WO2018034920A1 - Pulvérisation de naloxone liquide - Google Patents

Pulvérisation de naloxone liquide Download PDF

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Publication number
WO2018034920A1
WO2018034920A1 PCT/US2017/046198 US2017046198W WO2018034920A1 WO 2018034920 A1 WO2018034920 A1 WO 2018034920A1 US 2017046198 W US2017046198 W US 2017046198W WO 2018034920 A1 WO2018034920 A1 WO 2018034920A1
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WO
WIPO (PCT)
Prior art keywords
formulation
formulations
naloxone
liquid spray
contain
Prior art date
Application number
PCT/US2017/046198
Other languages
English (en)
Inventor
Kiran AMANCHA
Shivani CHILAMPALLI
Thrimoorthy Potta
Ningxin YAN
Venkat R. Goskonda
Original Assignee
Insys Development Company, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US15/238,909 external-priority patent/US10722510B2/en
Priority claimed from US15/601,331 external-priority patent/US10617686B2/en
Application filed by Insys Development Company, Inc. filed Critical Insys Development Company, Inc.
Priority to CA3033897A priority Critical patent/CA3033897C/fr
Priority to CN201780063967.6A priority patent/CN109922805A/zh
Priority to AU2017312811A priority patent/AU2017312811B2/en
Priority to EP17841883.6A priority patent/EP3500261A4/fr
Priority to JP2019508941A priority patent/JP7114570B2/ja
Publication of WO2018034920A1 publication Critical patent/WO2018034920A1/fr
Priority to JP2022081328A priority patent/JP7455157B2/ja

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Classifications

    • 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
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K9/0043—Nose
    • 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
    • A61K9/08—Solutions

Definitions

  • the invention is directed to liquid spray formulations containing naloxone, a pharmaceutically acceptable salt thereof, or a derivative thereof.
  • the invention is further directed to methods of treating opioid dependence, opioid overdose, and congenital insensitivity to pain with anhidrosis by administering liquid spray formulations containing naloxone, pharmaceutically acceptable salts thereof, or derivatives thereof to a patient in need thereof.
  • Naloxone has the followin structure and is synthesized from thebaine:
  • Naloxone is most commonly used to treat patients suffering from opioid dependence or overdose because it is a competitive ⁇ -opioid antagonist that blocks the effects of opioids, Naloxone is currently available in Suboxone ® (Suboxone is a registered trademark of Reckitt Benckiser Healthcare (UK) Limited) as tablet or sublingual film strip formulations.
  • Suboxone ® contains buprenorphine and naloxone in a 4: 1 ratio
  • Naloxone is also available as an aqueous nasal spray under the trademark Narcan® (Narcan is a registered trademark of Adapt Pharma Operations Limited LLC, "Adapt Pharma”), which contains 4.42% w/w naloxone hydrochloride dihydrate, 0.01% w/w benzalkonium chloride ("B C") as a preservative, 0.74% w/w sodium chloride as an isotonicity agent and 0,2 % w/w edetate disodium dihydrate (“EDTA”) as a stabilizing agent.
  • Narcan® Narcan is a registered trademark of Adapt Pharma Operations Limited LLC, "Adapt Pharma”
  • B C benzalkonium chloride
  • EDTA % w/w edetate disodium dihydrate
  • Adapt Pharma has U.S. Patent Nos.
  • Naloxone has also been used as a treatment for cognitive insensitivity to pain with anhidrosis.
  • Insensitivity to pain with cognitive anhidrosis is a disorder in which the patient cannot feel pain.
  • Naloxone may be administered orally, intravenously, by injection or via the nasal mucosa.
  • Naloxone has a low mean serum half-life when administered parentally. The quick metabolism may require repeat, dosing or cause patient discomfort between doses, Enteral administration has low bioavailability due to hepatic first pass metabolism,
  • liquid spray formulations of the present invention are for intranasal and/or sublingual administrate on.
  • the invention is directed to liquid spray formulations comprising an effective amount of naloxone, a pharmaceutically acceptable salt thereof, or a derivative thereof, water, and a chelating agent, wherein the formulation does not contain an isotonicity agent or a buffer.
  • the stable liquid spray formulations of the present invention are suitable for intranasal administration.
  • liquid spray formulations of the present invention do not contain an isotonicity agent
  • liquid spray formulations of the present invention do not contain sodium chloride.
  • liquid spray formulations of the present invention do not contain benzalkonium chloride, [00014] In another aspect, the liquid spray formulations of the present invention do not contain a buffer.
  • liquid spray formulations of the present invention do not contain citric acid.
  • liquid spray formulations of the present invention do not contain an alcohol.
  • the invention is directed to methods for treating opioid dependence comprising administering the liquid spray formulations of the present invention to a patient in need of opioid dependence treatment, wherein administration occurs either intranasaliy, sublinguals or intranasals and sublinsually. wherein if administration occurs intranasaliy and sublingual. ⁇ ' administration occurs simultaneously, sequentially or concomitantly.
  • the invention is directed to methods for treating opioid overdose comprising administering the liquid spray formulations of the present invention to a patient in need of opioid overdose treatment, wherein administration occurs either intranasaliy. sublingual! ⁇ 7 or intranasaliy and subhngually. wherein if administration occurs intranasaliy and sublingually administration occurs simultaneously, sequentially or concomitantly.
  • the invention is directed to methods for treating congenital insensitivity to pain with anhidrosis comprising administering the liquid spray formulations of the present invention to a patient in need of treatment for congenital insensitivity to pain with anhidrosis, wherein administration occurs either intranasaliy, sublingually or intranasaliy and sublingually, wherein if administration occurs intranasaliy and sublingually administration occurs simultaneously, sequentially or concomitantly,
  • Figure 1 Mean plasma concentration of Formulations #9 A, #9A repeat #8 A, #8AF and #7AF normalized to a 4-mg dosage. Values based on a geometric mean.
  • liquid naloxone formulations that are stable and comfortable to the user despite containing no buffer or isotonicity agent.
  • the formulations that do not contain an alcohol are especially suitable for administration to children. Further, the alcohol- free formulations may be suitable for patients in recovery from alcohol addiction.
  • the liquid naloxone formulation is a spray.
  • the liquid naloxone formulation is in a simple solution form.
  • the term "simple solution” refers to a solution in which the solute(s) has fully dissolved in the solvent.
  • stable includes but is not limited physical and chemical stability.
  • the present invention is directed to liquid spray formulations comprising an effective amount of naloxone, a pharmaceutically acceptable salt thereof, or a derivative thereof, water, and a chelating agent, wherein the formulation does not contain an isotonicity agent or a buffer.
  • liquid spray formulations of the present invention is for intranasal administration
  • liquid spray formulations of the present invention do not contain sodium chloride, citric acid, benzyl alcohol, or benzalkonium chloride.
  • the present invention is directed to liquid spray formulations comprising an effective amount of naloxone, a pharmaceutically acceptable salt thereof, or a derivative thereof, a co-solvent selected from the group consisting of a alcohol, a glycol, and a combination thereof water, and edetate disodium dihydrate as a chelating agent, wherein the formulation does not contain an isotonicity agent, or a buffer.
  • liquid spray formulation of claim 4 wherein the alcohol is ethanol (dehydrated alcohol) and the glycol is propylene glycol.
  • liquid spray formulations of the present invention have a pH from about 3.0 to about 6.0, more preferably about 4.5.
  • the present invention is directed to liquid spray formulations comprising an effective amount of naloxone, a pharmaceutically acceptable salt thereof, or a derivative thereof, water, a chelating agent, and an antioxidant, preferably sodium ascorbate, wherein the formulation does not contain an isotonicity agent or a buffer.
  • the present invention is directed to liquid spray formulations comprising:
  • naloxone from about 1% to about 16% w/w naloxone, a pharmaceutically acceptable salt or a derivative thereof, preferably from about 2% to about 10% w/w; from about 10% to about 99% w/w water;
  • a chelating agent preferably edetate disodium dehydrate
  • the formulation does not contain an isotonicity agent or a buffer.
  • liquid spray formulations of the present invention do not contain an alcohol.
  • the present invention is directed to liquid spray formulations comprising:
  • naloxone from about 3 % to about 16% w/w naloxone, a pharmaceutically acceptable salt or a derivative thereof, preferably from about 2%> to about 10%> w/w;
  • a chelating agent preferably edetate disodium dihydrate
  • the formulation does not contain an isotonicity agent, a buffer or a co-solvent.
  • the present invention is directed to liquid spray formulations comprising:
  • naloxone from about 1% to about 16% w/w naloxone, a pharmaceutically acceptable salt or a derivative thereof, preferably from about 2% to about 10% w/w;
  • a chelating agent preferably edetate disodium dihydrate
  • a co-solvent selected from the group consisting of ethanol, propylene glycol and a combination thereof preferably ethanoi at a concentration from about 2% to about 50% w/w, or a combination of propylene glycol at a concentration from about 5% to about 10% w/w and ethanol at a concentration from, about 2% to about 50% w/w or a combination of ethanol at about 20 % w/w and propylene glycol at about 5 % w/w or a combination of ethanol at about 50 % w/w and propylene glycol at about 5 % w/w,
  • a co-solvent selected from the group consisting of ethanol, propylene glycol and a combination thereof preferably ethanoi at a concentration from about 2% to about 50% w/w, or a combination of propylene glycol at a concentration from about 5% to about 10% w/w and ethanol at a concentration from, about 2% to about 50% w/w or a
  • the present invention is directed to liquid spray formulations comprising
  • naloxone from about 1% to about 16% w/w naloxone, a pharmaceutically acceptable salt or a derivative thereof, preferably from about 2% to about 10% w/w;
  • a chelating agent preferably edeiate di sodium dihydrate
  • propylene glycol as a co-solvent at a concentration from about 5% to about 10% w/w, wherein the formulation does not contain an isotonicity agent, a buffer or an alcohol.
  • the liquid spray formulations of the present invention comprise a preservative selected from the group consisting of butyl paraben, methyl paraben, ethyl paraben, propyl paraben, sodium benzoate, benzoic acid and a combination thereof, preferably from about 0.005% to about 0.2% w/w methyl paraben and more preferably 0,1% w/w methyl paraben.
  • liquid spray formulations of the present invention do not contain a preservative.
  • liquid spray formulations of the present invention are administered in a nasal spray device.
  • liquid spray formulations of the present invention are administered in a nasal spray device that is capable of producing a droplet size distribution wherein greater than 90% of the composition particles are greater than 10 microns in diameter during administration or a droplet size distribution wherein:
  • the mean Dv(10) is from about 5 to about 40 microns during administration
  • the mean Dv(50) is from about 20 to about 80 microns during administration; and the mean Dv(90) is from about 50 to about 700 microns during administration, or a spray plume that has an ovality ratio of from about 1.0 to 2.5, or a spray plume width from about 25 to about 70 millimeters during administration and a spray plume angle from about 15 to about 70 degrees during administration,
  • liquid spray formulations of the present invention are administered in a nasal spray device that has a single reservoir comprising about 125 ⁇ to 127 pL of the formulation.
  • the liquid spray formulations of the present invention are administered in a nasal spray device that delivers about 100 ⁇ of the formujaiion by a single actuation.
  • the invention is directed io liquid spray ormulations comprising an effective amount of naloxone, a pharmaceutically acceptable salt or a derivative thereof, water as a solvent, a eo-solvent and an antioxidant or chelating agent.
  • naloxone is in salt form.
  • the invention is directed to liquid spray formulations comprising an effective amount of naloxone, a pharmaceutically acceptable salt or a derivative thereof, water as a solvent, a co-solvent and a permeation enhancer or chelating agent.
  • naloxone is in salt form.
  • the co-solvent may be an alcohol, a glycol, or a mixture thereof.
  • the formulations preferably contain from about 5 to about 90% w/w co-solvent. More preferably the formulations contain from about 10 % to about 70 % w/w from about 10 % to about 55% w/w or from about 40% to about 65% w/w or from about 45% to about 60 % w/w or from about 45 %> to about 55 % w/w co-solvent. In a preferred embodiment, the formulations contain about 10% w/w, about 12% w/w, about 25% w/w or about 55 % w/w co-solvent.
  • the formulations contain about 10 % w/w ethanol as a co-solvent or about 2% to about 45% ethanol as a co-solvent, or about 10% to about 20% ethanol as a co-solvent, or about 10 % w/w propylene glycol and about 2% w/w ethanol as a co-solvent or about 20% w/w ethanol and about 5% w/w propylene glycol as a eo-solvent or about 50% w/w ethanol and 5 % w/w propylene glycol as co- solvent.
  • Suitable antioxidants include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), methionine, sodium ascorbate, sodium thiosulfate, thioglycerol, ascorbic acid, ascorbyi palmitaie, propyl gallate, dL-alpha-tocopherol. sodium sulfite, sodium metahisulfite. sodium bisulfite cysteine hydrochloride, glutathione and a combination thereof.
  • Presently preferred antioxidants include BHA.
  • BHT sodium thiosulfate, dL alpha-tocopherol (Vitamin E) and sodium ascorbate.
  • the amount of antioxidant included in the formulation is from about 0.001 % to about 0,5% w/w. [00047] In another preferred embodiment, the amount of antioxidant is about 0.01 % w/w of
  • the antioxidant is a mixture of about 0.01% w/w of
  • BHA and about 0.005% w/w of BHT.
  • the antioxidant is about 0.01% w/w of sodium thiosulfate.
  • the antioxidant is about 0.3 % w/w dL alpha-tocopherol.
  • the antioxidant is about 0,02% w/w of sodium ascorbate.
  • formulations of the present invention contain from about 10% to about 99% w/w water, more preferably, from about 10% to about 98% w/w water, more preferably from about 35% to about 85% w/w, more preferably from about 35% to about 84% w/w and more preferably about 29.8%, 33.2%, 33.32 %, 34.5%, or 35.5%,37.5%, 65.2%, 71.1%, 79.3%, 81.1%, or 83.9% w/w water.
  • Hydro-alcohol formulations of the present invention preferably contain from about 40 % to about 90% w/w water, more preferably, from about 50 % to about 90 % w/w water. In preferred embodiments, hydro- alcoholic formulations contain about from about 30 % to about 80 % w/w water,
  • the formulations of the present invention have a pH of from about 2 to about 7. In a more preferred embodiment, the formulations of the present invention have a pH of from about 3 to about 6, even more preferably from about 3 to about 4.5.
  • the formulations of the present invention have a pH of about 3.0 ⁇ 0.2 or 3.5 ⁇ 0.2 or 4.0 ⁇ 0.2 or 4,5 ⁇ 0.2.
  • the formulations contain ethanol as the co- solvent.
  • the formulations contain propylene glycol as the co-solvent.
  • the formulations contain a mixture of ethanol and propylene glycol as the co-solvent.
  • the formulations of the present Invention contain a chelating agent.
  • the chelating agent is edetaie disodiurn dihydrate, (also known as edetaie disodiurn or ethylenediaminetetraacetic acid disodiurn salt or EDTA) preferably at a concentration from about 0.0001 % to about 0.5% w/w and more preferably from about 0.001% to about 0.05% w/w and even more preferably from about 0.005% to about 0.05% w/w and even more preferably from about 0.001% to about 0.02% w/w,
  • the present invention is directed to liquid spray formulations comprising naloxone, a pharmaceutically acceptable salt or a derivative thereof, in an amount from about 1 % to about 16 % w/w, water in an amount from about 1 0% to about 95% w/w, a co-solvent in an amount from about 2% to about 90% w/w, and a chelating agent in an amount from about 0.0001 % to 0.05% w/w,
  • the present invention is directed to liquid spray formulations comprising naloxone, a. pharmaceutically acceptable salt or a derivative thereof, in an amount from about 1 % to about 20 % w/w, water in an amount from about 30 % to about 99% w/w, a co-solvent in an amount from about 2% to about 90% w/w, and a chelating agent in an amount from about 0.0005% to 0.05% w/w.
  • the liquid spray formulations of the present invention further comprise a permeation enhancer selected from the group consisting of menthol in an amount from about 0.001% to about ' 10.0% w/w, caprylic acid in an amount from about 0.1% to 10% w/w, benzaikonium chloride ("BKC”) in an amount from about 0.001% to 10 % w/w and a combination thereof.
  • a permeation enhancer selected from the group consisting of menthol in an amount from about 0.001% to about ' 10.0% w/w, caprylic acid in an amount from about 0.1% to 10% w/w, benzaikonium chloride ("BKC”) in an amount from about 0.001% to 10 % w/w and a combination thereof.
  • the formulation contains edetate disodium dihydrate as the chelating agent at 0.001 % w/w or 0.05 % w/w.
  • the present invention is directed to naloxone, a pharmaceutically acceptable salt or a derivative thereof, in an amount from about 24% to about 16% w/w, water in an amount from about 20% to about 85% w/w, a co-sol vent in an amount from about 5% to about 55% w/w, and a chelating agent in an amount from about 0.0001% to 0.05%.
  • naloxone is a salt.
  • the formulation further comprises a permeation enhancer selected from menthol in an amount from about 0.01 % to about 10 % w/w, caprylic acid in an amount from about 0.1 % to 10% w/w, BKC in an amount from about 0.001% to 10 % w/w, and a combination thereof.
  • a permeation enhancer selected from menthol in an amount from about 0.01 % to about 10 % w/w, caprylic acid in an amount from about 0.1 % to 10% w/w, BKC in an amount from about 0.001% to 10 % w/w, and a combination thereof.
  • the chelating agent is edetate disodium dihydrate, preferably at a concentration from about 0.001% to about 0.5% w/w.
  • the present invention is directed to naloxone, a pharmaceutically acceptable salt or a derivative thereof, in an amount from about 1% to about 10% w/w, water in an amount from about 30% to about 85% w/w, a co-solvent in an amount from about 7% to about 55% w/w, and a chelating agent in an amount from about 0,0001 % to 0.05%,
  • naloxone is a salt.
  • the formulation further comprises a preservative, preferably from about 0.01 to about 0.5% w/w.
  • a preservative preferably from about 0.01 to about 0.5% w/w.
  • the chelating agent is edetate disodium dihydrate.
  • the preservative is methyl paraben.
  • formulations of the present invention do not contain a preservative.
  • the present invention is directed to naloxone, a pharmaceutically acceptable salt or a derivative thereof in an amount from about 1 % to about 10% w/w, water in an amount from about 35% to about 85%o w/w, a co-solvent in an amount from about 7%> to about 55% w/w, and a chelating agent in an amount from about 0.001% to about 0.02% w/w.
  • naloxone is a salt.
  • the formulation also contains a preservative in an amount from about 0.05% to about 0.2% w/w.
  • the formulation contains edetate disodium dihydrate as the chelating agent,
  • the present invention is directed to liquid spray formulations comprising naloxone hydrochloride dihydrate from about 1% to about 10% w/w, water from about 35% to about 84% w/w, ethanol from about 2% to about 50% w/w, EDTA from about 0.001 % to about 0.02% w'w and optionally propylene glycol from about 5% to about 10% w/w and optionally, methyl paraben at about 0.1% w/w.
  • liquid spray formulations of the present invention do not contain an isotonicity agent.
  • liquid spray formulations of the present invention do not contain sodium chloride.
  • liquid spray formulations of the present invention do not contain benzalkoniurn chloride.
  • liquid spray formulations of the present invention do not contain a buffer.
  • liquid spray formulations of the present invention do not contain citric acid.
  • the formulations of the present invention contain citric acid or sodium hydroxide or hydrochloric acid solution as a pH adjuster.
  • succinate maleate, gentisinate, funiarate, gluconate, gluearonate, saccharate, formate, benzoate, glutarnaie, raetbanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., l J '-methylene-bis-(2- hydroxy-3-naphthoate)) salts.
  • the pharmaceutically acceptable salt is hydrochloride.
  • naloxone derivatives of naloxone that can be used in accordance with the current invention include but are not limited to 3 ⁇ 0-acyl 5 phenylhydrazone, and methiodide derivatives.
  • the solvent, used with the present invention is United States Pharmacopeia (“USP”) purified water.
  • USP United States Pharmacopeia
  • Co-solvents that can be used in accordance with the current invention are alcohols, and glycols or a mixture thereof.
  • Alcohols that can be used in accordance with the current invention include but are not limited to methanol, efhanol (also known as dehydrated alcohol), propyl alcohoL butyl alcohol and the like, but do not include benzyl alcohoL
  • alcohol includes ail alcohols including benzyl alcohol.
  • Glycols that can be used in accordance with the current invention include but are not limited to propylene glycol, polypropylene glycol, and butylene glycol and polyethylene glycols such as PEG 200, PEG 300, PEG 400 and PEG 600 and the like.
  • the co-solvent is ethanoi or propylene glycol or a mixture thereof.
  • the amount of co-solvent included i the formulation is from about 2% to about 90% w/w. In other more preferred embodiments, the amount of co-solvent included in the formulation is about 5% or about 10% w/w propylene glycol. In other more preferred embodiments, the amount of co-solvent included in the formulation is about 2%, about 10%, about 20% or about 50% w/w ethanol.
  • the co-solvent is a mixture of propylene glycol at about 5% w/w and ethanol at about 50% w/w, or a mixture of propylene glycol at about 5% w/w and ethanol at about 20% w/w, or a mixture of propylene glycol at about 10% w/w and ethanol at about 10% w/w, or propylene glycol at about 10% w/w and ethanol at about 2% w/w or 1 0% w/w ethanol.
  • Solubilizers that can be used in accordance with the current invention are hydroxypropyl beta-cyclodextrin (" ⁇ ") and sulfobutylether cyclodextrin or a mixture thereof,
  • the solubilizer is HPpCD
  • the amount of HPpCD is about 30% w/w
  • Permeation enhancers that can be used in accordance with the current invention include but are not limited to menthol, limonene, carvone, methyl chitosan, polysorbates including Tween ® 80 (polysorbate 80; Tween is a registered trademark of Uniqema Americas, LLC), sodium lauryl sulfate, glyceryl oleate, caprylic acid, pelargonic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, oleic acid, stearic acid, linolenic acid, arachidonie acid, benzalkonium chloride (BK.C), cetyipyridium chloride, edetate disodium dihydrate, sodium desoxychoiate, sodium deoxyglyeolate, sodium glycochoiate, sodium caprate, sodium tauroeholate, sodium hydroxybenzoyal amino caprylate, dodeeyi dimethyl amino
  • the amount of permeation enhancer is from about
  • the formulations contain from about 0.01 % to about 5.0% w/w permeation enhancer. In a preferred embodiment, the formulations contain from about 0.02% to about 2.0 % w/w permeation enhancer, in a most preferred embodiment, the formulations contain 2.0 % w/w permeation enhancer.
  • the permeation enhancer is L-menthol, caprylic acid,
  • the preferred amount of L- menthol is from about 0.001% to about 10,0 % w/w
  • caprylic acid is from about 0, 1% to about 10% w/w
  • BKC is from about 0,001 to about 10 % w/w
  • EDTA is from about 0.0005% to 0, 1% w/w.
  • the formulations contain from about 0.01% to about 0,5% w/w L-menfhoi, about 0.5% to about 5% w/w caprylie acid, about 0.005 to about 0.1 % w/w BKC, about 0.005% to about 0.05% w/w EDTA, or a combination thereof.
  • the formulations contain from about 0.02%o to about Q.5%> w/w L-menthol, about 1 % to about 2% w/w caprylie acid, about 0.01 to about 0.1% w/w BKC, about 0.005 to about 0.05 % w/w EDTA or a combination thereof. In a most preferred embodiment, the formulations contain about 0.5 % w/w L-menthol, about 2% w/w caprylie acid, about 0.01 % w/w BKC, about 0,005 % edetate disodium dihydrate, or a combination thereof.
  • the permeation enhancer is about 0.5% w/w of menthol.
  • the permeation enhancer is about 2.0 % w/w caprylie acid
  • the permeation enhancer is about 0.01 % w/w ot benzalkonium chloride (BKC).
  • the permeation enhancer is about 0,005%, 0.01%,
  • EDTA edetate disodium dihydrate
  • the permeation enhancer is a combination of 2.0 % w/w caprylie acid and 0.01% w/w of benzalkonium chloride.
  • Formulations of the present, invention may have a pH range from about 2.0 to about
  • pH adjusters that can be used in accordance with the present invention include but are not limited to citric acid and sodium hydroxide.
  • the amount of sodium hydroxide or citric acid is from about 0.002% to about 0.03% w/w, in more preferred embodiments, the amount of sodium hydroxide is about 0.015%t w/w. In other more preferred embodiments, the amount of sodium hydroxide is about 0.012% w/w.
  • the formulation contains a permeation enhancer, a sweetener, a sweetness enhancer, a pH modifier, a flavoring agent, a preservative, or a combination thereof,
  • the formulations contain a sweetener,
  • the sweetener is selected from the group consisting of sucraiose, aspartame, saccharin, dextrose, mannitol, glycerin, and xylitoi.
  • the formulations contain from about 0.001% w/w to about 2% w/w of sweetener, in a more preferred embodiment, the formulations contain from about 0,05% w/w to about 1% w/w of the sweetener, in a most preferred embodiment, the formulations contain sucralose as sweetener at about 0.8% w/w.
  • the formulations contain a flavoring agent.
  • the formulations contain a flavoring agent selected from the group consisting of peppermint oil, menthol, spearmint oil, citrus oil, cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orange oil, and a combination thereof.
  • Other appropriate flavoring agents known by those of skill in art could also be added to formulations of the present invention, in a preferred embodiment, the formulations contain from about 0.001% w/w to about 1% w/w of the flavoring agent, in a more preferred embodiment, the formulations contain from about 0.005% w/w to about 0.5% w/w of the flavoring agent. In a most preferred embodiment, the formulations contain strawberry as flavoring agent at about 0.08% w/w.
  • the formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv(lO) is from about 1 1 to about 35 microns during administration.
  • the formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv(50) is from about 25 to about 55 microns during administration.
  • the formulations of the present invention are capable of producing a droplet size distribution wherei the mean Dv(90) is from about 75 to about 600 microns during administration.
  • the formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv(90) is from about 85 to about 500 microns during administration.
  • the invention is directed to stable liquid spray formulations comprising an effective amount of naloxone, a pharmaceutically acceptable salt or a derivative thereof water, a chelating agent and optionally, a co-solvent and the formulations do not contain an alcohol.
  • the invention is directed to stable liquid spray formulations comprising an effective amount of naloxone, a pharmaceutically acceptable salt or a derivative thereof, water, and a permeation enhancer or a chelating agent, and optionally, a co- solvent and the formulations do not contain an alcohol,
  • the stable liquid spray formulations of the present invention contain a preservative, preferably from about 0.01% to about 0.5% w/w.
  • the preservative is methyl paraben
  • the stable liquid spray formulations of the present invention do not contain a preservative.
  • the stable liquid spray formulations of the present invention are suitable for nasal administration.
  • liquid spray formulations of the present invention do not contain an isotonicity agent.
  • liquid spray formulations of the present invention do not contain sodium chloride.
  • liquid spray formulations of the present invention do not contain benzalkonium chloride.
  • liquid spray formulations of the present invention do not contain a buffer.
  • liquid spray formulations of the present invention do not contain citric acid
  • the liquid spray formulation comprises from about
  • the liquid spray formulation comprises from about 1 % w/w to about 12% w/w naloxone or a salt or derivative thereof. In an even more preferred embodiment, the formulations contain from about 2% w/w to about 10% w/w naloxone or a salt or derivative thereof.
  • the formulations contain from about 20% w/w to about
  • the formulations contain from about 30% w/w to about 98% w/w water, in a more preferred embodiment, the formulations contain from about 80% w/w to about 98% w/w water, in a most preferred embodiment, the formulations contain from about 81% w/w to about 98% w/w water.
  • Aqueous formulations of the present invention preferably contain from about 70% to about 99% w/w water, more preferably, from about 80% to about 99% w/w water. In most preferred embodiments, aqueous formulations contain about from about 84% to about 98%> w/w water.
  • the formulations contain from about 5% w/w to about 50% w/w glycerol, In a preferred embodiment, the formulations contain from about 10% w/w to about 40% w/vv glycerol, in a more preferred embodiment, the formulations contain from about 15% w/vv to about 35% w/w glycerol.
  • the formulations may contain from about 0.1% w/w to about 50% w/w polyethylene glycol 400. In a more preferred embodiment, the formulations contain from about 10% w/w to about 40% w/w polyethylene glycol 400,
  • the formulations contain from about 0.1% w/w to about
  • the formulations contain from about 10% w/w to about 40% w/w propylene glycol. In an even more preferred embodiment, the present invention contains from about 5% to about 10% w/w propylene glycol
  • the formulation contains a pharmaceutically acceptable salt of naloxone.
  • the formulation contains a salt selected from the group consisting of hydrochloride, citrate, halide, phosphate, sulfate, acetate, ascorbate, maleate, succinate, carbonate, mesylate and lactate.
  • a salt selected from the group consisting of hydrochloride, citrate, halide, phosphate, sulfate, acetate, ascorbate, maleate, succinate, carbonate, mesylate and lactate.
  • the antioxidant is selected from the group consisting of ascorbic acid, cysteine HQ monohydrate, citric acid, ethylenediamine tetra acetic acid (EDTA), methionine, sodium citrate, sodium ascorbate, sodium thiosulfate, sodium metahisulfite, sodium bisulfite, glutathione and thioglycerol.
  • EDTA ethylenediamine tetra acetic acid
  • the formulations contain from about 0.0001% w/vv to about 0.5% w/w of the antioxidant. In a more preferred embodiment, the formulations may contain from about 0.005% w/w to about 0.2% w/w of the antioxidant. In a most preferred embodiment, the formulations contain G.05%w/w or 0.02% w/w of the antioxidant.
  • the formulations of the present invention contain a chelating agent.
  • the chelating agent is edeiate disodium dihydrate
  • the formulations contain from about 0.0001 % to about 0.5% w/w of the chelating agent. In a preferred embodiment, the formulations contain from about 0,001% to about 0.50% w/w of the chelating agent. In a more preferred embodiment, the formulations contain from about 0,005% to about 0.05% w/w of the chelating agent.
  • the formulation contains a permeation enhancer, a sweetener, a sweetness enhancer, a pH modifier, a flavoring agent, a preservative, or a combination thereof.
  • the formulation contains a permeation enhancer.
  • the permeation enhancer is selected from the group consisting of menthol, limonene, carvone, methyl chitosan, capryhc acid pelargonic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, oleic acid, stearic acid, Hnoienic acid, arachidonic acid, polysorbates including Tween ® 80, sodium edetate, benzalkonium chloride (BKC), cetylpyridinium chloride, sodium lauryl sulfate, citric acid, sodium desoxycho!ate, sodium deoxyglycolate, glyceryl oleate, glyceryl monostearate, Sodium hydroxybenzoyal amino caprylate, sodium eaprate, dodecyl dimethyl aminopropionate, L-lysine, sodium glycocholate, citric acid,
  • the permeation enhancer is selected from the group consisting of polysorbates including Tween ⁇ 80, sodium edetate, benzalkonium chloride (BKC), cetylpyridinium chloride, sodium lauryl sulfate, citric acid, sodium desoxycholate, sodium deoxyglycolate, glyceryl oleate, glyceryl monostearate, L-lysine, sodium glycocholate, sodium taurocholate, citric acid, and a combination thereof.
  • the permeation enhancer is selected from the group consisting of menthol, caprylic acid and BKC.
  • the amount of permeation enhancer is from about
  • the formulations contain from about 0.001% to about 2.5% w/w permeation enhancer. In a most preferred embodiment, the formulations contain from about 0,02% to about 2.0 % w/w permeation enhancer.
  • the permeation enhancer is menthol, caprylic acid, BKC or a combination thereof
  • the preferred amount of L-menthol is from about 0.001 % to about 10 % w/w
  • caprylic acid is from about 0.1% to 10% w/w
  • BKC is from about 0.001 to 10% w/w.
  • the formulations contain from about 0,01 % to about 0.5% w/w L- menthol, about 0.5% to 5% w/w caprylic acid, about 0.005 to 0.1% w/w BKC.
  • the formulations contain from about 0.02% to about 0.5% w/w L-menthol, about 3 %t to 2% w w caprylic acid, about 0.01 to 0, 1 % w/w BKC, In a most preferred embodiment, the formulations contain about 0.5 % w/w L-menthoi, about 2% w/w caprylic acid and about 0,005 w/w B C.
  • the permeation enhancer is about 0.5% w/w of menthol.
  • the permeation enhancer is about 2.0 % w/w caprylic acid.
  • the permeation enhancer is about 0.01 % w/w of benzalkonium chloride (BKC),
  • the formulations contain a sweetener,
  • the sweetener is selected from the group consisting of sucralose, aspartame, saccharin, dextrose, mannitol, glycerin, and xylitol.
  • the formulations contain from about 0.001% w/w to about 2% w/w of sweetener.
  • the formulations contain from about 0.05% w/w to about 1 % w/w of the sweetener.
  • the formulations contain sucralose as a sweetener at about 0.8% w/w.
  • the formulation may contain a sweetness enhancer, an ammonium salt form of crade and refined Glycyrrhizic Acid, for example, Magnasweet ® product (available from Mafco Worldwide Corporation, Magnasweet is a registered trademark of Mafco Worldwide Corporation), Magnasweet ⁇ products use the ammonium salt forms of crade and refined Glycyrrhizic Acid.
  • Glycyrrhizic Acid is also available as a pure derivative in the sodium and potassium salt forms.
  • the formulations contain a pH modifier.
  • the pH modifier adjusts the pH of the formulation to from about 2 to about 7.
  • the pH modifier adjusts the pH of the formulation to from about 3 to about 6, from about 4 to about 5 or from about 2 to about 4.
  • the pH modifier adjusts the pH of the formulations to about 2.5, or 3, or 4,5 ⁇ 0.1.
  • the formulations contain a flavoring agent.
  • the formulations contain a flavoring agent selected from the group consisting of peppermint oil, menthol, spearmint oil, citrus oil, cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orange oil, and a combination thereof.
  • Other appropriate flavoring agents known by those of skill in the art could also be added to formulations of the present invention.
  • the formulations contain from about 0.001 % w/w to about 1 % w/w of the flavoring agent.
  • the formulations contain from about 0.005% w/w to about 0,5% w/w of the flavoring agent.
  • the formulations contain strawberry as the flavoring agent at about 0.08% w/w.
  • the formulations may contain a preservative.
  • the preservative is selected from the group consisting of butyl paraben, methyl paraben, ethyl paraben, propyl paraben, sodium benzoate, and benzoic acid.
  • the formulations contain .from about 0.001% w/w to about 1 % w/w of the preservative.
  • the formulations contain from about 0,005% w/w to about 0.2% w/w of the preservative.
  • the formulations contain methyl paraben as a preservative at about. 0.1% w/w.
  • the invention is directed to stable liquid spray formulations comprising from about 1% to about 16% w/w naloxone, a pharmaceutically acceptable salt or a derivative thereof, about 10% to about 98% w/w water, about 0.005% to about 0.05% w/w of a chelating agent, preferably edetate disodium dihydrate and optionally, about 2% to about 90% w/w of a co-solvent, preferably propylene glycol and the formul ations do not contain an alcohol.
  • a chelating agent preferably edetate disodium dihydrate
  • a co-solvent preferably propylene glycol and the formul ations do not contain an alcohol.
  • the invention is directed to stable liquid spray forniulations comprising from about 1% to about 16% w/w naloxone, a pharmaceutically acceptable salt or a derivative thereof, about 30% to about. 98% w/w water, about 0,005% to about 0.05% w/w of a chelating agent, preferably edetate disodium dihydrate and optionally, about 5% to about 55% w/w of a co-solvent, preferably propylene glycol and the formulations do not contain an alcohol,
  • the invention is directed to stable liquid spray formulations comprising from about 1% to about 10% w/w naloxone, a pharmaceutically acceptable salt, or a derivative thereof, about 80% to about 98% w/w water, about 0.005% to about 0.05% w/w of a chelating agent, preferably edetate disodium dihydrate and optionally, about 5% to about 10% w/w of a co-solvent, preferably propylene glycol, and optionally about 0.1% w/w of a preservative, preferably methyl paraben and the formulations do not contain an alcohol
  • the formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv(10) is from about 12 to about 20 microns during administration.
  • the formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv(50) is from about 25 to about 35 microns during administration.
  • the formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv(90) is from about 40 lo aboul 150 microns during administration.
  • the formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv( 0) is from about 60 to about 1 10 microns during administration,
  • the Invention is directed to treating patients by administering the formulations (with or without an alcohol) of the present invention to the patient.
  • the formulations are administered in order to treat opioid dependence, opioid overdose, and or congenital insensitivity to pain with anhidrosis.
  • % w/w refers to the percent weight of the total formulation.
  • the term "effective amount” refers to the amount necessary to treat a patient in need thereof.
  • patient refers but is not limited to a person that is being treated for opioid dependence, opioid overdose, insensitivity to pain with anhidrosis, or another affliction or disease, that can be treated with naloxone,
  • pharmaceutically acceptable' ' ' refers to ingredients that are not biologically or otherwise undesirable in a sublingual or intranasal dosage form.
  • stable refers to formulations which maintain greater than 95% purity following at least four weeks at about 40°C.
  • the (alcohol and alcohol-free) formulations of the present invention are propellant free.
  • propellant free refers to a formulation that is not administered using compressed gas.
  • the terra “isotonicity agent” refers to any compound used to alter or regulate the osmotic pressure of a formulation.
  • buffer refers to any compound used to maintain the pi! of a formulation
  • Liquid spray formulations were created by first degassing ethanoi and USP purified water, separately. Next, the ethanoi and purified water were each purged with nitrogen. Soluble excipients were then dissolved in either the ethanoi or the purified water based on their solubility. Next, the solutions were combined. Naloxone was added to the final solution and mixed until dissolved.
  • the stability data was collected at zero, one, two, three, four, and eight weeks at 55°C and at zero, four, and eight weeks at 40°C.
  • Assay and impurities were detected using high performance liquid chromatography with an ultraviolet detector.
  • the assay was performed at 288 nm and indicated as a % of initial concentration, For all impurities, analysis was performed at 240 nm and expressed as a % area.
  • Impurity D ( 1.14 ND ND ND
  • Liquid naloxone formulations of the present invention contained less than one percent total impurities after eight weeks at 40°C. This is a stark contrast to the control formulation which contained 7.6% impurities at the same time. Specifically, the formulations which contained sodium thiosulfate or BHA and BHT resulted in 0% detected impurities after eight weeks. Also, formulations which contain sodium ascorbate (0.02% wtAvt) and edetate disodium dihydrate (0.005% wt/wt) resulted in only 0.29% total impurities after 3 months.
  • Impuri y 0.66 ND ND ND 0.54% 0.33% 0.35%
  • Impurity F 0.93 ND ND ND ND ND ND ND ND ND
  • a challenge of creating a Naloxone sublingual and/or intranasal spray formulation is that it must be capable of producing spray droplets that are over 10 microns in diameter. Spray droplets 10 microns or smaller could be inhaled into the lungs.
  • the optimal particle size for sublingual and intranasal spray droplets is from 20 to about 200 microns in diameter. It is desirable for the formulation to have droplet sizes near 20 because this increases the surface area and increased surface area exposure is one factor that contributes to a high bioavailabi lity. Sublingual and intranasal formulations should be able to maintain a consistent droplet size throughout its shelf life.
  • Droplet analysis was conducted using standard laser analysis procedures known by those of skill in the art. Droplet size distribution (Dvl O, Dv50, Dv90. and Span were tested at two distances, 3 cm and 6 cm). Dvl O refers to droplet size tor which 10% of the total volume is obtained; Dv50 refers to droplet size for which 50% of the total volume is obtained; Dv90 refers to droplet size for which 90% of the total volume is obtained; Span refers to distribution span (Dv90-Dvl 0)/Dv50; %RSD refers to the percent relative standard deviation. The results of these tests can be seen below in ' Fables 4 to 9. Applicant found during testing that formulations of the present invention yielded desirable droplet sizes for sublingual and intranasal administration. The testing also revealed that the formulation dose remains consistent when administered with a spray pump.
  • Formulation #5A of the present invention provided excellent plume geometry and spray patterns.
  • 000162 In order to prepare a naloxone liquid formiilaiion, the components as indicated in
  • Impurity F 1 0.93 ND ND ND ND I ND 1
  • Liquid naloxone formulations of the present invention contained less than 0.8% of total impurities after four weeks at 55°C. This is a stark contrast to the control formulation which contained 0.96% impurities after 1 week at 55°C. Specifically, the formulations which contained sodium ascorbate or edetate disodium dihydrate exhibited lower impurities after four weeks. Additionally, the formulations which contained edetate disodium dihydrate were very stable. T ables 13A to 13 C. Stability Data for Liquid Naloxone Spray Formulations stored at. 4 Q °C under f ⁇ 1 ⁇ 4.Relative :i3 ⁇ 4m3 ⁇ 4 3 ⁇ 4)f
  • naloxone formulations of the present invention contained less than 0.45% of total impurities after four weeks at 40°C.
  • naloxone formulations #1 AF to #6AF were clear and colorless after several cycles of freezing and thawing. This study further demonstrates the stability of the formulations. fe tfrljg-fc Droplet fe ing
  • the optimal particle size for sublingual and intranasal spray droplets is from 20 to about 200 microns in diameter. It is desirable, for the formulation to have droplet sizes near 20 because this increases the surface area and increased surface area exposure is one factor that contributes to a high bioavailability. Sublingual and intranasal formulations should be able to maintain a consistent droplet size tliroughout its shelf life.
  • Droplet analysis was conducted using standard laser analysis procedures known by those of skill in the art. Droplet size distribution (Dvl 0, Dv50, Dv90, and Span were tested at two distances, 3 cm and 6 cm), Dvl O refers to droplet size for which 10% of the total volume is obtained; Dv50 refers to droplet size for which 50% of the total volume is obtained; Dv90 refers to droplet, size for which 90% of the total volume is obtained; Span refers to distribution span (Dv90-Dvl 0)/Dv50; %RSD refers to the percent relative standard deviation, The results of these tests can be seen below in Tables 15 to 20. Applicant found during testing that formulations of the present invention yielded desirable droplet sizes for sublingual and intranasal administration. The testing also revealed that the fornuilaiion dose remains consistent when administered with a spray pump.
  • Formulation #1AF of the present invention provided excellent plume geometry and spray patterns.
  • naloxone liquid formulations In order to prepare naloxone liquid formulations, the components as indicated in Tables 22, 23 and 24 below were weighed. The components were mixed until a clear solution was formed.
  • naloxone formulations #8 A and #9 A were clear and colorless after several cycles of freezing and thawing. This study further demonstrates the stability of the formulations.
  • the optimal particle size for sublingual and intranasal spray droplets is from 20 to about 200 microns in diameter, it. is desirable tor the formulation, to have droplet sizes near 20 because this increases the surface area and increased surface area exposure is one factor that contributes to a high bioavailability.
  • Sublingual and intranasal formulations should be able to maintain a consistent droplet size throughout its shelf life.
  • Droplet analysis was conducted using standard laser analysis procedures known by those of skill in the art. Droplet size distribution (DvI O, Dv50, Dv90, and Span were tested at two distances, 3 em and 6 cm).
  • DvlO refers to droplet size for which 10% of the total volume is obtained:
  • Dv50 refers to droplet size for which 50% of the total volume is obtained:
  • Dv90 refers to droplet size for which 90% of the total volume is obtained:
  • Span refers to distribution span (Dv90-DvlO)/Dv5G; %RSD refers to the percent relative standard deviation. The results of these tests can be seen below in Tables 26 to 41. Applicant found during testing that formulations of the present invention yielded desirable droplet sizes for sublingual and intranasal administration. The testing also revealed that the formulation dose remains consistent when administered with a spray pump.
  • Protocol was a single dose crossover study. Five healthy male Yucatan minipigs weighing approximately forty kilograms each were sublingually administered the formulations of Table 21. The minipigs were fasted overnight and through four hours' post admin stration. Administration was followed by a one week washout period. Blood samples were taken prior to administration and 1, 3, 5, 7, 10, 15, 30 min, 1, 2, 4, 8 and 24 hours' post dose. Blood samples were measured for naloxone concentrations via liquid chroraatography-tandera mass
  • Table 42 Summary of pharmacokinetic parameters for naloxone after sublingual administration of single doses of 4 mg and .16 mg of naloxone formulations to Yucatan minipigs under fasted conditions.
  • the peak mean naloxone concentration was significantly higher for formulation #9A and #8 A over #8AF and #7AF. Additionally, the area under the concentrati n-time curve from time-zero to the time of the last quantifiable concentration was significantly higher for formulations #9A and #8 A over #8AF and #7AF. To determine if this result was based on the four-fold increase in the dose of naloxone in formulation #9A and #8A over #8AF and #7AF the geometric mean was normalized to 4 mg dose. See Figure 1 . A similar pattern remains even after normalizaiion. Further, the peak mean naloxone concentration was significantly higher for formulation #9 A, over #8A, which cannot be explained by the dosage as formulations #9A and #8A were each administered at 16 mg doses.
  • formulation #9A reached about 80% of its peak mean, naloxone concentration within 3 minutes of administration.
  • formulation #8 A had reached only 35% of its peak mean naloxone concentration within 7 minutes, #8AF 38% in 7 minutes and #7AF 19% in 7 minutes.
  • formulation #9A reached 19% ' of its AUC(o-t) within 15 minutes of administration, #8A reached 7.9% in 15 minutes, #8AF reached 8.8% in 1 5 minutes and #7AF reached 5.6% in 15 minutes.
  • Formulation #9 A, # 10A, and 1 1A from Table 21 above was subjected to stability testing at 25°C/60% RH ⁇ 5%, 40°C/75% ⁇ 5% relative humidity and 55°C ⁇ 2°C.
  • the stability data was collected at predetermined time points.
  • Assay and impurities were detected using high performance liquid chromatography with an ultraviolet detector. The assay was performed at 288 nm and indicated as a % of initial concentration. For all impurities, analysis was performed at 240 nrn and expressed as a % area. Amounts of particular impurities are listed in Tables 43 A to I as a percentage of the area of each formulation along with amount of total impurities.
  • formulation #9 A, #10A, and # 1 1 A demonstrates satisfactory stability with no significant increase in indi vidual or total impurities. Based upon these results, the formulation containing 0.02 % w/w of sodium ascorbate as an antioxidant and 0.001 % edetate disodium dihydrate as a chelating agent is chemically stable. Additionally, formulations containing 0,01 % and 0.005%) edetate disodium dihydrate as a chelating agent are chemically stable.
  • Protocol design was a Phase I. open-label, randomized, single-dose, five-way crossover study. The study assessed the bioavailability of a single 8 milligrams and 16 milligrams dose of naloxone in a formulation of the present invention either mtranasally or sublingual!)' to a single 0.4 milligram intramuscular dose of naloxone under fasted conditions. 145 subjects were randomly assigned to one of five groups including 8 milligrams sublingual dose, 16 milligrams sublingual dose, 8 milligrams intranasal dose, 16 milligrams intranasal dose and 0.4 milligram naloxone dose. Plasma concentrations were taken at pre-dose, 0.03, 0.07, 0.1 , 0.13, 0.17, 0.25, 0.5, L 2 4, 8 and 12 hours' post-dose.
  • SL denotes sublingual administration
  • N denotes number of subjects tested

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Abstract

La présente invention concerne des formulations liquides stables contenant de la naloxone, un de ses sels pharmaceutiquement acceptables ou un de ses dérivés. L'invention concerne en outre des procédés permettant de traiter la dépendance aux opioïdes, la surdose d'opioïdes et l'insensibilité congénitale à la douleur avec anhidrose par l'administration des formulations liquides de la présente invention par voie intranasale à un patient en ayant besoin. En outre, l'invention concerne un procédé de traitement de la dépendance aux opioïdes, d'une surdose d'opioïdes et d'une insensibilité congénitale à la douleur avec anhidrose par l'administration intranasale des formulations de naloxone de la présente invention.
PCT/US2017/046198 2016-08-17 2017-08-10 Pulvérisation de naloxone liquide WO2018034920A1 (fr)

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CA3033897A CA3033897C (fr) 2016-08-17 2017-08-10 Pulverisation de naloxone liquide
CN201780063967.6A CN109922805A (zh) 2016-08-17 2017-08-10 液体纳洛酮喷雾
AU2017312811A AU2017312811B2 (en) 2016-08-17 2017-08-10 Liquid naloxone spray
EP17841883.6A EP3500261A4 (fr) 2016-08-17 2017-08-10 Pulvérisation de naloxone liquide
JP2019508941A JP7114570B2 (ja) 2016-08-17 2017-08-10 液体ナロキソンスプレー
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US15/238,909 US10722510B2 (en) 2014-07-08 2016-08-17 Liquid naloxone spray
US15/238,909 2016-08-17
US15/601,331 US10617686B2 (en) 2014-07-08 2017-05-22 Liquid naloxone spray
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EP3500261A1 (fr) 2019-06-26
MA45995A (fr) 2019-06-26
JP7455157B2 (ja) 2024-03-25
AU2017312811A1 (en) 2019-03-07
EP3500261A4 (fr) 2020-05-06
JP2022119843A (ja) 2022-08-17
AU2017312811A8 (en) 2019-03-14
JP7114570B2 (ja) 2022-08-08
CA3033897C (fr) 2024-03-26
CN109922805A (zh) 2019-06-21
JP2019528278A (ja) 2019-10-10
AU2017312811B2 (en) 2023-03-16
CA3033897A1 (fr) 2018-02-22

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