CA3033897C

CA3033897C - Liquid naloxone spray

Info

Publication number: CA3033897C
Application number: CA3033897A
Authority: CA
Inventors: Kiran AMANCHA; Shivani CHILAMPALLI; Thrimoorthy Potta; Ningxin YAN; Venkat R. Goskonda
Original assignee: Hikma Pharmaceuticals USA Inc
Current assignee: Hikma Pharmaceuticals USA Inc
Priority date: 2016-08-17
Filing date: 2017-08-10
Publication date: 2024-03-26
Anticipated expiration: 2037-08-10
Also published as: JP2019528278A; JP7114570B2; AU2017312811A1; AU2017312811B2; JP2022119843A; MA45995A; AU2017312811A8; CA3033897A1; EP3500261A1; EP3500261A4; WO2018034920A1; CN109922805A; JP7455157B2

Abstract

The invention provides stable liquid formulations containing naloxone, a pharmaceutically acceptable salt, or a derivative thereof. The invention further provides methods for treating opioid dependence, opioid overdose, and congenital insensitivity to pain with anhidrosis by administering the liquid formulations of the present invention intranasally to a patient in need thereof. Further, the invention provides a method of treating opioid dependence-, opioid overdose, and congenital insensitivity to pain with anhidrosis by administering intranasally the naloxone formulations of the present invention.

Description

LIQUID NALOXONE SPRAY
Field of the Invention [0001] 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.
Background of the Invention

[0002] Naloxone has the following structure and is synthesized from thebaine:
H 401,

[0003] 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 ("BKC") 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. Adapt Pharma has U.S. Patent Nos. 9,211,253, 9,468,747 and 9,561,117 listed in the U.S. Food and Drug Administration's Orange Book for Narcan 4 milligram nasal spray. Each of these patents discloses and claims naloxone formulations containing an isotonicity agent Additional Adapt Pharma also has U.S. Patent No. 9,480,644 listed in the Orange Book for a 2-milligram naloxone nasal spray, which discloses and claims naloxone formulations that also contain an isotonicity agent. U.S. Patent Nos. 9,192,570 and 9,289,425 assigned to Indivior, Inc Date recue/Date Received 202401-22 disclose and claim naloxone nasal sprays that contain both citric acid as a buffer and benzyl alcohol as an anti-microbial agent.

[0004] One issue with other opioid dependence treatments is that they can become addictive. Naloxone, however, does not appear to be addictive and patients do not build up a tolerance.

[0005] 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.

[0006] 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.

[0007] Accordingly, while there are some naloxone formulations currently available, there is a need for safe and effective liquid spray formulations that are stable including physically and chemically stable and contain naloxone, pharmaceutically acceptable salts or a derivative thereof.
Summary of the Invention

[0008] The liquid spray formulations of the present invention are for intranasal and/or sublingual administration.

[0009] In one aspect, 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.

[00010] In another aspect, the stable liquid spray formulations of the present invention are suitable for intranasal administration.

[00011] In another aspect, the liquid spray formulations of the present invention do not contain an isotonicity agent.

[00012] In another aspect, the liquid spray formulations of the present invention do not contain sodium chloride.

[00013] In another aspect, the liquid spray formulations of the present invention do not contain benzalkonium chloride.

Date recue/Date Received 202401-22

[00014] In another aspect, the liquid spray formulations of the present invention do not contain a buffer.

[00015] In another aspect, the liquid spray formulations of the present invention do not contain citric acid.

[00016] In another aspect, the liquid spray formulations of the present invention do not contain an alcohol.

[00017] In yet another aspect, 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 intranasally, sublingually or intranasally and sublingually, wherein if administration occurs intranasally and sublingually administration occurs simultaneously, sequentially or concomitantly.

[00018] In a further aspect, 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 intranasally, sublingually or intranasally and sublingually, wherein if administration occurs intranasally and sublingually administration occurs simultaneously, sequentially or concomitantly.

[00019] In an additional aspect, 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 intranasally, sublingually or intranasally and sublingually, wherein if administration occurs intranasally and sublingually administration occurs simultaneously, sequentially or concomitantly.
Brief Description of the Figures

[00020] Figure 1. Mean plasma concentration of Formulations #9A, #9A
repeat #8A, #8AF
and #7AF normalized to a 4-mg dosage. Values based on a geometric mean.
Detailed Description of the Invention

[00021] Applicants have created new 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.

Date recue/Date Received 202401-22

[00022] In a preferred embodiment, the liquid naloxone formulation is a spray. In yet a more preferred embodiment, the liquid naloxone formulation is in a simple solution form. As used herein, the term "simple solution" refers to a solution in which the solute(s) has fully dissolved in the solvent.

[00023] As used herein, the term "stable" includes but is not limited physical and chemical stability.

[00024] In one embodiment, 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.

[00025] In another embodiment, the liquid spray formulations of the present invention is for intranasal administration.

[00026] In another embodiment, the liquid spray formulations of the present invention do not contain sodium chloride, citric acid, benzyl alcohol, or benzalkonium chloride.
1000271 In another embodiment, 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 an 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.
[00028] In another embodiment, the present invention is directed to a liquid spray formulation 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 and wherein the formulation further comprises a co-solvent selected from the group consisting of ethanol, propylene glycol, and a combination thereof. In another embodiment, the liquid spray formulations of the present invention have a pH from about 3.0 to about 6.0, more preferably about 4.5.
1000291 In another embodiment, 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.

Date recue/Date Received 202401-22 [00030] In another embodiment, the present invention is directed to liquid spray formulations comprising:
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;
from about 0.0001% to 0.05% w/w of a chelating agent, preferably edetate disodium dehydrate, wherein the formulation does not contain an isotonicity agent or a buffer.
[00031] In another embodiment, the liquid spray formulations of the present invention do not contain an alcohol.
[00032] In another embodiment, the present invention is directed to liquid spray formulations comprising:
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 80% to about 98% w/w water;
from about 0.0001% to 0.05% w/w of a chelating agent, preferably edetate disodium dihydrate, wherein the formulation does not contain an isotonicity agent, a buffer or a co-solvent.
[00033] In another embodiment, the present invention is directed to liquid spray formulations comprising:
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 35% to about 85% w/w water;
from about 0.0001% to 0.05% w/w of a chelating agent, preferably edetate disodium dihydrate; and from about 2% to about 90% w/w of a co-solvent selected from the group consisting of ethanol, propylene glycol and a combination thereof, preferably ethanol 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 Date recue/Date Received 202401-22 % w/w or a combination of ethanol at about 50 % w/w and propylene glycol at about 5 %
w/w, wherein the formulation does not contain an isotonicity agent or a buffer.
[00034] In another embodiment, the present invention is directed to liquid spray formulations comprising 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 35% to about 85% w/w water;
from about 0.0001% to 0.05% w/w of a chelating agent, preferably edetate disodium dihydrate; and 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.
[00035] In another embodiment, 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.
[00036] In another embodiment, the liquid spray formulations of the present invention do not contain a preservative.
[00037] In another embodiment, the liquid spray formulations of the present invention are administered in a nasal spray device.
[00038] In another embodiment, the 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 Date recue/Date Received 202401-22 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.
[00039] In another embodiment, the liquid spray formulations of the present invention are administered in a nasal spray device that has a single reservoir comprising about 125 p.1 to 127 pit of the formulation.
[00040] In another embodiment, the liquid spray formulations of the present invention are administered in a nasal spray device that delivers about 100 pd., of the formulation by a single actuation.
Formulations with An Alcohol [00041] In one embodiment, 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 an antioxidant or chelating agent. In a preferred embodiment, naloxone is in salt form.
[00042] In another embodiment, 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. In a preferred embodiment, naloxone is in salt form.
[00043] 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. In a more preferred embodiment, 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 co-solvent or about 50% w/w ethanol and 5 % w/w propylene glycol as co-solvent.
[00044] Suitable antioxidants include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), methionine, sodium ascorbate, sodium thiosulfate, thioglycerol, ascorbic Date recue/Date Received 2024-01-22 acid, ascorbyl palmitate, propyl gallate, dL-alpha-tocopherol, sodium sulfite, sodium metabisulfite, 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.
[00045] In a preferred embodiment, the amount of antioxidant included in the formulation is from about 0.001% to about 0.5% w/w.
[00046] In another preferred embodiment, the amount of antioxidant is about 0.01% w/w of BHA.
[00047] In an alternative embodiment, the antioxidant is a mixture of about 0.01% w/w of BHA and about 0.005% w/w of BHT.
[00048] In yet another embodiment, the antioxidant is about 0.01% w/w of sodium thi osul fate.
[00049] In a preferred embodiment, the antioxidant is about 0.3 % w/w dL
alpha-tocopherol.
[00050] In a most preferred embodiment, the antioxidant is about 0.02% w/w of sodium asc orb ate.
[00051] In the present formulations, water is used as the solvent.
Preferably, 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%, 31.32 %, 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.
[00052] In a preferred embodiment, 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.
[00053] In a most preferred embodiment, 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.
[00054] In another preferred embodiment, the formulations contain ethanol as the co-solvent.

Date recue/Date Received 202401-22 1000551 In yet another preferred embodiment, the formulations contain propylene glycol as the co-solvent.
[00056] In a more preferred embodiment, the formulations contain a mixture of ethanol and propylene glycol as the co-solvent.
[00057] In another embodiment, the formulations of the present invention contain a chelating agent. In a preferred embodiment, the chelating agent is edetate disodium dihydrate, (also known as edetate disodium or ethylenediaminetetraacetic acid disodium 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.
[00058] In a preferred embodiment, 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 10%
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.
[00059] In a preferred embodiment, 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.
[00060] In a preferred embodiment, 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, benzalkonium chloride ("BKC") in an amount from about 0.001% to 10 %
w/w and a combination thereof.
[00061] In another preferred embodiment, the formulation contains edetate disodium dihydrate as the chelating agent at 0.001 % w/w or 0.05 % w/w.
[00062] In yet another embodiment, 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-solvent 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%.

Date recue/Date Received 202401-22 In a preferred embodiment of the formulation, naloxone is a salt. In yet another preferred embodiment, 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.
[00063] In another preferred embodiment, the chelating agent is edetate disodium dihydrate, preferably at a concentration from about 0.001% to about 0.5% w/w.
[00064] In yet another embodiment, 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%, In a preferred embodiment of the formulation, naloxone is a salt. In another preferred embodiment, the formulation further comprises a preservative, preferably from about 0.01%
to about 0.5% w/w.
In a more preferred embodiment the chelating agent is edetate disodium dihydrate. In another preferred embodiment, the preservative is methyl paraben.
[00065] In another embodiment, formulations of the present invention do not contain a preservative.
[00066] In a further embodiment, 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% 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. In a preferred embodiment of this formulation, naloxone is a salt. In another preferred embodiment, the formulation also contains a preservative in an amount from about 0.05% to about 0.2% w/w. In yet another preferred embodiment, the formulation contains edetate disodium dihydrate as the chelating agent.
[00067] In a further embodiment, 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.
[00068] In another embodiment, the liquid spray formulations of the present invention do not contain an isotonicity agent.
Date recue/Date Received 202401-22 [00069] In another embodiment, the liquid spray formulations of the present invention do not contain sodium chloride.
[00070] In another embodiment, the liquid spray formulations of the present invention do not contain benzalkonium chloride.
[00071] In another embodiment, the liquid spray formulations of the present invention do not contain a buffer.
[00072] In another embodiment, the liquid spray formulations of the present invention do not contain citric acid.
[00073] In some embodiments, the formulations of the present invention contain citric acid or sodium hydroxide or hydrochloric acid solution as a pH adjustor.
[00074] Pharmaceutically acceptable salts that can be used in accordance with the current invention include but are not limited to hydrochloride, hydrochloride dihydrate, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-n aphth o ate)) salts.
[00075] In preferred embodiments, the pharmaceutically acceptable salt is hydrochloride.
[00076] Derivatives of naloxone that can be used in accordance with the current invention include but are not limited to 3-0-acyl, phenylhydrazone, and methiodide derivatives.
[00077] The solvent used with the present invention is United States Pharmacopeia ("USP") purified water.
[00078] Co-solvents that can be used in accordance with the current invention are alcohols, and glycols or a mixture thereof.
[00079] Alcohols that can be used in accordance with the current invention include but are not limited to methanol, ethanol (also known as dehydrated alcohol), propyl alcohol, butyl alcohol and the like, but do not include benzyl alcohol.
[00080] In formulations of the current invention that do not contain an alcohol, the term "alcohol" includes all alcohols including benzyl alcohol.

Date recue/Date Received 202401-22 [00081] 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.
[00082] In preferred embodiments, the co-solvent is ethanol or propylene glycol or a mixture thereof.
[00083] In another preferred embodiment, the amount of co-solvent included in 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.
[00084] In other more preferred embodiments 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 10% w/w ethanol.
[00085] Solubilizers that can be used in accordance with the current invention are hydroxypropyl beta-cyclodextrin ("HPI3CD") and sulfobutylether cyclodextrin or a mixture thereof.
[00086] In preferred embodiments, the solubilizer is HPI3CD.
[00087] In more preferred embodiments the amount of HPI3CD is about 30%
w/w.
[00088] 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, arachidonic acid, benzalkonium chloride (BKC), cetylpyridium chloride, edetate disodium dihydrate, sodium desoxycholate, sodium deoxyglycolate, sodium glycocholate, sodium caprate, sodium taurocholate, sodium hydroxybenzoyal amino caprylate, dodecyl dimethyl aminopropionate, L-lysine, glycerol oleate, glyceryl monostearate, citric acid, and peppermint oil.
Preferably the permeation enhancer is selected from the group consisting of menthol, benzalkonium chloride, edetate disodium dihydrate, caprylic acid, and a combination thereof.

Date recue/Date Received 202401-22 [00089] In preferred embodiments, the amount of permeation enhancer is from about 0.001% to about 10 % w/w. In a more preferred embodiment, 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.
[00090] In preferred embodiment, the permeation enhancer is L-menthol, caprylic acid, BKC, edetate disodium dihydrate (EDTA) or combination thereof, 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, and EDTA is from about 0.0005% to 0.1% w/w. In a more preferred embodiment, the formulations contain from about 0.01% to about 0.5% w/w L-menthol, about 0.5% to about 5% w/w caprylic 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. In an even more preferred embodiment, the formulations contain from about 0.02% to about 0.5%
w/w L-menthol, about 1% to about 2% w/w caprylic 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 caprylic acid, about 0.01 %
w/w BKC, about 0.005 % edetate disodium dihydrate, or a combination thereof.
[00091] In yet another embodiment, the permeation enhancer is about 0.5%
w/w of menthol.
[00092] In yet another preferred embodiment, the permeation enhancer is about 2.0 % w/w caprylic acid.
[00093] In a most preferred embodiment, the permeation enhancer is about 0.01% w/w of benzalkonium chloride (BKC).
[00094] In a most preferred embodiment, the permeation enhancer is about 0.005%, 0.01%, 0.015% or 0.02% w/w of edetate disodium dihydrate (EDTA).
[00095] In a further most preferred embodiment, the permeation enhancer is a combination of 2.0 % w/w caprylic acid and 0.01% w/w of benzalkonium chloride.
[00096] Formulations of the present invention may have a pH range from about 2.0 to about 7.0, preferably from about 3 to about 6 and more preferably from about 3 to about 4.5 pH, most preferably 3 or 4.5 01, pH adjustors that can be used in accordance with the present invention include but are not limited to citric acid and sodium hydroxide. In preferred embodiments, the amount of sodium hydroxide or citric acid is from about 0.002% to about 0.03%
w/w. In more Date recue/Date Received 202401-22 preferred embodiments, the amount of sodium hydroxide is about 0.015% w/w. In other more preferred embodiments, the amount of sodium hydroxide is about 0.012% w/w.
[00097] In a further embodiment, the formulation contains a permeation enhancer, a sweetener, a sweetness enhancer, a pH modifier, a flavoring agent, a preservative, or a combination thereof.
[00098] In a preferred embodiment, the formulations contain a sweetener. In a more preferred embodiment, the sweetener is selected from the group consisting of sucralose, aspartame, saccharin, dextrose, mannitol, glycerin, and xylitol. In a preferred embodiment, 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.
[00099] In another embodiment, the formulations contain a flavoring agent.
In a preferred embodiment, 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.
[000100] In yet another embodiment, the formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv(10) is from about 11 to about 35 microns during administration.
[000101] In a further embodiment, 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.
[000102] In yet another embodiment, the formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv(90) is from about 75 to about 600 microns during administration. Preferably, 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.

Date recue/Date Received 202401-22 Formulations Without An Alcohol [000103] In a further embodiment, 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.
[000104] In a further embodiment, 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.
[000105] In another embodiment, the stable liquid spray formulations of the present invention contain a preservative, preferably from about 0.01% to about 0.5%
w/w. In a more preferred embodiment, the preservative is methyl paraben.
[000106] In another embodiment, the stable liquid spray formulations of the present invention do not contain a preservative.
[000107] In another embodiment, the stable liquid spray formulations of the present invention are suitable for nasal administration.
[000108] In another embodiment, the liquid spray formulations of the present invention do not contain an isotonicity agent.
[000109] In another embodiment, the liquid spray formulations of the present invention do not contain sodium chloride.
[000110] In another embodiment, the liquid spray formulations of the present invention do not contain benzalkonium chloride.
[000111] In another embodiment, the liquid spray formulations of the present invention do not contain a buffer.
[000112] In another embodiment, the liquid spray formulations of the present invention do not contain citric acid.
[000113] In a preferred embodiment, the liquid spray formulation comprises from about 0.01% w/w to about 20 % w/w naloxone or a salt or derivative thereof. In a more preferred embodiment, the liquid spray foimulation 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.
Date recue/Date Received 202401-22 [000114] In another embodiment, the formulations contain from about 20% w/w to about 99% water. In a preferred embodiment, 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.
[000115] In an embodiment, 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/w glycerol. In a more preferred embodiment, the formulations contain from about 15% w/w to about 35% w/w glycerol.
[000116] In another embodiment, 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.
[000117] In another embodiment, the formulations contain from about 0.1%
w/w to about 50% w/w propylene glycol. In a more preferred embodiment, 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.
[000118] In another embodiment, the formulation contains a pharmaceutically acceptable salt of naloxone. In a preferred embodiment, the formulation contains a salt selected from the group consisting of hydrochloride, citrate, halide, phosphate, sulfate, acetate, ascorbate, maleate, succinate, carbonate, mesylate and lactate. One of skill in the art could use other pharmaceutically acceptable naloxone salts in the formulations of the present invention.
[000119] In a preferred embodiment, the antioxidant is selected from the group consisting of ascorbic acid, cysteine HC1 monohydrate, citric acid, ethylenediamine tetra acetic acid (EDTA), methionine, sodium citrate, sodium ascorbate, sodium thiosulfate, sodium metabisulfite, sodium bisulfite, glutathione and thioglycerol. Other appropriate antioxidants known by those of skill in the art could also be added to formulations of the present invention.
[000120] In a preferred embodiment, the formulations contain from about 0.0001% w/w to about 0.5% w/w of the antioxidant. In a more preferred embodiment, the formulations may contain Date recue/Date Received 202401-22 from about 0.005% w/w to about 0.2% w/w of the antioxidant. In a most preferred embodiment, the formulations contain 0.05%w/w or 0.02% w/w of the antioxidant.
[000121] In another embodiment, the formulations of the present invention contain a chelating agent. In a preferred embodiment, the chelating agent is edetate disodium dihydrate [000122] In an embodiment, 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.
[000123] In a further embodiment, the formulation contains a permeation enhancer, a sweetener, a sweetness enhancer, a pH modifier, a flavoring agent, a preservative, or a combination thereof.
[000124] In another embodiment, the formulation contains a permeation enhancer. In a preferred embodiment, the permeation enhancer is selected from the group consisting of menthol, limonene, carvone, methyl chitosan, caprylic acid pelargonic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, oleic acid, stearic acid, linolenic acid, arachidonic acid, polysorbates including Tween 80, sodium edetate, benzalkonium chloride (BKC), cetylpyridinium chloride, sodium lauryl sulfate, citric acid, sodium desoxycholate, sodium deoxyglycolate, glyceryl oleate, glyceryl monostearate, Sodium hydroxybenzoyal amino caprylate, sodium caprate, dodecyl dimethyl aminopropionate, L-lysine, sodium glycocholate, citric acid, peppermint oil and a combination thereof. In a more preferred embodiment, the permeation enhancer is selected from the group consisting of polysorbates including Tweenhi 80, sodium edetate, benzalkonium chloride (BKC), cetylpyridiniurn 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. In an even more preferred embodiment, the permeation enhancer is selected from the group consisting of menthol, caprylic acid and BKC.
[000125] In preferred embodiments, the amount of permeation enhancer is from about 0.001% to about 10 % w/w. In a more preferred embodiment, 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.

Date recue/Date Received 202401-22 [000126] In a preferred embodiment, 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. In a more preferred embodiment, 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. In an even more preferred embodiment, the formulations contain from about 0.02% to about 0.5%
w/w L-menthol, about 1% 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-menthol, about 2% w/w caprylic acid and about 0.005 w/w BKC.
[000127] In yet another embodiment, the permeation enhancer is about 0.5%
w/w of menthol.
[000128] In yet another preferred embodiment, the permeation enhancer is about 2.0 % w/w caprylic acid.
[000129] In a most preferred embodiment, the permeation enhancer is about 0.01% w/w of benzaikonium chloride (BKC).
[000130] In a preferred embodiment, the formulations contain a sweetener.
In a more preferred embodiment, the sweetener is selected from the group consisting of sucralose, aspartame, saccharin, dextrose, mannitol, glycerin, and xylitol. In a preferred embodiment, 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 a sweetener at about 0.8% w/w.
[000131] In a further embodiment, the formulation may contain a sweetness enhancer, an ammonium salt form of crude 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 crude and refined Glycyrrhizic Acid. Glycyrrhizic Acid is also available as a pure derivative in the sodium and potassium salt forms.
[000132] In another embodiment, the formulations contain a pH modifier. In a preferred embodiment, the pH modifier adjusts the pH of the formulation to from about 2 to about 7. In a more preferred embodiment, 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. In most preferred embodiments, the pH modifier adjusts the pH of the formulations to about 2.5, or 3, or 4.5 0.1.

Date recue/Date Received 202401-22 [000133] In another embodiment, the formulations contain a flavoring agent.
In a preferred embodiment, 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. 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 the flavoring agent at about 0.08% w/w.
[000134] In yet another embodiment, the formulations may contain a preservative. In a preferred embodiment, the preservative is selected from the group consisting of butyl paraben, methyl paraben, ethyl paraben, propyl paraben, sodium benzoate, and benzoic acid. In a preferred embodiment, the formulations contain from about 0.001% w/w to about 1% w/w of the preservative. In a more preferred embodiment, the formulations contain from about 0.005% w/w to about 0.2% w/w of the preservative. In a most preferred embodiment, the formulations contain methyl paraben as a preservative at about 0.1% w/w.
[000135] In a further embodiment, 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 dihych-ate and optionally, about 2%
to about 90% w/w of a co-solvent, preferably propylene glycol and the formulations do not contain an alcohol.
[000136] In a further embodiment, 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 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.
[000137] In a further embodiment, 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 Date recue/Date Received 202401-22 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.
[000138] In yet another embodiment, 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.
[000139] In a further embodiment, 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.
[000140] In yet another embodiment, the formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv(90) is from about 40 to about 150 microns during administration. Preferably, the formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv(90) is from about 60 to about 110 microns during administration.
[000141] All claims, aspects and embodiments of the invention, and specific examples thereof, are intended to encompass equivalents thereof.
[000142] In a further embodiment, the invention is directed to treating patients by administering the formulations (with or without an alcohol) of the present invention to the patient.
In a preferred embodiment, the formulations are administered in order to treat opioid dependence, opioid overdose, and/or congenital insensitivity to pain with anhidrosis.
Definitions [000143] As used herein, all numerical values relating to amounts, weights, and the like, that are defined as "about" each particular value is plus or minus 10%. For example, the phrase "about 10% w/w" is to be understood as "9% to 11% w/w." Therefore, amounts within 10%
of the claimed value are encompassed by the scope of the claims.
[000144] As used herein "% w/w" refers to the percent weight of the total formulation.
[000145] As used herein the term "effective amount" refers to the amount necessary to treat a patient in need thereof.
Date recue/Date Received 202401-22 [000146]
As used herein the term "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.
[000147]
As used herein the phrase "pharmaceutically acceptable" refers to ingredients that are not biologically or otherwise undesirable in a sublingual or intranasal dosage form.
[000148]
As used herein, "stable" refers to formulations which maintain greater than 95%
purity following at least four weeks at about 40 C.
[000149]
Preferably, the (alcohol and alcohol-free) formulations of the present invention are propellant free. As used herein, "propellant free" refers to a formulation that is not administered using compressed gas.
[000150]
As used herein, the term "isotonicity agent" refers to any compound used to alter or regulate the osmotic pressure of a formulation.
[000151]
As used herein, the twin "buffer" refers to any compound used to maintain the pH
of a formulation.
[000152]
The following examples are intended to illustrate the present invention and to teach one of ordinary skill in the art how to make and use the invention. They are not intended to be limiting in any way.
Examples Example 1: Preparation of Naloxone Formulations Containing Ethanol [000153]
Liquid spray formulations were created by first degassing ethanol and USP
purified water, separately. Next, the ethanol and purified water were each purged with nitrogen. Soluble excipients were then dissolved in either the ethanol or the purified water based on their solubility.
Next, the solutions were combined. Naloxone was added to the final solution and mixed until dissolved.
[000154] Strawberry flavor was used as the source of the flavoring agent.
Table 1. Stable Liquid Naloxone Spray Formulations Formulation Control #1A #2A #3A #4A #5A #6A #7A
Naloxone Hydrochloride 2.44 2.44 2.44 2.44 2.44 4M0 6.7 10.1 Dihydrate Water (USP) 37.56 37.55 37.55 37.54 37.54 34.45 33.23 29.83 Ethanol 55 55 55 55 55 55 55 Propylene Glycol 5 5 5 5 5 5 5 5 Date recue/Date Received 202401-22 L-menthol 0.05 Sodium Thiosulfate 0.01 0.01 Citric Acid 0.0025 Flavoring agent 0.08 MIN
Edetate disodiiim 0.005 0.005 0.005 0.005 0.005 0.005 dihydrate BHA 0.01 BHT 0.005 Waif Bir, Sodium Ascorbate 0.02 0.02 0.02 0.02 values = % w/w Example 2: Stability Testing of Naloxone Formulations The formulations listed in Table 1 were subjected to stability testing at 40 C
and 55 C 2 C under 75% 5% relative humidity for eight weeks. 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.
Amounts of particular impurities are listed in Tables 2A to 2F and 3A to 3H as a percentage of the area of each formulation along with amount of total impurities. "BQL" refers to "Below Quantifiable Limit" and "ND" refers to "Not Detected."
Tables 2A to 2F. Stability Data for Liquid Naloxone Spray Formulations stored at 40 C 2 C
under 75% 5% relative humidity 2A. Stability of Control Stored at 40 C
Naloxone RRT T=0 4 Weeks 8 Weeks Impurity C 0.66 ND 0.81% 0.92%
Impurity A 0.83 ND 0.37% 0.51%
Impurity F 0.93 ND ND ND
Impurity D 1.14 ND ND ND
Impurity E 2.85 ND 5.59% 5.53%
Impurity B 3.21 ND ND ND
0.30 ND 0.13% 0.18%
Unknown Impurities 0.50 ND 0.28% 0.46%
Total Impurities 0.00% 7.18% 7.60%

Date recue/Date Received 202401-22 2B. Stability of Form. #1A (with Sod. Thiosulphate & Citric Acid) Stored at 40 C
Naloxone RRT T=0 4 Weeks 8 Weeks Impurity C 0.66 _ ND BQL BQL
Impurity A 0.83 ND BQL BQL
Impurity F 0.93 ND ND ND
Impurity D 1.14 ND ND ND
Impurity E 2.85 ND ND ND
Impurity B 3.21 ND ND ND
Total Impurities 0.00% 0.00% 0.00%
2C. Stability of Form. #2A (with Sod. Thiosulphate & Edetate Disodium Dihydrate) Stored at 40 C
Naloxone RRT T=0 4 Weeks 8 Weeks Impurity C 0.66 ND BQL BQL
Impurity A 0.83 ND BQL BQL
Impurity F 0.93 ND ND ND
Impurity D 1.14 ND ND ND
Impurity E 2.85 ND ND ND
Impurity B 3.21 ND ND ND
Total Impurities 0.00% 0.00% 0.00%
2D. Stability of Form. #3A (with BHA & BHT) Stored at 40 C
Naloxone RRT T=0 4 Weeks 8 Weeks Impurity C 0.66 _ ND BQL BQL
Impurity A 0.83 ND BQL BQL
Impurity F 0.93 ND ND ND
Impurity D 1.14 ND ND ND
Impurity E 2.85 ND ND ND
Impurity B 3.21 ND ND ND
Total Impurities 0.00% 0.00% 0.00%
2E. Stability of Form. #4A (with Sod. Ascorbate and Edetate Disodium Dihydrate) Stored at 40 C
Naloxone RRT T=0 4 Weeks 8 Weeks Impurity C 0.66 ND BQL BQL
Impurity A 0.83 ND 0.15% 0.19%
Impurity F 0.93 ND ND ND

Date recue/Date Received 202401-22 Impurity D 1.14 ND ND ND
Impurity E 2.85 ND ND ND
Impurity B 3.21 ND ND ND
Total Impurities 0.00% 0.15% 0.19%
2F. Stability of Form. #5A (with Sod. Ascorbate and Edetate Disodium Dihydrate) Stored at Naloxone RRT T=0 4 Weeks 3 Months _ Assay (%) 100 97.77 97.6 Impurity C 0.66 ND ND 0.03 Impurity A 0.83 0.11 0.12 0.15 Impurity F 0.93 ND ND ND
Impurity D 1.14 ND ND ND
Impurity E 2.85 ND 0.13 0.13 Impurity B 3.21 ND ND ND
Total Impurities 0.11% 0.25% 0.29%
[000156] 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% wt/wt) and edetate disodium dihydrate (0.005% wt/wt) resulted in only 0.29% total impurities after 3 months.
Tables 3A to 3H. Stability Data for Liquid Naloxone Spray Formulations stored at 55 C 2 C
3A. Stability of Control Stored at 55 C
Naloxone RRT T=0 1 Week 2 Weeks 3 Weeks 4 Weeks 8 Weeks Impurity C 0.66 ND ND ND 0.54% 0.33% 0.35%

Impurity A 0.83 ND ND ND 1.31% 1.39% 1.59%

Impurity F 0.93 _ ND ND ND ND ND ND
Impurity D 1.14 ND ND ND ND ND ND
Impurity E 2.85 ND ND ND ND ND ND
Impurity B 3.21 ND ND ND ND ND ND
0.30 - - - 0.1% 0.32%
Unknown 0.35 - - - 0.15% 0.16% 0.08%

Impurities 0.50 - - - 0.83% 0.81% 0.67%

______________ 2.85 - - 4% 7.50% 6.65%

Date recue/Date Received 202401-22 Total Impurities 0.00% 0.00% 0.00% 6.83%
10.29% 9.66%
3B. Stability of Form. #1A (with Sod. Thiosulphate & Citric Acid) Stored at 55 C
Naloxone RRT T=0 . 1 Week 2 Weeks 3 Weeks 4 Weeks . 8 Weeks Impurity C 0.66 ND ND ND 0.12% 0.37% 0.29%
Impurity A 0.83 ND ND ND 0.14% 0.67% 1.01%
Impurity F 0.93 ND ND _ ND ND ND ND
Impurity D 1.14 ND ND ND ND ND ND
Impurity E 2.85 ND ND ND 0.55% 1.88% 1.52%
Impurity B 3.21 ND _ ND ND ND ND ND
Unknown 0.32 0.09% 0.25%
Impurities 0.52 - 0.06% 0.51% 0.59%
Total Impurities _ 0.00% 0.00% 0.00% 0.87% 3.52%
3.66%
3C. Stability of Form. #2A (with Sod. Thiosulphate & Edetate Disodium Dihydrate) Stored at 55 C
Naloxone RRT T=0 1 Week 2 Weeks 3 Weeks 4 Weeks 8 Weeks Impurity C 0.66 ND ND ND ND BQL BQL
Impurity A 0.83 , ND ND ND BQL 0.07% 0.11%
Impurity F 0.93 ND ND ND ND ND ND
Impurity D 1.14 ND ND ND ND ND ND
Impurity E 2.85 _ ND ND ND ND ND ND
Impurity B 3.21 ND ND ND ND ND ND
Unknown 0.52 0.08%
Impurities Total 0.00% 0.00% 0.00% 0.00% 0.07% 0.19%
Impurities 3D. Stability of Form. #3A (with BHA & BHT) Stored at 55 C
Naloxoni s 8 Weeks Impurity C 0.66 ND ND ND ND ND BQL
Impurity A 0.83 ND ND ND BQL 0.07% 0.13%
Impurity F 0.93 ND ND ND ND ND ND
Impurity D 1.14 ND ND ND ND ND ND
Impurity E 2.85 ND ND ND ND ND , ND
Impurity B 3.21 ND ND ND ND ND ND
Unknown 0.50 - - - 0.08%
Impurities Date recue/Date Received 202401-22 Total 0.00% 0.00% 1 0.00% 0.00% 0.07%
0.21%
impurities 3E. Stability of Form. #4A (with Sod. Ascorbate and Edetate Disodium Dihydrate) Stored at Naloxone RRT T=0 1 Week 2 Weeks 3 Weeks 4 Weeks 8 Weeks Impurity C 0.66 ND ND ND ND ND
0.06%
Impurity A 0.83 ND ND NI) 0.11% 0.19%
0.19%
Impurity F 0.93 ND ND ND ND ND ND
Impurity D 1.14 ND ND ND ND ND ND
Impurity E 2.85 ND ND ND ND ND ND
Impurity B 3.21 ND ND ND ND ND ND
Total 0.00% 0.00% 0.00% 0.11% 0.19% 0.25%
Impurities 3F. Stability of Form. # 5A (with Sod. Ascorbate and Edetate Disodium Dihydrate) Stored at Naloxone RRT T=0 2 Weeks 4 Weeks 6 Weeks 8 Weeks Assay (%) 100 102.37 98.75 98.51 100.76 Impurity C 0.66 ND ND ND ND 0.05%
Impurity A 0.83 0.11 0.14 0.15 0.19 0.17%
Impurity F 0.93 ND ND ND ND ND
Impurity D 1.14 ND ND ND ND ND
Impurity E 2.85 ND 0.13 0.11 0.12 0.12%
Impurity B 3.21 ND ND ND ND ND
0.49 - - - 0.06% 0.05%
Unknown 0.79 - - - 0.03%
Impurities 3.90 - - 0.05% 0.07% 0.05%
Total 0.11% 0.27% 0.31% 0.47% 0.44%
Impurities 3H. Stability of Form. #6A (with Sod. Ascorbate and Edetate Disodium Dihydrate) Stored at Naloxone RRT T=0 2 Weeks 4 Weeks 8 Weeks Assay (%) 100.00 101.35 102.69 102.99 Impurity C 0.66 ND BQL BQL 0.08%
Impurity A 0.81 BQL 0.08% 0.19% 0.18%
Impurity F 0.93 ND ND ND ND

Date recue/Date Received 202401-22 Impurity D _ 1.14 ND ND _ ND ND
Impurity E 2.85 0.04% 0.07% 0.06% 0.10%
Impurity B 3.21 ND ND ND 0.12%
Unknown 0.50 - 0.06%
Impurities Total Impurities 0.04% 0.15% 0.25% 0.54%
3G. Stability of Form. #7A (with Sod. Ascorbate and Edetate Disodium Dihydrate) Stored at RRT T=0 2 Weeks 4 Weeks 8 Weeks Assay (%) 100.00 100.91 100.92 102.05 Impurity C 0.66 ND 0.06% 0.05% 0.11%
Impurity A 0.81 BQL 0.11% 0.22% 0.17%
Impurity F 0.93 ND ND ND ND
Impurity D 1.14 ND ND ND ND
Impurity E 2.85 0.06% 0.07% 0.06% 0.11%
Impurity B 3.21 ND ND ND 0.13%
Unknown 0.50 - - 0.05%
Impurities 2.41 - 0.05%
Total Impurities 0.06% 0.24% 0.33% 0.62%
[000157] Similar to the stability study at 40 C, all of the formulations of the present invention had significantly fewer impurities at eight weeks compared to the control. The superior stability characteristics of the formulations of the present invention will allow the formulations to be effective when used by patients.
Example 3: Droplet Testing [000158] In order to determine the spray profile of Formulation #5A, it was subjected to standardized droplet testing. 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

27 Date recue/Date Received 202401-22 bioavailability. Sublingual and intranasal formulations should be able to maintain a consistent droplet size throughout its shelf life.
[000159] Droplet analysis was conducted using standard laser analysis procedures known by those of skill in the art. Droplet size distribution (Dv10, Dv50, Dv90, and Span were tested at two distances, 3 cm and 6 cm). Dv10 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-Dv10)/Dv50; %RSD refers to the percent relative standard deviation. The results of these tests can be seen below in Tables 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.
Table 4. Spray Profile of Naloxone Spray Formulation #5A, Particle Size at 3 cm Particle Size Formulation #5A
DV(10) DV(50) DV(90) %<10 pi Span Actuation 1 14.79 28.92 389.9 1.225 .. 12.97 Actuation 2 17.98 32.05 455.6 0.001 .. 13.65 3 cm Actuation 3 13.46 36.92 584.8 4.747 15.48 Average 15.41 32.63 476.8 1.991 14.03 Table 5. Spray Profile of Naloxone Spray Formulation #5A, Particle Size at 6 cm Particle Size Formulation #5A
DV(10) DV(50) DV(90) %<10 Span Actuation 1 20.58 38.64 498.6 1.918 .. 12.37 Actuation 2 18.67 37.59 529.4 1.537 .. 13.59 6 cm Actuation 3 21.26 36.44 452.3 1.767 11.83 Average 20.17 37.56 493.4 1.741 12.60 Table 6. Spray Profile of Naloxone Spray Formulation #5A, Spray Pattern at 3 cm Spray Pattern Formulation #5A
Dmin (mm) Dmax (mm) Ovality Ratio Actuation 1 21.2 33.4 1.577 3 cm Actuation 2 23.5 31.5 1.342

28 Date recue/Date Received 202401-22 Actuation 3 17.6 30.9 1.755 Average 20.8 31.9 1.558 Table 7. Spray Profile of Naloxone Spray Formulation #SA, Spray Pattern at 6 cm Spray Pattern Formulation #5A
Dmin (mm) Dmax (mm) Ovality Ratio Actuation 1 24.5 55.6 2.268 Actuation 2 34.3 49.7 1.447 6 cm Actuation 3 33.9 52 1.535 Average 30.9 52.4 1.750 Table 8. Spray Profile of Naloxone Spray Formulation #5A, Plume geometry data at 3 cm Plume Geometry Formulation #5A Angle Width (mm) (0) Actuation 1 28.7 51.1 Actuation 2 25.5 45.9 3 cm Actuation 3 35.4 60.4 Average 29.9 52.5 Table 9. Spray Profile of Naloxone Spray Foimulation #5A, Plume geometry data at 6 cm Plume Geometry Formulation #5A Angle Width (mm) (0) Actuation 1 54.3 48.4 Actuation 2 52.6 47.3 6 cm Actuation 3 Average 53.5 47.9 10001601 As can be seen in Tables 4 to 9, Formulation #5A of the present invention provided excellent plume geometry and spray patterns.
Example 4: Preparation of Naloxone Formulations that are Alcohol-Free 10001611 In order to prepare a naloxone liquid formulation, the components as indicated in "Table 10. The Components ofFormulation MP' below were weighed. The components were mixed until a clear solution was formed.

29 Date recue/Date Received 202401-22 [000162] Naloxone HCL dihydrate base U.S.P. was used as the source of naloxone in the formulations that follow. Methyl paraben, U.S.P., (available from Spectrum) was used as the preservative source. Strawberry flavor, Nat&Art 915.0543 U, (available from FONA) was used as the source of flavoring agent. Edetate Disodium Dihydrate, U.S.P., (available from Spectrum) was used as the source of chelating agent or as antioxidant. Water, U.S.P., purified, (available from RICCA) was used as the source of solvent.
Table 10. The Components of Formulation #1AF
Ingredients % w/w Naloxone HC1 Dihydrate 4.82 Sucralose 0.80 Methyl Paraben 0.10 0.08 Flavoring agent 0.05 Edetate Disodium Dihydrate Water USP 94.15 100.0 Example 5. Preparation of Additional Naloxone Liquid Formulations [000163] In order to prepare naloxone liquid formulations, the components as indicated in "Table 11. The Components of Control and Formulations #1AF to #6AF" below were weighed.
The components were mixed until a clear solution was formed.
Strawberry flavoring was used as the source of flavoring agent.
Table 11. The Components of Control and Formulations #1AF to #6AF
Formulation Control #1AF #2AF #3AF #4AF #5AF #6AF
Naloxone HCL Dihydrate 4.83 4.82 4.89 4.89 4.89 4.83 4.82 Water (USP) 94.19 94.15 95.01 94.08 93.98 94.16 94.15 Sucralose 0.8 0.8 0.8 0.8 0.8 0.8 Methyl Paraben 0.1 0.1 0.1 0.1 0.1 0.1 Flavoring 0.08 0.08 0.08 0.08 0.08 0.08 0.08 Edetate Disodium Dihydrate iL 0.05 0.005 0.05 0.05 0.005 0.05 L-cysteine Hydrochloride 11111 0.1 Monohydrate Sodium Ascorbate 0.02 0.02 pH 3.03 2.5 4.46 4.16 2.56 3.02 3 Date recue/Date Received 202401-22 Example 6: Stability Testing of Naloxone Formulations 10001641 The formulations listed in Table 11 were subjected to stability testing at 40 C and 55 C 2 C under 75% 5% relative humidity for eight weeks. The stability data was collected at zero, one, two, three, four, at 55 C and at zero, four 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. Amounts of particular impurities are listed in Tables 12Ato 12G and 13A to 13C as a percentage of the area of each formulation along with amount of total impurities. "BQL" refers to "Below Quantifiable Limit" and "ND" refers to "Not Detected." "Ppm" refers to parts per million.
Tables 12A to 12G. Stability Data for Liquid Naloxone Spray Formulations stored at 55 C
12A. Stability of Control Stored at 55 C
Naloxone RRT T=0 1 Week 55 C
Assay (%) 100 101.48 Impurity C 0.66 ND ND
Impurity A 0.83 0.15 0.15 Impurity F 0.93 ND ND
Impurity D 1.14 ND ND
Impurity E 3.20 0.07 0.62 Impurity B 3.40 ND ND
Unknown 0.49 0.07 Impurities 0.59 0.12 Total 0.22% 0.96%
Impurities 12B. Stability of Form. #2AF (with Sod. ascorbate & Edetate Disodium Dihydrate) Stored at Naloxone RRT T=0 1 Week 2 Weeks 3 Weeks 4 Weeks pH 4.469 4.21 4.239 4.02 4.224 Assay (%) 100 99.6 101.48 98.07 98.00 Impurity C 0.66 ND BQL BQL BQL BQL
Impurity A 0.83 BQL 0.09 0.28 0.27 0.18%
Impurity F 0.93 ND ND ND ND ND
Impurity D 1.14 ND ND ND ND ND

Date recue/Date Received 202401-22 Impurity E 3.20 ND ND ND ND ND
Impurity B 3.40 ND ND ND ND ND
0.33 - - 0.07 0.1 0.13 0.49 - 0.05 0.07 0.07%
Unknown 0.56 - 0.08 0.08 0.09 0.08 Impurities 0.59 - 0.07 0.12 0.14 0.14 3.90 - 0.09 0.15 0.13 0.14 _ Total Impurities 0.00% 0.33% 0.82% 0.80%
0.74%
12C. Stability of Form. #3AF (Edetate Disodium Dihydrate) Stored at 55 C
Naloxone RRT T=0 1 Weeks 2 Weeks 3 Weeks 4 Weeks pH 4.16 4.23 4.168 3.94 4.33 Assay (%) 100 100.5 100.7 98.03 98.63 Impurity C 0.66 ND ND ND ND ND
Impurity A 0.83 BQL BQL 0.21 0.18 0.07 Impurity F 0.93 ND ND ND ND ND
Impurity D 1.14 ND ND ND ND ND
Impurity E 3.20 0.13 0.11 0.09 0.09 0.08 Impurity B 3.40 ND ND ND ND ND
0.33 0.11 0.12 0.18 0.49 0.09 0.1 0.11%
Unknown 0.59 ND 0.12 0.11 0.14 0.15 Impurities 3.67 - , - - 0.07 , 3.90 - 0.08 0.14 0.13 0.13 Total Impurities 0.13% 0.31% 0.72% 0.76% 0.79%
12D. Stability of Form. #4AF (Edetate Disodium Dihydrate and L-Cysteine hydrochloride) Stored at 55 C
Naloxone RRT T=0 1 Week 2 Weeks 3 Weeks 4 Weeks pH 2.56 2.5 2.44 2.38 2.413 _ Assay (%) 100 98.5 100.03 97.87 98.59 Impurity C 0.66 ND ND 0.13 0.11 0.09%
Impurity A 0.83 BQL ND 0.22 0.29 0.17%
Impurity F 0.93 ND ND ND ND ND

Date recue/Date Received 202401-22 Impurity D L14 ND ND ND ND ND
Impurity E 3.20 ND ND ND ND ND
Impurity B 3.40 ND ND ND ND ND
Unknown 0.56 NI) ND 0.05 0.07 0.06 Impurities Total Impurities 0.00% 0.00% 0.40% 0.47% 0.32%
12E. Stability of Form. #5AF (Edetate Di sodium dihydrate and Sodium ascorbate) Stored at Naloxone RRT T=0 1 Week 2 Weeks pH NP NP 3.185 Assay (%) _ 100 98.37 98.12 Impurity C 0.66 ND BQL BQL
Impurity A 0.83 0.15 0.18 0.11 Impurity F 0.93 ND ND ND
Impurity D 1.14 ND ND ND
Impurity E 3.20 0.07 0.16 0.12 Impurity B 3.40 ND ND ND
Total Impurities 0.22% 0.34% 0.23%
12F. Stability of Form. #6AF (Edetate Disodium Dihydrate) Stored at 55 C
Naloxone RRT T=0 1 Week 2 Weeks 3 Weeks 4 Weeks pH 3.013 3.443 3.132 3.241 3.21 Assay (%) 100.00% 98.34% 98.36% 98.34% 100.07%
Impurity C 0.66 0.10% 0.10% 0.21% 0.13% ..
0.13%
Impurity A _ 0.83 BQL BQL BQL BQL BQL
Impurity F _ 0.93 ND ND ND ND ND
7479 1.
Impurity D 1.14 ND 0.83 ppm 1. ND
PPm PPm Impurity E 3.20 0.15% 0.15% 0.15% 0.17%
0.17%
Impurity B 3.40 ND ND ND ND ND
Unknown 0.49 0.06% 0.06% 0.12%
Impurities 0.77 - - BQL BQL 0.05%
Total Impurities 0.25% 0.25% 0.42% 0.36% 0.47%

Date recue/Date Received 202401-22 12G. Stability of Form. #1AF (Edetate Disodium Dihydrate) Stored at 55 C
Naloxone RRT T=0 1 Week 2 Weeks 3 Weeks 4 Weeks pH 2.505 2.907 2.581 2.616 2.62 Assay (%) 100.00% 107.80% 100.51% 100.17% 102.39%
Impurity C 0.66 0.10% 0.10% 0.10% 0.10% 0.09%
Impurity A 0.83 BQL BQL BQL BQL BQL
Impurity F 0.93 ND ND ND ND ND
Impurity D 1.14 NP 0.95 ppm 1.25 ppm 1.59 ppm ND
Impurity E 3.20 0.15% 0.14% 0.15% 0.16% 0.18%
Impurity B 3.40 ND ND ND ND ND
0.06 0.13% 0.13% 0.13% 0.13% ND
Unknown 0.49 0.08% 0.06% 0.05%
Impurities 4.63 ND ND ND BQL ND
Total Impurities 0.38% 0.37% 0.46% 0.45% 0.32%
[000165] 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 disoditun dihydrate were very stable.
Tables 13A to 13C. Stability Data for Liquid Naloxone Spray Formulations stored at 40 C under 75% Relative Humidity 13A. Stability of Form. #2AF (with Sod. ascorbate & Edetate Disodium Dihydrate) Stored at 40 C under 75% Relative Humidity Naloxone RRT T=0 4 Weeks pH 4.469 4.394 Assay (%) 100 98.12 Impurity C 0.66 ND 0.06 Impurity A 0.83 BQL 0.12 Impurity F 0.93 ND ND
Impurity D 1.14 ND ND
Impurity E 3.20 ND ND

Date recue/Date Received 202401-22 Impurity B 3.40 ND ND
0.49 ND 0.06 Unknown 0.59 ND 0.06 Impurities 3.90 ND 0.14 Total Impurities 0.00% 0.44%
13B. Stability of Form. #3AF (Edetate Disodium Dihydrate) Stored at 40 C under 75% Relative Humidity Naloxone RRT T=0 4 Weeks pH 4.16 4.596 Assay (%) 100 99.69 Impurity C 0.66 ND ND
Impurity A 0.83 BQL BQL
Impurity F 0.93 ND ND
Impurity D 1.14 ND ND
Impurity E 3.20 0.13 ND
Impurity B 3.40 ND ND
Unknown 0.59 ND 0.11 Impurities 3.90 ND 0.11 Total Impurities 0.13% 0.22%
13C. Stability of Form. 111AF (Edetate Disodium Dihydrate and L-Cysteine hydrochloride) Stored at 40 C under 75% Relative Humidity Naloxone RRT T=0 Weeks pH 2.56 2.502 Assay (%) 100 97.08 Impurity C 0.66 ND ND
Impurity A 0.83 BQL BQL
Impurity F 0.93 ND ND
Impurity D 1.14 ND ND
Impurity E 3.20 ND ND
Impurity B 3.40 ND ND
Total Impurities 0.00% 0.00%
Date recue/Date Received 202401-22 10001661 The naloxone formulations of the present invention contained less than 0.45% of total impurities after four weeks at 40 C.
Example 7: Freeze/Thaw Testing 10001671 In order to further determine the stability of Formulations #1AF
and #6AF, the formulations were subjected to standard freeze/thaw stability testing. The results are below in "Table 14. Stability of Formulations filAF and it-6AF to Freeze/Thaw Testing."
Table 14. Stability of Formulations #1AF and #6AF to Freeze/Thaw Testing Formulation #1AF to Drug Cycle 1, - Cycle 1, Cycle 2, - Cycle 2, Cycle 3, - Cycle 3, #6AF Substance t=0 20 C 25 C 20 C 25 C 20 C

Date Observed:

Physical appearance clear clear clear clear clear Clear clear clear Color colorless colorless colorless colorless colorless colorless colorless Colorless [000168] The naloxone formulations #1AF to #6AF were clear and colorless after several cycles of freezing and thawing. This study further demonstrates the stability of the formulations.
Example 8: Droplet Testing [000169] In order to determine the spray profile of Formulation #1AF, it was subjected to standardized droplet testing. As previously explained, 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 throughout its shelf life.
10001701 Droplet analysis was conducted using standard laser analysis procedures known by those of skill in the art. Droplet size distribution (Dv10, Dv50, Dv90, and Span were tested at two distances, 3 cm and 6 cm). Dv10 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-Dv10)/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.

Date recue/Date Received 202401-22 The testing also revealed that the formulation dose remains consistent when administered with a spray pump.
Table 15. Spray Profile of Naloxone Spray Formulation #1AF, Particle Size at 3 cm Particle Size Fonnulati on #1AF
DV(10) DV(50) DV(90) %<10 II Span Actuation 1 13.16 26.23 63.21 2.792 1.908 Actuation 2 11.52 27 90.85 6.547 2.939 3 cm Actuation 3 12.95 28.39 144 3.505 4.615 Average 12.54 27.21 99.4 4.281 3.15 Table 16. Spray Profile of Naloxone Spray Formulation #1AF, Particle Size at 6 cm Particle Size Formulation #1AF
DV(10) DV(50) DV(90) %<l0j.t Span Actuation 1 20.18 32.51 53.9 1.198 1.037 Actuation 2 18.02 31.45 58.48 0.024 1.286 6 cm Actuation 3 16.81 33.44 77.92 1.799 1.828 Average 18.34 32.47 63.4 1.007 1.38 Table 17. Spray Profile of Naloxone Spray Formulation #1AF, Spray Pattern at 3 cm Spray Pattern Faimulation #1AF
Dmin (mm) Dmax (mm) Ovality Ratio Actuation 1 26.5 41.3 1.557 Actuation 2 24.8 43.5 1.751 3 cm Actuation 3 29 40.6 1.402 Average 26.8 41.8 1.570 Table 18. Spray Profile of Naloxone Spray Formulation #1AF, Spray Pattern at 6 cm Spray Pattern Formulation #1AF
Dmin (mm) Dmax (mm) Ovality Ratio Actuation 1 52.6 68.6 1.304 Actuation 2 40.3 61.4 1.524 6 cm Actuation 3 47.5 59.7 1.256 Average 46.8 63.2 1.361 Table 19. Spray Profile of Naloxone Spray Formulation #1AF, Plume geometry data at 3 cm Date recue/Date Received 202401-22 Plume Geometry Formulation #1AF
Width (mm) Angle ( ) Actuation 1 39.7 66.7 Actuation 2 37.7 64.3 3 cm Actuation 3 33.5 58 Average 37.0 63.0 Table 20. Spray Profile of Naloxone Spray Formulation #1AF, Plume geometry data at 6 cm Plume Geometry Formulation #1AF
Width (mm) Angle ( ) Actuation 1 63 54.9 Actuation 2 67.1 58.3 6 cm Actuation 3 68 59 Average 66.0 57.4 10001711 As can be seen in Tables 15 to 20, Formulation #1AF of the present invention provided excellent plume geometry and spray patterns.
Example 9. Preparation of Additional Naloxone Liquid Formulations 10001721 In order to prepare naloxone liquid formulations, the components as indicated in "Table 21. The Components of Formulations #8A, #9A, #7AF and #8AF" below were weighed.
The components were mixed until a clear solution was formed.
Strawberry flavoring was used as the source of flavoring agent.
Table 21. The Components of Formulations #8A, #9A, #7AF and #8AF
Formulation Control #8A #9A #7AF #8AF
Naloxone 2.44 10.419 10.265 4.4196 4.4196 Water (USP) 37.56 29.506 31.324 94.769 94.779 Ethanol 55 55 50 111111111 -Propylene Glycol 5 5 5 L-menthol 0.05 0.5 Egg BKC 0.01 O.() I
Sodium Chloride Flavoring agent 0.08 I
aletate disodium dihydrate 111 0.005 F 0.001 0.001 0.001 Sucralose 0.8 Caprylic Acid 2 Date recue/Date Received 202401-22 Sodium Ascorbate 0.02 0.02 DID
pH- 4.5 0.2 Example 10. Preparation of Additional Naloxone Nasal Spray Formulations [000173] 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.
Table 22. Stable Naloxone Nasal Spray Formulations #10A #11A #12A #13A #14A #15A #16A
Naloxone 9.49 8.85 8.75 8.57 4.0 8.75 8.75 Water (USP) 35.505 66.14 71.135 79.31 83.88 81.135 81.135 Ethanol 50.0 20.0 10.0 2.0 2.0 10.0 10.0 Propylene Glycol 5.0 5.0 10.0 10.0 10.0 -EDTA 0.005 0.01 0.015 0.02 0.02 0.015 0.015 Methyl Paraben - 0.1 0.1 0.1 0.1 0.1 pH 4.5 0.1 4.5 0.1 4.5 0.1 4.5 0.1 4.5 0.1 4.5 0.1 3.0 0.1 Table 23. Stable Naloxone Nasal Spray Formulations #17A #18A #19A #20A
Naloxone 2.405 2.52 4.788 4.477 Water (USP) 42.594 72.738 40.207 40.513 Ethanol 50.0 20.0 50.0 20.0 Propylene Glycol 5.0 5.0 5.0 5.0 EDTA 0.005 0.01 0.005 0.01 pH 4.5 0.1 4.5 0.1 4.5 0.1 4.5 0.1 values = % w/w Table 24. Stable Non-Alcoholic Naloxone Nasal Spray Formulations #9AF #10AF #11AF #12AF
Naloxone 4.83 4.4 8.55 4.0 Water (USP) 95.02 90.495 81.33 85.88 Propylene Glycol - 5.0 10.0 10.0 Date recue/Date Received 2024-01-22 EDTA 0.05 0.005 0.02 0.02 Methyl Paraben 0.1 0.1 0.1 0.1 pH 3.0+0.1 4.5+0.1 4.5+0.1 4.5+0.1 values = % w/w 10001741 All formulations of Tables 22, 23 and 24 were stable upon mixing.
Formulations of Tables 22, 23 and 24 differ from prior art naloxone nasal spray formulations because the formulations of Tables 22, 23 and 24 do not contain an isotonicity agent, specifically sodium chloride, a buffer, specifically citric acid, an anti-microbial agent, specifically benzyl alcohol or benzalkonium chloride. Further, formulations of Tables 22, 23 and 24 contain EDTA at a concentration of no more than 0.05% w/w.
Table 25. Stability of Formulations # 9A and # 8A to Freeze/Thaw Testing Drug Cycle 1, Cycle 1, Cycle 2, Cycle 2, Cycle 3, Cycle 3, Formulation Substance t4I 20 C 40 C 20 C 40 C 20 C

Date Observed:

Physical appearance clear clear clear clear clear Clear clear clear Color colorless colorless colorless colorless colorless colorless colorless Colorless [000175] The naloxone formulations #8A and #9A were clear and colorless after several cycles of freezing and thawing. This study further demonstrates the stability of the formulations.
Example 11: Droplet Testing [000176] In order to determine the spray profile of Formulation #9A, it was subjected to standardized droplet testing. As previously explained, 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 throughout its shelf life.
[000177] Droplet analysis was conducted using standard laser analysis procedures known by those of skill in the art. Droplet size distribution (Dv10, Dv50, Dv90, and Span were tested at Date recue/Date Received 202401-22 two distances, 3 cm and 6 cm). Dv10 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-Dv10)/Dv50; %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.
Table 26. Spray Profile of naloxone Spray Formulation #9A, Particle Size at 3 cm Particle Size Formulation #9A
DV(10) DV(50) DV(90) %<10p, Span Actuation 1 23.06 44.28 99.7 0 1.731 Actuation 2 22.08 44.34 104.4 0.661 1.856 3 cm Actuation 3 22.27 55.05 107.5 1.012 2.82 Average 22.47 47.89 103.9 0.558 2.14 Table 27. Spray Profile of Naloxone Spray Formulation #9A, Particle Size at 6 cm Particle Size Formulation #9A
DV(10) DV(50) DV(90) %<10p Span Actuation 1 28.54 51.29 91.87 2.113 1.235 Actuation 2 25.75 50.01 103.7 1.594 1.56 6 cm Actuation 3 31.99 51.77 85 0 1.024 Average 28.76 51.02 93.5 1.236 1.27 Table 28. Spray Profile of Naloxone Spray Formulation #9A, Spray Pattern at 3 cm Spray Pattern Formulation #9A Dmin Dmax Ovality (mm) (mm) Ratio Actuation 1 14.7 22.7 1.544 Actuation 2 14.4 21.8 1.517 3 cm Actuation 3 15.2 20.9 1.372 Average 14.8 21.8 1.478 Table 29. Spray Profile of Naloxone Spray Formulation #9A, Spray Pattern at 6 cm Date recue/Date Received 202401-22 Spray Pattern Formulation #9A Dmin Dmax Ovality (mm) (mm) Ratio Actuation 1 23.5 30.4 1.291 Actuation 2 24.5 41.8 1.707 6 cm Actuation 3 20.5 32.7 1.597 Average 22.8 35.0 1.532 Table 30. Spray Profile of Naloxone Spray Formulation #9A, Plume geometry data at 3 cm Plume Geometry Formulation #9A
Width (mm) Angle ( ) Actuation 1 22.5 39.9 Actuation 2 15.5 28.6 3 cm Actuation 3 25.7 44.3 _ Average 21.2 37.6 Table 31. Spray Profile of Naloxone Spray Formulation #9A, Plume geometry data at 6 cm Plume Geometry Formulation #9A
Width (mm) Angle ( ) Actuation 1 26.4 24.3 Actuation 2 25 23.3 6 cm Actuation 3 37.6 33.2 Average 29.7 26.9 Table 32. Spray Profile of Naloxone Spray Formulation # 10A, Particle Size at 3 cm Particle Size Formulation # 10A
DV(10) DV(50) DV(90) %<10g Span Actuation 1 19.84 46.86 112.10 3.744 2.011 3 cm Actuation 2 21.21 48.69 110.70 2.503 1.837 Average 20.53 47.77 111.40 1.924 3.124 Table 33. Spray Profile of Naloxone Spray Formulation # 10A, Spray Pattern at 3 cm Formulation # 10A Spray Pattern Date recue/Date Received 202401-22 Dmin Dmax Ovality ________________________________ (mm) (mm) Ratio 14.6 18.4 14.6 1.261 14.1 17.9 14.1 1.265 3 cm 15.1 17.9 15.1 1.182 14.6 18.1 14.6 1.2 Table 34. Spray Profile of Naloxone Spray Formulation # 10A, Spray Pattern at 6 cm Spray Pattern Formulation # 10A Dmin Dmax Ovality (mm) (mm) Ratio Actuation 1 23.7 29.8 1.259 Actuation 2 20.2 31.6 1.566 6 cm Actuation 3 22.0 32.0 1.453 Average 22.0 31.20 1.40 Table 35. Spray Profile of Naloxone Spray Formulation #10A, Plume geometry data at 3 cm Plume Geometry Formulation # 10A
Width (mm) Angle ( ) Actuation 1 36.7 19.97 3 cm Actuation 2 36.82 19.97 Average 36.76 19.97 Table 36. Spray Profile of Naloxone Spray Formulation # 10A, Plume geometry data at 6 cm Plume Geometry Formulation #10A
Width (mm) Angle ( ) Actuation 1 27.23 29.29 6 cm Actuation 2 21.96 23.3 Average 24.60 26.30 Table 37. Spray Profile of Naloxone Spray Formulation # 11A, Particle Size at 3 cm Particle Size Formulation # 11A
DV(10) _ DV(50) DV(90) %<101.1 Span Actuation 1 15.7 38.14 90.81 4.56 1.969 3 cm Actuation 2 15.11 37.9 86.75 5.09 1.89 Average 15.405 38.02 88.78 4.83 1.93 Date recue/Date Received 202401-22 Table 38. Spray Profile of Naloxone Spray Formulation # 11A, Spray Pattern at 3 cm Spray Pattern Formulation # 11A Dmin Dmax Ovality (mm) (mm) Ratio Actuation 1 15.9 22.4 1.410 Actuation 2 18.8 20.4 1.086 3 cm Actuation 3 16.2 22.5 1.392 Average 16.9 21.8 1.30 Table 39. Spray Profile of Naloxone Spray Formulation # 11A, Spray Pattern at 6 cm Spray Pattern Formulation # 11A Dmin Dmax Ovality (mm) (mm) Ratio Actuation 1 20.8 29.4 1.411 Actuation 2 20.8 31.1 1.495 6 cm Actuation 3 23.1 31.8 1.376 Average 21.6 30.8 1.40 Table 40. Spray Profile of Naloxone Spray Formulation #11A, Plume geometry data at 3 cm Plume Geometry Formulation # 11A
Width (mm) Angle ( ) Actuation 1 31.30 19.98 3 cm Actuation 2 36.63 19.97 Average 33.97 19.98 Table 41. Spray Profile of Naloxone Spray Formulation # 11A, Plume geometry data at 6 cm Plume Geometry Formulation #11A
Width (mm) Angle ( ) Actuation 1 21.1 16.98 6 cm Actuation 2 21.22 22.64 Average 21.16 19.81 10001781 As can be seen in Tables 26 to 41, Formulation #9A, # 10A, and 11A of the present invention provided excellent plume geometry and spray patterns.

Date recue/Date Received 202401-22 Example 12. Pharmacokinetic Analysis [000179] The naloxone formulations described in Example 9, Table 21 of the instant specification were used. For formulations #7AF and #8AF a 4-mg dose was administered. For formulations #8A and #9A a 16-mg dose was administered.
Pharmacokinetic and Bioavailability Analysis [000180] 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 administration.
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 chromatography-tandem mass spectrometry.
[000181] The following pharmacokinetic parameters were calculated: peak concentration in plasma (Cmax) and area under the concentration-time curve from time-zero to the time of the last quantifiable concentration (AUCo-t).
Results and Conclusions [000182] Results of the pharmacokinetic and statistical analysis for the naloxone formulations in Table 21 of the present invention are shown in Table 42.
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.
Parameter* #7AF #8AF #8A #9A
#9A (repeat) C. (ng/mL) 8.9 2.2 6.8 2.2 26.3 1.8 86.4 2.4 58.6 2.8 Conc. @ 1 min NA 0.1 NA 24.2 NA
(ng/mL) Conc. @ 3 min 0.2 0.3 5 68.5 12.9 (ng/mL) Conc. @ 5 min 1.4 1.9 6.3 62.7 36.9 (ng/mL) Conc. @ 7 min 1.6 2.6 9.1 28.8 50.5 (ng/mL) 746.2 2.2 432.3 2.0 2382.5 2.0 3108.5 2.2 3564.8 2.8 (ng*min/mL) AUC @ 15 min 41.6 38 188.2 615.8 515.6 (ng*min/mL) Date recue/Date Received 202401-22 AUC @ 30 min 151.8 106.8 504.4 987.4 1063.3 (ng*min/mL) *Geometric mean geometric standard deviation. Sample size is 5.
10001831 The peak mean naloxone concentration was significantly higher for formulation #9A and #8A over #8AF and #7AF. Additionally, the area under the concentration-time curve from time-zero to the time of the last quantifiable concentration was significantly higher for formulations #9A and #8A 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 normalization. Further, the peak mean naloxone concentration was significantly higher for formulation #9A, over #8A, which cannot be explained by the dosage as formulations #9A and #8A were each administered at 16 mg doses.
[000184] Additionally, formulation #9A reached about 80% of its peak mean naloxone concentration within 3 minutes of administration. In comparison, formulation #8A had reached only 35% of its peak mean naloxone concentration within 7 minutes, #8AF 38% in 7 minutes and #7AF 19% in 7 minutes. In a similar comparison formulation #9A reached 19%
of its AUC(0_0 within 15 minutes of administration, #8A reached 7.9% in 15 minutes, #8AF reached 8.8% in 15 minutes and #7AF reached 5.6% in 15 minutes.
[000185] Administration of naloxone in formulations with co-solvents resulted in superior bioavailability. Compare formulation #9A and #8A to #8AF and #7AF. Further, the addition of permeation enhancers such as caprylic acid and BKC resulted in further increase in bioavailability. Compare formulations #9A to #8A and #7AF to #8AF.
Example 13. Stability testing of additional Naloxone Formulations [000186] Formulation #9A, # 10A, and 11A 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 nm 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.
Table 43A. Stability Data for the Formulation #9A Stored at 25 C 2 C /60%
+5% RH

Date recue/Date Received 202401-22 Naloxone RRT T=0 4 Weeks 3 Months 6 months Clear, Physical appearance (Clarity, Clear, Clear, Clear, Pale yellow Color) Colorless Colorless Colorless Assay (%) 100 98.7 99.01 98.89 Impurity C 0.53 ND 0.01 ND ND
Impurity A 0.63 0.02 0.03 0.02 0.04 Impurity F 0.93 ND ND ND ND
Impurity D 1.14 , ND ND ND , ND
Impurity E 1.42 0.05 0.02 0.02 0.03 Impurity B 1.87 ND ND ND ND
Unknown Impurities 0.90 ND ND 0.07 0.04 1.48 ND 0.01 0.05 0.1 Total Impurities 0.07% 0.07% 0.16%
0.21%
ND = Not Detected ppm = parts per million Table 43B. Stability Data for the Formulation #9A Stored at 40 C 2 C / 75 %
5% RH
Naloxone RRT T=0 4 Weeks 3 Months 6 months Clear, Physical appearance Clear, Clear, Clear, light light brownish (Clarity, Color) Colorless light yellow yellow brownish yellow Assay (%) 100 99.09 98.63 98.08 Impurity C 0.53 ND 0.01 0.01 0.02 Impurity A 0.63 0.02 0.04 0.06 0.16 Impurity F 0.93 ND ND ND ND
Impurity D 1.14 ND ND ND ND
Impurity E 1.42 0.05 _ 0.01 0.01 0.02 Impurity B 1.87 ND ND ND ND
0.56 ND 0.05 0.04 0.10 0.71 ND _ 0.04 _ 0.03 0.06 0.79 ND ND 0.01 0.05 0.90 ND ND 0.05 ND
Unknown Impurities 1.23 ND ND ND 0.05 1.27 ND _ ND 0.02 0.05 1.48 ND 0.07 0.14 0.21 1.56 ND ND ND 0.07 1.84 ND ND 0.05 0.02 Date recue/Date Received 202401-22 Total Impurities 0.07% 0.22% 0.42% 0.81%
ND = Not Detected ppm = parts per million Table 43C. Stability Data for the Formulation # 9A Stored at 55 C 2 C
Naloxone RRT T=0 4 Weeks 6 Weeks 8 Weeks Physical appearance Clear, Clear, Clear, Clear, (Clarity, Color) Colorless yellow yellow yellow Assay (%) 100 97.28 97.28 94.28 Impurity C 0.53 ND 0.03 0.03 0.04 Impurity A 0.63 0.02 0.21 0.28 0.39 Impurity F 0.93 ND ND ND ND
36 9.
Impurity D 1.14 ND ND ND
, PPm Impurity E 1.42 0.05 0.05 0.05 0.05 Impurity B 1.87 ND ND ND ND
0.56 ND 0.13 0.14 0.19 0.71 ND 0.06 0.07 0.06 0.79 ND 0.08 0.11 0.19 1.13 ND 0.01 0.05 0.05 1.23 ND 0.04 0.06 0.08 Unknown Impurities 1.30 ND ND ND 0.06 1.38 ND 0.02 0.06 0.12 1.48 _ ND 0.11 0.12 0.13 1.54 ND 0.06 0.07 0.15 1.66 ND 0.03 0.05 ND
Total Impurities 0.07% 0.83% 1.09% 1.51%
Table 43D. Stability Data for the Formulation # 10A Stored at 25 C 2 C / 60%
5% RH
Naloxone RRT T=0 4 Weeks 8 Weeks Physical appearance Clear, Clear, Clear, (Clarity, Color) Colorless Colorless Colorless Assay (%) 100 98.9 101.55 Naloxone N-oxide ND NT) NT) Impurity C 0.53 ND ND ND
Impurity A 0.63 ND ND ND

Date recue/Date Received 202401-22 Impurity F 0.93 ND ND ND
Impurity D 1.14 ND ND ND
Impurity E 1.42 0.05 0.04 0.04 Impurity B 1.87 ND ND ND
1.07 0.07 0.08 0.1 1.50 ND 0.07 0.11 Total Impurities 0.12% 0.19% 0.25%
Table 43E. Stability Data for the Formulation # 10A Stored at 40 C 2 C /75 % 5% RH
Naloxone RRT T-0 4 Weeks 8 Weeks Physical appearance Clear, Clear, Clear, (Clarity, Color) Colorless Colorless Colorless Assay (%) 100 100.65 99.4 Naloxone n-oxide ND 0.02 NP
Impurity C 0.53 ND ND ND
Impurity A 0.63 ND 0.01 ND
Impurity F 0.93 ND ND ND
Impurity D 1.14 ND ND NP
Impurity E 1.42 0.05 0.04 0.14 Impurity B 1.87 ND ND ND
0.71 0.01 0.05 0.03 Unknown Impurities 1.07 0.07 0.05 0.08 1.50 ND 0.14 0.21 Total Impurities 0.13% 0.31% 0.46%
Table 43F. Stability Data for the Formulation # 10A Stored at 55 C 2 C
Naloxone RRT T=0 1 Weeks , 2 Weeks 4 Weeks 8 Weeks Physical Clear, Clear, Clear, Clear, Clear, appearance Light Colorless Colorless yellow yellow (Clarity, Color) yellow -Assay (%) 100 98.11 98.89 99.96 100.34 Naloxone n-ND ND 0.05 0.03 NP
oxide Impurity C 0.53 ND 0.01 0.01 0.01 0.01 Date recue/Date Received 202401-22 Impurity A 0.63 ND 0.02 0.02 0.03 0.03 Impurity F 0.93 ND ND ND ND ND
Impurity D 1.14 ND ND 2.31 ppm NP NP
Impurity E 1.42 0.05 0.04 0.02 0.01 0.02 _ Impurity B 1.87 ND ND ND ND ND
0.56 ND 0.02 0.02 0.02 0.06 0.71 0.01 0.05 0.03 0.02 0.03 0.75 ND ND 0.03 0.03 0.05 Unknown 1.07 0.07 0.07 0.07 0.07 0.07 Impurities 1.27 ND ND ND 0.04 0.08 1.30 ND ND 0.01 0.04 0.05 1.39 ND ND 0.02 0.03 0.05 1.50 ND 0.1 0.14 0.17 0.18 Total Impurities 0.13% 0.31% 0.42% 0.50% 0.63%
Table 43G. Stability Data for the Formulation # 11A Stored at 25 C 2 C / 60%
5% RH
Naloxone RRT T=0 4 Weeks 8 Weeks Physical appearance (Clarity, Clear, Clear, Clear, Color) Colorless Colorless Colorless Assay (%) 100 101.44 104.95 Naloxone n-oxide ND ND NP
Impurity C 0.53 ND ND ND
Impurity A 0.61 ND ND 0.01 Impurity F 0.93 ND ND ND
Impurity D 1.14 ND ND ND
Impurity E 1.42 0.03 0.09 0.03 Impurity B 1.87 ND ND ND
0.71 0.02 0.05 0.06 Unknown Impurities 1.07 0.07 0.1 0.1 1.50 ND 0.02 0.04 Total Impurities 0.12% 0.17% 0.24%
Table 43H. Stability Data for the Formulation # 11A Stored at 40 C 2 C /75 % 5% RH
Naloxone RRT T=0 4 Weeks 8 Weeks Date recue/Date Received 202401-22 Physical appearance Clear, Clear, Clear, (Clarity, Color) Colorless Colorless Colorless Assay (%) 100 100.39 101.31 Naloxone n-oxide ND 0.02 ND
Impurity C 0.53 ND 0.01 ND
_ Impurity A 0.61 ND 0.02 0.03 _ Impurity F 0.93 ND ND ND
Impurity D 1.14 ND ND ND
_ Impurity E 1.42 0.03 0.05 0.04 Impurity B 1.87 ND ND ND
0.71 0.02 0.06 0.04 1.07 0.07 0.05 0.06 Unknown Impurities 1.27 ND ND 0.07 1.50 ND 0.05 0.08 Total Impurities 0.12% 0.26% 0.32%
Table 431. Stability Data for the Formulation if 11A Stored at 55 C 2 C
Naloxone RRT T=.0 1 Weeks 2 Weeks 4 Weeks 8 Weeks Physical Clear, Clear, Clear, Clear, Clear, appearance Colorless Colorless Light Light (Clarity, Color) yellow yellow yellow Assay (%) 100 98.48 102.74 101.14 103.18 Naloxone n-ND ND 0.04 0.02 NP
oxide (%) Impurity C 0.53 ND ND 0.01 0.02 0.01 Impurity A 0.61 ND 0.03 0.04 0.05 0.07 Impurity F 0.93 ND ND ND ND ND
Impurity D 1.14 ND ND 3 .18ppm ND
Impurity E 1.42 0.03 0.04 0.02 0.02 0.04 Impurity B 1.87 ND ND ND ND ND
0.71 0.02 0.07 0.04 0.02 0.02 1.07 0.07 0.09 0.07 0.06 0.09 1.16 ND ND 0.01 0.02 0.05 Unknown 1.30 ND ND 0.02 0.05 0.03 Impurities 1.32 ND ND ND 0.01 0.06 1.50 ND 0.01 0.05 0.10 0.13 1.59 ND ND ND 0.02 0.05 Date recue/Date Received 202401-22 1.62 ND ND ND 0.01 0.07 1.63 ND ND ND ND 0.07 1.73 ND ND 0.02 0.03 0.05 Total Impurities 0.12% 0.24% 0.32% 0.43%
0.74%
ND = Not Detected ppm = parts per million [000187] The data suggest that formulation #9A, #10A, and #1 lA
demonstrates satisfactory stability with no significant increase in individual 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.
Example 14. Intranasal and Sublingual Administration of Naloxone Spray Formulations Method [000188] 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 intranasally or sublingually 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, 1, 2 4, 8 and 12 hours' post-dose.
Results [000189] As seen in Table 31 below each of intranasal administration and sublingual administration resulted in significantly greater plasma concentrations than intramuscular administration at all time points tested up to 1 hour after administration.
Further intranasal administration of naloxone resulted in significantly greater plasma concentration than sublingual administration at all times points tested up to 1 hour after administration.
[000190] However, at 2 and 4 hours post-dose the mean plasma concentration of naloxone in subjects that were intranasally administered 16 milligrams of naloxone was significantly lower Date recue/Date Received 202401-22 than that for those subject that were sublingually administered 16 milligrams of naloxone. The same pattern was found with those subjects administered 8 milligram doses of naloxone.
[000191] Further, peak concentration in plasma (C.) and area under the concentration-time curve from time-zero to 1 hour post dose (AUC) followed the exact same pattern as described above for mean plasma concentrations.
Table 44. Mean Plasma Concentration for 8 mg and 16 mg Intranasal and Sublingual Administration Parameters* 8 mg SL 8 mg IN 16 mg SL
16 mg IN 0.4 mg IM

Conc. @ 0.03 h 0.18 0.29 6.19 14.47 0.52 0.8 9.29 14.31 0.15 0.29 (ng/mL) Conc. @ 0.07 h 0.62 0.96 13.95 19.06 1.69 1.85 29.69 28.01 0.36 0.38 (ng/mL) Conc. @ 0.1 h 0.88 0.94 18.75 15.61 2.31 2.08 46.34 36.64 0.51 0.41 (ng/mL) Conc. @ 0.13 h 1.17 1.13 20.48 13.11 3.16 3.39 49.31 33.98 0.58 0.39 (ng/mL) Conc. @ 0.17 h 1.54 1.1 19.96 10.73 3.63 3.83 45.77 24.58 0.63 0.36 (ng/mL) Conc. @ 0.25 h 1.98 1.29 16.49 6.71 4.39 4.24 35.04 13.23 0.69 0.4 (ng/mL) Conc. @ 0.5 h 2.03 1.28 9.88 4.42 3.94 2.96 22.35 8.19 0.62 0.22 (ng/mL) Conc. @ 1 h 1.61 0.85 6.29 2.7 2.96 1.66 14.07 5.61 0.51 0.16 (ng/mL) C.,, (ng/mL) 2.03 20.48 4.39 49.31 0.69 AUC @ lh 1.68 11.18 3.42 24.91 0.57 (ng*h/mL) *Mean Standard Deviation SL denotes sublingual administration IN denotes intranasal administration IM denotes intramuscular administration N denotes number of subjects tested h denotes hours Date recue/Date Received 202401-22

Claims

1. A liquid intranasal spray formulation comprising naloxone, or a pharmaceutically acceptable salt thereof, or a derivative thereof, from about 10 to about 20%
w/w ethanol, water, and a chelating agent, wherein the formulation does not contain an isotonicity agent or a buffer, wherein w/w denotes weight by total weight of the formulation and wherein the derivative thereof is selected from the group consisting of 3-0-acyl, phenylhydrazone, and methiodide derivatives.

2. The liquid spray formulation of claim 1, wherein the formulation does not contain sodium chloride, citric acid, benzyl alcohol, or benzalkonium chloride.

3. The liquid spray formulation of claim 1, wherein:
the formulation further comprises a glycol; and the chelating agent is edetate disodium dihydrate.

4. The liquid spray formulation of claim 3, wherein the glycol is propylene glycol.

5. The liquid spray formulation of claim 1, wherein the formulation has a pH
from about 3.0 to about 6Ø

6. The liquid spray formulation of claim 1, wherein the formulation further comprises an antioxidant.

7. The liquid spray formulation of claim 6, wherein the antioxidant is sodium ascorbate.

8. A liquid intranasal spray formulation comprising:
from about 1% to about 16% w/w naloxone, or a pharmaceutically acceptable salt thereof, or a derivative thereof;
from about 10% to about 20% w/w ethanol;
from about 10% to about 89% w/w water; and from about 0.0001% to 0.05% w/w of a chelating agent, wherein the formulation does not contain an isotonicity agent or a buffer, wherein w/w denotes weight by total weight of the formulation and wherein the derivative thereof is selected from the group consisting of 3-0-acyl, phenylhydrazone, and methiodide derivatives.

9. The liquid spray formulation of claim 8, wherein:
naloxone, or a pharmaceutically acceptable salt or is at a concentration from about 2% to about 10% w/w.

Date recue/Date Received 202401-22

10. The liquid spray formulation of claim 8, wherein water is at a concentration from about 80% to about 89% w/w.

11. The liquid spray formulation of claim 8, wherein water is at a concentration from about 35% to about 85% w/w and wherein the chelating agent is edetate disodium dihydrate and wherein the formulation further comprises from about 2% to about 54% w/w propylene glycol.

12. The liquid spray formulation of claim 11, wherein the propylene glycol is at a concentration from about 5% to about 10% w/w.

13. The liquid spray formulation of claim 11, wherein the propylene glycol is at a concentration of about 5 % w/w.

14. The liquid spray formulation of claim 8, wherein the chelating agent is edetate disodium dihydrate.

15. The liquid spray formulation of claim 1, wherein the formulation is for administration by a nasal spray device.

16. The liquid spray formulation of claim 15, wherein the nasal spray device has a single reservoir comprising about 125 j.tl to 127 L of the formulation.

17. The liquid spray formulation of claim 15, wherein about 100 L of the formulation is delivered by a single actuation.
Date recue/Date Received 202401-22