mg of pentazocine are delivered in a single inspiration.
[0085] Typically, the delivered condensation aerosol results in a peak plasma concentration of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil in the mammal in less than 1 h. Preferably, the peak plasma concentration is reached in less than 0.5 h. More preferably, the peak plasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).
[0086] In a kit aspect of the present invention, a kit for delivering an opioid through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of an opioid; and, b) a device that forms an opioid aerosol from the composition, for inhalation by the mammal. Preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of an Opioid.
[0087] Typically, the device contained in the kit comprises: a) an element for heating the opioid composition to form a vapor; b) an element allowing the vapor to cool to form an aerosol; and, c) an element permitting the mammal to inhale the aerosol.
[0088] In another kit aspect of the present invention, a kit for delivering morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil; and, b) a device that forms a morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil aerosol from the composition, for inhalation by the mammal. Preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil.
[0089] Typically, the device contained in the kit comprises: a) an element for heating the morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil composition to form a vapor; b) an element allowing the vapor to cool to form an aerosol; and, c) an element permitting the mammal to inhale the aerosol.
BRIEF DESCRIPTION OF THE FIGURE
[0090] FIG. 1 shows a cross-sectional view of a device used to deliver opioid aerosols to a mammal through an inhalation route.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0091] “Aerodynamic diameter” of a given particle refers to the diameter of a spherical droplet with a density of 1 g/mL (the density of water) that has the same settling velocity as the given particle.
[0092] “Aerosol” refers to a suspension of solid or liquid particles in a gas.
[0093] “Aerosol drug mass density” refers to the mass of opioid per unit volume of aerosol.
[0094] “Aerosol mass density” refers to the mass of particulate matter per unit volume of aerosol.
[0095] “Aerosol particle density” refers to the number of particles per unit volume of aerosol.
[0096] “Amorphous particle” refers to a particle that does not contain more than 50 percent by weight of a crystalline form. Preferably, the particle does not contain more than 25 percent by weight of a crystalline form. More preferably, the particle does not contain more than 10 percent by weight of a crystalline form.
[0097] “Buprenorphine” refers to 17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-α-methyl-6,14-ethanomorphinan-7-methanol.
[0098] “Buprenorphine degradation product” refers to a compound resulting from a chemical modification of buprenorphine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
[0099] “Butorphanol” refers to 17-(cyclobutylmethyl)morphinan-3,14-diol.
[0100] “Butorphanol degradation product” refers to a compound resulting from a chemical modification of butorphanol. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis. An example of a degradation product is a compound of molecular formula C5H8O.
[0101] “Codeine” refers to 7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol.
[0102] “Codeine degradation product” refers to a compound resulting from a chemical modification of codeine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
[0103] “Condensation aerosol” refers to an aerosol formed by vaporization of a substance followed by condensation of the substance into an aerosol.
[0104] “Fentanyl” refers to N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide.
[0105] “Fentanyl degradation product” refers to a compound resulting from a chemical modification of fentanyl. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
[0106] “Hydromorphone” refers to 4,5-epoxy-3-hydroxy-17-methylmorphinan-6-one.
[0107] “Hydromorphone degradation product” refers to a compound resulting from a chemical modification of hydromorphone. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
[0108] “Inhalable aerosol drug mass density” refers to the aerosol drug mass density produced by an inhalation device and delivered into a typical patient tidal volume.
[0109] “Inhalable aerosol mass density” refers to the aerosol mass density produced by an inhalation device and delivered into a typical patient tidal volume.
[0110] “Inhalable aerosol particle density” refers to the aerosol particle density of particles of size between 100 nm and 5 microns produced by an inhalation device and delivered into a typical patient tidal volume.
[0111] “Mass median aerodynamic diameter” or “MMAD” of an aerosol refers to the aerodynamic diameter for which half the particulate mass of the aerosol is contributed by particles with an aerodynamic diameter larger than the MMAD and half by particles with an aerodynamic diameter smaller than the MMAD.
[0112] “Meperidine” refers to 1-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester.
[0113] “Meperidine degradation product” refers to a compound resulting from a chemical modification of meperidine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
[0114] “Methadone” refers to 6-dimethylamino-4,4-diphenyl-3-heptanone.
[0115] “Methadone degradation product” refers to a compound resulting from a chemical modification of methadone. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
[0116] “Morphine” refers to 7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol.
[0117] “Morphine degradation product” refers to a compound resulting from a chemical modification of morphine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
[0118] “Nalbuphine” refers to 17-(cyclobutylmethyl)-4,5-epoxy-morphinan-3,6,14-triol.
[0119] “Nalbuphine degradation product” refers to a compound resulting from a chemical modification of nalbuphine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
[0120] “Naloxone” refers to 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one.
[0121] “Naloxone degradation product” refers to a compound resulting from a chemical modification of naloxone. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
[0122] “Naltrexone” refers to 17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-morphinan-6-one.
[0123] “Naltrexone degradation product” refers to a compound resulting from a chemical modification of naltrexone. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
[0124] “Opioid degradation product” refers to a compound resulting from a chemical modification of an opioid. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
[0125] “Oxycodone” refers to 4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one.
[0126] “Oxycodone degradation product” refers to a compound resulting from a chemical modification of oxycodone. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
[0127] “Pentazocine” refers to 1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol.
[0128] “Pentazocine degradation product” refers to a compound resulting from a chemical modification of pentazocine. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
[0129] “Rate of aerosol formation” refers to the mass of aerosolized particulate matter produced by an inhalation device per unit time.
[0130] “Rate of inhalable aerosol particle formation” refers to the number of particles of size between 100 nm and 5 microns produced by an inhalation device per unit time.
[0131] “Rate of drug aerosol formation” refers to the mass of aerosolized opioid produced by an inhalation device per unit time.
[0132] “Remifentanil” refers to 3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid methyl ester.
[0133] “Remifentanil degradation product” refers to a compound resulting from a chemical modification of remifentanil. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
[0134] “Settling velocity” refers to the terminal velocity of an aerosol particle undergoing gravitational settling in air.
[0135] “Typical patient tidal volume” refers to 1 L for an adult patient and 15 mL/kg for a pediatric patient.
[0136] “Vapor” refers to a gas, and “vapor phase” refers to a gas phase. The term “thermal vapor” refers to a vapor phase, aerosol, or mixture of aerosol-vapor phases, formed preferably by heating.
Formation of Opioid Containing Aerosols
[0137] Any suitable method is used to form the aerosols of the present invention. A preferred method, however, involves heating a composition comprising an opioid to form a vapor, followed by cooling of the vapor such that it condenses to provide an opioid comprising aerosol (condensation aerosol). The composition is heated in one of four forms: as pure active compound (e.g., pure morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil); as a mixture of active compound and a pharmaceutically acceptable excipient; as a salt form of the pure active compound; and, as a mixture of active compound salt form and a pharmaceutically acceptable excipient.
[0138] Salt forms of opioids (e.g., morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil) are either commercially available or are obtained from the corresponding free base using well known methods in the art. A variety of pharmaceutically acceptable salts are suitable for aerosolization. Such salts include, without limitation, the following: hydrochloric acid, hydrobromic acid, acetic acid, maleic acid, formic acid, and fumaric acid salts.
[0139] Pharmaceutically acceptable excipients may be volatile or nonvolatile. Volatile excipients, when heated, are concurrently volatilized, aerosolized and inhaled with the opioid. Classes of such excipients are known in the art and include, without limitation, gaseous, supercritical fluid, liquid and solid solvents. The following is a list of exemplary carriers within the classes: water; terpenes, such as menthol; alcohols, such as ethanol, propylene glycol, glycerol and other similar alcohols; dimethylformamide; dimethylacetamide; wax; supercritical carbon dioxide; dry ice; and mixtures thereof.
[0140] Solid supports on which the composition is heated are of a variety of shapes. Examples of such shapes include, without limitation, cylinders of less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness and virtually any shape permeated by small (e.g., less than 1.0 mm-sized) pores. Preferably, solid supports provide a large surface to volume ratio (e.g., greater than 100 per meter) and a large surface to mass ratio (e.g., greater than 1 cm2per gram).
[0141] A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet of 0.25 mm thickness has a surface to volume ratio of approximately 8,000 per meter. Rolling the sheet into a hollow cylinder of 1 cm diameter produces a support that retains the high surface to mass ratio of the original sheet but has a lower surface to volume ratio (about 400 per meter).
[0142] A number of different materials are used to construct the solid supports. Classes of such materials include, without limitation, metals, inorganic materials, carbonaceous materials and polymers. The following are examples of the material classes: aluminum, silver, gold, stainless steel, copper and tungsten; silica, glass, silicon and alumina; graphite, porous carbons, carbon yams and carbon felts; polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coated variants of materials are used as well.
[0143] Where aluminum is used as a solid support, aluminum foil is a suitable material. Examples of silica, alumina and silicon based materials include amphorous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (an alumina of defined surface area greater than 2 m2/g from Aldrich, St. Louis, Mo.) and a silicon wafer as used in the semiconductor industry. Carbon yarns and felts are available from American Kynol, Inc., New York, N.Y. Chromatography resins such as octadecycl silane chemically bonded to porous silica are exemplary coated variants of silica.
[0144] The heating of the opioid compositions is performed using any suitable method. Examples of methods by which heat can be generated include the following: passage of current through an electrical resistance element; absorption of electromagnetic radiation, such as microwave or laser light; and, exothermic chemical reactions, such as exothermic solvation, hydration of pyrophoric materials and oxidation of combustible materials.
Delivery of Opioid Containing Aerosols
[0145] Opioid containing aerosols of the present invention are delivered to a mammal using an inhalation device. Where the aerosol is a condensation aerosol, the device has at least three elements: an element for heating an opioid containing composition to form a vapor; an element allowing the vapor to cool, thereby providing a condensation aerosol; and, an element permitting the mammal to inhale the aerosol. Various suitable heating methods are described above. The element that allows cooling is, in it simplest form, an inert passageway linking the heating means to the inhalation means. The element permitting inhalation is an aerosol exit portal that forms a connection between the cooling element and the mammal's respiratory system.
[0146] One device used to deliver the opioid containing aerosol is described in reference to FIG. 1. Delivery device 100 has a proximal end 102 and a distal end 104, a heating module 106, a power source 108, and a mouthpiece 110. An opioid composition is deposited on a surface 112 of heating module 106. Upon activation of a user activated switch 114, power source 108 initiates heating of heating module 106 (e.g, through ignition of combustible fuel or passage of current through a resistive heating element). The opioid composition volatilizes due to the heating of heating module 106 and condenses to form a condensation aerosol prior to reaching the mouthpiece 110 at the proximal end of the device 102. Air flow traveling from the device distal end 104 to the mouthpiece 110 carries the condensation aerosol to the mouthpiece 110, where it is inhaled by the mammal.
[0147] Devices, if desired, contain a variety of components to facilitate the delivery of opioid containing aerosols. For instance, the device may include any component known in the art to control the timing of drug aerosolization relative to inhalation (e.g., breath-actuation), to provide feedback to patients on the rate and/or volume of inhalation, to prevent excessive use (i.e., “lock-out” feature), to prevent use by unauthorized individuals, and/or to record dosing histories.
Dosage of Opioid Containing Aerosols
[0148] The dosage amount of an opiod in aerosol form is generally no greater than twice the standard dose of the drug given orally. For instance, morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, and pentazocine, are given at strengths of 15 mg, 15 mg, 25 mg, 0.3 to 0.6 mg, 0.1 to 0.4 mg, 10 mg, 0.4 to 2 mg, 0.5 to 2 mg, 2 to 4 mg, 5 mg, 50 mg, 2.5 to 10 mg, and 30 mg, respectively for the treatment of pain, alcohol addiction and maintenance of opioid addicts. As aerosols, 5 mg to 25 mg of morphine, 5 mg to 25 mg of codeine, 15 mg to 35 mg of naltrexone, 0.1 to 1 mg of buprenorphine, 0.01 to 0.8 mg of fentanyl, 1 to 30 mg of nalbuphine, 0.05 to 3.5 mg of naloxone, 0.1 to 3 mg of butorphanol, 0.1 to 10 mg of hydromorphone, 0.5 to 10 mg of oxycodone, 5 to 100 mg of meperidine, 0.25 to 20 mg of methadone, and 3 to 50 mg of pentazocine are generally provided for the same indications. A typical dosage of an opioid aerosol is either administered as a single inhalation or as a series of inhalations taken within an hour or less (dosage equals sum of inhaled amounts). Where the drug is administered as a series of inhalations, a different amount may be delivered in each inhalation.
[0149] One can determine the appropriate dose of opioid containing aerosols to treat a particular condition using methods such as animal experiments and a dose-finding (Phase I/II) clinical trial. One animal experiment involves measuring plasma concentrations of drug in an animal after its exposure to the aerosol. Mammals such as dogs or primates are typically used in such studies, since their respiratory systems are similar to that of a human. Initial dose levels for testing in humans is generally less than or equal to the dose in the mammal model that resulted in plasma drug levels associated with a therapeutic effect in humans. Dose escalation in humans is then performed, until either an optimal therapeutic response is obtained or a dose-limiting toxicity is encountered.
Analysis of Opioid Containing Aerosols
[0150] Purity of an opioid containing aerosol is determined using a number of methods, examples of which are described in Sekine et al., Journal of Forensic Science32:1271-1280 (1987) and Martin et al., Journal of Analytic Toxicology13:158-162 (1989). One method involves forming the aerosol in a device through which a gas flow (e.g., air flow) is maintained, generally at a rate between 0.4 and 60 L/min. The gas flow carries the aerosol into one or more traps. After isolation from the trap, the aerosol is subjected to an analytical technique, such as gas or liquid chromatography, that permits a determination of composition purity.
[0151] A variety of different traps are used for aerosol collection. The following list contains examples of such traps: filters; glass wool; impingers; solvent traps, such as dry ice-cooled ethanol, methanol, acetone and dichloromethane traps at various pH values; syringes that sample the aerosol; empty, low-pressure (e.g., vacuum) containers into which the aerosol is drawn; and, empty containers that fully surround and enclose the aerosol generating device. Where a solid such as glass wool is used, it is typically extracted with a solvent such as ethanol. The solvent extract is subjected to analysis rather than the solid (i.e., glass wool) itself. Where a syringe or container is used, the container is similarly extracted with a solvent.
[0152] The gas or liquid chromatograph discussed above contains a detection system (i.e., detector). Such detection systems are well known in the art and include, for example, flame ionization, photon absorption and mass spectrometry detectors. An advantage of a mass spectrometry detector is that it can be used to determine the structure of opioid degradation products.
[0153] Particle size distribution of an opioid containing aerosol is determined using any suitable method in the art (e.g., cascade impaction). An Andersen Eight Stage Non-viable Cascade Impactor (Andersen Instruments, Smyrna, Ga.) linked to a furnace tube by a mock throat (USP throat, Andersen Instruments, Smyrna, Ga.) is one system used for cascade impaction studies.
[0154] Inhalable aerosol mass density is determined, for example, by delivering a drug-containing aerosol into a confined chamber via an inhalation device and measuring the mass collected in the chamber. Typically, the aerosol is drawn into the chamber by having a pressure gradient between the device and the chamber, wherein the chamber is at lower pressure than the device. The volume of the chamber should approximate the tidal volume of an inhaling patient.
[0155] Inhalable aerosol drug mass density is determined, for example, by delivering a drug-containing aerosol into a confined chamber via an inhalation device and measuring the amount of active drug compound collected in the chamber. Typically, the aerosol is drawn into the chamber by having a pressure gradient between the device and the chamber, wherein the chamber is at lower pressure than the device. The volume of the chamber should approximate the tidal volume of an inhaling patient. The amount of active drug compound collected in the chamber is determined by extracting the chamber, conducting chromatographic analysis of the extract and comparing the results of the chromatographic analysis to those of a standard containing known amounts of drug.
[0156] Inhalable aerosol particle density is determined, for example, by delivering aerosol phase drug into a confined chamber via an inhalation device and measuring the number of particles of given size collected in the chamber. The number of particles of a given size may be directly measured based on the light-scattering properties of the particles. Alternatively, the number of particles of a given size is determined by measuring the mass of particles within the given size range and calculating the number of particles based on the mass as follows: Total number of particles=Sum (from size range 1 to size range N) of number of particles in each size range. Number of particles in a given size range=Mass in the size range/Mass of a typical particle in the size range. Mass of a typical particle in a given size range=π*D3*φ/6, where D is a typical particle diameter in the size range (generally, the mean boundary MMADs defining the size range) in microns, φ is the particle density (in g/mL) and mass is given in units of picograms (g−12).
[0157] Rate of inhalable aerosol particle formation is determined, for example, by delivering aerosol phase drug into a confined chamber via an inhalation device. The delivery is for a set period of time (e.g., 3 s), and the number of particles of a given size collected in the chamber is determined as outlined above. The rate of particle formation is equal to the number of 100 nm to 5 micron particles collected divided by the duration of the collection time.
[0158] Rate of aerosol formation is determined, for example, by delivering aerosol phase drug into a confined chamber via an inhalation device. The delivery is for a set period of time (e.g., 3 s), and the mass of particulate matter collected is determined by weighing the confined chamber before and after the delivery of the particulate matter. The rate of aerosol formation is equal to the increase in mass in the chamber divided by the duration of the collection time. Alternatively, where a change in mass of the delivery device or component thereof can only occur through release of the aerosol phase particulate matter, the mass of particulate matter may be equated with the mass lost from the device or component during the delivery of the aerosol. In this case, the rate of aerosol formation is equal to the decrease in mass of the device or component during the delivery event divided by the duration of the delivery event.
[0159] Rate of drug aerosol formation is determined, for example, by delivering an opioid containing aerosol into a confined chamber via an inhalation device over a set period of time (e.g., 3 s). Where the aerosol is pure opioid, the amount of drug collected in the chamber is measured as described above. The rate of drug aerosol formation is equal to the amount of opioid collected in the chamber divided by the duration of the collection time. Where the opioid containing aerosol comprises a pharmaceutically acceptable excipient, multiplying the rate of aerosol formation by the percentage of opioid in the aerosol provides the rate of drug aerosol formation.
Utility of Opioid Containing Aerosols
[0160] The morphine, codeine, fentanyl, nalbuphine, butorphanol, hydromorphone, oxycodone, meperidine, pentazocine, remifentanil, or sufentanil containing aerosols of the present invention are typically used to treat pain. Naltrexone and naloxone are typically used to treat alcohol abuse and to provide opioid reversal. Buprenorphine and methadone are typically used in the maintenance of opioid addicts. Other opioids are generally provided for the types of indications listed above.
[0161] The following examples are meant to illustrate, rather than limit, the present invention.
[0162] Morphine sulfate, codeine, naltrexone hydrochloride, buprenorphine hydrochloride, fentanyl citrate, nalbuphine hydrochloride, naloxone hydrochloride, butorphanol tartrate, hydromorphone hydrochloride, oxycodone hydrochloride, meperidine hydrochloride, methadone hydrochloride, and pentazocine are commercially available from Sigma (www.sigma-aldrich.com). Other opioids can be obtained from commercial sources or synthesized using standard methods in the art.
EXAMPLE 1
General Procedure for Obtaining Free Base of a Compound Salt
[0163] Approximately 1 g of salt (e.g., mono hydrochloride) is dissolved in deionized water (˜30 mL). Three equivalents of sodium hydroxide (1 N NaOHaq) is added dropwise to the solution, and the pH is checked to ensure it is basic. The aqueous solution is extracted four times with dichloromethane (˜50 mL), and the extracts are combined, dried (Na2SO4) and filtered. The filtered organic solution is concentrated using a rotary evaporator to provide the desired free base. If necessary, purification of the free base is performed using standard methods such as chromatography or recrystallization.
EXAMPLE 2
General Procedure for Volatilizing Compounds From Halogen Bulb
[0164] A solution of drug in approximately 120 μL dichloromethane is coated on a 3.5 cm×7.5 cm piece of aluminum foil (precleaned with acetone). The dichloromethane is allowed to evaporate. The coated foil is wrapped around a 300 watt halogen tube (Feit Electric Company, Pico Rivera, Calif.), which is inserted into a glass tube sealed at one end with a rubber stopper. Running 90 V of alternating current (driven by line power controlled by a variac) through the bulb for 3.5-5 s affords thermal vapor (including aerosol), which is collected on the glass tube walls. Reverse-phase HPLC analysis with detection by absorption of 225 nm light is used to determine the purity of the aerosol. (When desired, the system is flushed through with argon prior to volatilization.) To obtain higher purity aerosols, one can coat a lesser amount of drug, yielding a thinner film to heat. A linear decrease in film thickness is associated with a linear decrease in impurities.
[0165] The following aerosols were obtained using this procedure: morphine (3.1 mg, 100% purity); codeine (1.01 mg, 100% purity); naltrexone (1 mg, 97.4% purity); buprenorphine (1.1 mg, 98.7% purity); fentanyl (0.13 mg, 100% purity); nalbuphine (0.4 mg, 100% purity); naloxone (1.07 mg, 99.24% purity); and, butorphanol (1.38 mg, 97.2% purity).
EXAMPLE 3
Particle Size, Particle Density, and Rate of Inhalable Particle Formation of Buprenorphine Aerosol
[0166] A solution of 1.5 mg buprenorphine in 100 μL 50/50 mixture of dichloromethane and methyl ethyl ketone was spread out in a thin layer on the central portion of a 3.5 cm×7 cm sheet of aluminum foil. The dichloromethane and methyl ethyl ketone mixture were allowed to evaporate. Assuming a drug density of about 1 g/cc, the calculated thickness of the buprenorphine coating on the 24.5 cm2aluminum solid support, after solvent evaporation, is about 0.6 microns. The aluminum foil was wrapped around a 300 watt halogen tube, which was inserted into a T-shaped glass tube. Both of the openings of the tube were left open and the third opening was connected to a 1 liter, 3-neck glass flask. The glass flask was further connected to a large piston capable of drawing 1.1 liters of air through the flask. Alternating current was run through the halogen bulb by application of 90 V using a variac connected to 110 V line power. Within 1 s, an aerosol appeared and was drawn into the 1 L flask by use of the piston, with collection of the aerosol terminated after 6 s. The aerosol was analyzed by connecting the 1 L flask to an eight-stage Andersen non-viable cascade impactor. Results are shown in table 1. MMAD of the collected aerosol was 1.1 microns with a geometric standard deviation of 4.2. Also shown in table 1 is the number of particles collected on the various stages of the cascade impactor, given by the mass collected on the stage divided by the mass of a typical particle trapped on that stage. The mass of a single particle of diameter D is given by the volume of the particle, πD3/6, multiplied by the density of the drug (taken to be 1 g/cm3). The inhalable aerosol particle density is the sum of the numbers of particles collected on impactor stages 3 to 8 divided by the collection volume of 1 L, giving an inhalable aerosol particle density of 7.2×107particles/mL. The rate of inhalable aerosol particle formation is the sum of the numbers of particles collected on impactor stages 3 through 8 divided by the formation time of 6 s, giving a rate of inhalable aerosol particle formation of 1.2×1010particles/second.
| TABLE 1 |
|---|
| Determination of the characteristics of a buprenorphine |
| condensation aerosol by cascade impaction using an Andersen 8-stage |
| non-viable cascade impactor run at 1 cubic foot per minute air flow. |
EXAMPLE 4
Drug Mass Density and Rate of Drug Aerosol Formation of Buprenorphine Aerosol
[0167] A solution of 1.2 mg buprenorphine in 100 μL 50/50 mixture of dichloromethane and methyl ethyl ketone was spread out in a thin layer on the central portion of a 3.5 cm×7 cm sheet of aluminum foil. The dichloromethane and methyl ethyl ketone were allowed to evaporate. Assuming a drug density of about 1 g/cc, the calculated thickness of the buprenorphine coating on the 24.5 cm2aluminum solid support, after solvent evaporation, is about 0.5 microns. The aluminum foil was wrapped around a 300 watt halogen tube, which was inserted into a T-shaped glass tube. Both of the openings of the tube were left open and the third opening was connected to a 1 liter, 3-neck glass flask. The glass flask was further connected to a large piston capable of drawing 1.1 liters of air through the flask. Alternating current was run through the halogen bulb by application of 90 V using a variac connected to 110 V line power. Within seconds, an aerosol appeared and was drawn into the 1 L flask by use of the piston, with formation of the aerosol terminated after 6 s. The aerosol was allowed to sediment onto the walls of the 1 L flask for approximately 30 minutes. The flask was then extracted with acetonitrile and the extract analyzed by HPLC with detection by light absorption at 225 nm. Comparison with standards containing known amounts of buprenorphine revealed that 0.2 mg of >99% pure buprenorphine had been collected in the flask, resulting in an aerosol drug mass density of 0.2 mg/L. The aluminum foil upon which the buprenorphine had previously been coated was weighed following the experiment. Of the 1.2 mg originally coated on the aluminum, 0.7 mg of the material was found to have aerosolized in the 6 s time period, implying a rate of drug aerosol formation of 0.1 mg/s.
Claims
What is claimed is:
1. A composition for delivery of a therapeutic compound comprising a condensation aerosol
a) formed by volatilizing a therapeutic compound selected from the group consisting of naltrexone, buprenorphine, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, methadone, remifentanil, or sufentanil under conditions effective to produce a heated vapor of the compound and condensing the heated vapor of the compounds to form condensation aerosol particles, and
b) wherein said condensation aerosol particles are characterized by less than 5% compound degradation products and
c) aerosol MMAD less than 3 μm.
2. The composition according to claim 1, wherein said therapeutic compound is in free base form.
3. The composition according to claim 1, wherein the condensation aerosol particles are by less than 2.5 percent by weight of naltrexone, buprenorphine, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, methadone, remifentanil, or sufentanil degradation products.
4. The composition according to claim 1, wherein the condensation aerosol particles comprise at least 90 percent by weight of naltrexone, buprenorphine, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, methadone, remifentanil, or sufentanil.
5. The composition according to claim 4, wherein the aerosol has a mass median aerodynamic diameter less than 2 microns.
6. The composition according to claim 5, wherein the condensation aerosol particles comprise at least 95 percent by weight of naltrexone, buprenorphine, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, methadone, remifentanil, or sufentanil.
7. A method of producing the therapeutic compound naltrexone, buprenorphine, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, methadone, remifentanil, or sufentanil in an aerosol form comprising:
a) volatilizing a therapeutic compound selected from the group consisting of naltrexone, buprenorphine, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, methadone, remifentanil, or sufentanil, under conditions effective to produce a heated vapor of the compound-and,
b) during said volatilizing, passing air through the heated vapor to produce aerosol particles of the compound comprising less than 5% compound degradation products and
c) aerosol MMAD is less than 3 μm.
8. The method according to claim 7, wherein the aerosol particles are formed at a rate of greater than 1 mg/sec.
9. The method according to claim 7, wherein the aerosol has a mass median aerodynamic diameter of less than 2 microns.
10. The method according to claim 7, wherein said volatilizing includes heating a coating which includes the therapeutic compound, which is formed on a solid support having the surface texture of a metal foil, to a temperature sufficient to volatilize the compound from the coating.
11. The method according to claim 10, wherein said solid support comprises aluminum or stainless steel.
12. The method according to claim 11, wherein said solid support has a thickness of 0.25 mm or less.
13. The method according to claim 12, wherein the aerosol particles comprise at least 95 percent by weight of naltrexone, buprenorphine, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, methadone, remifentanil, or sufentanil.
14. The composition according to claim 1, wherein said therapeutic compound is hydromorphone.
15. The composition according to claim 1, wherein said therapeutic compound is remifentanyl or sufentanyl.
16. The composition according to claim 1, wherein said therapeutic compound is buprenorphine, nalbuphine, or butorphanol.
17. The composition according to claim 1, wherein said therapeutic compound is methadone.
18. The composition according to claim 1, wherein said therapeutic compound is naltrexone or naloxone.
19. A composition for delivery of fentanyl comprising a condensation aerosol
a) formed by volatilizing fentanyl under conditions effective to produce a heated vapor of fentanyl, and condensing the heated vapor of fentanyl to form condensation aerosol particles, and
b) wherein said condensation aerosol particles are characterized by less than 2.5% compound degradation products, and
c) aerosol MMAD is less than 3 μm.
20. The composition according to claim 19, wherein said fentanyl is in a freebase form.
21. The composition according to claim 19, wherein the condensation aerosol particles comprise less than 1 percent by weight of fentanyl degradation products.
22. The composition according to claim 19, wherein the condensation aerosol particles comprise at least 90 percent by weight of fentanyl.
23. The composition according to claim 19, wherein the condensation aerosol particles comprise at least 95 percent by weight of fentanyl.
24. A method of producing the therapeutic compound morphine or fentanyl in an aerosol form comprising
a) volatilizing a therapeutic compound selected from the group consisting of morphine or fentanyl under conditions effective to produce a heated vapor of the compound and
b) during said volatilizing, passing air through the heated vapor to produce aerosol particles of the compound comprising less than 2.5% compound degradation products and
c) aerosol MMAD is less than 3 μm.
25. The method according to claim 24, wherein the aerosol particles are formed at a rate greater than 1 mg/sec.
26. The method according to claim 24, wherein said volatilizing includes heating a coating which includes the therapeutic compound, which is formed on a solid support having the surface texture of a metal foil to a temperature sufficient to volatilize the compound from the coating.
27. The method according to claim 26, wherein said solid support comprises aluminum or stainless steel.
28. The method according to claim 27, wherein said solid support has a thickness of 0.25 mm or less.
Patent Citations (53)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| US3393197(A) | 1968-07-01 | Pachter et al. | Applicant |
| USRE30285(E) | 1980-05-01 | Babington | Applicant |
| US5388574(A) | 1995-02-01 | Ingebrethsen | Applicant |
| US5451408(A) | 1995-09-01 | Mezei et al. | Applicant |
| US5543434(A) | 1996-08-01 | Weg | Applicant |
| US5544646(A) | 1996-08-01 | Lloyd et al. | Applicant |
| US5655523(A) | 1997-08-01 | Hodson et al. | Applicant |
| US5694919(A) | 1997-12-01 | Rubsamen et al. | Applicant |
| US5724957(A) | 1998-03-01 | Rubsamen et al. | Applicant |
| US5735263(A) | 1998-04-01 | Rubsamen et al. | Applicant |
| US5758637(A) | 1998-06-01 | Ivri et al. | Applicant |
| US5910301(A) | 1999-06-01 | Farr et al. | Applicant |
| US5915378(A) | 1999-06-01 | Lloyd et al. | Applicant |
| US5934272(A) | 1999-08-01 | Lloyd et al. | Applicant |
| US5957124(A) | 1999-09-01 | Lloyd et al. | Applicant |
| US5960792(A) | 1999-10-01 | Lloyd et al. | Applicant |
| US6041777(A) | 2000-03-01 | Faithfull et al. | Examiner |
| US6095153(A) | 2000-08-01 | Kessler et al. | Applicant |
| US6102036(A) | 2000-08-01 | Slutsky et al. | Applicant |
| US6306431(B1) | 2001-10-01 | Zhang et al. | Applicant |
| US6514482(B1) | 2003-02-01 | Bartus et al. | Examiner |
| US6591839(B2) | 2003-07-01 | Meyer et al. | Applicant |
| US2002/0058009(A1) | 2002-05-01 | Bartus et al. | Applicant |
| US2003/0032638(A1) | 2003-02-01 | Kim et al. | Applicant |
| EP358114 | 1990-03-01 | Applicant | |
| WO90/07333 | 1990-07-01 | Applicant | |
| WO91/07947 | 1991-06-01 | Applicant | |
| WO95/31182 | 1995-11-01 | Applicant | |
| WO96/09846 | 1996-04-01 | Applicant | |
| WO96/13161 | 1996-05-01 | Applicant | |
| WO96/13290 | 1996-05-01 | Applicant | |
| WO96/13291 | 1996-05-01 | Applicant | |
| WO96/13292 | 1996-05-01 | Applicant | |
| WO96/30068 | 1996-10-01 | Applicant | |
| WO97/27804 | 1997-08-01 | Applicant | |
| WO98/22170 | 1998-05-01 | Applicant | |
| WO98/31346 | 1998-07-01 | Applicant | |
| WO98/36651 | 1998-08-01 | Applicant | |
| WO99/16419 | 1999-04-01 | Applicant | |
| WO99/64094 | 1999-12-01 | Applicant | |
| WO/00176 | 2000-01-01 | Applicant | |
| WO/00215 | 2000-01-01 | Applicant | |
| WO/29053 | 2000-05-01 | Applicant | |
| WO/35417 | 2000-06-01 | Applicant | |
| WO/47203 | 2000-09-01 | Applicant | |
| WO/64940 | 2000-11-01 | Applicant | |
| WO/66084 | 2000-11-01 | Applicant | |
| WO/66206 | 2000-11-01 | Applicant | |
| WO/76673 | 2000-12-01 | Applicant | |
| WO1/05459 | 2001-01-01 | Applicant | |
| WO1/17568 | 2001-03-01 | Applicant | |
| WO1/41732 | 2001-06-01 | Applicant | |
| WO2/24158 | 2002-03-01 | Applicant |
Non-Patent Literature (29)
- Bennett, R.L. et al. (1981). “Patient-Controlled Analgesia: A New Concept of Postoperative Pain Relief,” Annual Surg. 195(6):700-705.Applicant
- Campbell, Fiona A. et al. (2001) “Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review,” BMJ, 323 pp. 1-6.Applicant
- Carroll, M.E. et al. (1990), “Cocaine-base smoking in rhesus monkeys: reinforcing and physiological effects,” Psychopharmacology (Berl). 102:443-450.Applicant
- Cichewicz, Diana L. et al. (1999) Enhancement of u Opioid Antinociception by Oral Delta-9-Tetrahydrocannabinol: Dose-Response Analysis and Receptor Identification, The Journal of Pharmacology and Experimental Therapeutics 289(2):859-867.Applicant
- Clark, A. and Byron, P. (1986). “Dependence of Pulmonary Absorption Kinetics on Aerosol Particle Size,” Z. Erkrank. 166:13-24.Applicant
- Darquenne, C. et al. (1997). “Aerosol Dispersion in Human Lung: Comparison Between Numerical Simulations and Experiments for Bolus Tests,” American Physiological Society. 966-974.Applicant
- Davies, C.N. et al. (May 1972). “Breathing of Half-Micron Aerosols,” Journal of Applied Physiology. 32(5):591-600.Applicant
- Dershwitz, M., M.D., et al. (Sep. 2000). “Pharmacokinetics and Pharmacodynamics of Inhaled versus Intravenous Morphine in Healthy Volunteers,” Anesthesiology. 93(3): 619-628.Applicant
- Finlay, W.H. (2001). “The Mechanics of Inhaled Pharmaceutical Aerosols”, Academic Press: San Diego Formula 2.39. pp. 3-14 (Table of Contents). pp. v-viii.Applicant
- Gonda,I. (1991). “Particle Deposition in the Human Respiratory Tract,” Chapter 176, The Lung: Scientific Foundations. Crystal R.G. and West, J.B. (eds.), Raven Publishers, New York. pp. 2289-2294.Applicant
- Graves, D.A. et al. (1983). “Patient-Controlled Analgesia,” Annals of Internal Medicine. 99:360-366.Applicant
- Hatsukami D, et al. (May 1990) “A method for delivery of precise doses of smoked cocaine-base to humans.” Pharmacology Biochemistry & Behavior. 36(1):1-7.Applicant
- Heyder, J. et al. (1986). “Deposition of Particles in the Human Respiratory Tract in the Size Range 0.005-15 μm,” J. Aerosol Sci. 17(5):811-822.Applicant
- Huizer, H., “Analytical studies on illicit heron. V. Efficacy of volatilization during heroin smoking.” Pharmaceutisch Weekblad Scientific Edition (1987). 9(4):203-211.Applicant
- Hurt, R.D., MD and Robertson, C.R., PhD, (Oct. 1998). “Prying Open the Door to the Tobacco Industry's Secrets About Nicotin: The Minnesota Tobacco Trial,” JAMA 280(13):1173-1181.Applicant
- Lichtman, Aron H. et al. (2000) “Pharmacological evaluation of aerosolized cannabinoids in mice,” European Journal of Pharmacology 399:141-149.Applicant
- Martin, B.R. and Lue, L.P. (May/Jun. 1989). “Pyrolysis and Volatilization of Cocaine,” Journal of Analytical Toxicology 13:158-162.Applicant
- Mattox, A.J. and Carroll, M.E., (1996). “Smoked heroin self-administration in rhesus monkeys,” Psychopharmacology, 125:195-201.Applicant
- Meng, Y. et al. Inhalation Studies With Drugs of Abuse, NIDA Research Monograph, (1997) 173:201-224.Applicant
- Meng, Y., et al. (1999). “Pharmacological effects of methamphetamine and other stimulants via inhalation exposure,” Drug and Alcohol Dependence. 53:111-120.Applicant
- Pankow, J.F. et al. (1997). “Conversion of Nicotine in Tobacco Smoke to Its Volatile and Available Free-Base Form Through the Action of Gaseous Ammonia,” Envron. Sci. Technol. 31:2428-2433.Applicant
- Pankow, J. (Mar. 2000). ACS Conference-San Francisco-Mar. 26, 2000. Chemistry of Tobacco Smoke. pp. 1-8.Applicant
- Seeman, J. et al. (1999). “The Form of Nicotine in Tobacco. Thermal Transfer of Nicotine and Nicotine Acid Salts to Nicotine in the Gas Phase,” J. Agric. Food Chem. 47(12):5133-5145.Applicant
- Sekine, H. and Nakahara, Y. (1987). “Abuse of Smoking Methamphetamine Mixed with Tobacco: 1. Inhalation Efficiency and Pyrolysis Products of Methamphetamine,” Journal of Forensic Science 32(5):1271-1280.Applicant
- Vapotronics, Inc. (1998) located at http://www.vapotronics.com.au/banner.htm., 11 pages, (visited on Jun. 5, 2000).Applicant
- Ward, M.E. MD, et al. (Dec. 1997). “Morphine Pharmacokinetics after Pulmonary Administration from a Novel Aerosol Delivery System,” Clinical Pharmacology & Therapeutics 62(6):596-609.Applicant
- Wood, R.W. et al. (1996). “Generation of Stable Test Atmospheres of Cocaine Base and Its Pyrolyzate, Methylecgonidine, and Demonstration of Their Biological Activity.” Pharmacology Biochemistry & Behavior. 55(2):237-248.Applicant
- Lichtman, Aron H., et al., “Inhalation exposure to volatilized opioids produces antinociception in mice,” Journal of Pharmacology and Experimental Therapeutics, vol. 279(1), 1996, pp. 69-76 XP-001118649.Applicant
- Office Action mailed Aug. 13, 2003 for US application 10/153,313 filed May 21, 2002 “Delivery of Benzodiazepines Through an Inhalation Route”.Applicant