WO2002094234A1 - Delivery of opioids through an inhalation route - Google Patents
Delivery of opioids through an inhalation route Download PDFInfo
- Publication number
- WO2002094234A1 WO2002094234A1 PCT/US2002/016099 US0216099W WO02094234A1 WO 2002094234 A1 WO2002094234 A1 WO 2002094234A1 US 0216099 W US0216099 W US 0216099W WO 02094234 A1 WO02094234 A1 WO 02094234A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- aerosol
- percent
- particles
- weight
- naltrexone
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/423—Oxazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/49—Cinchonan derivatives, e.g. quinine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F24—HEATING; RANGES; VENTILATING
- F24V—COLLECTION, PRODUCTION OR USE OF HEAT NOT OTHERWISE PROVIDED FOR
- F24V30/00—Apparatus or devices using heat produced by exothermal chemical reactions other than combustion
Definitions
- 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.
- compositions contain at least one active ingredient that provides for observed therapeutic effects.
- active ingredients given in such opioid compositions are morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, and sufentanil.
- 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.
- 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.
- the opioid is not morphine or heroin.
- the aerosol has a mass of at least 1 ⁇ g.
- the aerosol has a mass of at least 10 ⁇ g. More preferably, the aerosol has a mass of at least 20 ⁇ g.
- the particles comprise less than 10 percent by weight of opioid degradation products.
- 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,
- the particles comprise less than 90 percent by weight of water.
- 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,
- 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.
- 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.
- the aerosol has an inhalable aerosol particle density greater than
- the aerosol has an inhalable aerosol particle density greater than 10 particles/mL or 10 particles/mL.
- the aerosol particles have a mass median aerodynamic diameter of less than 5 microns.
- 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).
- 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.
- 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.
- 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.
- 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.
- the aerosol has a mass of at least 1 ⁇ g.
- the aerosol has a mass of at least 10 ⁇ g. More preferably, the aerosol has a mass of at least 20 ⁇ g.
- 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.
- 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.
- 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.
- the particles comprise less than 90 percent by weight of water.
- 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.
- the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 25 mg/L.
- 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.
- the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 25 mg/L.
- 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.
- the aerosol comprises naltrexone
- the aerosol has an inhalable aerosol drug mass density of between 15 mg/L and 35 mg/L.
- 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.
- the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 1 mg/L.
- 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.
- the aerosol has an inhalable aerosol drug mass density of between 0.01 mg L and 0.8 mg/L.
- 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.
- the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 30 mg/L.
- 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.
- the aerosol has an inhalable aerosol drug mass density of between 0.05 mg/L and 3.5 mg/L.
- 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
- the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 3 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.15 mg/L and 2.75 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 2.5 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 10 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 7.5 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.4 mg/L and 5 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 10 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.75 mg/L and 0.8 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 0.6 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 100 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 7.5 mg/L and 80 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 60 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.25 mg/L and 20 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 17.5 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.75 mg/L and 15 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 3 mg/L and 50 mg/L.
- 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
- the aerosol has an inhalable aerosol particle density greater than
- the aerosol has an inhalable aerosol particle density greater than 10 7 particles/mL or 10 8 particles/mL.
- the aerosol particles have a mass median aerodynamic diameter of less than 5 microns.
- 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).
- 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.
- 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.
- 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.
- the opioid is not morphine or heroin.
- the particles comprise at least 5 percent by weight of an opioid.
- 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.
- the aerosol has a mass of at least 1 ⁇ g.
- the aerosol has a mass of at least 10 ⁇ g. More preferably, the aerosol has a mass of at least 20 ⁇ g.
- the particles comprise less than 10 percent by weight of opioid degradation products.
- 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
- the particles comprise less than 90 percent by weight of water.
- 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,
- 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.
- 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.
- the particles of the delivered condensation aerosol have a mass median aerodynamic diameter of less than 5 microns.
- 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).
- the delivered aerosol has an inhalable aerosol particle density greater than 10 6 particles/mL.
- the aerosol has an inhalable aerosol particle density greater than 10 7 particles/mL or 10 8 particles/mL.
- the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 10 particles per second.
- the aerosol is formed at a rate greater than 10 9 inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 10 10 inhalable particles per second.
- the delivered condensation aerosol is formed at a rate greater than
- the aerosol is formed at a rate greater than 0.75 mg/second.
- the aerosol is formed at a rate greater than 1 mg/second, 1.5 mg/second or
- the delivered condensation aerosol results in a peak plasma concentration of an opioid in the mammal in less than 1 h.
- 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).
- 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.
- 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.
- 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, bupreno hine, fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil.
- 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.
- 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,
- the aerosol has a mass of at least 1 ⁇ g.
- the aerosol has a mass of at least 10 ⁇ g. More preferably, the aerosol has a mass of at least 20 ⁇ g.
- 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.
- 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.
- 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.
- the particles comprise less than 90 percent by weight of water.
- 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,
- 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.
- 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.
- the particles of the delivered condensation aerosol have a mass median aerodynamic diameter of less than 5 microns.
- 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).
- the delivered aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 25 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 7.5 mg/L and 22.5 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 20 mg/L.
- the delivered aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 25 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 7.5 mg/L and 22.5 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 20 mg/L.
- the delivered aerosol has an inhalable aerosol drug mass density of between 15 mg/L and 35 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 17.5 mg/L and 32.5 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 20 mg/L and 30 mg/L.
- the delivered aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 1 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.15 mg/L and 0.8 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 0.6 mg/L.
- the delivered aerosol has an inhalable aerosol drug mass density of between 0.01 mg/L and 0.8 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.02 mg/L and 0.6 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.3 mg/L and 0.4 mg/L.
- the delivered aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 30 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 27.5 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 25 mg/L.
- the delivered aerosol has an inhalable aerosol drug mass density of between 0.05 mg/L and 3.5 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 3 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 2.5 mg/L.
- the delivered aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 3 mg/L.
- 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
- the delivered aerosol has an inhalable aerosol drag mass density of between 0.1 mg/L and 10 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and
- the aerosol has an inhalable aerosol drug mass density of between 0.4 mg/L and 5 mg/L.
- the delivered aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 10 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.75 mg/L and 0.8 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 0.6 mg/L.
- the delivered aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 100 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 7.5 mg/L and 80 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 10 mg/L and 60 mg/L.
- the delivered aerosol has an inhalable aerosol drug mass density of between 0.25 mg/L and 20 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 17.5 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 0.75 mg/L and 15 mg/L.
- the delivered aerosol has an inhalable aerosol drug mass density of between 3 mg/L and 50 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 45 mg/L.
- the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 40 mg/L.
- the delivered aerosol has an inhalable aerosol particle density greater than 10 6 particles/mL.
- the aerosol has an inhalable aerosol particle density greater than 10 7 particles/mL or 10 8 particles/mL.
- the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 10 8 particles per second.
- the aerosol is formed at a rate greater than 10 9 inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 10 10 inhalable particles per second.
- the delivered condensation aerosol is formed at a rate greater than
- the aerosol is formed at a rate greater than 0.75 mg/second.
- the aerosol is formed at a rate greater than 1 mg/second, 1.5 mg/second or
- the condensation aerosol comprises morphine
- between 5 mg and 25 mg of morphine are delivered to the mammal in a single inspiration.
- the condensation aerosol comprises codeine
- between 5 mg and 25 mg of codeine are delivered to the mammal in a single inspiration.
- condensation aerosol comprises naltrexone
- between 15 mg and 35 mg of naltrexone are delivered to the mammal in a single inspiration.
- naltrexone 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.
- the condensation aerosol comprises buprenorphine
- between 0.1 mg and 1 mg of buprenorphine are delivered to the mammal in a single inspiration.
- the condensation aerosol comprises fentanyl
- between 0.01 mg and 0.8 mg of fentanyl are delivered to the mammal in a single inspiration.
- condensation aerosol comprises nalbuphine
- between 1 mg and 30 mg of nalbuphine are delivered to the mammal in a single inspiration.
- nalbuphine 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.
- condensation aerosol comprises naloxone
- 0.05 mg and 3.5 mg of naloxone are delivered to the mammal in a single inspiration.
- naloxone 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.
- condensation aerosol comprises butorphanol
- 0.1 mg and 3 mg of butorphanol are delivered to the mammal in a single inspiration.
- 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.
- the condensation aerosol comprises hydromorphone
- between 0.1 mg and 10 mg of hydromorphone are delivered to the mammal in a single inspiration.
- 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.
- condensation aerosol comprises oxycodone
- 0.5 mg and 10 mg of oxycodone are delivered to the mammal in a single inspiration.
- 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.
- the condensation aerosol comprises meperidine
- between 5 mg and 100 mg of meperidine are delivered to the mammal in a single inspiration.
- 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.
- condensation aerosol comprises methadone
- methadone 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.
- condensation aerosol comprises pentazocine
- pentazocine 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.
- 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.
- 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).
- kits for delivering an opioid through an inhalation route to a mammal 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.
- 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.
- 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.
- kits 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 which comprises: a) a composition comprising at least 5 percent by weight of morphine, codeine, naltrexone, bupreno ⁇ hine, fentanyl, nalbuphine, naloxone, butorphanol, hydromo ⁇ hone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil; and, b) a device that forms a mo ⁇ hine, codeine, naltrexone, bupreno ⁇ hin
- 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 mo ⁇ hine, codeine, naltrexone, bupreno ⁇ hine, fentanyl, nalbuphine, naloxone, buto ⁇ hanol, hydromo ⁇ hone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil.
- the device contained in the kit comprises: a) an element for heating the mo ⁇ hine, codeine, naltrexone, bupreno ⁇ hine, fentanyl, nalbuphine, naloxone, buto ⁇ hanol, hydromo ⁇ hone, 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.
- FIG. 1 shows a cross-sectional view of a device used to deliver opioid aerosols to a mammal through an inhalation route.
- 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.
- Alcohol refers to a suspension of solid or liquid particles in a gas.
- Alcohol drug mass density refers to the mass of opioid per unit volume of aerosol.
- Aerosol mass density refers to the mass of particulate matter per unit volume of aerosol.
- Aerosol particle density refers to the number of particles per unit volume of aerosol.
- Amo ⁇ hous 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
- the particle does not contain more than 10 percent by weight of a crystalline form.
- Bindreno ⁇ hine refers to 17-(cyclopropylmethyl)- ⁇ -( 1 , 1 -dimethylethyl)-
- Boreno ⁇ hine degradation product refers to a compound resulting from a chemical modification of bupreno ⁇ hine.
- the modification for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
- buto ⁇ hanol refers to 17-(cyclobutylmethyl)mo ⁇ hinan-3 , 14-diol.
- buto ⁇ hanol degradation product refers to a compound resulting from a chemical modification of buto ⁇ hanol.
- 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 C 5 H 8 O.
- Codeine refers to 7,8-didehydro-4,5-epoxy-3-methoxy-l 7- methylmo ⁇ hinan-6-ol.
- 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.
- Condensation aerosol refers to an aerosol formed by vaporization of a substance followed by condensation of the substance into an aerosol.
- Fentanyl refers to N-phenyl-N-[l -(2-phenylethyl)-4- piperidinyl]propanamide.
- 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.
- Haldromo ⁇ hone refers to 4,5-epoxy-3-hydroxy-17-methylmo ⁇ hinan-6- one.
- Hydromo ⁇ hone degradation product refers to a compound resulting from a chemical modification of hydromo ⁇ hone.
- the modification for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
- 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.
- Inhalable aerosol mass density refers to the aerosol mass density produced by an inhalation device and delivered into a typical patient tidal volume.
- Inhalable aerosol particle density refers to the aerosol particle density of particles of size between 100 rim and 5 microns produced by an inhalation device and delivered into a typical patient tidal volume.
- 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.
- Meperidine refers to l-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester.
- 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.
- Methodhadone refers to 6-dimethylamino-4,4-diphenyl-3-heptanone.
- Metalhadone 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.
- Mo ⁇ hine refers to 7,8-didehydro-4,5-epoxy-17-methylmo ⁇ hinan-3,6- diol.
- Mo ⁇ hine degradation product refers to a compound resulting from a chemical modification of mo ⁇ hine.
- the modification for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.
- Nealbuphine refers to 17-(cyclobutylmethyl)-4,5-epoxy-mo ⁇ hinan-3,6, 14- triol.
- Nealbuphine 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.
- Naloxone refers to 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)mo ⁇ hinan-
- 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.
- Naltrexone refers to 17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy- mo ⁇ hinan-6-one.
- 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.
- Oxycodone refers to 4,5-epoxy-14-hydroxy-3-methoxy-17- methylmo ⁇ hin.m-6-one.
- 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.
- Pentazocine refers to l,2,3,4,5,6-hexahydro-6,l l-dimethyl-3-(3-methyl-2- butenyl)-2,6-methano-3-benzazocin-8-ol.
- 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.
- Rate of aerosol formation refers to the mass of aerosolized particulate matter produced by an inhalation device per unit time.
- 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.
- Rateate of drug aerosol formation refers to the mass of aerosolized opioid produced by an inhalation device per unit time.
- Remifentanil refers to 3-[4-methoxycarbonyl-4-[(l- oxopropyl)phenylamino]-l-piperidine]propanoic acid methyl ester.
- 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.
- Settling velocity refers to the terminal velocity of an aerosol particle undergoing gravitational settling in air.
- Typical patient tidal volume refers to 1 L for an adult patient and 15 mL/kg for a pediatric patient.
- Vapor refers to a gas
- vapor phase refers to a gas phase
- thermal vapor refers to a vapor phase, aerosol, or mixture of aerosol-vapor phases, formed preferably by heating. Formation of Opioid Containing Aerosols
- any suitable method is used to form the aerosols of the present invention.
- a preferred method 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).
- composition is heated in one of four forms: as pure active compound (e.g., pure mo ⁇ hine, codeine, naltrexone, bupreno ⁇ hine, fentanyl, nalbuphine, naloxone, buto ⁇ hanol, hydromo ⁇ hone, 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.
- pure active compound e.g., pure mo ⁇ hine, codeine, naltrexone, bupreno ⁇ hine, fentanyl, nalbuphine, naloxone, buto ⁇ hanol, hydromo ⁇ hone, oxycodone, meperidine, methadone, pentazocine, remifentanil,
- Salt forms of opioids are either commercially available or are obtained from the corresponding free base using well known methods in the art.
- opioids e.g., mo ⁇ hine, codeine, naltrexone, bupreno ⁇ hine, fentanyl, nalbuphine, naloxone, buto ⁇ hanol, hydromo ⁇ hone, oxycodone, meperidine, methadone, pentazocine, remifentanil, or sufentanil
- Such salts include, without limitation, the following: hydrochloric acid, hydrobromic acid, acetic acid, maleic acid, formic acid, and fumaric acid salts.
- compositions 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.
- 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
- 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 cm 2 per gram).
- a solid support of one shape can also be transformed into another shape with different properties.
- 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).
- 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.
- aluminum foil is a suitable material.
- 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 m 2 /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, NY. Chromatography resins such as octadecycl silane chemically bonded to porous silica are exemplary coated variants of silica.
- the heating of the opioid compositions is performed using any suitable method.
- methods by which heat can be generated include the following: passage of current through an electrical resistance element; abso ⁇ tion 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.
- Opioid containing aerosols of the present invention are delivered to a mammal using an inhalation device.
- 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.
- an 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.
- 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.
- 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.
- Devices contain a variety of components to facilitate the delivery of opioid containing aerosols.
- 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.
- the dosage amount of an opiod in aerosol form is generally no greater than twice the standard dose of the drug given orally.
- mo ⁇ hine, codeine, naltrexone, bupreno ⁇ hine, fentanyl, nalbuphine, naloxone, buto ⁇ hanol, hydromo ⁇ hone, 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,
- 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.
- 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 drag 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.
- 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 Science 32:1271-1280 (1987) and Martin et al, Journal of Analytic Toxicology 13:158-162 (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.
- the aerosol is subjected to an analytical technique, such as gas or liquid chromatography, that permits a determination of composition purity.
- 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.
- a solid such as glass wool
- 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.
- the container is similarly extracted with a solvent.
- the gas or liquid chromatograph discussed above contains a detection system (i.e., detector).
- detection systems are well known in the art and include, for example, flame ionization, photon abso ⁇ tion 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.
- 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.
- Inhalable aerosol mass density is determined, for example, by delivering a drag-containing aerosol into a confined chamber via an inhalation device and measuring the mass collected in the chamber.
- 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.
- 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.
- 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.
- 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.
- Number of particles in a given size range Mass in the size range/Mass of a typical particle in the size range.
- Rate of inhalable aerosol particle formation is determined, for example, by delivering aerosol phase drag 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.
- 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.
- the mass of particulate matter may be equated with the mass lost from the device or component during the delivery of the aerosol.
- 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.
- Rate of drag 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 drag 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.
- the mo ⁇ hine, codeine, fentanyl, nalbuphine, buto ⁇ hanol, hydromo ⁇ hone, 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.
- Bupreno ⁇ hine and methadone are typically used in the maintenance of opioid addicts.
- Other opioids are generally provided for the types of indications listed above.
- Mo ⁇ hine sulfate, codeine, naltrexone hydrochloride, bupreno ⁇ hine hydrochloride, fentanyl citrate, nalbuphine hydrochloride, naloxone hydrochloride, buto ⁇ hanol tartrate, hydromo ⁇ hone 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.
- salt e.g., mono hydrochloride
- deionized water -30 mL
- Three equivalents of sodium hydroxide (I N NaOH aq ) 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 (Na 2 SO ) 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.
- a solution of 1.5 mg bupreno ⁇ hine in 100 ⁇ L 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 x 7 cm sheet of aluminum foil.
- the dichloromethane and methyl ethyl ketone mixture were allowed to evaporate.
- 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.
- 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, ⁇ D 3 /6, multiplied by the density of the drug (taken to be 1 g/cm 3 ).
- 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 x 10 7 particles/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 x 10 10 particles/second.
- Table 1 Determination of the characteristics of a bupreno ⁇ hine condensation aerosol by cascade impaction using an Andersen 8-stage non- viable cascade impactor run at 1 cubic foot per minute air flow.
- a solution of 1.2 mg bupreno ⁇ hine in 100 ⁇ L 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 x 7 cm sheet of aluminum foil.
- the dichloromethane and methyl ethyl ketone were allowed to evaporate.
- 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.
- 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 abso ⁇ tion at 225 nm.
- Comparison with standards containing known amounts of bupreno ⁇ hine revealed that 0.2 mg of > 99%) pure bupreno ⁇ hine had been collected in the flask, resulting in an aerosol drag mass density of 0.2 mg/L.
- the aluminum foil upon which the bupreno ⁇ hine 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.
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ529421A NZ529421A (en) | 2001-05-24 | 2002-05-21 | Delivery of opioids through an inhalation route |
DK02731894T DK1389096T3 (en) | 2001-05-24 | 2002-05-21 | Administration of opiates through an inhalation route |
PCT/US2002/016099 WO2002094234A1 (en) | 2001-05-24 | 2002-05-21 | Delivery of opioids through an inhalation route |
CA002446916A CA2446916C (en) | 2001-05-24 | 2002-05-21 | Delivery of opioids through an inhalation route |
EP02731894A EP1389096B9 (en) | 2001-05-24 | 2002-05-21 | Delivery of opioids through an inhalation route |
DE60231611T DE60231611D1 (en) | 2001-05-24 | 2002-05-21 | ADMINISTRATION OF OPIOIDES BY INHALATION |
AU2002303833A AU2002303833B2 (en) | 2001-05-24 | 2002-05-21 | Delivery of opioids through an inhalation route |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US29420301P | 2001-05-24 | 2001-05-24 | |
US60/294,203 | 2001-05-24 | ||
US31747901P | 2001-09-05 | 2001-09-05 | |
US60/317,479 | 2001-09-05 | ||
PCT/US2002/016099 WO2002094234A1 (en) | 2001-05-24 | 2002-05-21 | Delivery of opioids through an inhalation route |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002094234A1 true WO2002094234A1 (en) | 2002-11-28 |
Family
ID=27761269
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2002/016099 WO2002094234A1 (en) | 2001-05-24 | 2002-05-21 | Delivery of opioids through an inhalation route |
Country Status (3)
Country | Link |
---|---|
DE (1) | DE60231611D1 (en) |
DK (1) | DK1389096T3 (en) |
WO (1) | WO2002094234A1 (en) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004043428A2 (en) * | 2002-08-29 | 2004-05-27 | Novadel Pharma Inc. | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
GB2403711A (en) * | 2003-07-07 | 2005-01-12 | Gw Pharma Ltd | Drug dispenser with controlled access |
WO2005061033A1 (en) * | 2003-12-15 | 2005-07-07 | Alexza Pharmaceuticals, Inc. | Treatment of breakthrough pain by drug aerosol inhalation |
WO2008080170A1 (en) * | 2006-12-22 | 2008-07-03 | Alexza Pharmaceuticals, Inc. | Mixed drug aerosol compositiions |
CN103728403A (en) * | 2013-08-30 | 2014-04-16 | 宜昌人福药业有限责任公司 | Method for detecting relevant substance in hydrochloric acid remifentanil active ingredient |
US8955512B2 (en) | 2001-06-05 | 2015-02-17 | Alexza Pharmaceuticals, Inc. | Method of forming an aerosol for inhalation delivery |
US8991387B2 (en) | 2003-05-21 | 2015-03-31 | Alexza Pharmaceuticals, Inc. | Self-contained heating unit and drug-supply unit employing same |
US9078816B2 (en) | 1997-10-01 | 2015-07-14 | Suda Ltd. | Buccal, polar and non-polar spray containing ondansetron |
US11083850B2 (en) | 2018-08-21 | 2021-08-10 | Vivera Pharmaceuticals Inc. | Secure smart dosing system with automated delivery, measurement, and management |
US11090449B2 (en) | 2018-08-21 | 2021-08-17 | Vivera Pharmaceuticals Inc. | Smart inhaler device with automated dose delivery, measurement, and management |
US11311460B1 (en) | 2018-08-08 | 2022-04-26 | Telemedicine Health, Inc. | Method and apparatus of secure storage for dispensing of opioids (SSDO) |
US11642473B2 (en) | 2007-03-09 | 2023-05-09 | Alexza Pharmaceuticals, Inc. | Heating unit for use in a drug delivery device |
US11854680B1 (en) | 2018-08-08 | 2023-12-26 | Telemedicine Health, Inc. | Narcotics and opioids secure storage and dispensing apparatus and method of use |
US11862303B1 (en) | 2018-04-19 | 2024-01-02 | Telemedicine Health, Inc. | Collection of digital health hubs with artificial intelligence |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998031346A1 (en) * | 1997-01-16 | 1998-07-23 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
WO2000035417A1 (en) * | 1998-12-11 | 2000-06-22 | Pharmachemie B.V. | Pharmaceutical preparation for inhalation of an opioid |
WO2002024158A2 (en) * | 2000-09-19 | 2002-03-28 | Advanced Inhalation Research, Inc. | Pulmonary delivery in treating disorders of the central nervous system |
-
2002
- 2002-05-21 DE DE60231611T patent/DE60231611D1/en not_active Expired - Lifetime
- 2002-05-21 WO PCT/US2002/016099 patent/WO2002094234A1/en not_active Application Discontinuation
- 2002-05-21 DK DK02731894T patent/DK1389096T3/en active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998031346A1 (en) * | 1997-01-16 | 1998-07-23 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
WO2000035417A1 (en) * | 1998-12-11 | 2000-06-22 | Pharmachemie B.V. | Pharmaceutical preparation for inhalation of an opioid |
WO2002024158A2 (en) * | 2000-09-19 | 2002-03-28 | Advanced Inhalation Research, Inc. | Pulmonary delivery in treating disorders of the central nervous system |
Non-Patent Citations (1)
Title |
---|
LICHTMAN, A.H.; MENG, Y.; MARTIN B.R.: "Inhalation exposure to volatilized opioids produces antinociception in mice", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 279, no. 1, 1996, pages 69 - 76, XP001118649 * |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9078816B2 (en) | 1997-10-01 | 2015-07-14 | Suda Ltd. | Buccal, polar and non-polar spray containing ondansetron |
US11065400B2 (en) | 2001-06-05 | 2021-07-20 | Alexza Pharmaceuticals, Inc. | Aerosol forming device for use in inhalation therapy |
US9687487B2 (en) | 2001-06-05 | 2017-06-27 | Alexza Pharmaceuticals, Inc. | Aerosol forming device for use in inhalation therapy |
US8955512B2 (en) | 2001-06-05 | 2015-02-17 | Alexza Pharmaceuticals, Inc. | Method of forming an aerosol for inhalation delivery |
US9439907B2 (en) | 2001-06-05 | 2016-09-13 | Alexza Pharmaceutical, Inc. | Method of forming an aerosol for inhalation delivery |
US9308208B2 (en) | 2001-06-05 | 2016-04-12 | Alexza Pharmaceuticals, Inc. | Aerosol generating method and device |
WO2004043428A3 (en) * | 2002-08-29 | 2004-10-21 | Novadel Pharma Inc | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
WO2004043428A2 (en) * | 2002-08-29 | 2004-05-27 | Novadel Pharma Inc. | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
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 |
GB2403711A (en) * | 2003-07-07 | 2005-01-12 | Gw Pharma Ltd | Drug dispenser with controlled access |
WO2005061033A1 (en) * | 2003-12-15 | 2005-07-07 | Alexza Pharmaceuticals, Inc. | Treatment of breakthrough pain by drug aerosol inhalation |
WO2008080170A1 (en) * | 2006-12-22 | 2008-07-03 | Alexza Pharmaceuticals, Inc. | Mixed drug aerosol compositiions |
US11642473B2 (en) | 2007-03-09 | 2023-05-09 | Alexza Pharmaceuticals, Inc. | Heating unit for use in a drug delivery device |
CN103728403A (en) * | 2013-08-30 | 2014-04-16 | 宜昌人福药业有限责任公司 | Method for detecting relevant substance in hydrochloric acid remifentanil active ingredient |
CN103728403B (en) * | 2013-08-30 | 2015-10-07 | 宜昌人福药业有限责任公司 | The detection method of related substance in a kind of remifentanil hydrochloride bulk drug |
US11862303B1 (en) | 2018-04-19 | 2024-01-02 | Telemedicine Health, Inc. | Collection of digital health hubs with artificial intelligence |
US11311460B1 (en) | 2018-08-08 | 2022-04-26 | Telemedicine Health, Inc. | Method and apparatus of secure storage for dispensing of opioids (SSDO) |
US11854680B1 (en) | 2018-08-08 | 2023-12-26 | Telemedicine Health, Inc. | Narcotics and opioids secure storage and dispensing apparatus and method of use |
US11083850B2 (en) | 2018-08-21 | 2021-08-10 | Vivera Pharmaceuticals Inc. | Secure smart dosing system with automated delivery, measurement, and management |
US11090449B2 (en) | 2018-08-21 | 2021-08-17 | Vivera Pharmaceuticals Inc. | Smart inhaler device with automated dose delivery, measurement, and management |
Also Published As
Publication number | Publication date |
---|---|
DK1389096T3 (en) | 2009-06-22 |
DE60231611D1 (en) | 2009-04-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7169378B2 (en) | Delivery of opioids through an inhalation route | |
AU2002303833A1 (en) | Delivery of opioids through an inhalation route | |
WO2002094234A1 (en) | Delivery of opioids through an inhalation route | |
WO2002094233A1 (en) | Delivery of antiemetics through an inhalation route | |
AU2008200911B2 (en) | Delivery of opioids through an inhalation route | |
WO2002094216A2 (en) | Delivery of stimulants through an inhalation route | |
WO2002094231A1 (en) | Delivery of analgesics through an inhalation route | |
WO2002094229A1 (en) | Delivery of muscle relaxants through an inhalation route | |
WO2002094235A1 (en) | Delivery of compounds for the treatment of parkinsons through an inhalation route | |
WO2002094240A1 (en) | Delivery of physiologically active compounds through an inhalation route | |
WO2002094239A1 (en) | Delivery of diphenhydramine through an inhalation route |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG UZ VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2002303833 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 529421 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2446916 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002731894 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2002731894 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
NENP | Non-entry into the national phase |
Ref country code: JP |
|
WWW | Wipo information: withdrawn in national office |
Country of ref document: JP |
|
ENP | Entry into the national phase |
Ref document number: 2002303833 Country of ref document: AU Date of ref document: 20020521 Kind code of ref document: B |