WO2020132263A1 - Compositions, devices, and methods for the treatment of overdose and reward-based disorders - Google Patents

Compositions, devices, and methods for the treatment of overdose and reward-based disorders Download PDF

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Publication number
WO2020132263A1
WO2020132263A1 PCT/US2019/067513 US2019067513W WO2020132263A1 WO 2020132263 A1 WO2020132263 A1 WO 2020132263A1 US 2019067513 W US2019067513 W US 2019067513W WO 2020132263 A1 WO2020132263 A1 WO 2020132263A1
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Prior art keywords
recited
naltrexone
formulation
intranasal
pharmaceutically acceptable
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PCT/US2019/067513
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English (en)
French (fr)
Inventor
Edward T. Maggio
Roger CRYSTAL
Mark ELLISON
Phil Skolnick
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Aegis Therapeutics, Inc.
Opiant Pharmaceuticals, Inc.
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Publication date
Application filed by Aegis Therapeutics, Inc., Opiant Pharmaceuticals, Inc. filed Critical Aegis Therapeutics, Inc.
Priority to MX2021007522A priority Critical patent/MX2021007522A/es
Priority to CA3124202A priority patent/CA3124202A1/en
Priority to EP19898164.9A priority patent/EP3897579A4/en
Priority to AU2019403368A priority patent/AU2019403368A1/en
Priority to KR1020217022386A priority patent/KR20210131996A/ko
Priority to CN201980092189.2A priority patent/CN113573696A/zh
Priority to JP2021535535A priority patent/JP2022514340A/ja
Priority to SG11202106531VA priority patent/SG11202106531VA/en
Publication of WO2020132263A1 publication Critical patent/WO2020132263A1/en
Priority to IL284117A priority patent/IL284117A/en

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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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Definitions

  • the invention relates generally to pharmaceutical compositions and more particularly to intranasal formulations comprising naltrexone and forms thereof, and methods of use thereof in the treatment of and conditions such as opioid overdose and symptoms thereof, and disorders such as alcohol use disorder including administering an intranasal formulation of the opioid antagonist naltrexone.
  • Naltrexone was initially developed to treat opioid dependence due to its effect of blocking the euphoric effects of opioids.
  • Naltrexone tablet formulations for oral administration have been used for treating opioid addiction since 1984.
  • Long-acting depot forms of naltrexone to be administered once monthly or longer were developed to improve compliance. Data from clinical trials demonstrated that the depot formulations were effective in reducing relapse to opioid use.
  • naltrexone Vivitrol®
  • alcohol can stimulate the brain’s reward circuitry and can reinforce the continued drinking of alcohol.
  • the problematic drinking of alcohol that becomes sufficiently severe is given the medical diagnosis of alcohol use disorder (AUD).
  • AUD alcohol use disorder
  • 3.3 million deaths or 5.9 percent of all global deaths (7.6% for men and 4.0% for women) were attributable to alcohol consumption (WHO Global Status Report on Alcohol and Health, 2014).
  • DSM Diagnostic and Statistical Manual of Mental Disorders
  • any individual meeting two of the eleven criteria during the same 12-month period receives a diagnosis of AUD.
  • the severity of an AUD— mild, moderate, or severe— is based on the number of criteria met.
  • individuals are screened using the Alcohol Use Disorders Identification Test (AUDIT). People with AUD drink to excess and, consequently, can endanger both themselves and others.
  • AUDIT Alcohol Use Disorders Identification Test
  • Alcohol abuse is a drinking pattern that results in significant and recurrent adverse consequences. Alcohol abusers may fail to fulfill major school, work, or family obligations. People with alcoholism (also known as alcohol dependence) have lost reliable control of their alcohol use and are often unable to stop drinking once they start. Alcohol dependence is characterized by tolerance (the need to drink more to achieve the same "high") and withdrawal symptoms if drinking is suddenly stopped. Withdrawal symptoms may include nausea, sweating, restlessness, irritability, tremors, hallucinations and convulsions.
  • Non-drug reward-based disorders manifest in similar psychological and behavioral patterns as substance use disorders. Specifically, craving, impaired control over the behavior, tolerance, withdrawal, and high rates of relapse can be seen in subjects who suffer from addictive behavior that has negative consequences to the person's physical, mental, social or financial well-being. (See, e.g., Marks, 1990; Lejoyeux et al, 2000; National Institute on Drug Abuse (NIDA) et al, 2002; Potenza, 2006; and Olsen, 2011). Drugs and non-drug rewards also demonstrate similar physiological manifestations. For example, functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al,
  • An intranasal (IN) formulation of naltrexone has the potential to be used for reversing opioid overdose, and for treating reward-based disorders without the use of needles or an extended-release formulation. While studies have shown that opioid antagonists, such as naltrexone, administered in oral or injectable forms, can reverse opioid overdose, and can decrease alcohol drinking and operant responding for it, there remains a substantial need for a simple, fast and compliant means of treating such conditions.
  • intranasal formulations comprising an aqueous solution comprising naltrexone or a pharmaceutically acceptable salt thereof.
  • Also disclosed herein are methods of treatment of opioid overdose or a reward- based disorder such as alcohol use disorder (AUD) in a subject comprising administering to the subject an IN formulation comprising a therapeutically effective amount of naltrexone or a pharmaceutically acceptable salt thereof.
  • AUD alcohol use disorder
  • Figure 1 shows the mean naltrexone plasma concentration versus time profiles following the administration of Test Product 1, Test Product 2, Test Product 3 and Reference Product, in linear scale out to 12 hours.
  • Figure 2 shows the mean natlrexone plasma concentration versus time profiles following the administration of Test Product 1, Test Product 2, Test Product 3 and Reference Product, in semi-logarithmic scale out to 12 hours.
  • Figure 3 shows the mean 6[S-naltrcxol (the main naltrexone metabolite) plasma concentration versus time (truncated at 12h) profiles following the administration of Test Product 1 , Test Product 2, Test Product 3 and Reference Product, in linear scale out to 12 hours.
  • Embodiment 1 an intranasal formulation comprising an aqueous solution comprising between about 1 mg and about 4 mg naltrexone, or a pharmaceutically acceptable salt thereof.
  • Embodiment 2 an intranasal formulation comprising, in a volume of about 50 to about 250 pL (preferably about 50 to about 150 pL), an aqueous solution comprising between about 10 mg/mL and about 40 mg/mL (preferably about 10 mg/mL and about 30 mg/mL) naltrexone, or a pharmaceutically acceptable salt thereof.
  • Embodiment 3 The formulation as recited in either Embodiment 1 or Embodiment 2, additionally comprising:
  • an amount of water sufficient to achieve a final volume of about 50 to about 250 pL (preferably about 50 to about 150 pL).
  • Embodiment 4 The formulation as recited in Embodiment 3, comprising:
  • the absorption enhancer between about 0.05 mg and about 2.5 mg of the absorption enhancer; and an amount of water sufficient to achieve a final volume of about 50 to about 250 pL (preferably about 50 to about 150 pL).
  • Embodiment 5 The formulation as recited in Embodiment 3, comprising:
  • naltrexone or a pharmaceutically acceptable salt thereof
  • Embodiment 6 The formulation as recited in either Embodiment 4 or Embodiment 5, wherein:
  • the isotonicity agent is NaCl
  • the preservative is benzalkonium chloride
  • the stabilizing agent is disodium edetate; and the absorption enhancer is an alkylsaccharide.
  • Embodiment 7 The formulation as recited in Embodiment 6, wherein the alkylsaccharide is dodecyl maltoside.
  • Embodiment 8 The formulation as recited in Embodiment 7, comprising:
  • dodecyl maltoside between about 0.05 mg and about 2.5 mg of dodecyl maltoside; and an amount of water sufficient to achieve a final volume of about 50 to about 250 pL (preferably about 50 to about 150 pL).
  • Embodiment 9 The formulation as recited in Embodiment 8, comprising between about 0.1 mg to about 0.5 mg of dodecyl maltoside.
  • Embodiment 10 The formulation as recited in Embodiment 9, comprising about 0.25 mg of dodecyl maltoside.
  • Embodiment 11 The formulation as recited in Embodiment 8, comprising about 0.2 mg and about 0.3 mg of disodium edetate.
  • Embodiment 12 The formulation as recited in Embodiment 9, comprising:
  • an amount of water sufficient to achieve a final volume of about 50 to about 250 pL (preferably about 50 to about 150 pL).
  • Embodiment 13 The formulation as recited in Embodiment 10, wherein the amount of water is sufficient to achieve a final volume of about 80 to about 120 pL.
  • Embodiment 14 The formulation as recited in Embodiment 11, wherein the amount of water is sufficient to achieve a final volume of about 100 pL.
  • Embodiment 15 The formulation as recited in Embodiment 7, comprising:
  • naltrexone or a pharmaceutically acceptable salt thereof between about 0.1% and about 1.2% ofNaCl;
  • Embodiment 16 The formulation as recited in Embodiment 15, comprising between about 0.1% to about 0.5% of dodecyl maltoside.
  • Embodiment 17 The formulation as recited in Embodiment 16, comprising about 0.25% of dodecyl maltoside.
  • Embodiment 18 The formulation as recited in Embodiment 15, comprising about 0.2% and about 0.3% of disodium edetate.
  • Embodiment 19 The formulation as recited in Embodiment 17, comprising:
  • naltrexone or a pharmaceutically acceptable salt thereof
  • Embodiment 20 The formulation as recited in Embodiment 19, wherein the amount of water is sufficient to achieve a final volume of about 50 to about 150 pL.
  • Embodiment 21 The formulation as recited in Embodiment 20, wherein the amount of water is sufficient to achieve a final volume of about 100 pL.
  • Embodiment 22 The formulation as recited in any of Embodiments 1-21, wherein the naltrexone is naltrexone hydrochloride.
  • Embodiment 23 The formulation as recited in Embodiment 22, comprising about 1.2 mg, about 1.6 mg, about 2.0 mg, or about 3.0 mg naltrexone or an equivalent amount of naltrexone hydrochloride.
  • Embodiment 24 a method of treatment of opioid overdose or a reward-based disorder in a subject, comprising administering to the subject an intranasal formulation comprising an aqueous solution comprising between about 1 mg and about 4 mg naltrexone or a pharmaceutically acceptable salt thereof.
  • Embodiment 25 a method of treatment of opioid overdose or a reward-based disorder in a subject, comprising administering to the subject a first intranasal formulation comprising an aqueous solution comprising between about 1 mg and about 4 mg naltrexone or a pharmaceutically acceptable salt thereof and administrating a second intranasal formulation comprising an aqueous solution comprising between about 1 mg and about 4 mg naltrexone or a pharmaceutically acceptable salt thereof.
  • Embodiment 26 a method of treatment of opioid overdose or a reward-based disorder in a subject, comprising administering to the subject an intranasal formulation comprising, in a volume of about 50 to about 250 pL (preferably about 50 to about 150 pL), an aqueous solution comprising between about 10 mg/mL and about 40 mg/mL (preferably about 10 mg/mL and about 30 mg/mL) naltrexone or a pharmaceutically acceptable salt thereof.
  • an intranasal formulation comprising, in a volume of about 50 to about 250 pL (preferably about 50 to about 150 pL), an aqueous solution comprising between about 10 mg/mL and about 40 mg/mL (preferably about 10 mg/mL and about 30 mg/mL) naltrexone or a pharmaceutically acceptable salt thereof.
  • Embodiment 27 a method treatment of opioid overdose or a reward-based disorder in a subject, comprising administering to the subject a first intranasal formulation comprising, in a volume of about 50 to about 250 ul, an aqueous solution comprising between about 10 mg/mL and about 40 mg/mL naltrexone or a pharmaceutically acceptable salt thereof and administrating a second intranasal formulation comprising, in a volume or about 50 to about 250 pL, an aqueous solution comprising between about 10 mg/mL and about 40 mg/mL naltrexone or a pharmaceutically acceptable salt thereof.
  • Embodiment 28 The method as recited in either Embodiment 25 or claim Embodiment 27 wherein the second intranasal formulation is administered between about 1 hour and about 3 hours after the administration of the first intranasal formulation.
  • Embodiment 30 The method as recited in Embodiment 29, wherein the intranasal formulation comprises:
  • the absorption enhancer between about 0.05 mg and about 2.5 mg of the absorption enhancer; and an amount of water sufficient to achieve a final volume of about 50 to about 250 pL (preferably about 50 to about 150 pL).
  • Embodiment 31 The method as recited in Embodiment 29, wherein the intranasal formulation comprises:
  • naltrexone or a pharmaceutically acceptable salt thereof
  • Embodiment 32 The method as recited in either Embodiment 30 or Embodiment 28, wherein:
  • the preservative is benzalkonium chloride
  • the stabilizing agent is disodium edetate
  • the absorption enhancer is an alkylsaccharide.
  • Embodiment 33 The method as recited in Embodiment 32, wherein the alkylsaccharide is dodecyl maltoside.
  • Embodiment 34 The method as recited in Embodiment 33, wherein the intranasal formulation comprises:
  • an amount of water sufficient to achieve a final volume of about 50 to about 250 pL (preferably about 50 to about 150 pL).
  • Embodiment 35 The method as recited in Embodiment 34, wherein the intranasal formulation comprises between about 0.1 mg to about 0.5 mg of dodecyl maltoside.
  • Embodiment 36 The method as recited in Embodiment 35, wherein the intranasal formulation comprises about 0.25 mg of dodecyl maltoside.
  • Embodiment 37 The method as recited in Embodiment 34, wherein the intranasal formulation comprises between about 0.2 mg and about 0.3 mg of disodium edetate.
  • Embodiment 38 The method as recited in Embodiment 36, wherein the intranasal formulation comprises:
  • an amount of water sufficient to achieve a final volume of about 50 to about 250 pL (preferably about 50 to about 150 pL).
  • Embodiment 39 The method as recited in Embodiment 38, wherein the amount of water is sufficient to achieve a final volume of about 50 to about 150 pL.
  • Embodiment 40 The method as recited in Embodiment 39, wherein the amount of water is sufficient to achieve a final volume of about 100 pL.
  • Embodiment 41 The method as recited in Embodiment 33, comprising:
  • naltrexone or a pharmaceutically acceptable salt thereof
  • Embodiment 42 The method as recited in Embodiment 41, wherein the intranasal formulation comprises between about 0.1% to about 0.5% of dodecyl maltoside.
  • Embodiment 43 The method as recited in Embodiment 42, wherein the intranasal formulation comprises about 0.25% of dodecyl maltoside.
  • Embodiment 44 The method as recited in Embodiment 41, wherein the intranasal formulation comprises between about 0.2% and about 0.3% of disodium edetate.
  • Embodiment 45 The method as recited in Embodiment 43, wherein the intranasal formulation comprises:
  • naltrexone or a pharmaceutically acceptable salt thereof between about 0.3% and about 0.7% of NaCl;
  • Embodiment 46 The method as recited in Embodiment 45, wherein the amount of water is sufficient to achieve a final volume of about 50 to about 150 mT.
  • Embodiment 47 The method as recited in Embodiment 46, wherein the amount of water is sufficient to achieve a final volume of about 100 mE.
  • Embodiment 48 The method as recited in any of Embodiments 24-47, wherein the naltrexone is naltrexone hydrochloride.
  • Embodiment 49 The method as recited in Embodiment 48, wherein the intranasal formulation comprises about 1.2 mg, about 1.6 mg, about 2.0 mg, or about 3.0 mg naltrexone or an equivalent amount of naltrexone hydrochloride.
  • Embodiment 50 The method as recited in any of Embodiments 24-49, wherein the method treats opioid overdose.
  • Embodiment 51 The method as recited in any of Embodiments 24-49, wherein the method treats a reward-based disorder.
  • Embodiment 52 The method as recited in Embodiment 48, wherein the reward- based disorder is a substance use disorder.
  • Embodiment 53 The method as recited in Embodiment 48, wherein the substance use disorder is alcohol use disorder.
  • Embodiment 54 The method as recited in Embodiment 53, wherein the intranasal formulation comprising naltrexone is administered prior to ingestion of alcohol.
  • Embodiment 55 The method as recited in Embodiment 54, wherein the intranasal formulation comprising naltrexone is administered about 1-2 hours prior to ingestion of alcohol.
  • Embodiment 56 The method as recited in Embodiment 54, wherein the intranasal formulation comprising naltrexone is administered about 0.5 to about 1 hours prior to ingestion of alcohol.
  • Embodiment 57 The method as recited in Embodiment 54, wherein the intranasal formulation comprising naltrexone is administered about 10 to about 30 minutes prior to ingestion of alcohol.
  • Embodiment 58 The method as recited in Embodiment 54, wherein the intranasal formulation comprising naltrexone is administered about 5 to about 10 minutes prior to ingestion of alcohol.
  • Embodiment 59 The method as recited in Embodiment 53, wherein the intranasal formulation comprising naltrexone is administered contemporaneously with the ingestion of alcohol.
  • Embodiment 57 The method as recited in Embodiment 53, wherein the intranasal formulation comprising naltrexone is administered within 0.5 hours after commencement of ingestion of alcohol.
  • Embodiment 58 The method as recited in any of Embodiments 24-57, wherein the intranasal formulation comprising naltrexone is administered to a subject from once to four times per day.
  • Embodiment 59 The method as recited in Embodiment 58, wherein the intranasal formulation comprising naltrexone is administered in doses of about 1.2 mg, about 1.6 mg, about 2 mg, or about 3 mg throughout the day as needed by the subject.
  • Embodiment 60 The method as recited in Embodiment 58, wherein the intranasal formulation comprising naltrexone is administered as a first dose of about 1.2 mg, about 1.6 mg, about 2 mg, or about 3 mg in the morning, and subsequent doses of about 1.2 mg, about 1.6 mg, about 2 mg, or about 3 mg as needed prior to consumption of alcohol.
  • Embodiment 61 A multi-dose device adapted for nasal delivery of a pharmaceutical formulation to a subject experiencing an opioid overdose or having a reward-based disorder, comprising a plurality of doses each comprising an intranasal formulation as recited in any of Embodiments 1-23.
  • Embodiment 62 The device as recited in Embodiment 61, wherein about 0.05 to about 0.2 mL (preferably about 0.05 to about 0.15 mL) of said formulation is delivered to the subject in each dose.
  • Embodiment 63 The device as recited in Embodiment 62, wherein about 0.1 mL of said formulation is delivered to the subject in each dose.
  • Embodiment 64 The formulation, method, or device as recited in any one of the preceding Embodiments, wherein:
  • the amount comprised is about 3 mg naltrexone, or a pharmaceutically acceptable salt thereof; or where the method recites“comprising between about 10 mg/mL and about 40 mg/mL (preferably about 10 mg/mL and about 30 mg/mL) naltrexone, or a pharmaceutically acceptable salt thereof’, the concentration comprised is about 30 mg/mL mg naltrexone, or a pharmaceutically acceptable salt thereof.
  • Embodiment 64 Also provided is a formulation chosen from those described in the
  • ranges of values are disclosed, unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values.
  • the range “from 2 to 6 doses” is intended to include two, three, four, five, and six doses, since doses come in integer units.
  • the range“from 1 to 3 mM (micromolar),” which is intended to include 1 mM, 3 mM, and everything in between to any number of significant figures (e.g., 1.255 mM, 2.1 mM, 2.9999 mM, etc.).
  • the term“about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a range.
  • the term“about” should be understood to mean the greater of the range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures, and the range which would encompass the recited value plus or minus 20%.
  • absorption enhancer refers to a functional excipient included in formulations to improve the absorption of a pharmacologically active drug. This term usually refers to an agent whose function is to increase absorption by enhancing membrane permeation, rather than increasing solubility. As such, such agents are sometimes called permeation enhancers.
  • absorption enhancers examples include aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramides, cetylpyridinium chloride, chitosan, cyclodextrins, deoxycholic acid, decanoyl carnitine, dodecyl maltoside, EDTA, glycocholic acid, glycodeoxycholic acid, glycofurol, glycosylated sphingosines, glycyrrhetinic acids, 2-hydroxypropyl- b-cyclodextrin, laureth-9, lauric acid, lauroyl carnitine, sodium lauryl sulfate, lysophosphatidylcholine, menthol, poloxamer 407 or F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, polysorbate 80, propylene glycol, quillaja saponin, salicylic acid, sodium salt, b-s
  • Alkylsaccharides e.g., nonionic alkylsaccharide surfactants such as alkylglycosides and sucrose esters of fatty acids that consist of an aliphatic hydrocarbon chain coupled to a sugar moiety by a glycosidic or ester bond, respectively
  • cyclodextrins cyclic oligosaccharides composed of six or more monosaccharide units with a central cavity, which form inclusion complexes with hydrophobic molecules and they have primarily been used to increase drug solubility and dissolution and to enhance low molecular weight drug absorption
  • chitosans linear cationic polysaccharides produced from the deacetylation of chitin
  • bile salts and their derivatives such as sodium glycocholate, sodium taurocholate, and sodium taurodihydrofusidate
  • the term“addiction,” as used herein, refers to a medical condition characterized by compulsive engagement in rewarding stimuli despite adverse consequences.
  • the term, “addictive behavior,” as used herein, refers to a behavior that is both rewarding and reinforcing.
  • the term“agonist,” as used herein, refers to a moiety that interacts with and activates a receptor, and thereby initiates a physiological or pharmacological response characteristic of that receptor.
  • the term“antagonist,” as used herein, refers to a moiety that competitively binds to a receptor at the same site as an agonist (for example, the endogenous ligand), but which does not activate the intracellular response initiated by the active form of the receptor and can thereby inhibit the intracellular responses by an agonist or partial agonist.
  • An antagonist does not diminish the baseline intracellular response in the absence of an agonist or partial agonist.
  • inverse agonist refers to a moiety that binds to the endogenous form of the receptor or to the constitutively activated form of the receptor and which inhibits the baseline intracellular response initiated by the active form of the receptor below the normal base level of activity which is observed in the absence of an agonist or partial agonist.
  • alcohol use disorder is defined by criteria set forth the Diagnostic and Statistical Manual of Mental Disorders (DSM, most recent revision, presently DSM-Y) in the US, or by similar criteria set forth in corresponding well-accepted standards such as the World Health Organization’s ICD (International Statistical Classification of Diseases and Related Health Problems, most recent revision, presently the ICD- 10).
  • Related terms and disorders include "alcohol abuse” and “alcohol dependence” (used in DSM-IY), “alcohol harmful use” and “alcohol dependence syndrome” (used in the ICD-10), and alcoholism.
  • antimicrobial preservative refers to a pharmaceutically acceptable excipient with antimicrobial properties which is added to a pharmaceutical composition to maintain microbiological stability. Compounds act both as preservatives and stabilizers.
  • disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms“disorder,”“syndrome,” and“condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • composition is used herein interchangeably with the term “Pharmaceutical formulation,” or just “formulation,” and denotes an active pharmaceutical ingredient (i.e., a drug substance) in combination with at least one pharmaceutically acceptable excipient or carrier.
  • the term“equivalent,” as used herein refers to a weight of the opioid antagonist naltrexone and pharmaceutically acceptable salts thereof that is equimolar to a specified weight of naltrexone hydrochloride.
  • excipient refers to a natural or synthetic substance formulated alongside the active ingredient of a medication, included for the purpose of long term stabilization, bulking up solid formulations, or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility.
  • terapéuticaally effective dose refers to a dose that is effective to treat a disease, to decrease one or more observable symptoms of a disease, or to delay onset or progression of or mitigate the symptoms of a more serious condition that often follows after the condition that a patient is currently experiencing.
  • a therapeutically effective dose may, but need not necessarily, completely eliminate all symptoms of the disease.
  • the term“in need of treatment” and the term“in need thereof’ when referring to treatment are used interchangeably and refer to a judgment made by a caregiver (e.g . physician, nurse, nurse practitioner, that a subject will benefit from treatment.
  • two embodiments are“mutually exclusive” when one is defined to be something which is different than the other.
  • an embodiment wherein the amount of naltrexone hydrochloride is specified to be 3 mg is mutually exclusive with an embodiment wherein the amount of naltrexone hydrochloride is specified to be 2 mg.
  • an embodiment wherein the amount of naltrexone hydrochloride is specified to be 4 mg is not mutually exclusive with an embodiment in which less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
  • naloxone refers to a compound of the following structure:
  • naloxone a pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • the CAS registry number for naloxone is 465-65-6.
  • Other names for naloxone include: 17-allyl-4,5a-epoxy-3,14- dihydroxymorphinan-6-one; (-)-17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one; 4,5a- epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one; and (-)-12-allyl-7,7a,8,9- tctrahydro-3,7a-dihydroxy-4a//-8,9c-iminocthanophcnanthro[4,5- c ⁇ 7]iuran-5('6//)-onc.
  • Naloxone hydrochloride may be anhydrous (CAS Reg. No. 357-08-4) and also forms a dihydrate (CAS No. 51481-60-8). It has been sold under various brand names including Narcan®, Nalone®, Nalossone®, Naloxona®, Naloxonum®, Narcanti®, and Narcon®.
  • naltrexone a pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • the CAS registry number for naltrexone is 16590-41-3.
  • Other names for naltrexone include: 17-(cyclopropylmethyl)-4,5a- epoxy- 3,14-dihydroxymorphinan-6-one; (5a)-17-(cyclopropylmethyl)-3,14-dihydroxy-4,5- epoxymorphinan-6-one; and (1S,5R, 13 R, 17S)-4-(cyclopropyl methyl)- 10, 17-dihydroxy- 12- oxa-4-azapentacyclo[9.6.1.01,13.05,17.07,18]octadeca-7(18),8,10-trien-14-one.
  • Naltrexone hydrochloride includes“naltrexone hydrochloride.”
  • Naltrexone hydrochloride has been marketed under the trade names Antaxone®, Depade®, Nalorex®, Revia®, Trexan®, Yivitrex®, and Yivitrol®.
  • methylnaltrexone refers to a pharmaceutically acceptable salt comprising the cation (5 a)- 17-(cyclopropylmethyl)-3, 14-dihydroxy- 17-methyl- 4,5-epoxymorphinanium-17-ium-6-one a compound of the following structure:
  • X is a pharmaceutically acceptable anion.
  • Methylnaltrexone bromide (CAS Reg. No. 75232-52-7) has been marketed under the trade name Relistor®.
  • nalmefene refers to 17-cyclopropylmethyl-4,5a-epoxy- 6-methylenemorphinan-3,14-diol, a compound of the following structure:
  • Nalmefene hydrochloride (CAS Reg. No. 58895-64-0) has been marketed under the trade names Nalmetrene®, Cervene®, Revex®, Arthrene®, and Incystene®.
  • opioid antagonist includes, in addition to naltrexone and pharmaceutically acceptable salts thereof: naloxone, methylnaltrexone, and nalmefene, and pharmaceutically acceptable salts thereof.
  • the opioid antagonist is naltrexone hydrochloride.
  • the opioid antagonist is naloxone.
  • the opioid antagonist is methylnaltrexone bromide.
  • the nasally administering is accomplished using a device described herein.
  • composition refers to a composition comprising at least one active ingredient; including but not limited to, salts, solvates and hydrates of the opioid antagonist naltrexone, whereby the composition is amenable to use for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
  • the term“reinforcing stimuli,” as used herein refers to stimuli that increase the probability of repeating behaviors paired with them.
  • rewarding stimuli refers to stimuli that the brain of a subject interprets as intrinsically positive or as something to be approached.
  • a rewarding stimulus typically results in the release of dopamine in the brain of the subject.
  • subject is intended to be synonymous with“patient,” and refers to any mammal (preferably human) afflicted with a condition likely to benefit from a treatment with a therapeutically effective amount of the opioid antagonist naltrexone or a salt thereof.
  • the term“substance use disorder” is defined by criteria set forth the Diagnostic and Statistical Manual of Mental Disorders (DSM, most recent revision, presently DSM-Y) in the US, or by similar criteria set forth in corresponding well-accepted standards such as the World Health Organization’s ICD (International Statistical Classification of Diseases and Related Health Problems, most recent revision, presently the ICD- 10).
  • Related terms and disorders include "substance abuse” and "substance dependence” (used in DSM-IY). Substance use disorders occur when the recurrent use of alcohol and/or drugs causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home.
  • a diagnosis of substance use disorder is based on evidence of impaired control, social impairment, risky use, and pharmacological criteria.
  • Substances which may be the focus of a substance use disorder include abusable substances such as opioids, alcohol, tobacco, cannabinoids, stimulants such as cocaine and amphetamines, depressants such as benzodiazepines, hallucinogens, inhalants, and the like.
  • Alcohol use disorder is a substance use disorder.
  • Substance use disorders may be considered“reward-based disorders.”
  • tonicity agent refers to a compound which modifies the osmolality of a formulation, for example, to render it isotonic.
  • Tonicity agents include, dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine and the like.
  • “treating,”“treatment,” and the like means ameliorating a disorder, so as to reduce or eliminate its cause, its progression, its severity, or one or more of its symptoms, or otherwise beneficially alter the disease in a subject.
  • the term “AUC” refers to the area under the drug plasma concentration-time curve.
  • the term“AUCo-”or“AUCo-inf” refers to the area under the drug plasma concentration time curve extrapolated to ⁇ (infinity).
  • bioavailability (F) refers to the fraction of a dose of drug that is absorbed from its site of administration and reaches, in an unchanged form, the systemic circulation.
  • absolute bioavailability is used when the fraction of absorbed drug is related to its IV bioavailability. It may be calculated using the following formula:
  • the term“ti/2” or“half-life” refers to the amount of time required for half of a drug to be eliminated from the body or the time required for a drug concentration to decline by half.
  • CV coefficient of variation
  • the term“elimination rate constant (l)” refers to the fractional rate of drug removal from the body. This rate is constant in first-order kinetics and is independent of drug concentration in the body l is the slope of the plasma concentration-time line (on a logarithmic y scale).
  • the term“l z ,” as used herein, refers to the terminal phase elimination rate constant, wherein the“terminal phase” of the drug plasma concentration-time curve is a straight line when plotted on a semilogarithmic graph.
  • the terminal phase is often called the “elimination phase” because the primary mechanism for decreasing drug concentration during the terminal phase is drug elimination from the body.
  • the distinguishing characteristic of the terminal elimination phase is that the relative proportion of drug in the plasma and peripheral volumes of distribution remains constant. During this“terminal phase” drug returns from the rapid and slow distribution volumes to the plasma, and is permanently removed from the plasma by metabolism or renal excretion.
  • Opioid receptor antagonists are a well-recognized class of chemical agents. They have been described in detail in the scientific and patent literature.
  • Naltrexone and its active metabolite 6[S-naltrexol are opioid antagonists, with no agonist properties, at the m-opioid receptor (MOR), the k-opioid receptor (KOR), and the d-opioid receptor (DOR).
  • Naltrexone operates by reversibly blocking the opioid receptors thereby attenuating the effects of opioids.
  • naltrexone likely modulates the dopaminergic mesolimbic pathway (one of the primary centers for risk-reward analysis in the brain, and a tertiary pleasure center) which is believed to be a major center of the reward associated with addiction that all major drugs of abuse are believed to activate.
  • the mechanism of action may be antagonism to endogenous opiates such as tetrahydropapaveroline, whose production is augmented in the presence of alcohol.
  • Naltrexone is commercially available as a hydrochloride salt.
  • Naltrexone hydrochloride (17-(cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxymorphinan-6-one) is used to prevent euphorigenic effects in the treatment of patients addicted to opioids. It markedly blocks the physical dependence to intravenously administered opioids and motivates withdrawal from opioid dependency, but the patient does not develop tolerance or dependence to naltrexone. Naltrexone is also effective in reducing the craving for alcohol in the treatment of alcoholism, especially when combined with psychosocial therapy.
  • naltrexone When naltrexone is administered intranasally, rather than orally, the bioavailability is significantly higher. When administered orally, despite being nearly completely absorbed from the gastrointestinal tract, naltrexone undergoes rapid and extensive first-pass metabolism to 6-[S-naltrexol. As a result, the amount of naltrexone reaching systemic circulation is limited. The oral bioavailability of naltrexone has been reported to be as low as 5%. Gonzalez and Brogden, Drugs 35: 192-213, 1988. Studies presented herein found the oral bioavailability of naltrexone to be similarly low, about 9%.
  • naltrexone a pharmaceutical composition to a patient, comprising a therapeutically effective amount of the opioid antagonist naltrexone.
  • the therapeutically effective amount per dose is equivalent to about 1 to about 4 mg of naltrexone hydrochloride. In certain embodiments, the therapeutically effective amount is equivalent to about 1 to about 3 mg of naltrexone hydrochloride.
  • the therapeutically effective amount per dose is equivalent to about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4.0 mg of naltrexone hydrochloride.
  • the therapeutically effective amount per dose is equivalent to about 1.2 mg of naltrexone hydrochloride.
  • the therapeutically effective amount per dose is equivalent to about 1.6 mg of naltrexone hydrochloride. In certain embodiments, the therapeutically effective amount per dose is equivalent to about 2.0 mg of naltrexone hydrochloride. In certain embodiments, the therapeutically effective amount per dose is equivalent to about 3.0 mg of naltrexone hydrochloride. Multiple doses in succession may be taken to achieve therapeutic efficacy.
  • the opioid antagonist is anhydrous naltrexone hydrochloride.
  • opioid antagonists described herein include m-opioid, k-opioid, and d-opioid receptor antagonists.
  • useful opioid receptor antagonists include naltrexone, naloxone, methylnaltrexone, and nalmefene.
  • Other useful opioid receptor antagonists are known in the art (e.g., U.S. Patent No. 4,987,136).
  • compositions comprising the opioid antagonist naltrexone.
  • the pharmaceutical compositions comprise the opioid antagonist naltrexone and a pharmaceutically acceptable carrier.
  • the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not overly deleterious to the recipient thereof.
  • Some embodiments of the present invention include a method of producing a pharmaceutical composition comprising admixing the opioid antagonist naltrexone and a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions are applied directly to the nasal cavity using the devices described herein. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • Liquid preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions. Additional ingredients in liquid preparations may include: antimicrobial preservatives, such as benzalkonium chloride, methylparaben, sodium benzoate, benzoic acid, phenyl ethyl alcohol, and the like, and mixtures thereof; surfactants such as Polysorbate 80 NF, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitan monoisostearate, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate
  • the opioid antagonist when an opioid antagonist is administered intranasally prior to ingestion of alcohol to treat AUD, the opioid antagonist is absorbed quickly, i.e., within about fifteen to about thirty minutes and/or yielding a time to the maximum plasma concentration (Tmax) of about 25 to about 40 minutes.
  • Tmax time to the maximum plasma concentration
  • the opioid antagonist is absorbed within the first 15 min after administration and the time to the maximum plasma concentration (Tmax) is 25 min or less.
  • the opioid antagonist is absorbed within the first 30 min after administration and the Tmax is 40 min or less.
  • alkylglycosides of the present invention may include, but not limited to: alkylglycosides, such as octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-,hexadecyl-, heptadecyl-, and octadecyl- a- or b-D-maltoside, - glucoside or -sucroside; alkyl thiomaltosides, such as heptyl, octyl, dodecyl-, tridecyl-, and tctradccyl-[]-D-thiomaltosidc; alkyl thioglucosides, such as heptyl- or octyl 1-thio a- or b-D
  • the hydrophobic alkyl can thus be chosen of any desired size, depending on the hydrophobicity desired and the hydrophilicity of the saccharide moiety.
  • one preferred range of alkyl chains is from about 9 to about 24 carbon atoms.
  • An even more preferred range is from about 9 to about 16 or about 14 carbon atoms.
  • some preferred glycosides include maltose, sucrose, and glucose linked by glycosidic linkage to an alkyl chain of 9, 10, 12, 13, 14, 16, 18, 20, 22, or 24 carbon atoms, e.g., nonyl-, decyl-, dodecyl- and tetradecyl sucroside, glucoside, and maltoside, etc.
  • one alkyl saccharide is 1 -O-n-dodccyl-fl-D-maltopyranosidc (alternately referred to as lauryl-fl-D-maltopyranosidc, dodecyl maltopyranoside, dodecyl maltoside, Intravail®, and DDM; C24H46Q11).
  • Alkylsaccharides are used in commercial food and personal care products and have been designated Generally Recognized as Safe (GRAS) substances for food applications.
  • Alkylsaccharides are non-irritating enhancers of transmucosal absorption that are odorless, tasteless, non-toxic, non-mutagenic, and non-sensitizing in the Draize test up to a 25% concentration.
  • Alkylsaccharides increase absorption by increasing paracellular permeability, as indicated by a decrease in transepithelial electrical resistance; they may also increase transcytosis. The effect is short-lived.
  • Other alkylsaccharides include tetradecyl maltoside (TDM) and sucrose dodecanoate.
  • alkylglycosides occur as anomers.
  • dodecyl b-D-maltoside and dodecyl a-D-maltoside are two cyclic forms of dodecyl maltoside.
  • the two different anomers are two distinct chemical structures, and thus have different physical and chemical properties.
  • the alkylglycoside of the present invention is a b anomer.
  • the alkylglycoside is a b anomer of an alkylmaltoside, such as tetradecyl ⁇ -D-maltoside (TDM).
  • TDM tetradecyl ⁇ -D-maltoside
  • the alkylglycoside used is a substantially pure alkylglycoside.
  • a“substantially pure” alkylglycoside refers to one anomeric form of the alkylglycoside (either the a or b anomeric forms) with less than about 2% of the other anomeric form, preferably less than about 1.5% of the other anomeric form, and more preferably less than about 1% of the other anomeric form.
  • a substantially pure alkylgycoside contains greater than 98% of either the a or b anomer.
  • a substantially pure alkylgycoside contains greater than 99% of either the a or b anomer. In another aspect, a substantially pure alkylgycoside contains greater than 99.5% of either the a or b anomer. In another aspect, a substantially pure alkylgycoside contains greater than 99.9% of either the a or b anomer.
  • an intranasal formulation comprises about 0.001 % to about 5.0% dodecyl maltoside by weight. In certain embodiments, an intranasal formulation comprises about 0.01% to about 2.5% dodecyl maltoside. In certain embodiments, an intranasal formulation comprises about 0.05% to about 2.5% dodecyl maltoside. In certain embodiments, an intranasal formulation comprises about 0.1% to about 0.5% dodecyl maltoside. In certain embodiments, an intranasal formulation comprises about 0.15% to about 0.35% dodecyl maltoside. In certain embodiments, an intranasal formulation comprises about 0.15% to about 0.2% dodecyl maltoside.
  • an intranasal formulation comprises about 0.18% dodecyl maltoside. In certain embodiments, an intranasal formulation comprises about 0.2% to about 0.3% dodecyl maltoside. In certain embodiments, an intranasal formulation comprises about 0.25% dodecyl maltoside.
  • absorption enhancing excipients can alter the paracellular and/or transcellular pathways, others can extend residence time in the nasal cavity or prevent metabolic changes. Without an absorption enhancer, the molecular-weight limit for nasal absorption is about 1 kDa, while administration of drugs in conjunction with absorption enhancers can enable the absorption of molecules from 1-30 kDa. Intranasal administration of most absorption enhancers, however, can cause nasal mucosa damage. Maggio, J. Excipients and Food Chem. 5(2): 100-12, 2014.
  • absorption enhancers include aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramides, cetylpyridinium chloride, chitosan, cyclodextrins, deoxycholic acid, decanoyl carnitine, dodecyl maltoside, EDTA, glycocholic acid, glycodeoxycholic acid, glycofurol, glycosylated sphingosines, glycyrrhetinic acids, 2- hydroxypropyl- b-cyclodextrin, laureth-9, lauric acid, lauroyl carnitine, lauryl sulfate, lysophosphatidylcholine, menthol, poloxamer 407, poloxamer F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, polysorbate 80, propylene glycol, quillaja saponin, salicylic acid
  • opioid antagonist naltrexone described herein can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically acceptable carriers, outside those mentioned herein, are known in the art.
  • the opioid antagonist naltrexone described herein may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like, such as those pharmaceutically acceptable salts listed by Berge et al., Journal of Pharmaceutical Sciences, 66: 1-19 (1977).
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the opioid antagonist naltrexone described herein may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • the formulation is an aqueous solution.
  • the formulation comprises, per dose, between about 25 and about 200 pL of the aqueous solution.
  • the formulation comprises, per dose, between about 50 and about 200 pL of the aqueous solution.
  • the formulation comprises, per dose, not more than about 140 pL.
  • the formulation comprises, per dose, not more than about 100 pL.
  • the formulation comprises between about 1% (w/w) and about 4% (w/w) of naltrexone hydrochloride. In certain embodiments, the formulation comprises between about 1% (w/w) and about 3% (w/w) of naltrexone hydrochloride.
  • the formulation comprises about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4.0 % (w/w) of naltrexone hydrochloride. In certain embodiments, the formulation comprises about 1.2% (w/w) of naltrexone hydrochloride.
  • the formulation comprises about 1.6% (w/w) of naltrexone hydrochloride. In certain embodiments, the formulation comprises about 2% (w/w) of naltrexone hydrochloride. In certain embodiments, the formulation comprises about 3% (w/w) of naltrexone hydrochloride.
  • the formulation comprises between about 1 mg and about 4 mg of naltrexone hydrochloride. In certain embodiments, the formulation comprises between about 1 mg and about 3 mg of naltrexone hydrochloride. In certain embodiments, the formulation comprises between about 2 mg and about 4 mg of naltrexone hydrochloride.
  • the formulation comprises about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4.0 mg of naltrexone hydrochloride.
  • the formulation comprises about 1.2 mg of naltrexone hydrochloride.
  • the formulation comprises about 1.6 mg of naltrexone hydrochloride.
  • the formulation comprises about 2 mg of naltrexone hydrochloride.
  • the formulation comprises about 3 mg of naltrexone hydrochloride.
  • Aqueous formulations for intranasal administration disclosed herein may also include pharmaceutically acceptable excipients, such as one or more isotonicity agents, one or more preservatives, one or more stabilizing agents, one or more absorption enhancers, and one or more agents to adjust pH or buffer the solution.
  • pharmaceutically acceptable excipients such as one or more isotonicity agents, one or more preservatives, one or more stabilizing agents, one or more absorption enhancers, and one or more agents to adjust pH or buffer the solution.
  • the intranasal formulation additionally comprises am isotonicity agent, such as sodium chloride (NaCl).
  • am isotonicity agent such as sodium chloride (NaCl).
  • the intranasal formulation additionally comprises a compound which is a preservative and/or surfactant.
  • the preservative and/or surfactant is chosen from benzalkonium chloride, methylparaben, sodium benzoate, benzoic acid, phenyl ethyl alcohol, and the like, and mixtures thereof; surfactants such as Polysorbate 80 NF, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitan monoisostearate, sorbitan monooleate, sorbitan monolaurate, sorbitan mono
  • the intranasal formulation additionally comprises a stabilizing agent.
  • the stabilizing agent is disodium edetate (EDTA).
  • the pharmaceutical composition is in an aqueous solution of about 100 pL.
  • compositions in a device adapted for nasal delivery to a subject suffering AUD comprising a therapeutically effective amount of the opioid antagonist naltrexone or pharmaceutically acceptable salt thereof.
  • the device is pre-primed.
  • the device can be primed before use.
  • the device can be actuated with one hand.
  • Nasal delivery is considered an attractive route for systemic drug delivery, especially when rapid absorption and effect are desired.
  • nasal delivery may help address issues related to unpleasant taste, poor bioavailability, slow absorption, drug degradation, adverse events (AEs) in the gastrointestinal tract, and avoids first-pass metabolism and the hepatic toxicity associated with long-term oral naltrexone usage.
  • Liquid nasal formulations are mainly aqueous solutions, but suspensions and emulsions can also be delivered.
  • EMS emergency medical service
  • Some emergency medical service (EMS) programs have developed a system using existing technologies of an approved drug and an existing medical device to administer the opioid antagonist naloxone intranasally, albeit in a non-FDA approved manner. This has been accomplished by using the injectable formulation (1 mg/mL) and administering 1 mL per nostril via a marketed nasal atomizer/nebulizer device.
  • the system combines an FDA-approved naloxone injection product (with a Luer fitted tip, no needles) with a marketed, medical device called the Mucosal Atomization Device (MADTM Nasal, Wolfe Tory Medical, Inc.). This initiative is consistent with the U.S. Needlestick Safety and Prevention Act (Public Law 106- 430).
  • the EMS programs recognize limitations of this system, one limitation being that it is not assembled and ready-to-use.
  • this administration mode appears to be effective in reversing narcosis, the formulation is not concentrated for retention in the nasal cavity.
  • the 1 mL delivery volume per nostril is larger than that generally utilized for intranasal drug administration. Therefore, there is loss of drug from the nasal cavity, due either to drainage into the nasopharynx or externally from the nasal cavity.
  • the devices described herein are improved ready-to-use products specifically optimized, concentrated, and formulated for nasal delivery.
  • Metered spray pumps have dominated the nasal drug delivery market since they were introduced.
  • the pumps typically deliver 100 pL (or other volumes in the range of 25-200 pL, and higher) per spray, and they offer high reproducibility of the emitted dose and plume geometry in in vitro tests.
  • Examples of standard metered spray pumps include those offered by Aptar Pharma, Inc., such as the multi-dose“classic technology platform” nasal spray devices.
  • Such devices comprise a reservoir which holds multiple doses of the nasal spray formulation (e.g., 50, 100, 150, 200, 60, or 120 doses), a closure (e.g., screw, crimp, or snap-on), and an actuator which delivers anywhere from 45 to 1000 pL (e.g. 50, 100, 140, 150, or 200 pL) of fluid per actuation to comprise a single dose.
  • the actuator may be configured to count doses, deliver gel formulations, deliver in an upside-down configuration, etc.
  • preservative- free systems are also available, e.g. the Advanced Preservative Free (APF) system from Aptar, which is vented, contains a filter membrane for air flow which prevents contamination, has a metal-free fluid path for oxidizing formulations, and can be used in any orientation.
  • API Advanced Preservative Free
  • Additional nasal spray devices from Aptar and others are optimized with dispenser tips that prevent clogging (useful for high-viscosity and high-volatile formulations), actuators that do not need re-priming after long periods of disuse, etc.
  • the particle size and plume geometry can vary within certain limits and depend on the properties of the pump, the formulation, the orifice of the actuator, and the force applied.
  • the droplet size distribution of a nasal spray is a critical parameter, since it significantly influences the in vivo deposition of the drug in the nasal cavity.
  • the droplet size is influenced by the actuation parameters of the device and the formulation.
  • the prevalent median droplet size should be between about 30 and about 100 pm. If the droplets are too large (> about 120 pm), deposition takes place mainly in the anterior parts of the nose, and if the droplets are too small ( ⁇ about 10 pm), they can possibly be inhaled and reach the lungs, which should be avoided because of safety reasons.
  • benzalkonium chloride can affect the surface tension of droplets from a delivered nasal spray plume, producing spherical or substantially spherical particles having a narrow droplet size distribution (DSD), as well as the viscosity of a liquid formulation.
  • DSD narrow droplet size distribution
  • Plume geometry, droplet size and DSD of the delivered plume subsequent to spraying may be measured under specified experimental and instrumental conditions by appropriate and validated and/or calibrated analytical procedures known in the art. These include photography, laser diffraction, and impaction systems (cascade impaction, NGI). Plume geometry, droplet size and DSD can affect pharmacokinetic outcomes such as Cmax, Tmax, and linear dose proportionality.
  • Droplet size distribution can be controlled in terms of ranges for the D10, D50, D90, span [(D90-D10)/D50], and percentage of droplets less than 10 mm.
  • the formulation will have a narrow DSD.
  • the formulation will have a D(v,50) of 30-70 pm and a D(v, 90) ⁇ 100 pm.
  • the percent of droplets less than 10 pm will be less than 10%. In certain embodiments, the percent of droplets less than 10 pm will be less than 5%. In certain embodiments, the percent of droplets less than 10 pm will be less than 2%. In certain embodiments, the percent of droplets less than 10 pm will be less than 1%.
  • the formulation when dispensed by actuation from the device will produce a uniform circular plume with an ovality ratio close to 1.
  • Ovality ratio is calculated as the quotient of the maximum diameter (Dmax) and the minimum diameter (Dmin) of a spray pattern taken orthogonal to the direction of spray flow (e.g., from the“top”).
  • the ovality ratio is less than ⁇ 2.0.
  • the ovality ratio is less than ⁇ 1.5.
  • the ovality ratio is less than ⁇ 1.3.
  • the ovality ratio is less than ⁇ 1.2.
  • the ovality ratio is less than ⁇ 1.1.
  • the ovality ratio is about ⁇ 1.0.
  • solutions with a collapsible bag and a movable piston compensating for the emitted liquid volume offer the additional advantage that they can be emitted upside down, without the risk of sucking air into the dip tube and compromising the subsequent spray. This may be useful for some products where the patients are bedridden and where a head-down application is recommended.
  • Another method used for avoiding preservatives is that the air that replaces the emitted liquid is filtered through an aseptic air filter.
  • some systems have a ball valve at the tip to prevent contamination of the liquid inside the applicator tip (www.aptar.com). More recently, pumps have been designed with side-actuation and introduced for delivery of fluticasone furoate for the indication of seasonal and perennial allergic rhinitis.
  • the pump was designed with a shorter tip to avoid contact with the sensitive mucosal surfaces.
  • New designs to reduce the need for priming and re-priming, and pumps incorporating pressure point features to improve the dose reproducibility and dose counters and lock-out mechanisms for enhanced dose control and safety are available (www.rexam.com and www.aptar.com).
  • a nosepiece with a spray tip is fitted to a standard syringe.
  • the liquid drug to be delivered is first drawn into the syringe and then the spray tip is fitted onto the syringe.
  • This device has been used in academic studies to deliver, for example, a topical steroid in patients with chronic rhinosinusitis and in a vaccine study.
  • a pre-filled device based on the same principle for one or two doses is used to deliver the influenza vaccine FluMistTM (www.flumist.com), approved for both adults and children in the US market.
  • FluMistTM www.flumist.com
  • Pre -primed single- and bi-dose devices are also available, and consist of a reservoir, a piston, and a swirl chamber (see, e.g., the UDS UnitDose and BDS BiDoseTM devices from Aptar, formerly Pfeiffer).
  • the spray is formed when the liquid is forced out through the swirl chamber.
  • These devices are held between the second and the third fingers with the thumb on the actuator.
  • a pressure point mechanism incorporated in some devices secures reproducibility of the actuation force and emitted plume characteristics.
  • nasal migraine drugs like Imitrex ® (www.gsk.com) and Zomig ® (www.az.com; Pfeiffer/ Aptar single-dose device), the marketed influenza vaccine Flu-Mist (www.flumist.com; Becton Dickinson single dose spray device), and the intranasal formulation of naloxone for opioid overdose rescue , Narcan Nasal ® (narcan.com; Adapt Pharma) are delivered with this type of device.
  • the 90% confidence interval for dose delivered per actuation is ⁇ about 2%. In certain embodiments, the 95% confidence interval for dose delivered per actuation is ⁇ about 2.5%.
  • intranasal administration of drugs in large volume has encountered difficulty due to the tendency of some of the formulation to drip back out of the nostril or down the nasopharynx.
  • less than about 20% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
  • less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
  • less than about 5% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
  • Pre-metered presentations contain previously measured doses or a dose fraction in some type of units (e.g., single or multiple blisters or other cavities) that are subsequently inserted into the device during manufacture or by the patient before use.
  • Typical device-metered units have a reservoir containing formulation sufficient for multiple doses that are delivered as metered sprays by the device itself when activated by the patient.
  • a new nasal drug delivery method which can be adapted to any type of dispersion technology for both liquids and powders, is breath-powered Bi-DirectionalTM technology.
  • Breath-powered Bi-DirectionalTM devices consist of a mouthpiece and a sealing nosepiece with an optimized frusto-conical shape and comfortable surface that mechanically expands the first part of the nasal valve.
  • the user slides a sealing nosepiece into one nostril until it forms a seal with the flexible soft tissue of the nostril opening, at which point, it mechanically expands the narrow slit-shaped part of the nasal triangular valve.
  • the user then exhales through an attached mouthpiece.
  • the soft palate When exhaling into the mouthpiece against the resistance of the device, the soft palate (or velum) is automatically elevated by the positive oropharyngeal pressure, isolating the nasal cavity from the rest of the respiratory system.
  • This mechanism enables release of liquid or powder particles into an air stream that enters one nostril, passes entirely around the nasal septum, and exits through the opposite nostril.
  • Products are filled and sealed in this type of environment to minimize the microbial and particulate content of the in-process product and to help ensure that the subsequent sterilization process is successful.
  • the product, container, and closure have low bioburden, but they are not sterile.
  • the product in its final container is then subjected to a sterilization process such as heat or irradiation.
  • a sterilization process such as heat or irradiation.
  • the drug product, container, and closure are first subjected to sterilization methods separately, as appropriate, and then brought together. Because there is no process to sterilize the product in its final container, it is critical that containers be filled and sealed in an extremely high-quality environment. Aseptic processing involves more variables than terminal sterilization.
  • the individual parts of the final product are generally subjected to various sterilization processes. For example, glass containers are subjected to dry heat; rubber closures are subjected to moist heat; and liquid dosage forms are subjected to filtration. Each of these manufacturing processes requires validation and control.
  • naltrexone or a salt or hydrate thereof.
  • the Sinclair Method is a treatment for AUD that employs pharmacological extinction—the use of an opioid antagonist, such as naltrexone, to turn the habit-forming behavior of drinking alcohol into a habit-erasing behavior. The effect returns a person’s craving for alcohol to its pre-addiction state.
  • an opioid antagonist such as naltrexone
  • the method consists of taking an oral dose of naltrexone about 1, about 2, about 3, or about 4 hours before a subject ingests alcohol.
  • This pre-ingestion dose of oral naltrexone disrupts the body’s behavior and reward cycle thereby causing the person to want to drink less instead of more.
  • studies have shown that this methodology is equally effective with or without therapy, so subjects can choose whether or not to combine this treatment method with other therapies without negatively impacting the actual physical results.
  • the Sinclair Method calls for the use of oral naltrexone while the individual continues their normal drinking behavior. As a result, maintenance of the medication treatment protocol is expected to be much higher than abstinence alone.
  • a method of treatment of alcohol use disorder, or a related condition, in a subject comprising administering to the subject an intranasal formulation comprising a therapeutically effective amount of naltrexone or a pharmaceutically acceptable salt thereof.
  • the intranasal formulation comprising naltrexone is administered prior to ingestion of alcohol.
  • the intranasal formulation comprising naltrexone is administered about 1 to about 2 hours prior to ingestion of alcohol. In certain embodiments, the intranasal formulation comprising naltrexone is administered about 1 hour prior to ingestion of alcohol. In certain embodiments, the intranasal formulation comprising naltrexone is administered about 0.5 to about 1 hours prior to ingestion of alcohol. In certain embodiments, the intranasal formulation comprising naltrexone is administered about 10 to about 30 minutes prior to ingestion of alcohol. In certain embodiments, the intranasal formulation comprising naltrexone is administered about 5 to about 10 minutes prior to ingestion of alcohol. In certain embodiments, the intranasal formulation comprising naltrexone is administered just before ingestion of alcohol.
  • the intranasal formulation comprising naltrexone is administered contemporaneously with the ingestion of alcohol.
  • the intranasal formulation comprising naltrexone is administered just after ingestion of alcohol. In certain embodiments, the intranasal formulation comprising naltrexone is administered within an hour after commencement of ingestion of alcohol.
  • intranasal naltrexone has a rapid uptake via the nasal mucosa and rapid appearance in the plasma, as evidenced by the studies below, intranasal administration will permit the subject to dose naltrexone much more immediately before, and even contemporaneously with or after, ingestion if alcohol, and experience benefits such as extinction, reduction in craving, etc. It is expected that absorption enhancers will further this effect.
  • the alcohol use disorder is alcohol abuse. In certain embodiments, the alcohol use disorder is alcohol dependence. In certain embodiments, the alcohol use disorder is alcoholism.
  • the methods disclosed herein may be achieved by administration of various embodiments of the formulations disclosed herein, for example above in the section “Pharmaceutical Formulations,” the embodiments above, and the Examples below.
  • the formulations may be administered using devices known on the art, for example the devices disclosed herein in the section entitled“Nasal Drug Delivery Devices and Kits.”
  • any embodiment described above may be combined with any one or more other embodiment(s), provided the combination is not mutually exclusive.
  • AUD Alcohol use disorder
  • Individuals with alcohol use disorder will be treated with intranasal naltrexone and examined for abstinence, reduced consumption of alcohol, and/or extinguished consumption of alcohol.
  • Individuals with AUD are believed to release endogenous opioids upon the ingestion of alcohol.
  • the binding of these opioids to receptors in the brain may be responsible for the positive reinforcing effects of alcohol.
  • subjects e.g., about 10-20
  • AUD will make be admitted as in-patients to a study site.
  • An initial visit serves the purpose of screening, to confirm the diagnosis and obtain informed consent.
  • each subject During their in-patient stay (e.g., one or more weeks), each subject will receive a placebo or intranasal dose of naltrexone followed by the consumption one or more alcoholic beverages.
  • Naltrexone will be administered at the designated dose and by the designated method at about 0.25 to about 4 hrs before consumption of alcohol.
  • a dosing treatment is an intranasal formulation delivering about 1 to about 4 mg of naltrexone hydrochloride per administration, delivered by a single- or multi use spray device.
  • a dosing treatment is an intranasal formulation delivering a first dose of 3 mg of naltrexone hydrochloride in the morning, followed by subsequent doses of 3 mg of naltrexone hydrochloride throughout the day as needed by the patient.
  • Yet another example of a dosing treatment is an intranasal formulation delivering up to 12 mg of naltrexone hydrochloride per day.
  • the intranasal formulation of naltrexone may or may not contain an absorption enhancer, such as Intravail®.
  • Intravail® an absorption enhancer
  • ECG ECG
  • blood pressure ECG
  • heart rate ECG
  • respiration rate Approximately 1 hour prior to dosing, ECG, blood pressure, heart rate, and respiration rate will be measured and the time will be recorded. At approximately 1 and 4 hours after dosing, the ECG will be repeated and the time will be recorded. Vital signs including sitting (after 5 minutes) heart rate, blood pressure and respiration rate will be measured pre dose and approximately 1 and 4 hours after each dose. Adverse events (AEs) will be recorded and treatment terminated if necessary. The nasal passage will be examined at pre-dose, 5 minutes, 30 minutes, 60 minutes, 4 hours, and 24 hours post-dose after intranasal administration only.
  • AEs Adverse events
  • PK parameters of naltrexone and 6b- naltrexol Cmax, Tmax, AUCo-t, AUC 0 - , ti/2, lz, and apparent clearance (CL/F, naltrexone only) will be determined.
  • PK parameters of various AUD treatment protocols e.g., 4 mg intranasal with or without an absorption enhancer such as an alkylsaccharide; 50 mg oral tablet
  • IM intramuscular
  • the relative extent of intranasal (IN) and oral absorption (PO) absorption will be estimated from the dose-corrected AUCs.
  • ANOVA framework comparisons of IN-transformed PK parameters for IN and PO versus IM naltrexone treatments will be performed.
  • the 90% confidence interval for the ratio (IN/IM and PO/IM) of the geometric least squares means of AUC and Cmax parameters will be constructed for comparison of each treatment with IM naltrexone. These 90% confidence intervals will be obtained by exponentiation of the 90% confidence intervals for the difference between the least squares means based upon a log scale.
  • AEs will be coded using the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms and will be grouped by system, organ, class (SOC) designation. The severity, frequency, and relationship of AEs to study drug will be presented by preferred term by SOC grouping. Separate summaries will be provided for the 4 study periods: after the administration of each dose of study drug up until the time of the next dose of study drug or clinic discharge. Listings of each individual AE including start date, stop date, severity, relationship, outcome, and duration will be provided.
  • MedDRA Medical Dictionary for Regulatory Activities
  • Intranasal naltrexone may optionally be formulated with absorption-enhancing excipients.
  • Intravail ® One such excipient is the alkylsaccharide Intravail ® .
  • Concentrations of Intravail® in nasal formulations have generally been 0.1 % and 0.2% by weight. The present study will use a concentration of 0.25% by weight of an alkylsaccharide. Concentrations of 25% Intravail® were non-irritating in the rabbit eye model. The oral "no observable effect level" was approximately 20,000 to 30,000 mg/kg body weight. While there is no comparable intranasal data, the essential lack of oral safety suggests that the amount of an alkylsaccharide needed for nasal toxicity would be much higher than the amount that will be administered in this study.
  • Intranasal administration is expected to increase the rate of absorption as compared to oral administration.
  • Addition of Intravail ® is expected to further increase the rate of absorption from the nasal passages.
  • the study’s primary endpoints were the pharmacokinetic parameters (Cmax, Tmax, AUCo-t, and AUCo-inf) of the IN and oral naltrexone formulations compared with an IM dose of 2 mg of naltrexone.
  • Secondary endpoints included adverse events (AEs), vital signs (heart rate, sitting blood pressure, and respiration rate), electrocardiogram (ECG), clinical laboratory changes and nasal irritation using the nasal irritation scale.
  • AEs adverse events
  • vital signs heart rate, sitting blood pressure, and respiration rate
  • ECG electrocardiogram
  • Study design Fourteen healthy volunteers were enrolled and completed all study drug administrations and blood collections for PK assessments. This was an in-patient open- label, crossover study involving approximately 14 healthy volunteers.
  • Informed consent was obtained from all subjects, and all were screened for eligibility to participate in the study including medical history, physical examination, clinical chemistry, coagulation markers, hematology, infectious disease serology, urinalysis, urine drug and alcohol toxicology screen, vital signs and ECG.
  • ECG and vital signs were collected within the 10 minute period before the nominal time of blood collections.
  • ECG, vital signs were checked once per day.
  • Vital signs were also checked once on the day after naltrexone administration.
  • Clinical laboratory measurements were repeated after the last PK blood draw prior to clinic discharge. AEs were assessed by spontaneous reports by subjects, by examination of the nasal mucosa, by measuring vital signs, ECG, and clinical laboratory parameters.
  • BMI body mass index
  • any IN conditions including abnormal nasal anatomy, nasal symptoms (i.e., blocked and/or runny nose, nasal polyps, etc.);
  • systolic blood pressure less than 90 mm Hg or greater than 140 mm Hg; diastolic blood pressure less than 55 mmHg or greater than 90 mmHg; respiratory rate less than 8 respirations per minute or greater than 20 respirations per minute;
  • hepatitis B surface antigen HBsAg
  • hepatitis C virus antibody HCVAb
  • human immunodeficiency virus antibody HIYAb
  • ALT abnormal liver function test
  • AST total bilirubin
  • Naltrexone hydrochloride was obtained from Mallinckrodt Pharmaceuticals.
  • the IN (40 mg/mL) formulations were made by the staff pharmacist at Vince & Associates; the vehicle for the IN formulations was sterile water for injection.
  • the IM formulation (2 mg/mL) was made by the staff pharmacist at Vince & Associates; the vehicle was sterile saline for injection.
  • IN naltrexone was administered using an Aptar multi-dose device with the subject in a reclined position (approximately 45 degrees). The subject was instructed not to breathe through the nose when the IN dose of naltrexone was administered.
  • Naltrexone HCI for the IM injection was administered with a 23-g needle as a single 1-mL injection into the gluteus maximus muscle.
  • Naltrexone HCI for oral administration 50 mg tablet was sourced from a commercial supplier and administered with 240 mL water.
  • Naltrexone was administered on Days 1, 4, 7, and 10, in the following order: 4 mg naltrexone IN, 4 mg naltrexone plus Intravail® IN, 2 mg IM, and 50 mg oral. Subjects stayed in the in-patient facility for 13 days to complete the entire study and were discharged 2 days after the fourth dose.
  • PK Assessments Blood (4 mL) was collected in sodium heparin containing tubes for PK analysis prior to dosing and 2.5, 5, 10, 1.5, 20, 30, 45, 60 minutes and 2, 3, 4, 6, 8, 12, 16, 24, 30, 36, and 48 hours after the start of study drug administration. Plasma was separated from whole blood and stored frozen at ⁇ 20°C until assayed. Naltrexone and 6[S-naltrexol plasma concentrations were determined by liquid chromatography with tandem mass spectrometry at XenoBiotic laboratories, Inc., Plainsboro, New Jersey.
  • Pharmacokinetic parameters (C a x, Tmax and AUCs) for IN and PO naltrexone were compared with those for IM naltrexone. Dose-adjusted values for AUCs and Cmax were calculated. The relative extent of IN and PO absorption (IN and PO versus IM) will be estimated from the dose-corrected AUCs.
  • the mean concentration at 2.5 minutes postdose was 0.117 ng/mL.
  • Intravail® was added to the formulation, the mean concentration was 10 times greater (1.15 ng/mL) at 2.5 minutes.
  • the mean concentrations of naltrexone with and without Intravail® were 11.9 ng/mL and 1.51 ng/mL, respectively, an 8-fold difference.
  • the addition of 0.25% Intravail® to the IN formulation decreased median Tmax from 30 minutes to 10 minutes and increased Cmax almost 3-fold (15.7 versus 5.35 ng/mL).
  • Overall exposure as measured by AUCo-inf increased by 54%, indicating that the main effect of Intravail ® was to increase the rate of absorption more than the extent.
  • the mean plasma concentrations of naltrexone at 2.5 and 5 minutes after administration of 2 mg naltrexone IM were 0.678 ng/mL and 1.04 ng/mL, respectively.
  • the mean Cmax value of 4.10 ng/mL 20 minutes after the 2 mg IM dose was 23% less than after the 4 mg IN dose and 74% less compared to when Intravail ® was part of the IN formulation.
  • the mean Cmax value after the oral dose was 9.34 ng/mL, which was less than observed after the IN dose with Intravail ® even though 50 mg was administered orally compared to only 4 mg IN.
  • the mean terminal phase half-life (t1 ⁇ 2) of naltrexone was 1.97 hours to 2.52 hours after IM and IN administration.
  • the t1 ⁇ 2 was 6.41 hours after the oral dose.
  • GMR Geometric least-squares mean ratio between treatments (expressed as percentage of reference)
  • the mean t1 ⁇ 2 of the metabolite was 12.4 to 13.9 hours and was independent of the route of administration.
  • Table 6 sets forth simple aqueous solution formulations such as those used in the experiment above, to be dispensed in increments of about 100 pL.
  • naltrexone containing an efficacious amount of naltrexone
  • naltrexone quickly absorbed after administration, yielding a good Cmax and relatively short Tma X ;
  • a range of formulations were tested with the following observations.
  • a 50 mg/mL preparation of naltrexone HC1 was cloudy at room temperature, indicating incomplete dissolution; the solubility limit of naltrexone hydrochloride in solution at ambient temperature was determined to be approximately 40 mg/mL.
  • Several preparations were made at 30 mg/mL thereafter, which additionally contained fixed amounts of (dodecyl maltoside 0.25% ) and NaCl (about 0.74%), and varying amounts of preservative (benzalkonium chloride, 0-0.02%) and stabilizing agent (EDTA, 0-0.3%). Crystallization behavior and discoloration were visually monitored. All of these formulations developed crystals when stored under refrigerated conditions.
  • Naltrexone solutions tend to turn yellow with time, over the course of 0 to 3 months; formulations, containing 0.2% or 0.3% EDTA, did not form yellow solutions, whereas a formulation containing 0% or 0.1% EDTA did begin to yellow.
  • the 0.3% EDTA formulation appeared to resist yellowing for the longest period of time. Thereafter, a range of co-solvents were assessed for their potential to reduce crystallization of drug out of solution. Polyethylene glycol (PEG), propylene glycol, and benzyl alcohol were tested.
  • PEG-containing formulations did not prevent crystallization; propylene glycol containing formulations prevented crystallization but resulted in high osmolality, which would be expected to result in irritation of nasal membrane tissue; benzyl alcohol containing formulations prevented crystallization at low concentration. Total solid content was observed to be related to crystallization, and reducing the amount of naltrexone hydrochloride to produce the lower concentrations and the amount of NaCl in order to adjust for osmolality assisted in keeping the formulation in solution when stored under refrigerated conditions.
  • Four formulations of naltrexone suitable for intranasal administration are given below in Example 7.
  • naltrexone which each make 2000 liquid grams of the give formulation for intranasal administration for the treatment of disorders, including Alcohol Use Disorder, which may be dispensed in increments of, e.g., about 100 pL.
  • formulations above may be tested according to the procedures above in Examples A-E and according to methods known in the art; certain of these formulations have been tested in Example 8 below. It is expected that the pharmacokinetic properties of these formulations will be consistent with those of an effective medication to treat opioid overdose as well as to use in‘as needed’ fashion to treat multiple substance use disorders, exemplified by alcohol use disorder, and other reward-based disorders. These properties include a rapid onset (short Tmax), high plasma concentration, and short half-life relative to oral administration that can be achieved with these formulations.
  • a single-center, open-label, randomized, four-sequence, four- treatment, four- period crossover pilot study was completed in healthy male and nonpregnant female subjects. Twenty (20) healthy subjects were enrolled. Twenty-one (20) subjects completed the study and have evaluable data for all study periods.
  • Endpoints The primary study endpoint was to determine the pharmacokinetics of three different doses (1.2 mg, 1.6 mg, and 3 mg) of naltrexone hydrochloride nasal spray (Test Products 1, 2, and 3, respectively, also referred to herein as Tl, T2, and T3) compared to a 50 mg oral dose of naltrexone hydrochloride (Reference Product, also referred to herein as R) and to identify the intranasal dose of Test Product that could achieve naltrexone systemic exposure comparable to the 50 mg oral dose.
  • the secondary study endpoint was to assess the safety and tolerability of the Test Product, especially nasal irritation (e.g., erythema, edema and erosion).
  • Exclusion criteria at screening were: known hypersensitivity/allergy reaction to the study drug substance or any of the excipients; known severe hypersensitivity reaction to any other drug; any nasal conditions including abnormal nasal anatomy, nasal symptoms (i.e. blocked and/or runny nose, nasal polyps, etc.), rhinitis and other conditions that are known to impact nasal absorption or having a product sprayed in to the nasal cavity prior to drug administration; previous or current opioid, alcohol, or other drug dependence (excluding nicotine and caffeine), based on medical history; concurrent disease considered by the investigator to be clinically significant in the context of the study; need for concomitant treatment medication during the study; any medical condition (e.g.
  • gastrointestinal, renal or hepatic including peptic ulcer, inflammatory bowel disease or pancreatitis) or surgical condition (e.g. cholecystectomy, gastrectomy) that could affect drug pharmacokinetics (absorption, distribution, metabolism or excretion) or subject safety; current or recent (within 7 days prior to screening) upper respiratory tract infection; QTc interval > 450 msec for males and > 470 msec for females; positive result in urine drugs-of-abuse test, or ethanol breath test; use of a depot injection or an implant of any drug (all but contraceptives) within the previous 3 months; average weekly alcohol consumption of >14 units (12 grams per unit) for males and >7 units for females within the previous 6 months; average daily consumption of methylxanthines-containing beverages or food (e.g.
  • methylxanthines 100 mg of methylxanthines is equivalent to approximately 150 mL of coffee, 300 mL of tea, 75 mL of hot chocolate, 800 mL of cola, 300 mL of energy drinks, or 25 g chocolate bar; participation in any clinical trial within the previous 2 months, or in more than 2 clinical trials within the previous 12 months; blood donation or significant blood loss (> 450 mL) due to any reason or had plasmapheresis within the previous 2 months; difficulty in fasting or any dietary restriction such as lactose intolerance, vegan, low-fat, low sodium, etc., that may interfere with the diet served during the study; difficulty in donating blood on either arm; difficulty in swallowing capsules or tablets; if female, pregnant or breast-feeding; and any other condition that the Investigator considers rendering the subject unsuitable for the study.
  • Exclusion criteria at admission were: resting systolic blood pressure between 90 and 140 mmHg, inclusive, and diastolic blood pressure between 65 and 90, inclusive; resting heart rate between 40 and 100 bpm, inclusive; resting respiratory rate between 8 and 20, inclusive; QTcF interval >500 msec; significant arrhythmia defined as > 6 beats of supraventricular tachycardia or > 3beats of ventricular tachycardia; any recent disease or condition or treatment that, according to the Investigator, would put the subject at undue risk due to study participation or occurred at a timeframe in which may interfere with the pharmacokinetics of study drug; use of prescription or nonprescription medicinal products, including vitamins, food supplements, herbal supplements (including St John’s Wort), within the previous 14 days, unless in the Investigator’s opinion the medication would not interfere with the pharmacokinetics of study drug or compromise subject safety (the use of topical products without systemic absorption, or recommended contraceptives was acceptable); consumption of any alcoholic product within the
  • Pharmacokinetic parameters of naltrexone and 6[S-naltrexol were estimated with Phoenix ® WinNonlin ® version 8.1 (Certara USA Inc, Princeton, NJ) or higher, by using a non- compartmental approach with a In- linear terminal phase assumption. Actual times of blood sampling was used to estimate pharmacokinetic parameters.
  • Cmax maximum observed plasma concentration
  • Wx time of occurrence of Cmax
  • AUC area under the plasma concentration versus time curve
  • AUCo-t area under the plasma concentration versus time curve
  • l z apparent terminal elimination rate constant
  • ti/2 apparent terminal elimination half-life
  • Table 10 presents the average of naltrexone secondary pharmacokinetic parameters and respective summary statistics for twenty (20) subjects, following administration of Test 1 Product, Test 2 Product, Test 3 Product, and Reference Product.
  • Table 11 presents the average naltrexone pharmacokinetic parameters and respective summary statistics for twenty (20) subjects, following first and second administrations of Test 1 Product, Test 2 Product, Test 3 Product, and Reference Product
  • Table 12 presents the average of ⁇ b-naltrexol primary pharmacokinetic parameters and respective summary statistics for twenty (20) subjects, following administration of Test 1 Product, Test 2 Product, Test 3 Product, and Reference Product.
  • Table 13 presents the average of ⁇ b-naltrexol secondary pharmacokinetic parameters and respective summary statistics for twenty (20) subjects, following administration of Test 1 Product, Test 2 Product, Test 3 Product, and Reference Product.

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MX2021007522A MX2021007522A (es) 2018-12-20 2019-12-19 Composiciones, dispositivos y metodos para el tratamiento de trastornos por sobredosis y basados en recompensas.
CA3124202A CA3124202A1 (en) 2018-12-20 2019-12-19 Compositions, devices, and methods for the treatment of overdose and reward-based disorders
EP19898164.9A EP3897579A4 (en) 2018-12-20 2019-12-19 COMPOSITIONS, DEVICES AND METHODS FOR TREATING OVERDOSE AND REWARD-RELATED DISORDERS
AU2019403368A AU2019403368A1 (en) 2018-12-20 2019-12-19 Compositions, devices, and methods for the treatment of overdose and reward-based disorders
KR1020217022386A KR20210131996A (ko) 2018-12-20 2019-12-19 과다복용 및 보상-기반 장애의 치료를 위한 조성물, 장치 및 방법
CN201980092189.2A CN113573696A (zh) 2018-12-20 2019-12-19 用于治疗过剂量和奖赏系障碍的组合物、装置和方法
JP2021535535A JP2022514340A (ja) 2018-12-20 2019-12-19 過剰摂取および報酬に基づく障害を処置するための、組成物、装置、および方法
SG11202106531VA SG11202106531VA (en) 2018-12-20 2019-12-19 Compositions, devices, and methods for the treatment of overdose and reward-based disorders
IL284117A IL284117A (en) 2018-12-20 2021-06-17 Preparations, devices and methods for the treatment of disorders based on overdose and compensation

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US20110065628A1 (en) * 2007-08-27 2011-03-17 University Of Virginia Patent Foundation Medication Combinations for the Treatment of Alcoholism and Drug Addiction
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