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WO2025178942A1 - Compositions, formulations et procédés de stimulation de la respiration - Google Patents

Compositions, formulations et procédés de stimulation de la respiration

Info

Publication number
WO2025178942A1
WO2025178942A1 PCT/US2025/016458 US2025016458W WO2025178942A1 WO 2025178942 A1 WO2025178942 A1 WO 2025178942A1 US 2025016458 W US2025016458 W US 2025016458W WO 2025178942 A1 WO2025178942 A1 WO 2025178942A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
oil
doxapram
minutes
unit dose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/016458
Other languages
English (en)
Inventor
Joseph Michael NOUNOU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Auros Pharma LLC
Original Assignee
Auros Pharma LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US18/637,263 external-priority patent/US20250262218A1/en
Application filed by Auros Pharma LLC filed Critical Auros Pharma LLC
Publication of WO2025178942A1 publication Critical patent/WO2025178942A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant

Definitions

  • Drug overdose is a major social issue that affects all aspects of society.
  • Drug overdose in hospitals caused by opioids can often be treated using naloxone, which is an opioid antagonist.
  • Naloxone can quickly restore normal breathing to a person if their breathing has slowed or stopped because of an opioid overdose.
  • naloxone has little effect on high potency synthetic opiates like IMF (illegally manufactured fentanyl) seen in the community and non-opioid drug overdose, for example, caused by a stimulant such as methamphetamine or benzodiazepines.
  • compositions and methods for the treatment drug overdose caused by opioid, a non-opioid drug, a combination of both, as well as other respiratory arrest conditions at home where immediate access to a ventilator may not be available.
  • the compositions and methods here may be used for patients with respiratory arrest due to cardiopulmonary arrest or chronic obstructive pulmonary disease (COPD) exacerbations, potentially providing temporary respiratory support until respiration is recovered in a hospital setting.
  • COPD chronic obstructive pulmonary disease
  • the disclosure provides pharmaceutical compositions comprising doxapram.
  • the pharmaceutical composition comprises: i) a unit dose of doxapram from about 5 mg to about 600 mg; and ii) a lipid emulsion.
  • the lipid emulsion ranges from about 0.3% to about 3% (wt) of the pharmaceutical composition; optionally, about 1.0% to about 2.0% (wt) of the pharmaceutical composition.
  • the lipid emulsion comprises soybean oil and egg phospholipids; optionally, the pharmaceutical composition or the lipid emulsion further comprises glycerin.
  • the doxapram is at least 20 mg/mL.
  • the disclosure provides pharmaceutical compositions comprising: i) a respiratory stimulant, and ii) a suspension agent.
  • the respiratory stimulant comprises doxapram, nikethamide, pentetrazol. etamivan, bemegride, prethcamide, almitrine, dimefline, mepixanox, or any combination thereof.
  • the respiratory stimulant comprises doxapram.
  • a unit dose of the respiratory stimulant is about 5 mg to about 600 mg; optionally, about 10 to about 600 mg; optionally, about 50 to about 150 mg, optionally, about 100 or 300 mg.
  • a unit dose of the respiratory stimulant ranging from about 0.2 to about 20 mg/kg body weight.
  • the respirator ⁇ ' stimulant is encapsulated in the suspension agent.
  • the suspension agent comprises a phospholipid solution.
  • the suspension agent comprises a lipid emulsion; optionally, wherein the lipid emulsion comprises liposome or micelle.
  • the suspension agent e.g., the lipid emulsion
  • the suspension agent ranges from about 0.1% to about 90% (wt) of the pharmaceutical composition; optionally, from about 0.1% to about 30% (wt) of the pharmaceutical composition; optionally, from about 0.1% to about 10% (wt) of the pharmaceutical composition; optionally, from about 0.1 % to about 5% (wt) of the pharmaceutical composition; optionally, from about 0.1% to about 0.3%, from about 0.3% to about 1%, from about 1% to about 3%, or from about 3% to about 10%, (wt) of the pharmaceutical composition.
  • the suspension agent or the lipid emulsion comprises at least one oil and/or at least one phospholipid; preferably, the suspension agent or the lipid emulsion comprises at least one oil and at least one phospholipid.
  • the at least one oil is selected from the group consisting of soybean oil, olive oil, coconut oil, palm oil, canola oil, sunflower oil, com oil, peanut oil, safflower oil, cottonseed oil, sesame oil, flaxseed oil, walnut oil, avocado oil.
  • the at least one oil comprises soybean oil.
  • the at least one phospholipid is from soybeans, sunflower seeds, rapeseeds, egg yolks, wheat germ, com, peanuts, sesame seeds, rice bran, flaxseeds, pumpkin seeds, cashews, almonds, hazelnuts, pistachios, walnuts, pecans, macadamia nuts, brazil nuts, chia seeds, hemp seeds, poppy seeds, quinoa, oats, barley, rye.
  • the at least one phospholipid comprises egg phospholipids (e.g.. egg yolk phospholipids).
  • the ratio of the at least one oil (e.g., soybean oil) to the at least one phospholipid (e.g., egg phospholipids) is from about 7: 1 to about 13: 1, from about 13: 1 to about 20: 1, or from about 20: 1 to about 30: 1, by weight: optionally, from about 13:1 to about 20:1 by weight.
  • the at least one oil e.g., soybean oil
  • the at least one phospholipid e.g., egg phospholipids
  • the lipid emulsion comprises soybean oil, egg phospholipids, glycerin, or any combination thereof.
  • the respiratory stimulant e.g., doxapram
  • the respiratory stimulant is about 3 mg/mL.
  • the respiratory stimulant e.g., doxapram
  • At least 90%, at least 95%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%, of the doxapram is in (S)-enantiomer form.
  • the respiratory stimulant e.g., doxapram
  • the respiratory stimulant is in a sustained release dosage form.
  • the pharmaceutical composition is for intramuscular, subcutaneous, or transdermal, administration, optionally, for intramuscular administration.
  • the disclosure provides devices comprising at least one container, the at least one container comprising the pharmaceutical composition of the disclosure.
  • the disclosure provides devices comprising: a first container comprising a first pharmaceutical composition, wherein the first pharmaceutical composition comprises a respiratory stimulant and an opioid antagonist; and a second container comprising a second pharmaceutical composition, wherein the second pharmaceutical composition comprises a sustained release dosage form of the respiratory stimulant.
  • the disclosure provides devices comprising: i) a first container comprising a first pharmaceutical composition, wherein the first pharmaceutical composition comprises the respiratory stimulant and an opioid antagonist; and ii) a second container comprising a second pharmaceutical composition of the disclosure.
  • the first pharmaceutical composition comprises a unit dose of the opioid antagonist of about 0.05 mg to about 10 mg and a unit dose of the respiratory stimulant of about 5 mg to about 300 mg, and wherein the second pharmaceutical composition comprises a unit dose of the respiratory stimulant of about 10 mg to about 600 mg.
  • the first pharmaceutical composition comprises a unit dose of the opioid antagonist of about 1 mg to about 3 mg and a unit dose of the respiratory stimulant of about 50 mg to about 150 mg, and wherein the second pharmaceutical composition comprises a unit dose of the respirator ⁇ 7 stimulant of about 100 mg to about 300 mg.
  • the first pharmaceutical composition comprises a unit dose of the opioid antagonist of about 0.01 mg/kg body weight to about 1 mg/kg body weight and a unit dose of the respiratory stimulant of about 0. 1 mg/kg body weight to about 10 mg/kg body weight
  • the second pharmaceutical composition comprises a unit dose of the respiratory stimulant of about 0.2 mg/kg body weight to about 20 mg/kg body w eight.
  • the respiratory stimulant comprises doxapram, nikethamide, pentetrazol, etamivan, bemegride, prethcamide, almitrine, dimefline, or mepixanox.
  • the opioid antagonist comprises naloxone, naltrexone, nalbuphine, butorphanol, pentazocine, diprenorphine, dihydroetorphine, or any combination thereof; optionally, the opioid antagonist comprises naloxone.
  • the first pharmaceutical composition comprises doxapram and naloxone
  • the second pharmaceutical composition comprises doxapram; optionally, the doxapram in the second pharmaceutical composition is in a sustained release dosage form.
  • the first pharmaceutical composition comprises a unit dose of doxapram ranging from about 5 to about 300 mg; optionally, the unit dose of doxapram is about 50 or 150 mg.
  • the first pharmaceutical composition comprises a unit dose of naloxone ranging from about 0.05 to about 10 mg; optionally, the unit dose of naloxone is about 1 or 3 mg.
  • the second pharmaceutical composition comprises a unit dose of doxapram ranging from about 10 to about 600 mg; optionally, wherein the unit dose of doxapram is about 100 or 300 mg.
  • the first pharmaceutical composition comprises a unit dose of doxapram ranging from about 0.1 to about 10 mg/kg body weight.
  • the first pharmaceutical composition comprises a unit dose of naloxone ranging from about 0.01 to about 1 mg/kg body weight.
  • the second pharmaceutical composition comprises a unit dose of doxapram ranging from about 0.2 to about 20 mg/kg body weight.
  • the disclosure provides devices comprising: i) a first container comprising a first pharmaceutical composition, wherein the first pharmaceutical composition comprises doxapram and naloxone; and ii) a second container comprising a second pharmaceutical composition, wherein the second pharmaceutical composition comprises a sustained release dosage form of doxapram and a lipid emulsion, wherein the first pharmaceutical composition comprises a unit dose of naloxone of about 1 mg to about 3 mg and a unit dose of doxapram of about 50 mg to about 150 mg and the second pharmaceutical composition comprises a unit dose of doxapram of about 100 mg to about 300 mg, and wherein the lipid emulsion is about 0.1% to about 30% (wt) of the second pharmaceutical composition.
  • the device is suitable for administering the first and second pharmaceutical compositions.
  • the first and second pharmaceutical compositions are administered using an auto-injector.
  • the device, or the auto-injector is for administering the first pharmaceutical composition and the second pharmaceutical composition sequentially or concurrently.
  • the device or the auto-injector is for intramuscular, subcutaneous, or transdermal, administration.
  • the device further comprises a housing, wherein the first and second containers are located within the housing.
  • the disclosure provides methods for stimulating respiration, comprising administering to a subject in need thereof the pharmaceutical composition of the disclosure, the pharmaceutical composition in the device, or the first and the second pharmaceutical compositions in the device of the disclosure.
  • the method comprises a first pharmaceutical composition and a second first pharmaceutical composition, wherein the first pharmaceutical composition comprises a unit dose of naloxone of about 1 mg to about 3 mg and a unit dose of doxapram of about 50 mg to about 150 mg and the second pharmaceutical composition comprises a unit dose of doxapram of about 100 mg to about 300 mg, and wherein the lipid emulsion is about 0. 1% to about 30% (wt) of the second pharmaceutical composition.
  • the first pharmaceutical composition comprises a unit dose of naloxone of about 0.01 mg/kg body weight to about 1 mg/kg body weight and a unit dose of doxapram of about 0. 1 mg/kg body weight to about 10 mg/kg body weight and the second pharmaceutical composition comprises a unit dose of doxapram of about 0.2 mg/kg body weight to about 20 mg/kg body weight.
  • the doxapram is about 3 mg/mL.
  • the lipid emulsion is at a concentration of about 1.5% (wt) of the pharmaceutical composition, wherein the lipid emulsion is derived from INTRALIPID® 20% formulation (20% soybean oil, 1.2% egg phospholipids, 2.25% glycerin, and water), and wherein the doxapram is either in racemate or (S)-enantiomer form.
  • the device comprises at least one container, the at least one container comprising a pharmaceutical composition comprising a sustained release dosage form of a respiratory stimulant and a lipid emulsion.
  • the at least one container comprises a pharmaceutical composition disclosed herein.
  • the device comprises i) a first container comprising a first pharmaceutical composition, wherein the first pharmaceutical composition comprises the respiratory stimulant and an opioid antagonist; and ii) a second container comprising a second pharmaceutical composition, wherein the second pharmaceutical composition comprises the sustained release dosage form of the respiratory stimulant and the lipid emulsion.
  • the first pharmaceutical composition comprises a unit dose of the opioid antagonist of about 0.01 mg/kg body weight to about 1 mg/kg body w eight and a unit dose of the respiratory' stimulant of about 0.1 mg/kg body w eight to about 10 mg/kg body w eight and the second pharmaceutical composition comprises a unit dose of the respiratory stimulant of about 0.2 mg/kg body weight to about 20 mg/kg body weight.
  • the lipid emulsion encapsulates the respiratory stimulant, and wherein the lipid emulsion ranges from about 0.1% to about 90% (wt) of the second pharmaceutical composition.
  • the lipid emulsion is about 0.1% to about 30% (wt) of the second pharmaceutical composition.
  • the lipid emulsion comprises soybean oil.
  • devices comprising: i) a first container comprising a first pharmaceutical composition, wherein the first pharmaceutical composition comprises doxapram and naloxone; and ii) a second container comprising a second pharmaceutical composition, wherein the second pharmaceutical composition comprises a sustained release dosage form of doxapram and a lipid emulsion, wherein the first pharmaceutical composition comprises a unit dose of naloxone of about 1 mg to about 3 mg and a unit dose of doxapram of about 50 mg to about 150 mg and the second pharmaceutical composition comprises a unit dose of doxapram of about 100 mg to about 300 mg, and wherein the lipid emulsion is about 0.1% to about 30% (wt) of the second pharmaceutical composition.
  • the device is suitable for administering the first and second pharmaceutical compositions.
  • the first and second pharmaceutical compositions are administered using an auto-injector, wherein the administration occurs sequentially or concurrently.
  • a method comprises a first pharmaceutical composition and a second first pharmaceutical composition, wherein the first pharmaceutical composition comprises a unit dose of naloxone of about 1 mg to about 3 mg and a unit dose of doxapram of about 50 mg to about 150 mg and the second pharmaceutical composition comprises a unit dose of doxapram of about 100 mg to about 300 mg, and wherein the lipid emulsion is about 0. 1 % to about 30% (wt) of the second pharmaceutical composition.
  • FIG. 1 shows an exemplary device (e.g., auto-injector) described herein.
  • FIG. 2 shows exemplary pharmacokinetics of doxapram in various concentrations of lipid emulsion (0%, 0.5%, and 1.5%) administered intramuscularly to canines.
  • Blood samples were taken at baseline (0 minutes) and every 5 minutes over the course of 60 minutes to measure concentration (ng/dL) of doxapram.
  • the same three canines (beagles) were assessed at all lipid emulsion concentrations and doxapram concentrations were averaged for each study arm.
  • Lipid emulsion formulation 20% soybean oil, 1.2% egg phospholipids, 2.25% glycerin, and water.
  • the term “about” and its grammatical equivalents in relation to a reference numerical value and its grammatical equivalents as used herein can include a range of values plus or minus 10% from that value, such as a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.
  • the amount “about 10” includes amounts from 9 to 11.
  • drug form refers to a drug formulation which can be prescribed and/or administered to a subject and is meant to include any solid, semi-solid, liquid, suspension, frozen or freeze-dried preparation of a drug, including but not limited to. tablets, minitablets, soft or hard capsules, gel capsules, caplets, granules, pellets, micropellets, beads, powders, sachets, liquids, suspensions and the like.
  • immediate release dosage forms refers to dosage forms that are formulated to release an active drug immediately after administration (e.g., oral or parenteral); no deliberate effort is made to modify the drug release rate in immediate release dosage forms or formulations. Immediate-release products generally result in relatively rapid drug absorption and onset of accompanying pharmacodynamic effects.
  • immediate release dosage forms comprising a therapeutic agent can release at least about 50% of the therapeutic agent within about 5 minutes after the administration.
  • lipid emulsion refers to an emulsion of lipid for pharmaceutical use (e.g.. for human or veterinary use, such as canine).
  • lipid emulsion a commercially available version of lipid emulsion, sold under the trademark INTRALIPIDTM, is an emulsion of soybean oil, egg phospholipids and glycerin.
  • opioid antagonist is a drug which acts to block one or more of the opioid receptors in the central or peripheral nervous system, such as naloxone, naltrexone, nalbuphine, butorphanol, pentazocine, diprenorphine, and dihydroetorphine.
  • pharmaceutically acceptable salt is intended to mean those salts that retain one or more of the biological activities and properties of the free acids and bases and that are not biologically or otherwise undesirable.
  • pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-di oates, hexyne-l,6-dioates, benzoates, chloride, sulfates, pyrosul
  • the pharmaceutical composition of the disclosure comprises a pharmaceutically acceptable salt.
  • the chemical compound names disclosed herein include any pharmaceutically acceptable salt thereof.
  • doxapram refers to the chemical compound l-ethyl-4-(2-morpholinoethyl)-3,3-diphenyl-2-pyrrolidinone (CAS number 309-29-5), as well as its pharmaceutically acceptable salt, e.g., doxapram hydrochloride (1-ethyl- 4-(2-morpholinoethyl)-3,3-diphenyl-2-pyrrolidinone monohydrochloride, monohydrate).
  • naloxone also includes its pharmaceutically acceptable salt, e.g., naloxone hydrochloride.
  • respirator stimulant is a drug which acts to increase the action of the respirator) ⁇ system, such as doxapram, nikethamide, pentetrazol, etamivan, bemegride, prethcamide, almitrine, dimefline, and mepixanox.
  • sustained release refers to a dosage form that (in contrast to immediate-release dosage forms) delivers a drug for a prolonged period of time; it is meant to include any dosage form or formulation which is not an immediate release dosage form or formulation including those described in Chapter 17 of “ Applied Biopharmaceutics and Pharmacokinetics ", Sixth Edition: Shargel et al., which is incorporated herein by reference; thus for the purposes herein, “sustained release” or “SR” dosage forms can be used interchangeably with “extended release” or “ER” dosage forms, or “delayed release” or “DR” dosage forms.
  • a sustained release dosage form can release less than about 50% of a therapeutic agent within about 5 minutes after the administration. In some cases, a sustained release dosage form can release more than about 50% of a therapeutic agent in a time frame from about 5 minutes to about 30 minutes after the administration.
  • compositions and formulations are provided.
  • a respiratory stimulant can increase the action of the respiratory' system.
  • exemplary' respiratory' stimulants include, but are not limited to, doxapram, nikethamide, pentetrazol, etamivan, bemegride, prethcamide, almitrine. dimefline, and mepixanox.
  • a opioid antagonist can block one or more of the opioid receptors in the central or peripheral nervous system.
  • opioid antagonists include, but are not limited to, naloxone, naltrexone, nalbuphine, butorphanol, pentazocine, diprenorphine, and dihydroetorphine.
  • a respiratory stimulant comprises doxapram.
  • doxapram of the disclosure is in racemate.
  • doxapram of the disclosure is in (S)-enantiomer form.
  • at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%, of the doxapram is in (S)- enantiomer form.
  • doxapram stimulates an increase in tidal volume and respiratory rate.
  • doxapram is a white to off-white, odorless, crystalline powder that is stable in light and air.
  • doxapram is soluble in water, sparingly soluble in alcohol and practically insoluble in ether.
  • benzyl alcohol or chlorobutanol is added as a preservative agent in a commercially available form of doxapram.
  • a commercially available form of doxapram has a pH from 3.5-5.
  • a commercially available form of doxapram is in injection form.
  • Doxapram hydrochloride is sold under the trademark DOPRAMTM.
  • Doxapram can stimulate chemoreceptors in the carotid bodies of the carotid arteries, which in turn, stimulates the respirator ⁇ ' center in the brain stem.
  • Doxapram can be used in intensive care settings to stimulate the respiratory rate in patients with respiratory failure.
  • Doxapram can be useful for treating respiratory' depression in patients who have taken excessive doses of drugs such as buprenorphine or fentanyl analogues.
  • Doxapram can be as effective as pethidine in suppressing shivering after surgery.
  • a unit dose of a respiratory stimulant is about 5 mg to about 300 mg.
  • a unit dose of a respirator ⁇ ' stimulant e.g., doxapram
  • a unit dose of a respiratory stimulant is at most about 300 mg.
  • a unit dose of a respiratory stimulant is about 5 mg to about 10 mg.
  • about 5 mg to about 50 mg about 5 mg to about 100 mg, about 5 mg to about 150 mg, about 5 mg to about 200 mg, about 5 mg to about 250 mg, about 5 mg to about 300 mg, about 10 mg to about 50 mg, about 10 mg to about 100 mg, about 10 mg to about 150 mg, about 10 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 300 mg, about 50 mg to about 100 mg, about 50 mg to about 150 mg, about 50 mg to about 200 mg, about 50 mg to about 250 mg, about 50 mg to about 300 mg, about 100 mg to about 150 mg, about 100 mg to about 200 mg, about 100 mg to about 250 mg, about 100 mg to about 300 mg, about 150 mg to about 200 mg, about 150 mg to about 250 mg, about 150 mg to about 300 mg, about 200 mg to about 250 mg, about 200 mg to about 300 mg, or about 250 mg to about 300 mg.
  • a unit dose of a respiratory stimulant is about 5 mg, about 10 mg, about 50 mg, about 100 mg. about 150 mg, about 200 mg, about 250 mg, or about 300 mg. In aspects, a unit dose of a respiratory stimulant (e.g., doxapram) is about 50 mg to about 150 mg.
  • a unit dose of a respiratory stimulant is about 0.1 mg/kg body weight to about 10 mg/kg body weight. In aspects, a unit dose of a respiratory stimulant (e.g., doxapram) is at least about 0. 1 mg/kg body weight. In aspects, a unit dose of a respiratory stimulant (e.g., doxapram) is at most about 10 mg/kg body weight. In aspects, a unit dose of a respiratory stimulant (e.g., doxapram) is about 0. 1 mg/kg body weight to about 0.2 mg/kg body weight, about 0. 1 mg/kg body weight to about 0.5 mg/kg body weight, about 0.
  • Naloxone can be injected intravenously, with an onset of 1-2 minutes and a duration of up to 45 minutes. While the onset is achieved fastest through intravenous administration (IV) than through other routes of administration, it may be difficult to obtain venous access in patients who use IV drugs chronically. This may be an issue under emergency conditions.
  • Naloxone can also be administered via intramuscular or subcutaneous injection. The onset of naloxone provided through this route can be 2 to 5 minutes with a duration of around 30-120 min.
  • Naloxone administered intramuscularly can be provided through pre-filled syringes, vials, and auto-injector (such as ZIMHITM). Naloxone can also be administered intranasally, for example, for people who are unconscious or unresponsive.
  • a unit dose of an opioid antagonist is about 0.01 mg/kg body weight to about 1 mg/kg body weight. In aspects, a unit dose of an opioid antagonist (e.g., naloxone) is at least about 0.01 mg/kg body weight. In aspects, a unit dose of an opioid antagonist (e.g., naloxone) is at most about 1 mg/kg body weight.
  • a unit dose of an opioid antagonist is about 0.01 mg/kg body weight, about 0.05 mg/kg body weight, about 0.1 mg/kg body weight, about 0.5 mg/kg body weight, or about 1 mg/kg body weight.
  • a unit dose of a respiratory stimulant is about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 500 mg, or about 600 mg.
  • a unit dose of a respiratory stimulant is about 100 mg to about 300 mg.
  • a unit dose of a respiratory stimulant is about 0.2 mg/kg body w eight, about 0.5 mg/kg body weight, about 1 mg/kg body weight, about 2 mg/kg body weight, about 5 mg/kg body w eight, about 10 mg/kg body weight, or about 20 mg/kg body weight.
  • a respiratory stimulant e.g., doxapram
  • the concentration of a respiratory- stimulant is about 1 mg/mL to about 20 mg/mL.
  • the concentration of a respiratory stimulant is about 1 mg/mL, 2 mg/mL. 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL. 8 mg/mL, 9 mg/mL, 10 mg/mL, 11 mg/mL, 12 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 1 mg/mL, 17 mg/mL, 18 mg/mL, 19 mg/mL, or at least about 20 mg/mL.
  • the concentration of a respiratory stimulant is at least about 20 mg/mL, at least about 30 mg/mL, at least about 40 mg/mL, at least about 50 mg/mL. at least about 60 mg/mL, at least about 70 mg/mL, at least about 80 mg/mL, at least about 90 mg/mL, or at least about 100 mg/mL.
  • a respiratory stimulant e.g., doxapram
  • the concentration of a respiratory stimulant ranges from about 1 mg/mL to about 2 mg/mL, about 1 mg/mL to about 5 mg/mL, about 1 mg/mL to about 10 mg/mL, about 1 mg/mL to about 15 mg/mL, about 1 mg/mL to about 20 mg/mL, about 1 mg/mL to about 25 mg/mL, about 1 mg/mL to about 30 mg/mL, about 1 mg/mL to about 50 mg/mL, about 1 mg/mL to about 100 mg/mL, about 2 mg/mL to about 5 mg/mL, about 2 mg/mL to about 10 mg/mL, about 2 mg/mL to about 15 mg/mL, about 2 mg/mL to about 20 mg/mL, about 2 mg/mL to about 25 mg/mL, about 2 mg/mL to about 30 mg/mL, about 2 mg/mL to about 50 mg/mL, about 2 mg/mL,
  • the concentration of a respiratory stimulant is about 3 mg/mL. In aspects, the concentration of a respiratory stimulant (e.g., doxapram) is at least about 20 mg/mL. In aspects, the concentration of doxapram is about 3 mg/mL. In aspects, the concentration of doxapram is at least about 20 mg/mL.
  • the second pharmaceutical composition is in a sustained release dosage form.
  • the sustained release dosage form can release at least about 50%, 60%, 70%, 80%, or 90% of the therapeutic agent (e.g.. doxapram) in a time frame from about 5 minutes to about 30 minutes after the administration.
  • the sustained release dosage form can release at least about 50%, 60%, 70%, 80%, or 90% of the therapeutic agent (e.g., doxapram) in a time frame about 5 min to about 10 min, about 5 min to about 15 min, about 5 min to about 20 min, about 5 min to about 25 min.
  • the sustained release dosage form can release at least about 50%, 60%, 70%. 80%. or 90% of the therapeutic agent (e.g., doxapram) in a time frame about 10 min. about 15 min, about 20 min, about 25 min, or about 30 min.
  • the therapeutic agent e.g., doxapram
  • the second pharmaceutical composition comprises about 0.1 % of the suspension agent, about 0.5 % of the suspension agent, about 1 % of the suspension agent, about 10 % of the suspension agent, about 20 % of the suspension agent, about 30 % of the suspension agent, about 60 % of the suspension agent, or about 90 % of the suspension agent.
  • the second pharmaceutical composition comprises about 0.1% to about 30% of the suspension agent.
  • the second pharmaceutical composition comprises about 0.5% of the suspension agent.
  • the percent composition of the suspension agent is by weight (wt) of the second pharmaceutical composition.
  • the percent composition of the suspension agent is by volume (vol) of the second pharmaceutical composition.
  • the suspension agent comprises a phospholipid solution.
  • the suspension agent comprises liposome.
  • the suspension agent comprises micelle.
  • the suspension agent comprises a lipid emulsion (e.g., INTRALIPID®), for example, comprising soybean oil, egg phospholipids, glycerin, or any combination thereof.
  • INTRALIPID® is used for intravenous injection.
  • the INTRALIPID® 20% formulation comprises 20% soybean oil, 1.2% egg phospholipids, 2.25% glycerin, and water.
  • a lipid emulsion comprises soybean oil, egg phospholipids, glycerin, and water.
  • the pharmaceutical composition, the suspension agent, or the lipid emulsion comprises at least one oil and/or at least one phospholipid. In aspects, the pharmaceutical composition, the suspension agent, or the lipid emulsion, comprises at least one oil. In aspects, the pharmaceutical composition, the suspension agent, or the lipid emulsion, comprises at least one phospholipid. In aspects, the pharmaceutical composition, the suspension agent, or the lipid emulsion, comprises at least one oil and at least one phospholipid.
  • the at least one oil is derived from a food product.
  • the at least one oil is selected from the group consisting of soybean oil, olive oil, coconut oil, palm oil, canola oil. sunflower oil, com oil. peanut oil, safflower oil. cottonseed oil, sesame oil.
  • the at least one oil comprises soybean oil.
  • the at least one phospholipid is from soybeans, sunflower seeds, rapeseeds, egg yolks, wheat germ, com, peanuts, sesame seeds, rice bran, flaxseeds, pumpkin seeds, cashews, almonds, hazelnuts, pistachios, walnuts, pecans, macadamia nuts.
  • the at least one phospholipid comprises egg phospholipids.
  • the lipid emulsion comprises soybean oil, egg phospholipids, glycerin, or any combination thereof.
  • the pharmaceutical composition, or the lipid emulsion comprises soybean oil, and egg phospholipids.
  • the pharmaceutical composition, or the lipid emulsion comprises soybean oil. egg phospholipids, and glycerin.
  • drug delivery performance provided by the dosage forms described herein can be evaluated using a standard USP type 2 or USP type 7 dissolution apparatus set to 37° C ⁇ 2° C under the conditions described, for example, in the experimental examples provided herein.
  • the dissolution media may be selected from dissolution media known by those of skill in the art such as at least one of purified water. 0. IN HC1, simulated intestinal fluid, and others.
  • the amount of the unit dose can be about 1 ml, about 2 ml, about 3 ml, about 4 ml, about 5 ml, about 6 ml, about 8 ml, or about 10 ml.
  • the pharmaceutical compositions disclosed herein can comprise one or more pharmaceutically acceptable excipients including, but not limited to, binders, lubricants, glidants, disintegrants, diluents, coloring agents, suspension agents, and flavoring agents.
  • exemplary excipients are described in Remington, The Science and Practice of Pharmacy, 22nd Ed. 2013, which is incorporated herein by reference in its entirety 7 .
  • Other commonly used pharmaceutically acceptable excipients include, but are not limited to, water, magnesium stearate, starch, lactose, microcrystalline cellulose, stearic acid, sucrose, talc, silicon dioxide, gelatin, acacia, and dibasic calcium phosphate (Baldrick, P. (2000) Regul.
  • Excipients can be combined with active ingredients for example to enhance appearance, improve stability, aid processing or aid disintegration after administration.
  • the excipients include, but are not limited to: natural, modified-natural or synthetic mono-, oligo- or polysaccharides, where oligo- and polysaccharides may or may not be physically or chemically crosslinked; natural, modified-natural or synthetic mono-, oligo- and polypeptides or proteins, where oligo- and polypeptides and proteins may or may not be physically or chemically crosslinked; synthetic oligomers and polymers that may or may not be physically or chemically crosslinked; monomeric, hydrophobic, hydrophilic or amphoteric organic molecules; inorganic salts or metals; and combinations thereof.
  • therapeutic agents used herein such as, for example, doxapram and/or naloxone, may be combined with any excipient(s) known in the art that allow tailoring performance during manufacturing, administration and/or its in vitro and in vivo performance.
  • suspension agents are exemplified by, but are not limited to, acacia, agar, alginic acid, bentonite, calcium stearate, carbomers, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carrageenan, cellulose (powdered), ceratonia, colloidal silicon dioxide, dextrin, gelatin, guar gum, hectorite, hydrophobic colloidal silica, hydroxyethyl cellulose, hydroxy ethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, kaolin, magnesium aluminium silicate, maltitol solution, medium-chain triglycerides, methylcellulose, microcrystalline cellulose, phospholipids, polycarbophil, polyethylene glycol, polyoxyethylene sorbitan fatty acid esters,
  • pH adjusting agents may be used in the invention and can include acids, bases and many of the compounds/salts found in U.S. Pat. No. 8,263,650.
  • the pH adjusting agent is an acid, for example, acetic, acetylsalicylic, barbital, barbituric, benzoic, benzyl penicillin, boric, caffeine, carbonic, citric, dichloroacetic, ethylenediaminetetra-acetic acid (EDTA), formic, glycerophosphoric, glycine, lactic, malic, mandelic, monochloroacetic, oxalic, phenobarbital, phenol, picric, propionic, saccharin, salicylic, sodium dihydrogen phosphate, succinic, sulfadiazine, sulfamerazine, sulfapyridine, sulfathiazole, tartaric, trichloroacetic, and the like, or
  • a device disclosed herein can further comprise an auto-injector.
  • the device comprises a bifurcated auto-injector.
  • the auto-injector administers a pharmaceutical composition.
  • the auto-injector administers the first pharmaceutical composition and second pharmaceutical composition.
  • the auto-injector administers the first pharmaceutical composition and second pharmaceutical composition sequentially or concurrently.
  • the auto-injector administers the first pharmaceutical composition and second pharmaceutical composition sequentially.
  • the auto-injector administers the first pharmaceutical composition and second pharmaceutical composition concurrently.
  • the device can further comprise a housing, wherein the first and second containers are located within the housing.
  • the device comprising the auto-injector dispenses a predetermined dose of a medicament.
  • the device comprises a needle cover that is configured to move from a retracted position to an extended locked position.
  • the device comprises a first locking assembly to hold the needle cover in a locked retracted position and a second locking assembly to hold the needle cover in a locked extended position.
  • An exemplary device (e.g., auto-injector) 100 is shown in FIG. 1.
  • the device 100 comprises a first and a second container (e.g., in form of syringe 101), each container equipped with a retracted and/or spring actuated needle 102, a plunger 103, and/or a compressed spring 104.
  • the device 100 comprises a trigger 105.
  • the trigger 105 when the trigger 105 is activated, the compressed spring 104 is released, extending the plunger 103, actuating the needle 102, and pushing the medicament in syringe 101.
  • the medicament in syringe 101 is pushed into a subject in need thereof.
  • the medicament is pushed into a subject in need thereof via intramuscular injection.
  • the medicament is pushed into a subject in need thereof via subcutaneous injection.
  • the medicament is pushed into a subject in need thereof via intravenous injection.
  • the medicament is pushed into a subject in need thereof via intranasal administration.
  • a device can be included in an emergency kit.
  • a device can be incorporated in an algorithm for Advanced Cardiac Life Support (ACLS).
  • ACLS Advanced Cardiac Life Support
  • a device can be used at home.
  • a device can be used at a hospital, an addiction treatment center, a mental health center, an urgent care, and the like.
  • a method for stimulating respiration comprises administering a pharmaceutical composition to a subject in need thereof.
  • a method for stimulating respiration comprises administering a first pharmaceutical composition and a second pharmaceutical composition to a subject in need thereof, wherein the first pharmaceutical composition comprises a respirator ⁇ ' stimulant and an opioid antagonist; and the second pharmaceutical composition comprises a sustained release dosage form of the respiratory stimulant.
  • the subject is a human.
  • the subject is anon-human animal.
  • the non-human animal is a non-human vertebrate, a non-human primate, a cetacean, a mammal, a reptile, a bird, an amphibian, or a fish.
  • the non-human animal is a bovine. In aspects, the non-human animal is a mustelid, a captive mustelid, a rodent, a captive rodent, a raptor, or a captive bird. In aspects, the non-human animal is a canine. In aspects, the non-human animal is a feline.
  • a medicament, a pharmaceutical composition, and/or a formulation of the disclosure is administered.
  • a route for administration of a medicament, a pharmaceutical composition, and/or a formulation of the disclosure may be oral, sublingual, intravenous, nasal, inhalational, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, cutaneous, subcutaneous, transdermal. epidural, systemic, intratrachael, otic, intraocular, or intrathecal route.
  • the administration is via intramuscular injection.
  • the administration is via intramuscular injection.
  • the administration is via intranasal administration.
  • the administration is via subcutaneous injection.
  • the administration is via a device provided herein. In some cases, the device can contain a fixed dose combination of the pharmaceutical compositions. In some cases, the pharmaceutical composition is pre-mixed.
  • a subject in need thereof is administered one dose of a medicament, a pharmaceutical composition, and/or a formulation of the disclosure.
  • a subject in need thereof is administered two or more doses of medicament, a pharmaceutical composition, and/or a formulation of the disclosure.
  • a subject in need thereof is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to about 10 doses of a medicament, a pharmaceutical composition, and/or a formulation of the disclosure.
  • a subject in need thereof is administered about 1 to about 10 doses, about 1 to about 6 doses, about 2 to about 6 doses, about 2 to about 10 doses, about 1 to about 3 doses, or about 1 to about 4 doses of a medicament, a pharmaceutical composition, and/or a formulation of the disclosure.
  • one or more of a dose are administered using a device disclosed herein.
  • a subject in need thereof is administered a medicament, a pharmaceutical composition, and/or a formulation of the disclosure, or a device comprising the same.
  • a subject in need thereof is in need of respiration stimulation and/or displays abnormal respiration.
  • a subject in need thereof is in need of respiration stimulation.
  • a subject in need thereof displays abnormal respiration.
  • the subject has acute respiratory insufficiency superimposed on chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the subject is suffering from cardiopulmonary arrest.
  • the subject has one or more of the following conditions: respiratory depression, sedation, hypotension, adverse central nervous system effects, adverse cardiac effects, fever, chest pain, rapid breathing, labored breathing increased heart rate, increased blood pressure, sweating, convulsions, tremors, rise in body temperature, cardiovascular collapse, anxiety, agitation, and combative behavior, or any combination thereof.
  • a drug overdosage is caused by one or more opioids, for example, morphine, codeine, thebaine, oripavine, diacetylmorphine, 2.4-dinitrophenylmorphine, methylenedioxydimethylamphetamine, ehlomaltrexamine, dihydromorphine, hydromorphinol, nicomorphine, dipropanoylmorphine, desomorphine, acetylproprionylmorphine, methyldesorphine, N-phenethylnormorphine, 14-hydroxy dihydrocodeine (RAM-318), 7, 8- dihydro-14-hydroxy-N-phenethylnormorphme (RAM-378), dibenzoylmorphine, diacetyldihydromorphine, dibenzoylmorphine, 6-monoacetylcodeine (6-MAC), acetyldihydrocodeine, dihydroeodeme, nalbuphine
  • opioids for example
  • chloromorphide ethylmorphine, buprenorphine, fentanyl, alphamethylfentanyl, alfentanil, sufentanil, remifentanil, carfentanyl, ohmefentanyl, pethidine, ketobemidone, desmethylprodine (MPPP), allylprodine, prodine, l-methyl-4-phenyl-4-propionoxypiperidine (PEPAP), propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, levorphanol, methadone, dipipanone, levomethadyl acetate (LAAM), difenoxin, diphenoxylate, loperamide, dezoeine.
  • MPPP desmethylprodine
  • PEPAP allylprodine
  • prodine prodine
  • PEPAP l-methyl-4-phenyl-4-propionoxypiperidine
  • the opioid is oxymorphone. In aspects, the opioid is oxycodone.
  • a drug overdosage is caused by one or more benzodiazepine drugs including, but not limited to, alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam. diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, and loprazolam, and combinations thereof.
  • benzodiazepine drugs including, but not limited to, alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam. diazepam, flumazenil, flurazepam,
  • the drug overdosage can be caused by one or more barbiturate drugs selected from the group consisting of amobarbital, amobarbital sodium, aprobarbital, butabarbital sodium, hexobarbital sodium, mephobarbital, metharbital, methohexital sodium, pentobarbital sodium, phenobarbital, phenobarbital sodium, secobarbital sodium, taibutal, thiamylal sodium, and thiopental sodium, and combinations thereof.
  • barbiturate drugs selected from the group consisting of amobarbital, amobarbital sodium, aprobarbital, butabarbital sodium, hexobarbital sodium, mephobarbital, metharbital, methohexital sodium, pentobarbital sodium, phenobarbital, phenobarbital sodium, secobarbital sodium, taibutal, thiamylal sodium, and thiopental
  • a drug overdosage is caused by one or more insomnia drugs such as a non-benzodiazepine hypnotic, a direct GABA agonist, a positive allosteric modulator of GABA receptors, a histamine receptor antagonist, or a histamine receptor inverse agonist, or combinations thereof.
  • the insomnia drug can be, for example, zolpidem, zopiclone, eszopiclone, zaleplon, gaboxadol, indiplon, or abecamil, or combinations thereof.
  • a subject is assessed.
  • An assessment can occur at any point before, during, or after administration with a pharmaceutical composition (e.g., comprising doxapram).
  • a pharmaceutical composition e.g., comprising doxapram.
  • an assessment is performed before administration.
  • an assessment is performed during administration.
  • an assessment is performed post administration.
  • a subject is assessed by the minute, hourly, daily, weekly, monthly, or yearly.
  • an assessment comprises determining a concentration of a pharmaceutical composition (e.g., comprising doxapram) in a subject in need thereof post administration, or a sample taken therefrom.
  • a pharmaceutical composition e.g., comprising doxapram
  • an assessment comprises a pharmacokinetic (PK) assessment.
  • a sample is a blood sample or a plasma sample, or a combination of both.
  • a suitable assay to measure pharmacokinetics may comprise electrochemiluminescence (ECL) assay, a bead-based assay, a cell-based assay, and combinations thereof.
  • ECL electrochemiluminescence
  • a PK assessment to a pharmaceutical composition can occur about 0 minutes. 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes. 9 minutes, 10 minutes. 11 minutes, 12 minutes, 13 minutes. 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 27 minutes, 28 minutes, 29 minutes, 30 minutes, 31 minutes, 32 minutes, 33 minutes, 34 minutes, 35 minutes, 36 minutes, 37 minutes, 38 minutes, 39 minutes. 40 minutes, 41 minutes, 42 minutes. 43 minutes, 44 minutes, 45 minutes.
  • a PK assessment to a pharmaceutical composition can be assessed about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours. 9 hours, 10 hours, 11 hours, 12 hours, 13 hours. 14 hours. 15 hours. 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or at least about 24 hours post administration.
  • a PK assessment to a pharmaceutical composition can occur about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks. 3 weeks. 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks.
  • a PK assessment to a pharmaceutical composition can occur on about 0 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes and 60 minutes (or 1 hour) post administration.
  • a PK assessment to a pharmaceutical composition e.g., comprising doxapram
  • a PK assessment can occur at any point before, during, or after administration with a pharmaceutical composition (e.g., comprising doxapram).
  • a subject administered a pharmaceutical composition of the disclosure is assessed for Cmax of the pharmaceutical composition.
  • a subject administered a pharmaceutical composition of the disclosure reaches Cmax in less than about 1 minute, 2 minutes, 3 minutes, 4 minutes or 5 minutes.
  • a subject administered a pharmaceutical composition of the disclosure reaches Cmax in about 1 minute to about 180 minutes.
  • a subject administered a pharmaceutical composition of the disclosure reaches Cmax in about 1 minutes, 2 minutes, 3 minutes.
  • a subject administered a pharmaceutical composition of the disclosure reaches Cmax in about 1 minute to about 5 minutes, about 1 minute to about 15 minutes, about 5 minutes to about 15 minutes, about 5 minutes to about 30 minutes, about 15 minutes to about 30 minutes, about 1 minute to about 45 minutes, about 5 minutes to about 45 minutes, about 5 minutes to about 120 minutes, about 5 minutes to about 180 minutes, about 45 minutes to about 180 minutes, about 45 minutes to about 120 minutes, about 5 minutes to about 60 minutes, about 30 minutes to about 60 minutes, about 30 minutes to about 120 minutes, about 60 minutes to about 150 minutes, or about 60 minutes to about 180 minutes.
  • a subject administered a pharmaceutical composition of the disclosure reaches Cmax in about 1 minute to about 5 minutes. In aspects, a subject administered a pharmaceutical composition of the disclosure (e.g., comprising doxapram) reaches Cmax in about 15 minutes to about 30 minutes. In aspects, a subject administered a pharmaceutical composition of the disclosure (e.g., comprising doxapram) reaches Cmax in about 5 minutes to about 45 minutes.
  • a subject administered a pharmaceutical composition of the disclosure reaches Cmax and maintains a plasma concentration of more than about 1%, 2%, 3%, 4%, 5%. 6%, 7%, 8%. 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%,
  • a subject administered a pharmaceutical composition of the disclosure reaches Cmax and maintains a plasma concentration of more than about 1%, 2%, 3%. 4%, 5%, 6%. 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%,
  • a subject administered a pharmaceutical composition of the disclosure reaches Cmax and maintains a plasma concentration of more than about 5% of said Cmax for at least about 1 minute, 2 minutes. 3 minutes, 4 minutes, 5 minutes. 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 1 1 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 27 minutes, 28 minutes, 29 minutes, 30 minutes, 31 minutes. 32 minutes, 33 minutes, 34 minutes. 35 minutes, 36 minutes, 37 minutes.
  • a device comprising: a first container comprising a first pharmaceutical composition, wherein the first pharmaceutical composition comprises a respiratory stimulant and an opioid antagonist; and a second container comprising a second pharmaceutical composition, wherein the second pharmaceutical composition comprises a sustained release dosage form of the respiratory stimulant.
  • the respiratory stimulant comprises doxapram, nikethamide, pentetrazol, etamivan, bemegride, prethcamide, almitrine, dimefline, or mepixanox.
  • the opioid antagonist comprises naloxone, naltrexone, nalbuphine, butorphanol, pentazocine, diprenorphine, or dihydroetorphine.
  • the second pharmaceutical composition comprises a unit dose of doxapram ranging from about 0.2 to about 20 mg/kg body weight.
  • lipid emulsion comprises soybean oil, egg phospholipids, glycerin, or any combination thereof.
  • [00130] 23 The device of embodiment 22, wherein the auto-injector is suitable for administering the first and second pharmaceutical compositions sequentially or concurrently.
  • 24 The device of embodiment any one of embodiments 1-23, further comprising a housing, wherein the first and second containers are located within the housing.
  • 25 A method for stimulating respiration, comprising administering a first pharmaceutical composition and a second pharmaceutical composition to a subject in need thereof, wherein the first pharmaceutical composition comprises a respirators’ stimulant and an opioid antagonist; and the second pharmaceutical composition comprises a sustained release dosage form of the respiratory’ stimulant.
  • respiratory stimulant comprises doxapram, nikethamide, pentetrazol, etamivan, bemegride, prethcamide, almitrine, dimefline, or mepixanox.
  • opioid antagonist comprises naloxone, naltrexone, nalbuphine, butorphanol, pentazocine, diprenorphine, or dihydroetorphine.
  • lipid emulsion comprises soy bean oil, egg phospholipids, glycerin, or any combination thereof.
  • a pharmaceutical composition comprising doxapram and naloxone, wherein the pharmaceutical composition comprises a unit dose of doxapram ranging from about 5 to about 300 mg and a unit dose of naloxone ranging from about 0.05 to about 10 mg.
  • [00162] 55 The pharmaceutical composition of embodiment 54, wherein the unit dose of doxapram is about 50 or 150 mg.
  • [00163] 56 The pharmaceutical composition of any one of embodiments 54-55, wherein the unit dose of naloxone is about 1 or 3 mg.
  • a pharmaceutical composition wherein the pharmaceutical composition comprises a sustained release dosage form of doxapram comprising a lipid emulsion.
  • the unit dose of doxapram is about 10 to about 600 mg.
  • [00171] 64 The pharmaceutical composition of any one of embodiments 59-63, wherein the lipid emulsion comprises liposome or micelle.
  • lipid emulsion comprises soy bean oil, egg phospholipids, glycerin, or any combination thereof.
  • [00173] 66 A method for stimulating respiration, comprising administering the pharmaceutical composition of any one of embodiments 54-65 to a subject in need thereof. [00174] 67. The method of embodiment 66, wherein the subject has drug-induced postanesthesia respiratory 7 depression or apnea.
  • [00175] 68 The method of embodiment 66, wherein the subject has respiratory or central nervous system depression due to drug overdosage.
  • a pharmaceutical composition comprising doxapram, wherein the pharmaceutical composition comprises: i) a unit dose of doxapram from about 5 mg to about 600 mg; and ii) a lipid emulsion.
  • composition of embodiment 2, wherein the lipid emulsion comprises soy bean oil, egg phospholipids, glycerin, or any combination thereof.
  • lipid emulsion is at a concentration of about 1.5% (wt) of the pharmaceutical composition, wherein the lipid emulsion comprises 20% soybean oil, 1.2% egg phospholipids, 2.25% glycerin, and water, and wherein the doxapram is either in racemate or (S)-enantiomer form.
  • a device comprising at least one container, the at least one container comprising a pharmaceutical composition comprising a sustained release dosage form of a respiratory stimulant and a lipid emulsion.
  • the device of embodiment 8, comprising: i) a first container comprising a first pharmaceutical composition, wherein the first pharmaceutical composition comprises the respiratory stimulant and an opioid antagonist; and ii) a second container comprising a second pharmaceutical composition, wherein the second pharmaceutical composition comprises the sustained release dosage form of the respiratory stimulant and the lipid emulsion.
  • the first pharmaceutical composition comprises a unit dose of the opioid antagonist of about 0.05 mg to about 10 mg and a unit dose of the respiratory stimulant of about 5 mg to about 300 mg and the second pharmaceutical composition comprises a unit dose of the respiratory stimulant of about 10 mg to about 600 mg.
  • the first pharmaceutical composition comprises a unit dose of the opioid antagonist of about 1 mg to about 3 mg and a unit dose of the respiratory stimulant of about 50 mg to about 150 mg and the second pharmaceutical composition comprises a unit dose of the respiratory stimulant of about 100 mg to about 300 mg.
  • the first pharmaceutical composition comprises a unit dose of the opioid antagonist of about 0.01 mg/kg body weight to about 1 mg/kg body weight and a unit dose of the respiratory stimulant of about 0. 1 mg/kg body weight to about 10 mg/kg body weight and the second pharmaceutical composition comprises a unit dose of the respiratory stimulant of about 0.2 mg/kg body weight to about 20 mg/kg body weight.
  • lipid emulsion comprises soybean oil, egg phospholipids, glycerin, or any combination thereof.
  • the respiratory stimulant comprises doxapram, nikethamide, pentetrazol. etamivan, bemegride, prethcamide, almitrine, dimefline, or mepixanox and wherein the opioid antagonist compnses naloxone, naltrexone, nalbuphine, butorphanol, pentazocine, diprenorphine, or dihydroetorphine.
  • a device comprising: i) a first container comprising a first pharmaceutical composition, wherein the first pharmaceutical composition comprises doxapram and naloxone; and ii) a second container comprising a second pharmaceutical composition, wherein the second pharmaceutical composition comprises a sustained release dosage form of doxapram and a lipid emulsion, wherein the first pharmaceutical composition comprises a unit dose of naloxone of about 1 mg to about 3 mg and a unit dose of doxapram of about 50 mg to about 150 mg and the second pharmaceutical composition comprises a unit dose of doxapram of about 100 mg to about 300 mg, and wherein the lipid emulsion is about 0.1% to about 30% (wt) of the second pharmaceutical composition.
  • a method for stimulating respiration comprising administering a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises: i) a unit dose of doxapram from about 5 mg to about 600 mg; and ii) a lipid emulsion.
  • the lipid emulsion comprises soy bean oil, egg phospholipids, glycerin, or any combination thereof.
  • [00204] 27 The method of embodiment 22, comprising a first pharmaceutical composition and a second first pharmaceutical composition, wherein the first pharmaceutical composition comprises a unit dose of naloxone of about 1 mg to about 3 mg and a unit dose of doxapram of about 50 mg to about 150 mg and the second pharmaceutical composition comprises a unit dose of doxapram of about 100 mg to about 300 mg, and wherein the lipid emulsion is about 0.1% to about 30% (wt) of the second pharmaceutical composition.
  • the first pharmaceutical composition comprises a unit dose of naloxone of about 0.01 mg/kg body weight to about 1 mg/kg body weight and a unit dose of doxapram of about 0. 1 mg/kg body weight to about 10 mg/kg body weight and the second pharmaceutical composition comprises a unit dose of doxapram of about 0.2 mg/kg body weight to about 20 mg/kg body weight.
  • a pharmaceutical composition comprising doxapram. wherein the pharmaceutical composition comprises: i) a unit dose of doxapram from about 5 mg to about 600 mg; and ii) a lipid emulsion.
  • Embodiment 2 The pharmaceutical composition of Embodiment 1, wherein the lipid emulsion ranges from about 0.3% to about 3% (wt) of the pharmaceutical composition; optionally, about 1.0% to about 2.0% (wt) of the pharmaceutical composition.
  • Embodiment 3 The pharmaceutical composition of Embodiment 2, wherein the lipid emulsion comprises soybean oil and egg phospholipids; optionally, the pharmaceutical composition or the lipid emulsion further comprises glycerin.
  • Embodiment 4 The pharmaceutical composition of Embodiment 3, wherein the doxapram is at least 20 mg/mL. [00212] 5.
  • a pharmaceutical composition comprising: i) a respiratory stimulant, and ii) a suspension agent.
  • respirator ⁇ ' stimulant comprises doxapram, nikethamide, pentetrazol, etamivan, bemegride, prethcamide, almitrine, dimefline, mepixanox, or any combination thereof.
  • a unit dose of the respiratory stimulant is about 5 mg to about 600 mg; optionally, about 10 to about 600 mg; optionally, about 50 to about 150 mg, optionally, about 100 or 300 mg.
  • the suspension agent e.g., the lipid emulsion
  • the suspension agent ranges from about 0.1% to about 90% (wt) of the pharmaceutical composition; optionally, from about 0.1% to about 30% (wt) of the pharmaceutical composition; optionally, from about 0.1% to about 10% (wt) of the pharmaceutical composition; optionally, from about 0.1% to about 5% (wt) of the pharmaceutical composition; optionally, from about 0.1% to about 0.3%, from about 0.3% to about 1%, from about 1% to about 3%, or from about 3% to about 10%, (wt) of the pharmaceutical composition.
  • the suspension agent e.g., the lipid emulsion
  • the pharmaceutical composition of Embodiment 13, wherein the suspension agent e.g., the lipid emulsion ranges from about 0.3% to about 2.0% (wt), or about 0.5% to about 1.5% (wt) of the pharmaceutical composition; optionally, about 0.5% (wt) or about 1.5% (wt) of the pharmaceutical composition.
  • the suspension agent e.g., the lipid emulsion
  • the suspension agent or the lipid emulsion comprises at least one oil and/or at least one phospholipid; preferably, the suspension agent or the lipid emulsion comprises at least one oil and at least one phospholipid.
  • the at least one oil is selected from the group consisting of soybean oil, olive oil, coconut oil, palm oil.
  • canola oil sunflower oil, com oil, peanut oil, safflower oil, cottonseed oil, sesame oil, flaxseed oil, walnut oil, avocado oil, rice bran oil, grapeseed oil, almond oil, hazelnut oil, macadamia nut oil, pumpkin seed oil, hemp seed oil, camelina oil, mustard oil, pistachio oil, pecan oil, poppy seed oil, black seed oil, apricot kernel oil.
  • cherry kernel oil peach kernel oil, tamanu oil, borage oil, evening primrose oil, sea buckthorn oil, peri Ila oil, moringa oil, neem oil, karanja oil, jojoba oil, tung oil, camellia oil, tea seed oil, babassu oil, murumuru oil, safflower oil, fish oil, and any combination thereof.
  • the at least one phospholipid is from soybeans, sunflower seeds, rapeseeds, egg yolks, wheat germ, com, peanuts, sesame seeds, rice bran, flaxseeds, pumpkin seeds, cashews, almonds, hazelnuts, pistachios, walnuts, pecans, macadamia nuts, brazil nuts, chia seeds, hemp seeds, poppy seeds, quinoa, oats, barley, rye, millet, sorghum, buckwheat, amaranth, avocado, olives, cocoa beans, coconut, milk, butter, cheese, yogurt, beef liver, chicken liver, fish roe, mackerel, salmon, sardines, herring, anchovies, trout, halibut, tuna, egg whites, or any combination thereof.
  • the at least one phospholipid is from soybeans, sunflower seeds, rapeseeds, egg yolks, wheat germ, com, peanuts, sesame seeds, rice
  • a device comprising at least one container, the at least one container comprising the pharmaceutical composition of any one of Embodiments 1-28.
  • a device comprising: a first container comprising a first pharmaceutical composition, wherein the first pharmaceutical composition comprises a respiratory stimulant and an opioid antagonist; and a second container comprising a second pharmaceutical composition, wherein the second pharmaceutical composition comprises a sustained release dosage form of the respiratory stimulant.
  • a device comprising: i) a first container comprising a first pharmaceutical composition, wherein the first pharmaceutical composition comprises the respiratory stimulant and an opioid antagonist; and ii) a second container comprising a second pharmaceutical composition according to any one of Embodiments 1-28.
  • [00240] 33 The device of Embodiment 30 or 31, wherein the first pharmaceutical composition comprises a unit dose of the opioid antagonist of about 1 mg to about 3 mg and a unit dose of the respiratory stimulant of about 50 mg to about 150 mg, and wherein the second pharmaceutical composition comprises a unit dose of the respiratory stimulant of about 100 mg to about 300 mg.
  • 34 The device of Embodiment 30 or 31, wherein the first pharmaceutical composition comprises a unit dose of the opioid antagonist of about 0.01 mg/kg body weight to about 1 mg/kg body weight and a unit dose of the respiratory stimulant of about 0. 1 mg/kg body weight to about 10 mg/kg body weight, and wherein the second pharmaceutical composition comprises a unit dose of the respiratory 7 stimulant of about 0.2 mg/kg body weight to about 20 mg/kg body weight.
  • the opioid antagonist comprises naloxone, naltrexone, nalbuphine, butorphanol, pentazocine, diprenorphine. dihydroetorphine, or any combination thereof; optionally, the opioid antagonist comprises naloxone.
  • the first pharmaceutical composition comprises a unit dose of doxapram ranging from about 5 to about 300 mg; optionally, the unit dose of doxapram is about 50 or 150 mg.
  • the first pharmaceutical composition comprises a unit dose of naloxone ranging from about 0.05 to about 10 mg; optionally, the unit dose of naloxone is about 1 or 3 mg.
  • the second pharmaceutical composition comprises a unit dose of doxapram ranging from about 10 to about 600 mg; optionally, wherein the unit dose of doxapram is about 100 or 300 mg.
  • a device comprising: i) a first container comprising a first pharmaceutical composition, wherein the first pharmaceutical composition comprises doxapram and naloxone; and ii) a second container comprising a second pharmaceutical composition, wherein the second pharmaceutical composition comprises a sustained release dosage form of doxapram and a lipid emulsion, wherein the first pharmaceutical composition comprises a unit dose of naloxone of about 1 mg to about 3 mg and a unit dose of doxapram of about 50 mg to about 150 mg and the second pharmaceutical composition comprises a unit dose of doxapram of about 100 mg to about 300 mg, and wherein the lipid emulsion is about 0. 1% to about 30% (wt) of the second pharmaceutical composition.
  • a method for stimulating respiration comprising administering to a subject in need thereof the pharmaceutical composition of any one of Embodiments 1-28, or the pharmaceutical composition in the device of Embodiment 29, or the first and the second pharmaceutical compositions in the device of any one of Embodiments 30-49.
  • Embodiments 50-54 comprising a first pharmaceutical composition and a second first pharmaceutical composition
  • the first pharmaceutical composition comprises a unit dose of naloxone of about 1 mg to about 3 mg and a unit dose of doxapram of about 50 mg to about 150 mg
  • the second pharmaceutical composition comprises a unit dose of doxapram of about 100 mg to about 300 mg
  • the lipid emulsion is about 0.1% to about 30% (wt) of the second pharmaceutical composition.
  • the first pharmaceutical composition comprises a unit dose of naloxone of about 0.01 mg/kg body weight to about 1 mg/kg body weight and a unit dose of doxapram of about 0. 1 mg/kg body weight to about 10 mg/kg body weight and the second pharmaceutical composition comprises a unit dose of doxapram of about 0.2 mg/kg body weight to about 20 mg/kg body weight.
  • the wax paper was used to transfer the substrate to a test-tube containing 1 ml of room temperature distilled water and was mildly agitated to increase the rate of dissolution.
  • doxapram For adult dosages, 150 mg of doxapram and 3 mg of Naloxone is used in 3 mL aqueous solution.
  • 50 mg of doxapram and 1 mg of Naloxone is used in a 1 mL aqueous solution.
  • Example 2 preparation of the second pharmaceutical composition (doxapram sustained release dosage form)
  • doxapram sustained release dosage form doxapram sustained release dosage form
  • a lipid emulsion at a concentration of 0.5 wt%.
  • the lipid emulsion can be a sterile fat emulsion comprising 20% soybean oil, 1.2% egg yolk phospholipids, 2.25% glycerin, and water.
  • Sodium hydroxide can be added to adjust the pH of the lipid emulsion to about 8.0.
  • the wax paper was used to transfer the substrate to a test-tube containing 9.75 ml of room temperature distilled water and was mildly agitated to increase the rate of dissolution.
  • Example 3 Effect of lipid on doxapram rate of absorption in canines after intramuscular injection
  • Doxapram (3 mg/kg) was injected intramuscularly.
  • steps 1-9 were repeated, except the doxapram injection included the addition of a 20% lipid emulsion so that the final concentration of lipid was 0.5%.
  • steps 1-9 were repeated, except the doxapram injection included the addition of a 20% lipid emulsion so that the final concentration of lipid was 1.5%.
  • Table 1 provides a summary of the three study arms.

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Abstract

L'invention concerne des dispositifs, des compositions et des procédés pour stimuler la respiration à l'aide d'un stimulant respiratoire et/ou d'un antagoniste d'opioïde.
PCT/US2025/016458 2024-02-20 2025-02-19 Compositions, formulations et procédés de stimulation de la respiration Pending WO2025178942A1 (fr)

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US18/637,263 US20250262218A1 (en) 2024-02-20 2024-04-16 Compositions, formulations and methods for stimulating respiration

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0974364A1 (fr) * 1996-10-25 2000-01-26 Yoshitomi Pharmaceutical Industries, Ltd. Procede pour empecher la precipitation de medicaments
WO2007061529A1 (fr) * 2005-11-18 2007-05-31 Scidose Llc. Procede de lyophilisation et produits obtenus selon ledit procede
US8263650B2 (en) 1998-12-23 2012-09-11 Jazz Pharmaceuticals, Inc. Microbiologically sound and stable solutions of gamma-hydroxybutyrate salt for the treatment of narcolepsy
US20120270848A1 (en) * 2010-10-22 2012-10-25 Galleon Pharmaceuticals, Inc. Novel Compositions and Therapeutic Methods Using Same
WO2020236975A1 (fr) * 2019-05-22 2020-11-26 Pergolizzi Joseph V Méthodes et compositions pharmaceutiques pour traiter une surdose de médicament
WO2021174116A1 (fr) * 2020-02-27 2021-09-02 Torralva Medical Therapeutics Llc Procédés pour prévenir et renverser les effets d'une surdose d'opiacés et d'opioïdes

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0974364A1 (fr) * 1996-10-25 2000-01-26 Yoshitomi Pharmaceutical Industries, Ltd. Procede pour empecher la precipitation de medicaments
US8263650B2 (en) 1998-12-23 2012-09-11 Jazz Pharmaceuticals, Inc. Microbiologically sound and stable solutions of gamma-hydroxybutyrate salt for the treatment of narcolepsy
WO2007061529A1 (fr) * 2005-11-18 2007-05-31 Scidose Llc. Procede de lyophilisation et produits obtenus selon ledit procede
US20120270848A1 (en) * 2010-10-22 2012-10-25 Galleon Pharmaceuticals, Inc. Novel Compositions and Therapeutic Methods Using Same
WO2020236975A1 (fr) * 2019-05-22 2020-11-26 Pergolizzi Joseph V Méthodes et compositions pharmaceutiques pour traiter une surdose de médicament
WO2021174116A1 (fr) * 2020-02-27 2021-09-02 Torralva Medical Therapeutics Llc Procédés pour prévenir et renverser les effets d'une surdose d'opiacés et d'opioïdes

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BALDRICK, P., REGUL. TOXICOL. PHARMACOL., vol. 32, no. 2, 2000, pages 210
P. STAHL: "Handbook of Pharmaceutical Salts: Properties, Selection and Use", 4 August 2008, JOHN WILEY & SONS
REMINGTON, THE SCIENCE AND PRACTICE OF PHARMACY, no. 465-65-6, 2013

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