Compositions comprising setmelanotide and methods of treating opioid-induced respiratory depression

Abstract

Disclosed herein compositions comprising setmelanotide (SET) and methods of using those compositions to prevent and / or minimize one or more indexes of opioid-induced respiratory depression (OIRD) in a clinical setting and in an opioid overdose.

Description

COMPOSITIONS COMPRISING SETMELANOTIDE AND METHODS OF TREATING OPIOID-INDUCED RESPIRATORY DEPRESSIONI. CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 564.903 filed 13 March 2024, which is incorporated by reference herein in its entirety.II. BACKGROUND

[0002] The statistics are staggering. Approximately 225 people die each day from an opioid overdose. 88% of opioid-involved overdose deaths involved synthetic opioids. The primary cause of death associated with ultra-potent synthetic (UPS) opioids is opioid-induced respiratory' depression (OIRD), characterized by reduced respiratory rate, decreased airflow, and central apneas, ultimately resulting in severe hypoxemia and cardio-respiratory arrest.

[0003] Naloxone, a mu-opioid receptor (MOR) antagonist, rapidly reverses OIRD. However, it has a short half-life (~ 1 hr.) and therefore cannot cover the entire exposure to synthetic opioids that have far longer half-lives. Naloxone does not reverse non-MOR effects of UPS opioids such as muscle rigidity, does not relieve upper airway obstruction in patients with underlying obstructive sleep apnea (OSA), and may cause pulmonary edema. In addition, naloxone blocks the analgesic effects of opioids and causes acute withdrawal that often causes agitation, vomiting, and diarrhea. Another adverse outcome following overdose resuscitation using naloxone is often described as “rage’?that includes angry, hostile, combativeness, and / or aggressive outbursts with between 10.9% to 41% of all overdose reversals labelled as 'rage’ events. Another MOR antagonist, nalmefene, has a longer half-life (8-11 hr.), but it also causes similar adverse effects.

[0004] Consequently, alternative non-opioid receptor antagonist-based approaches to OIRD treatment and prevention are urgently needed. The compositions and methods disclosed herein meet this urgent need.III. BRIEF DESCRIPTION OF THE FIGURES

[0005] FIG. 1 shows that setmelanotide (SET, n = 8) administered 15 min after morphine decreased the apnea index and duration of apneas and increased respiratory' rate. RR is respiratory' rate; VEH is vehicle; ** is p < 0.001 and * is p < 0.05.

[0006] FIG. 2A shows that setmelanotide (SET, n = 6) administered 15 min after morphine had no effect on tail flick latency indicating no interference with analgesia. * is p < 0.05 compared to baseline for the M+V and f is p < 0.05 compared to baseline for the M+S. FIG. 2B shows baseline, M+V (morphine + vehicle), and M+S (morphine + setmelanotide). ** is p < 0.01 and ** is p < 0.001 compared to baseline.

[0007] FIG. 3 shows that setmelanotide (SET, n = 8) administered 15 minutes after fentanyl decreased the apnea index (events / hour (left panel) and duration (middle panel)) and increased respiratory rate (right panel). RR is respiratory rate; F + V is fentanyl + vehicle; F + S is (fentanyl + setmelanotide); **** is p < 0.0001 and * is p < 0.01.

[0008] FIG. 4 shows that setmelanotide (SET, n = 6) administered 10-15 minutes after fentanyl treated opioid-induced respiratory depression in rats. RR is respiratory rate; VEFI is vehicle (n = 8); *** is p < 0.001 and ** is p < 0.01; VT is tidal volume; VE is minute ventilation.

[0009] FIG. 5 shows that setmelanotide (SET, n = 6) administered 10-15 minutes after fentanyl decreased frequency of apneas in fentanyl-treated rats. VEH is vehicle (n = 8); ****, is p < 0.0001

[0010] FIG. 6 is a schematic showing that morphine and fentanyl bind to the p-opioid receptor (MOR) on neurons in the brainstem. The MOR neurons project to CO2 sensing neurons to the retrotrapezoid nucleus (RTN) in the rostral ventrolateral medulla. RTN neurons do not express MOR but carry melanocortin 4 receptors (MC4R). RTN neurons project to the neurons of the rostral ventral respiratory group (rVRG), which also express MOR. The rVRG neurons are monosynaptically connected to the respiratory phrenic motoneurons in the cervical spinal cord (SC) innervating the diaphragm, the main inspiratory muscle. Morphine and fentanyl inhibit M0R+ neurons in the rVRG and upstream in the brainstem, which inhibits respirator}' motoneurons leading to opioid-induced respiratory depression (OIRD). The MC4R agonist setmelanotide (SET) binds and activates the RTN neurons which activate rVRG neurons treating OIRD.IV. BRIEF SUMMARY

[0011] Disclosed herein is a pharmaceutical formulation comprising setmelanotide and one or more pharmaceutically acceptable carriers.

[0012] Disclosed herein is a pharmaceutical formulation comprising setmelanotide. naloxone, and one or more pharmaceutically acceptable carriers.

[0013] Disclosed herein is a pharmaceutical formulation comprising setmelanotide, nalmefene, and one or more pharmaceutically acceptable carriers.

[0014] Disclosed herein is a pharmaceutical formulation comprising setmelanotide and one or more opioid receptor antagonists, and one or more pharmaceutically acceptable carriers.

[0015] Disclosed herein is a pharmaceutical formulation comprising setmelanotide, naloxone, and one or more opioid receptor antagonists, and one or more pharmaceutically acceptable carriers.

[0016] Disclosed herein is a pharmaceutical formulation comprising setmelanotide, nalmefene, and one or more opioid receptor antagonists, and one or more pharmaceutically acceptable earners.

[0017] Disclosed herein is a pharmaceutical formulation comprising setmelanotide, one or more additional therapeutic agents, and one or more pharmaceutically acceptable earners.

[0018] Disclosed herein is a pharmaceutical formulation comprising setmelanotide, naloxone, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers.

[0019] Disclosed herein is a pharmaceutical formulation comprising setmelanotide, nalmefene, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers.

[0020] Disclosed herein is a pharmaceutical formulation comprising setmelanotide, one or more opioid receptor antagonists, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers.

[0021] Disclosed herein is a pharmaceutical formulation comprising setmelanotide, naloxone, one or more additional therapeutic agents, one or more opioid receptor antagonists, and one or more pharmaceutically acceptable carriers.

[0022] Disclosed herein is a pharmaceutical formulation comprising setmelanotide, nalmefene, one or more opioid receptor antagonists, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers.

[0023] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing an opioid overdose a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0024] Disclosed herein is a method of treating a subject suspected of experiencing an opioid overdose, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0025] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0026] Disclosed herein is a method of treating a subject suspected of experiencing opioid- induced respiratory depression (OIRD), the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0027] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) due to clinical administration of an opioid a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0028] Disclosed herein is a method of treating a subject suspected of experiencing opioid- induced respiratory depression (OIRD). the method comprising administering to a subject due toclinical administration of an opioid a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0029] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) due to opioid abuse or opioid misuse a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0030] Disclosed herein is a method of treating a subject suspected of experiencing opioid- induced respiratory depression (OIRD), the method comprising administering to a subject due to opioid abuse or opioid misuse a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0031] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing a morphine overdose a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0032] Disclosed herein is a method of treating a subject suspected of experiencing a morphine overdose, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0033] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing morphine-induced respiratory' depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0034] Disclosed herein is a method of treating a subject suspected of experiencing morphine- induced respiratory depression (OIRD), the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0035] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing a fentanyl overdose a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0036] Disclosed herein is a method of treating a subject suspected of experiencing a fentanyl overdose, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0037] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing fentanyl-induced respiratory depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0038] Disclosed herein is a method of treating a subject suspected of experiencing fentanyl- induced respiratory depression (OIRD), the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0039] Disclosed herein is a method of preventing OIRD, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation comprising SET, wherein the subject has received one or more opioids for pain management, wherein the pharmaceutical formulation does not disrupt and / or diminish and / or affect the analgesia provided to the subject by the one or more opioids, and wherein, following the administering step, the subject does not develop OIRD.

[0040] Disclosed herein is a method of preventing OIRD, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation, wherein the subject is receiving one or more opioids for pain management, wherein the pharmaceutical formulation comprising SET does not disrupt and / or diminish and / or affect the analgesia provided to the subject by the one or more opioids, and wherein, following the administering step, the subject does not develop OIRD.

[0041] Disclosed herein is a method of preventing OIRD, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation comprising SET, wherein the subject will receive one or more opioids for pain management, wherein the pharmaceutical formulation does not disrupt and / or diminish and / or affect the analgesia provided to the subject by the one or more opioids, and wherein, following the administering step, the subject does not develop OIRD.

[0042] Disclosed herein is a method of minimizing one or more symptoms of OIRD, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation comprising SET, wherein the subject has received one or more opioids for pain management, wherein the pharmaceutical formulation does not disrupt and / or diminish and / or affect the analgesia provided to the subject by the one or more opioids, and wherein, following the administering step, one or more symptoms of OIRD are reduced and / or minimized.

[0043] Disclosed herein is a method of minimizing one or more symptoms of OIRD, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation comprising SET. wherein the pharmaceutical formulation does not disrupt and / or diminish and / or affect the analgesia provided to the subject by the one or more opioids, and wherein, following the administering step, one or more symptoms of OIRD are reduced and / or minimized.

[0044] Disclosed herein is a method of minimizing one or more symptoms of OIRD, the method comprising administenng to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation comprising SET, wherein the pharmaceutical formulation does notdisrupt and / or diminish and / or affect the analgesia provided to the subject by the one or more opioids, and wherein, following the administenng step, one or more symptoms of OIRD are reduced and / or minimized.

[0045] Disclosed herein is a method of treating an opioid overdose, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0046] Disclosed herein is a method of treating a suspected opioid overdose, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0047] Disclosed herein is a method of treating an opioid overdose, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0048] Disclosed herein is a method of treating a suspected opioid overdose, the method comprising administering to a subject suspected of experiencing opioid-induced respiratory depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0049] Disclosed herein is a method of treating an opioid overdose, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) due to clinical administration of an opioid a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0050] Disclosed herein is a method of treating a suspected opioid overdose, the method comprising administering to a subject suspected of experiencing opioid-induced respiratory' depression (OIRD) due to clinical administration of an opioid a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0051] Disclosed herein is a method of treating an opioid overdose, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) due to opioid abuse or opioid misuse a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0052] Disclosed herein is a method of treating a suspected opioid overdose, the method comprising administering to a subject suspected of experiencing opioid-induced respiratory' depression (OIRD) due to opioid abuse or opioid misuse a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0053] Disclosed herein is a method of reducing aggression, anger, and / or violence associated with reversal of an opioid overdose, the method compnsing administering to a subject rn need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0054] Disclosed herein is a method of reducing aggression, anger, and / or violence associated with reversal of an opioid overdose due to clinical administration of an opioid, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0055] Disclosed herein is a method of reducing aggression, anger, and / or violence associated with reversal of an opioid overdose due to opioid abuse or opioid misuse, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0056] Disclosed herein is a method of reducing aggression, anger, and / or violence associated with reversal of an opioid overdose, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0057] Disclosed herein is a method of reducing aggression, anger, and / or violence associated with reversal of an opioid overdose due to clinical administration of an opioid, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0058] Disclosed herein is a method of reducing aggression, anger, and / or violence associated with reversal of an opioid overdose due to opioid abuse or opioid misuse, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.V. DETAILED DESCRIPTION

[0059] The present disclosure describes formulations, compounded compositions, kits, capsules, containers, and / or methods thereof. It is to be understood that the inventive aspects of which are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those disclosed herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0060] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.A. Definitions

[0061] Before the present compounds, compositions, articles, systems, devices, and / or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those disclosed herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0062] This disclosure describes inventive concepts with reference to specific examples. However, the intent is to cover all modifications, equivalents, and alternatives of the inventive concepts that are consistent with this disclosure.

[0063] In an aspect, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.

[0064] In an aspect, the phrase ‘consisting essentially oT limits the scope of a claim to the recited components in a composition or the recited steps in a method as well as those that do not materially affect the basic and novel characteristic or characteristics of the claimed composition or claimed method. The phrase ‘consisting of excludes any component, step, or element that is not recited in the claim. The phrase ‘comprising’ is synonymous with ‘including’, ‘containing', or ‘characterized by’, and is inclusive or open-ended. ‘Comprising’ does not exclude additional, unrecited components or steps.

[0065] In an aspect, when referring to any numerical value, the term ‘about’ means a value falling within a range that is ± 10% of the stated value.

[0066] Ranges can be expressed herein as from ‘about’ one particular value, and / or to ‘about’ another particular value. When such a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent ‘about,' it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as ‘about’ that particular value in addition to the value itself. For example, if the value ‘10’ is disclosed, then ‘about 10’ is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12. 13. and 14 are also disclosed.

[0067] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0068] In an aspect, the terms ‘optional’ or ‘optionally’ means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. In an aspect, a disclosed method can optionally comprise one or more additional steps, such as, for example, repeating an administering step or altering an administering step.

[0069] In an aspect, the term ‘subject’ refers to the target of administration, e.g., a human being. The term does not denote a particular age or sex, and thus, adult and child subjects, as well as fetuses, whether male or female, are intended to be covered. In an aspect, a subject can be a human patient. In an aspect, a subject can have an opioid dependence, be suspected of having opioid dependence, or be at risk of developing opioid dependence. In an aspect, a subject can use illicit opioids, be suspected of using illicit opioids, or be at risk of using illicit opioids. In an aspect, a subject can have one or more symptoms associated with and / or related to OIRD. In an aspect, a subject can have one or more symptoms associated with and / or related to OIRD due to clinical administration of an opioid (e.g., morphine) or due to a non-clinical administration of an opioid (e.g., illicit drug use).

[0070] In an aspect, the term ‘diagnosed’ means having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by one or more disclosed pharmaceutical formulations comprising SET. one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof, or by one or more disclosed methods. For example, ‘diagnosed with opioid overdose’ means having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition (such as an opioid overdose) that can be treated by one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof, or by one or more disclosed methods. For example, “suspected of having an opioid overdose” can mean having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition (such as an opioid overdose) that can likely be treated by one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof, or by one ormore disclosed methods. In an aspect, an examination can be physical, can involve various tests (e.g., blood tests, genotyping, biopsies, etc.), scans (e.g., CT scans, PET scans, etc.), and assays (e.g., enzymatic assay), or a combination thereof.

[0071] “In an aspect, a “patient” can refer to a subject requiring pain management using an opioid (such as, for example, oxycodone, morphine, hydrocodone, codeine, fentanyl, or any combinations thereof). In an aspect, a “patient” can refer to a subject using an opioid (such as, for example, oxycodone, morphine, hydrocodone, codeine, fentanyl, heroin, and any combinations thereof) in a non-clinical setting (i.e., illicit opioid use). In an aspect, a patient can refer to a subject that has been diagnosed with or is suspected of having an opioid misuse and / or an opioid overdose.

[0072] In an aspect, the phrase “identified to be in need of treatment for pain or pain management,” or the like, refers to selection of a subject based upon need for treatment of the pain. For example, a subject can be identified as having a need for treatment for pain or pain management (e.g., an opioid) based upon an earlier diagnosis by a person of skill and thereafter subjected to treatment for an opioid overdose. In an aspect, the identification can be performed by a person different from the person making the diagnosis. In an aspect, the administration can be performed by one who performed the diagnosis.

[0073] In an aspect, “inhibit”, “inhibiting”, and “inhibition” mean to diminish or decrease an activity, level, response, condition, severity, disease, or other biological parameter (such as, for example, one or more symptoms associated with and / or related to OIRD including, but not limited to, respiratory rate, apnea duration, apnea incidence, apnea index, etc.). This can include, but is not limited to, the complete ablation of the activity, level, response, condition, severity7, disease, or other biological parameter. This can also include, for example, a 10% inhibition or reduction in the activity, level, response, condition, severity, disease, or other biological parameter as compared to the native or control level (e.g., a subject not having received one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof). Thus, in an aspect, the inhibition or reduction can be a 10%, 20%, 30%, 40%, 50%. 60%. 70%. 80%, 90%, 100%. or any amount of reduction in between as compared to native or control levels. In an aspect, the inhibition or reduction can be 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% as compared to a native or control level (e.g., a subject not having received one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof). In an aspect, the inhibition or reduction can be 0-25%, 25-50%, 50-75%, or 75-100% as compared to native or control levels. In an aspect, anative or control level can be a pre-opioid misuse and / or pre-opioid overdoselevel.

[0074] In an aspect, “treat” or “treating” or “treatment” include palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the opioid misuse and / or the opioid overdose; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the opioid misuse and / or the opioid overdose; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the opioid misuse and / or the opioid overdose. In an aspect, the terms cover any treatment of a subject, including a mammal (e g. , a human), and includes: (i) preventing the opioid misuse and / or the opioid overdose from occurring in a subject that can be predisposed to the misuse and / or overdose but has not yet been diagnosed as having it; (ii) inhibiting the opioid misuse and / or the opioid overdose, i.e., arresting its development; or (iii) relieving the physiological change, disease, pathological condition, or disorder, z.e. , causing regression of the disease (such as. for example, one or more symptoms associated with and / or related to OIRD including, but not limited to. respiratory rate, apnea duration, apnea incidence, apnea index, etc.). For example, in an aspect, treating an opioid misuse and / or an opioid overdose can reduce the severity of an established opioid misuse and / or established opioid overdosein a subject by 1%- 100% as compared to a control (such as, for example, an individual not having an opioid misuse and / or an opioid overdose or an individual not having one or more symptoms of OIRD).

[0075] In an aspect, treating can refer to a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an opioid misuse and / or an opioid overdose or one or more symptoms associated with and / or related to OIRD including, but not limited to, respiratory’ rate, apnea duration, apnea incidence, apnea index, or any combination thereof. For example, treating a disease or disorder can reduce one or more symptoms of an opioid misuse and / or an opioid overdose in a subject by 1 %-l 00% as compared to a control (such as, for example, an opioid misuse and / or an opioid overdose). In an aspect, treating can refer to 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%. 20%. 30%. 40%, 50%, 60%, 70%. 80%, 90%, 100% reduction of one or more symptoms of an established opioid misuse and / or an established opioid overdose. It is understood that treatment does not necessarily refer to a cure or complete ablation or eradication of an opioid misuse and / or an opioid overdose). However, in an aspect, treatment can refer to a cure or complete ablation or eradication of an opioid misuse and / or an opioid overdose or one or more symptoms associated with and / or related to OIRD including, but not limited to, respiratory rate, apnea duration, apnea incidence, apnea index, or any7combination thereof).

[0076] In an aspect, the term “prevent” or “preventing” or “prevention” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening (including death), especially by advance action. It is understood that where reduce, inhibit, or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed. The words “prevent”, “preventing”, and “prevention” also refer to prophylactic or preventative measures for protecting or precluding a subject (e.g., an individual) not having a given (such as an opioid overdose) or related complication from progressing to that complication. In an aspect, preventing one or more symptoms associated with and / or related to OIRD including, but not limited to, respiratory rate, apnea duration, apnea incidence, apnea index, etc.

[0077] In an aspect, the term “side effect” refers to adverse effects or toxic effects produced by a drug including but not limited to on a tissue or organ system. Such conditions, for example, can include sedation, dizziness, nausea, vomiting, constipation, hyperalgesia, immunologic and hormonal dysfunction, muscle rigidity, myoclonus, bowel dysfunction (e.g., anorexia, gastro- oesophageal reflux, delayed digestion, abdominal pain, bloating) respiratory depression and death.

[0078] In an aspect, the terms “opioid toxicity” or “opioid overdose” refers to the effects of opioid drugs that are toxic to a subj ect, resulting in effects that may be mild, moderate or severe including but not limited to respiratory depression or ventilatory depression, hypoxia, loss of consciousness, decreased respiratory rate, decreased respiratory depth, apnea, delirium, hypotension, bradycardia, decreased body temperature, urinary retention, pupil miosis, sedation, dizziness, nausea, vomiting, constipation, hyperalgesia, immunologic and hormonal dysfunction, muscle rigidity, myoclonus, and bowel dysfunction. Opioid toxicity can be assessed by any appropriate method known to a clinical physician or skilled artisan. For example, opioid toxicity’ can be assessed by performing a central nervous system review by assessing for confusion, altered mental state, excessive drowsiness, lethargy, stupor, slurred speech (new onset), hypoventilation, shortness of breath, apnea, hypoxia, and / or hypercapnia; and / or cardiac review by assessing for bradycardia, hypotension, and / or shock.

[0079] The term “overdose” refers to a subject that takes a dose larger than originally intended that causes in one or more adverse effects.

[0080] In an aspect, the liquid setmelanotide (SET) formulation is a spray. In an aspect, the liquid setmelanotide (SET) formulation is in a simple solution form. In an aspect, the term “simple solution” refers to a solution in which the solute(s) has fully dissolved in the solvent.

[0081] In an aspect, the term “stable” includes but is not limited physical and chemical stability.

[0082] In an aspect, the terms “administering” and “administration” refer to any method of providing one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof, or by one or more disclosed methods to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, the following: oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, in utero administration, intratumoral administration, intrahepatic administration, intravaginal administration, ophthalmic administration, intraaural administration, subcutaneous administration, transnasal administration, otic administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-CSF administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can also include hepatic intraarterial administration or administration through the hepatic portal vein (HPV). Administration of one or more disclosed pharmaceutical formulations comprising SET. one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof can comprise administration directly into the CNS or the PNS. Administration can be continuous or intermittent. Administration can comprise a combination of one or more routes.

[0083] In an aspect, the skilled person can determine an efficacious dose, an efficacious schedule, and an efficacious route of administration for the one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof to treat or prevent an opioid overdose. In an aspect, the skilled person can also alter, change, or modify an aspect of an administering step to improve efficacy of one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof.

[0084] By “determining the amount” is meant both an absolute quantification of a particular analyte (e.g., biomarker for an opioid overdose due, for example) or a determination of the relative abundance of a particular analyte (e g., an opioid overdose). The phrase includes both direct or indirect measurements of abundance or both.

[0085] In an aspect, “modifying the method” can comprise modify ing or changing one or more features or aspects of one or more steps of a disclosed method. In an aspect, a method can be altered by changing the amount of the one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof, or by changing the frequency of administration of the one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or moredisclosed devices, or a combination thereof to a subject, by changing the duration of time that one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof is administered to a subject, or by substituting for one or more of the disclosed components and / or reagents with a similar or equivalent component and / or reagent. The same applies to all disclosed pharmaceutical formulations comprising SET, disclosed liquid sprays, disclosed devices, or a combination thereof.

[0086] In an aspect, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. In an aspect, a pharmaceutical carrier employed can be a solid, liquid, or gas. In an aspect, examples of solid carriers can include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. In an aspect, examples of liquid carriers can include sugar syrup, peanut oil, olive oil, and water. In an aspect, examples of gaseous carriers can include carbon dioxide and nitrogen. In preparing a disclosed composition for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs, and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms aremade by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0087] In an aspect, the term “excipient” refers to an inert substance which is commonly used as a diluent, vehicle, preservative, binder, or stabilizing agent, and includes, but is not limited to, proteins (e.g., serum albumin, etc.), amino acids (e.g., aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.), fatty acids and phospholipids (e.g., alkyl sulfonates, caprylate, etc.), surfactants (e.g.. SDS, polysorbate, nonionic surfactant, etc.), saccharides (e.g., sucrose, maltose, trehalose, etc.) and polyols (e.g., mannitol, sorbitol, etc.). See, also, for reference. Remington’s Pharmaceutical Sciences, (1990) Mack Publishing Co., Easton, Pa., which is hereby incorporated by reference in its entirety.

[0088] In an aspect, “concurrently” means (1) simultaneously in time, or (2) at different times during the course of a common treatment schedule.

[0089] In an aspect, the term “contacting” refers to bringing one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof together with a target area or intended target area in such a manner that the one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof can exert an effect on the intended target or targeted area either directly or indirectly. A target area or intended target area can be one or more of a subject's organs (e.g., lungs, heart, liver, kidney, brain, etc.) affected by an opioid misuse and / or an opioid overdose. In an aspect, a target area or intended target area can be any cell or any organ affected by an opioid misuse and / or an opioid overdose. In an aspect, a target area or intended target area can be any organ, tissue, or cells that are affected by an opioid misuse and / or an opioid overdose.

[0090] In an aspect, a unit used to measure the activity of many vitamins, hormones, enzymes, and drugs. In an aspect, an “International Unit” is the amount of a substance that has a certain biological effect.

[0091] In an aspect, "‘determining'' can refer to measuring or ascertaining the presence and severity of an opioid misuse and / or an opioid overdose. Methods and techniques used to determine the presence and / or severity of an opioid misuse and / or an opioid overdoseare typically known to the medical arts. For example, the art is familiar with the ways to identity and / or diagnose the presence, severity, or both of an opioid misuse and / or an opioid overdose.

[0092] In an aspect, “effective amount” and “amount effective” can refer to an amount that is sufficient to achieve the desired result such as, for example, the treatment and / or prevention of an opioid misuse and / or an opioid overdose or a suspected an opioid misuse and / or an opioid overdose, the terms “effective amount” and “amount effective” can refer to an amount that is sufficient to achieve the desired an effect on an undesired condition (such as, for example, one or more symptoms associated with and / or related to OIRD including, but not limited to, respiratory rate, apnea duration, apnea incidence, apnea index, etc.). For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. In an aspect, “therapeutically effective amount” means an amount of one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof that (i) treats the an opioid misuse and / or an opioid overdose, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the an opioid misuse and / or an opioid overdose, or (iii) delays the onset of one or more symptoms an opioid misuse and / or an opioid overdose. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity' of the opioid misuse and / or the opioid overdose; one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof employed; the disclosed methods employed; the age. body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof employed; the duration of the treatment; drugs used in combination or coincidental with the one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof employed, and other like factors well known in the medical arts. For example, it is w ell within the skill of the art to start doses of the one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until thedesired effect is achieved. If desired, then the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, a single dose of a disclosed pharmaceutical formulations comprising SET, a disclosed liquid spray, a disclosed device, or a combination thereof can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of an opioid misuse and / or an opioid overdose.

[0093] In an aspect, the term '‘pre-primed” refers to a device, such as a nasal spray which can deliver a pharmaceutical composition to a patient in need thereof with the first actuation of the spray pump, i.e., without the need to prime the pump prior to dosing, such as by actuating the pump one or more times until a spray appears.

[0094] In an aspect, the term “actuation” refers to operation of the device such that the pharmaceutical composition is delivered therefrom.

[0095] In an aspect, the term “prone” refers to a patient who is lying face down. In an aspect, the term “supine” refers to a subject who is lying face up. In an aspect, the term “recovery position"’ means a position of the human body in which a patient lies on his / her side, with a leg or knee out in front (e.g., to prevent rolling onto his / her stomach) and at least one hand supporting the head (e.g., to elevate the face to facilitate breathing and prevent inhalation of vomit).

[0096] In an aspect, the term “protective packaging” refers to overwrap. In an aspect, the term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such therapeutic products.

[0097] In an aspect, the term “in combination” in the context of the administration of other therapies (e.g., other agents) includes the use of more than one therapy (e.g., drug therapy). Administration “in combination with” one or more further therapeutic agents include simultaneous (e.g., concurrent) and consecutive administration in any order. The use of the term “in combination” does not restrict the order in which therapies are administered to a subject. By way of non-limiting example, a first therapy (e g., one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof) can be administered prior to (e.g.. 1 minute. 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours.48 hours. 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks), concurrently, or after (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks. 10 weeks, 11 weeks, or 12 weeks or longer) the administration of a second therapy to a subject having or diagnosed an opioid misuse and / or an opioid overdose.

[0098] In an aspect, when ranges of values are disclosed, and the notation “from m . . . to n2” or “betw een m . . . and m” is used, where m and m are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. In an aspect, this range may be integral or continuous between and including the end values. By way of example, in an aspect, the range “from 2 to 6 carbons” is intended to include tw o. three, four, five, and six carbons, since carbons come in integer units. Compare, by w ay of example, the range “from 1 to 3 pM (micromolar),” which is intended to include 1 pM. 3 pM, and everything in between to any number of significant figures (e.g., 1.255 pM. 2. 1 pM, 2.9999 pM, etc.).

[0099] In an aspect, the term “about,” , is intended to qualify the numerical values which it modifies, denoting such a value as variable within a range. When no range, such as a margin of error or a standard deviation to a mean value given in a chart or table of data, is recited, 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, considering significant figures, and the range which would encompass the recited value plus or minus 20%.

[0100] In an aspect, “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 nasal mucous-membrane permeation, rather than increasing solubility. As such, such agents are sometimes called permeation enhancers. In particular, disclosed absorption enhancers herein may improve paracellular transport (i.e.. passage through intercellular spaces and tight junctions), transcellular transport (i.e., passive diffusion or active transport across cellular membranes), or transcytosis (i.e., cellular vesicular uptake).

[0101] In an aspect, “active ingredient” or “pharmaceutically active compound” is defined in the context of a “pharmaceutical formulation” and is intended to mean a component of a pharmaceutical formulation that provides the primary pharmacological effect, as opposed to an“inactive ingredient”, which would generally be recognized as providing no pharmaceutical benefit.

[0102] In an aspect, "‘agonist” refers to a moiety that interacts with, and activates, a receptor and thereby initiates a physiological or pharmacological response characteristic of that receptor. In an aspect, “antagonist” 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. In an aspect, an antagonist does not diminish the baseline intracellular response in the absence of an agonist or partial agonist. In an aspect, “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.

[0103] In an aspect, “antimicrobial preservative” refers to a pharmaceutically acceptable excipient with antimicrobial properties which is added to a pharmaceutical composition to maintain microbiological stability.

[0104] In an aspect, “AUC” refers to the area under the drug plasma concentration-time curve. The term “AUCo-t,” , refers to the area under the drug plasma concentration-time curve from t=0 to the last measurable concentration. The term “AUCo-«>.” , refers to the area under the drug plasma concentration-time curve extrapolated to <x>. The term “AUCo-t / o,” , refers to the AUCo-t normalized to 0.4 mg IN nalmefene. The term “AUCO-WD,” , refers to the AUCo-«> normalized to 1.5 mg IM nalmefene.

[0105] In an aspect, “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. In an aspect, “absolute bioavailability” is used when the fraction of absorbed drug is related to its IV bioavailability. It can be calculated using the following formula:F (AUCextravascular / AUCintravenous) X (DoSCintravenous / DoSCextravascular)

[0106] In an aspect, “relative bioavailability (Frei)” is used to compare two different extravascular routes of drug administration, and it may be calculated using the following formula:Frei (AUC extravascular 1 / AUC extravascular) X (DoSCextravascular / DoSCextravascularl)

[0107] In an aspect, “clearance (CL)” refers to the rate at which a drug is eliminated divided by its plasma concentration, giving a volume of plasma from which drug is completely removed per unit of time. CL is equal to the elimination rate constant (k) multiplied by the volume of distribution (Va), wherein “Va” is the fluid volume that would be required to contain the amountof drug present in the body at the same concentration as in the plasma. The term “apparent clearance (CL / F)” refers to clearance that does not take into account the bioavailability of the drug. It is the ratio of the dose over the AUC.

[0108] In an aspect, "Cmax " refers to the maximum observed plasma concentration.

[0109] In an aspect, “coefficient of variation (CV)” refers to the ratio of the sample standard deviation to the sample mean. It is often expressed as a percentage.

[0110] In an aspect, “confidence interval” refers to a range of values which will include the true average value of a parameter a specified percentage of the time.

[0111] In an aspect, the term “device” refers to an apparatus capable of delivering a drug to subject in need thereof.

[0112] In an aspect, “delivery time” refers to the amount of time that elapses between a determination made by a healthcare professional, first responder, law enforcement (e.g., police, customs, and border patrol agents), military personnel, or an untrained individual, that an individual is in need of nasal delivery of an opioid antagonist and completion of the delivery.

[0113] In an aspect, “disease” 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 ty pically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

[0114] In an aspect, the term “drug raid” refers to the entry into and investigation of a facility or other site in which opioids are manufactured, stored, and / or distributed. It typically connotes such a facility / site which is, or is believed to be, in violation of the laws regulating controlled substances.

[0115] In an aspect, “elimination rate constant (X)” 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. X is the slope of the plasma concentration-time line (on a logarithmic y scale). In an aspect, the term “Xz” 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 semi- logarithmic graph. In an aspect, 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. Dunng 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.

[0116] In an aspect, ’ excipient" refers to a natural or synthetic substance formulated alongside the active ingredient of a medication, included for 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.

[0117] In an aspect, ‘Tilled” refers to an association between a device and a pharmaceutical composition, for example, when a disclosed pharmaceutical formulation comprising a therapeutically effective amount of SET is present within a reservoir that forms a part of a disclosed device.

[0118] In an aspect, the term “hydrate” refers to a disclosed opioid antagonist or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0119] In an aspect, “in need of treatment” and “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, medic, or other professional assessing a potential medical hazard and planning for), that a subject will benefit from treatment. An individual “who is at risk for incidental opioid overdose”, includes an individual who accidentally ingests opioids or who intentionally ingests opioids.

[0120] In an aspect, “nalmefene” refers to 17-cyclopropylmethyl-4,5a-epoxy-6- methylenemorphinan-3,14-diol. Nalmefene is commercially available as a hydrochloride salt and is a 6-methylene analog of naltrexone. Nalmefene hydrochloride is approved for opioid overdose reversal, and as disclosed herein, can be used to prevent incidental exposure to an opioid agonist and can be administered quickly and easily as a prophylactic measure by first responders, law enforcement (e.g., police, customs, and border patrol agents) and military’ personnel if contact with opioids, especially high potency synthetics, is either anticipated or suspected. In an aspect, Nalmefene hydrochloride (CAS Reg. No. 58895-64-0) has been marketed under the trade names Nalmetrene®, Cervene®, Revex®, Arthrene®, and Incystene®.

[0121] In an aspect, “nostril” is synonymous with “naris”.

[0122] In an aspect, “opioid overdose” refers to an acute medical condition caused by incidental exposure to an opioid agonist in a subject. Symptoms of opioid overdose include including respiratory depression (including postoperative opioid respiratory depression, acute lung injury’, and aspiration pneumonia), central nervous system depression (which may include sedation, altered level consciousness, miotic (constricted) pupils), and cardiovascular depression (which may include hypoxemia and hypotension). Visible signs of opioid overdose or suspected opioid overdose include: unresponsiveness and / or loss of consciousness (will not or cannot respond tostimuli such as shouting, shaking, or rubbing knuckles on sternum); slow, erratic, or stopped breathing; slow, erratic, or stopped pulse; deep snoring or choking / gurgling sounds; blue or purple fingernails or lips; pale and / or clammy face; slack or limp muscle tone; contracted pupils; and vomiting.

[0123] In an aspect, “actuation"’ refers to operation of the device such that the pharmaceutical formulation is delivered therefrom.

[0124] In an aspect, the term '‘pre-primed” refers to a device, such as a nasal spray which can deliver a pharmaceutical formulation comprising SET to a subject in need thereof with the first actuation of the spray pump, i.e., without the need to prime the pump prior to dosing, such as by actuating the pump one or more times until a spray appears.

[0125] In an aspect, “providing” in the context of providing a co-packaged drug product as disclosed herein to an individual includes co-packaging the drug product, prescribing the copackaged drug product, and dispensing the co-packaged drug product. The providing may be done either directly to an individual (for example, to an individual for whom an opioid agonist prescription is appropriate, or who is otherwise at risk of opioid overdose).

[0126] In an aspect, “solvate” refers to a disclosed opioid antagonist or a salt, thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and / or acceptable for administration to humans in trace amounts.

[0127] In an aspect, the term “sterile filling,” refers methods of manufacturing of a disclosed device and a disclosed pharmaceutical formulation comprising SET, such that the use of preservatives is not required. Sterile drug products may be produced using aseptic processing or terminal sterilization. Terminal sterilization usually involves filling and sealing product containers under high-quality environmental conditions. In an aseptic process, the drug product, container, and closure are first subjected to sterilization methods separately, as appropriate, and then brought together.

[0128] In an aspect, “protective packaging” refers to overwrap. In an aspect, the term “storagestable,” refers to a pharmaceutical formulation in which at least about 90% to 99.5% of the active ingredient remains in an undegraded state after storage of the pharmaceutical formulation at specified temperature and humidity for a specified time, for example, for 12 months at 25 °C and 60% relative humidity.

[0129] In an aspect, the term “substantially free of antimicrobial preservatives"’ is understood by one of ordinary skill in the art to describe a pharmaceutical formulation that compnses less than 1% w / w antimicrobial preservatives.

[0130] In an aspect, “prophylaxis"’ is synonymous with “prevention,” and is to be considered in its broadest context and refers to any medical or public health procedure employed to prevent an opioid misuse and / or an opioid overdose from occurring. It does not necessarily mean that the subject will not eventually experience an opioid misuse and / or an opioid overdose. In an aspect, prophylaxis may include the mitigation or amelioration of the symptoms of an opioid misuse and / or an opioid overdose or preventing or reducing the risk of developing an opioid misuse and / or an opioid overdose. In an aspect, “prophylaxis” may include reducing the severity of the onset of an opioid misuse and / or an opioid overdose.

[0131] In an aspect, “therapeutically effective amount” or “therapeutically effective dose” means an amount effective of one or more disclosed pharmaceutical formulations comprising SET. one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof to prevent opioid overdose or symptoms thereof caused by incidental exposure of an opioid agonist in a subj ect. Such an amount or dose may therefore also be referred to as a “prophylactically effective” amount or dose. Opioid overdose may be moderate, severe, or even fatal. In an aspect, a treatment or pharmaceutical formulation will be therapeutically effective to prevent even moderate opioid overdose, wherein a subject is temporarily physically or mentally impaired by an opioid agonist but is in no danger of impairment or harm beyond the agonist’s excretion from the subject. In an aspect, a treatment or formulation will be therapeutically effective to prevent severe overdose, wherein a subject is in danger of lasting or even permanent harm. In an aspect, one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or a combination thereof will be therapeutically effective to prevent fatal overdose.

[0132] In an aspect, “exposure” refers to an actual or anticipated contact between the subject and an opioid agonist. In an aspect, actual exposure refers to exposure that in fact occurs whether known or unknown. Anticipated exposure refers to any level of expected possibility of being exposed to an opioid.

[0133] In an aspect, “incidental exposure to opioid agonist by a subject” means that the exposure to opioid agonist is not voluntary and / or intended to self-intoxicate, but occurs as part of the subject’s activities in proximity to, or potential proximity to, the opioid agonist. In an aspect, workers acting in capacity as law enforcement, inspectors, public health field agents, may face the risk of incidental exposure during activities such as cleaning or performing inspections or investigations for and / or handling opioid agonists or materials that are associated with opioid agonists, such as laboratory equipment, containers, needles, pipes, or other objects. Additionally, military, law enforcement, or security personnel may face incidental exposure to opioid agonistwhen a third part ’ deliberately delivers an opioid agonist to incapacitate said personnel, for example as a gas. In an aspect, incidental exposure to opioid agonist includes, for example, exposure by inhalation to aerosolized opioid agonist and incidental transdermal exposure to opioid agonist.

[0134] In an aspect, the term “ti / 2” or ‘‘half-life,” refers to the amount of time required for half of a drug (for example, an opioid or an opioid antagonist) to be eliminated from the body or the time required for a drug concentration to decline by half.

[0135] In an aspect, the term “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.

[0136] In an aspect, the term “tomography,” refers to a process of imaging by sections. The images may be looked at individually, as a series of two-dimensional slices or together, as a computer-generated three-dimensional representation.

[0137] In an aspect, the term “Tmax.” refers to the time from administration of a disclosed pharmaceutical formulations to maximum drug plasma concentration.

[0138] In an aspect, the term “untrained individual” refers to an individual administering to subject an opioid antagonist using a disclosed device, wherein the individual is not a healthcare professional and has received no training in the use of the device.

[0139] In an aspect, Cmax refers to maximum plasma concentration, observed by inspection of individual study participant plots of plasma concentration versus time. In an aspect, Cmax / Dose refers to Cmax adjusted for the nominal administered dose. In an aspect, Tmax refers to time of maximum observed concentration, obtained directly from the observed concentration versus time data.

[0140] In an aspect, AUCo-t refers to the area under the concentration-time curve from time 0 (predose) to the time of last quantifiable concentration, calculated by the linear-updog-down trapezoidal method. In an aspect, AUCo-t / Dose refers to AUCo-t adjusted for the nominal administered dose. In an aspect, AUCo-inf refers to the area under the concentration-time curve from time 0 extrapolated to infinity, calculated as AUCo-t + Clast / Xz, where Clast is the observed last quantifiable concentration. In an aspect, AUCo-inf / Dose AUCo-inf adjusted for the nominal administered dose. In an aspect, AUC %ExtraPrefers to the percentage of AUCo-inf obtained by extrapolation, calculated as [(AUCo-inf - AUCo-t) / AUCo-inf] *100.

[0141] In an aspect, Az refers to Zz is the terminal-phase elimination rate constant, estimated by linear regression of logarithmically -transformed concentration versus time data. In an aspect, ti / 2refers to the terminal phase half-life for drug concentrations in plasma is calculated as: ti / 2 = ln(2) / z.

[0142] In an aspect, CL / F refers to apparent total body clearance is calculated as CL / F = Dose / AUCO-inf. In an aspect, Relative Ratio of dose-adjusted AUCinf following IN administration relative Bioavailability to dose-adjusted AUCinf following IM administration.

[0143] In an aspect, tidal volume (VT) is defined as the volume of gas entering and leaving the respiratory tract with each breath. This is a dynamic measurement and varies with the activity of the baby. For infants, tidal volume is usually expressed in units of mL. In an aspect, minute volume is the total volume of gas expired over a period of 1 minute. Accurate measurement of VT (no leak around endotracheal tube or face mask) and respiratory frequency (fR) allows estimation of minute ventilation as the product: VT fR; and is usually expressed in units of L / minute, or normalized for body weight as (L / minute) / kg.

[0144] In an aspect, functional residual capacity (FRC) is the volume of air in the lungs at the end of expiration of a normal, resting, tidal volume. Lung volume at FRC is maintained by the opposing forces of lung elastic recoil and chest wall outward recoil.

[0145] In an aspect, residual volume is the volume of air remaining in the respiratory system at the end of a maximum possible expiration.

[0146] In an aspect, thoracic gas volume (TGV) is the total amount of gas in the lung at end expiration, irrespective of whether the gas is in communication with the airways. In healthy infants without air trapping, FRC is equivalent to TGV.

[0147] In an aspect, expiratory’ reserve volume is the volume of air that is the difference between FRC and residual volume.

[0148] In an aspect, total lung capacity is the volume of air that is in the respiratory system at the end of a maximum possible inspiration.

[0149] Disclosed are the components to be used to prepare the disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations comprising SET as well as the disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations comprising SET used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and disclosed. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination andpermutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B- F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific claimed compositions and / or claimed methods.B. Opioids

[0150] Opioid receptors are G protein-coupled receptors (GPCRs) that are activated both by endogenous opioid peptides and by clinically important alkaloid analgesic drugs such as morphine. Opioids depress respiration, which is controlled principally through medullary respiratory centers with peripheral input from chemoreceptors and other sources. Opioids produce inhibition at the chemoreceptors via p-opioid receptors and in the medulla via p- and 5-opioid receptors. While there are a number of neurotransmitters mediating the control of respiration, glutamate and y-aminobutyric acid (GABA) are the major excitatory’ and inhibitory’ neurotransmitters, respectively. This explains the potential for interaction of opioids with benzodiazepines and alcohol: both benzodiazepines and alcohol facilitate the inhibitory effect of GABA at the GABAA receptor, while alcohol also decreases the excitatory effect of glutamate at NMDA receptors. Oxycodone and other opioid painkillers, as well as heroin and methadone are all implicated in fatal overdose. Heroin has three metabolites with opioid activity. Variation in the formation of these metabolites due to genetic factors and the use of other drugs could explain differential sensitivity’ to overdose. Metabolites of methadone contribute little to its action. However, variation in rate of metabolism due to genetic factors and other drugs used can modify methadone concentration and hence overdose risk. The degree of tolerance also determines risk. Tolerance to respiratory depression is less than complete, and may be slower than tolerance to euphoric and other effects. One consequence of this may be a relatively high risk of overdose among experienced opioid users. While agonist administration modifies receptor function, changes (usually in the opposite direction) also result from use of antagonists, for example, super sensitivity to opioids following a period of administration of antagonists such as naltrexone.

[0151] There are three principal types of opioid receptors: the 5-opioid receptor, the K-opioid receptor, and the p-opioid receptor. Opioid receptors are G protein-coupled receptors (GPCRs) that are activated both by endogenous opioid peptides, by clinically important alkaloid analgesic drugs such as morphine, and by synthetic analgesics such as methadone and fentanyl.

[0152] In an aspect, opioids can comprise alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphine, normorphine, norpipanone, opium, oxycodone, oxy morphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, homologues thereof, analogs thereof, and any mixtures thereof, or any combination thereof.

[0153] In the US, mortality rates closely correlate with opioid sales. In 2008, approximately 36,450 people died from drug overdoses. At least 14,800 of these deaths involved prescription opioid analgesics. Moreover, according to the Substance Abuse and Mental Health Sendees Administration, the number / rate of Americans 12 years of age and older who currently abuse pain relievers has increased by 20% between 2002 and 2009. In New York City, between 1990-2006, the fatality rate from prescription opioids increased seven-fold, from 0.39 per 100,000 persons to 2.7. Drugs classed as prescription opioids in this study include both typical analgesics, such as OxyContin® (oxycodone HC1 controlled-release) and methadone (used in the treatment of dependence on other opioids such as heroin and also prescribed for pain), but the increase in the rate of drug overdose over the 16 years of the study was driven entirely by overdoses of typical analgesics. Over the same period, methadone overdoses remained stable, and overdoses from heroin declined. Whites were more likely than blacks and Latinos to overdose on these analgesics, and deaths mostly occurred in neighborhoods with lower rates of poverty7, suggesting differential access to doctors who can write painkiller prescriptions may be a driving force behind the racial disparity (Cerda et al. (2013) Drug and Alcohol Dependence. 132(l-2):53-62).C. Setmelanotide

[0154] Setmelanotide is the first available anorexi genic agent, a melanocortin-4 receptor (MC4R) agonist for treating obesity caused by a rare genetic disorder. Setmelanotide was approved by the Food and Drug Administration (FDA) on November 25, 2020, for the indication of chronic weight management in adults and pediatrics six years of age and older due to the deficiency of proopiomelanocortin (POMC), proprotein convertase subtilisin / kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. Setmelanotide allows weight loss in patients with these genetic obesity disorders by restoring appetite control, thereby reducing food intake and weight gain. However, setmelanotide does not treat these hereditary defects which cause obesity.

[0155] Setmelanotide can bind to and activates multiple melanocortin receptors, including melanocortin-4 receptor (MC4R), melanocortin-3 receptor (MC3R), and melanocortin- 1 receptor (MC1R) selectively over melanocortin-2 receptor (MC2R) and melanocortin-5 receptor (MC5R). These melanocortin receptor systems consist of five 7-transmembrane G-protein coupled receptors, which are involved in many key physiological functions of the body, including feeding behavior, energy balance, sexual function and behavior, cardiovascular function, kidney function, immune response, etc. Setmelanotide is a type of MC4R agonist with 20-fold less activity at the melanocortin-3 receptor (MC3R) and melanocortin-1 receptor (MC1R). The MC4R can be endogenously activated by the binding of melanocyte-stimulating hormones (MSH), which are involved in responding to acute signal regulations of hunger and satiety (FIG. 6). Setmelanotide acts on the MC4R pathway to reverse hyperphagia and promote weight loss through decreased caloric intake and increased energy expenditure.D. CompositionsPharmaceutical Formulations

[0156] Disclosed herein is a pharmaceutical formulation comprising setmelanotide and one or more pharmaceutically acceptable carriers. Disclosed herein is a pharmaceutical formulation comprising setmelanotide, naloxone, and one or more pharmaceutically acceptable carriers. Disclosed herein is a pharmaceutical formulation comprising setmelanotide, nalmefene, and one or more pharmaceutically acceptable carriers. Disclosed herein is a pharmaceutical formulation comprising setmelanotide and one or more opioid receptor antagonists, and one or more pharmaceutically acceptable carriers. Disclosed herein is a pharmaceutical formulation comprising setmelanotide, naloxone, and one or more opioid receptor antagonists, and one or more pharmaceutically acceptable carriers.

[0157] Disclosed herein is a pharmaceutical formulation comprising setmelanotide, nalmefene, and one or more opioid receptor antagonists, and one or more pharmaceutically acceptable earners.

[0158] Disclosed herein is a pharmaceutical formulation comprising setmelanotide, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers. Disclosed herein is a pharmaceutical formulation comprising setmelanotide, naloxone, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers. Disclosed herein is a pharmaceutical formulation comprising setmelanotide, nalmefene, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers. Disclosed herein is a pharmaceutical formulation comprising setmelanotide, one or more opioid receptor antagonists, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers. Disclosed herein is a pharmaceutical formulation comprising setmelanotide, naloxone, one or more additional therapeutic agents, one or more opioid receptor antagonists, and one or more pharmaceutically acceptable carriers. Disclosed herein is a pharmaceutical formulation comprising setmelanotide, nalmefene, one or more opioid receptor antagonists, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers.

[0159] In an aspect, setmelanotide can comprise a pharmaceutically acceptable salt including pharmaceutically acceptable acid addition salt. In an aspect, naloxone can comprise a pharmaceutically acceptable salt including pharmaceutically acceptable acid addition salt. In an aspect, nalmefene can comprise a pharmaceutically acceptable salt including pharmaceutically acceptable acid addition salt.

[0160] In an aspect, setmelanotide can comprise an analogue.

[0161] In an aspect, a disclosed pharmaceutically acceptable acid addition salt can be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. In an aspect, representative acids can comprise 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 any combination thereof. In an aspect, pharmaceutically acceptable salts can comprise those listed by Berge et al. (1977) J. Pharma. Sci. 66: 1-19.

[0162] In an aspect, a disclosed acid addition salts can be obtained as the direct products of compound synthesis. In an aspect, a free base can 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.

[0163] In an aspect, naloxone is an opioid receptor antagonist that is approved for use by injection for the reversal of opioid overdose and for adjunct use in the treatment of septic shock. It is currently being used mainly in emergency departments and in ambulances by trained medicalprofessionals. There have been efforts to expand its use by providing the drug to some patients with take-home opioid prescriptions and those who inject illicit drugs, potentially facilitating earlier administration of the drug. The UN Commission on Narcotics Drugs “encourages all Member States to include effective elements for the prevention and treatment of drug overdose, in particular opioid overdose, in national drug policies, where appropriate, and to share best practices and information on the prevention and treatment of drug overdose, in particular opioid overdose, including the use of opioid receptor antagonists such as naloxone.”

[0164] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be administered to a subject in need thereof. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be formulated for administration and / or can be administered via one or more routes. Such methods are well known to those skilled in the art and include, but are not limited to, the following routes: oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, in utero administration, intrahepatic administration, intravaginal administration, ophthalmic administration, intraaural administration, otic administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-CSF administration, intra-arterial administration, intramuscular administration, and subcutaneous administration.

[0165] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be formulated for intravenous, intramuscular, sublingual, subcutaneous, intranasal, transnasal, oral, rectal, or transdermal administration.

[0166] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can provide long-lasting relief of one or more indexes of OIRD.

[0167] In an aspect, a therapeutically effective amount of setmelanotide and / or a salt and / or solvate thereof can comprise at least about 1 IU to at least about 200 IU. In an aspect, a therapeutically effective amount of setmelanotide and / or a salt and / or solvate thereof can comprise at least about 1 IU to at least about 10 IU, at least about 10 IU to at least about 20 IU, at least about 20 IU to at least about 30 IU, at least about 30 IU to at least about 40 IU, at least about 40 IU to at least about 50 IU, at least about 50 IU to at least about 60 IU, at least about 60 IU to at least about 70 IU, at least about 70 IU to at least about 80 IU, at least about 80 IU to at least about 90 IU, at least about 90 IU to at least about 100 IU, at least about 100 IU to at least about 110 IU, at least about 110 IU to at least about 120 IU, at least about 120 IU to at least about 130 IU, at least about 130 IU to at least about 140 IU, at least about 140 IU to at least about 150 IU, at least about 150 IU to at least about 160 IU, at least about 160 IU to at least about 170 IU, at least about 170IU to at least about 180 IU, at least about 180 IU to at least about 190 IU, or at least about 190 IU to at least about 200 IU. In an aspect, a therapeutically effective amount of setmelanotide and / or a salt and / or solvate thereof can comprise at least about 1 IU, at least about 2 IU, at least about 3 IU, at least about 4 IU, at least about 5 IU, at least about 6 IU, at least about 7 IU, at least about 8 IU, at least about 9 IU, at least about 10 IU, at least about 11 IU, at least about 12 IU, at least about 13 IU, at least about 14 IU, at least about 15 IU. at least about 16 IU, at least about 17 IU, at least about 18 IU, at least about 19 IU, or at least about 20 IU.

[0168] In an aspect, a disclosed pharmaceutical formulation can comprise between about 1% (w / v) and about 20% (w / v) of setmelanotide and / or a salt and / or solvate thereof. In an aspect, a disclosed pharmaceutical formulation can comprise between at least about 1% (w / v), at least about 2% (w / v), at least about 3% (w / v), at least about 4% (w / v), at least about 5% (w / v), at least about 6% (w / v), at least about 7% (w / v), at least about 8% (w / v), at least about 9% (w / v), at least about 10% (w / v), at least about 11% (w / v), at least about 12% (w / v), at least about 13% (w / v), at least about 14% (w / v), at least about 15% (w / v), at least about 16% (w / v), at least about 17% (w / v), at least about 18% (w / v), at least about 19% (w / v). or at least about 20% (w / v) of setmelanotide and / or a salt and / or solvate thereof. In an aspect, a disclosed pharmaceutical formulation can comprise comprises between at least about 1% (w / v) to at least about 5% (w / v), at least about 5% (w / v) to at least about 10% (w / v), at least about 10% (w / v) to at least about 15% (w / v), or at least about 15% (w / v) to at least about 20% (w / v) of setmelanotide and / or a salt and / or solvate thereof.

[0169] In an aspect, a disclosed pharmaceutical formulation can comprise between about 0.1 mg to about 5 mg of setmelanotide and / or a salt and / or solvate thereof. In an aspect, a disclosed pharmaceutical formulation can comprise between about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg. about1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3. 1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg. about 3.5 mg, about 3.6 mg. about3.7 mg, about 3.8 mg. about 3.9 mg, about 4.0 mg, about 4.1 mg. about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, or about 5.0 mg of setmelanotide and / or a salt and / or solvate thereof.

[0170] In an aspect, a disclosed pharmaceutical formulation can comprise setmelanotide and / or a salt and / or solvate thereof in a range of about 0.001 mg to about 5 mg per kilogram of the subject’s body weight.

[0171] In an aspect, a disclosed pharmaceutical formulation can comprise setmelanotide and / or a salt and / or solvate thereof in an amount of about 1 mg total, about 10 mg total, about 100 mg total, about 200 mg total, about 300 total mg, or about 350 total mg.In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise at least about 1 IU to at least about 200 IU of naloxone and / or a salt and / or solvate thereof. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise at least about 1 IU to at least about 10 IU, at least about 10 IU to at least about 20 IU, at least about 20 IU to at least about 30 IU, at least about 30 IU to at least about 40 IU, at least about 40 IU to at least about 50 IU, at least about 50 IU to at least about 60 IU, at least about 60 IU to at least about 70 IU, at least about 70 IU to at least about 80 IU, at least about 80 IU to at least about 90 IU, at least about 90 IU to at least about 100 IU, at least about 100 IU to at least about 110 IU, at least about 110 IU to at least about 120 IU, at least about 120 IU to at least about 130 IU, at least about 130 IU to at least about 140 IU, at least about 140 IU to at least about 150 IU, at least about 150 IU to at least about 160 IU. at least about 160 IU to at least about 170 IU, at least about 170 IU to at least about 180 IU, at least about 180 IU to at least about 190 IU, or at least about 190 IU to at least about 200 IU of naloxone and / or a salt and / or solvate thereof. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise at least about 1 IU, at least about 2 IU, at least about 3 IU, at least about 4 IU, at least about 5 IU, at least about 6 IU, at least about 7 IU. at least about 8 IU, at least about 9 IU, at least about 10 IU, at least about 11 IU, at least about 12 IU, at least about 13 IU, at least about 14 IU, at least about 15 IU, at least about 16 IU, at least about 17 IU, at least about 18 IU, at least about 19 IU, or at least about 20 IU of naloxone and / or a salt and / or solvate thereof.

[0172] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise between about 1% (w / v) and about 20% (w / v) of naloxone and / or a salt and / or solvate thereof. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise between at least about 1% (w / v), at least about 2% (w / v), at least about 3% (w / v), at least about 4% (w / v), at least about 5% (w / v). at least about 6% (w / v), at least about 7% (w / v), at least about 8% (w / v). at least about 9% (w / v), at least about 10% (w / v), at least about 11% (w / v), at least about 12% (w / v), at least about 13% (w / v), at least about 14% (w / v), at least about 15% (w / v), at least about 16% (w / v), at least about 17% (w / v), at least about 18% (w / v), at least about 19% (w / v), or at least about 20% (w / v) of naloxone and / or a salt and / or solvate thereof.

[0173] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise between at least about 1% (w / v) to at least about 5% (w / v), at least about 5% (w / v) to atleast about 10% (w / v), at least about 10% (w / v) to at least about 15% (w / v), or at least about 15% (w / v) to at least about 20% (w / v) of naloxone and / or a salt and / or solvate thereof.

[0174] For example, in an aspect, a disclosed naloxone can be naloxone hydrochloride dihydrate. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise at least about 1 IU to at least about 200 IU of nalmefene and / or a salt and / or solvate thereof. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise at least about 1 IU to at least about 10 IU, at least about 10 IU to at least about 20 IU, at least about 20 IU to at least about 30 IU, at least about 30 IU to at least about 40 IU, at least about 40 IU to at least about 50 IU, at least about 50 IU to at least about 60 IU, at least about 60 IU to at least about 70 IU, at least about 70 IU to at least about 80 IU, at least about 80 IU to at least about 90 IU, at least about 90 IU to at least about 100 IU, at least about 100 IU to at least about 110 IU, at least about 110 IU to at least about 120 IU, at least about 120 IU to at least about 130 IU, at least about 130 IU to at least about 140 IU, at least about 140 IU to at least about 150 IU, at least about 150 IU to at least about 160 IU. at least about 160 IU to at least about 170 IU, at least about 170 IU to at least about 180 IU, at least about 180 IU to at least about 190 IU, or at least about 190 IU to at least about 200 IU of nalmefene and / or a salt and / or solvate thereof. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise at least about 1 IU, at least about 2 IU, at least about 3 IU. at least about 4 IU, at least about 5 IU, at least about 6 IU, at least about 7 IU, at least about 8 IU. at least about 9 IU, at least about 10 IU, at least about 11 IU, at least about 12 IU, at least about 13 IU, at least about 14 IU, at least about 15 IU, at least about 16 IU, at least about 17 IU, at least about 18 IU, at least about 19 IU, or at least about 20 IU of nalmefene and / or a salt and / or solvate thereof.

[0175] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise between about 1% (w / v) and about 20% (w / v) of nalmefene and / or a salt and / or solvate thereof. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise between at least about 1% (w / v), at least about 2% (w / v), at least about 3% (w / v), at least about 4% (w / v), at least about 5% (w / v). at least about 6% (w / v), at least about 7% (w / v), at least about 8% (w / v). at least about 9% (w / v), at least about 10% (w / v), at least about 11% (w / v), at least about 12% (w / v), at least about 13% (w / v), at least about 14% (w / v), at least about 15% (w / v), at least about 16% (w / v), at least about 17% (w / v), at least about 18% (w / v), at least about 19% (w / v), or at least about 20% (w / v) of nalmefene and / or a salt and / or solvate thereof. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can comprise between at least about 1% (w / v) to at least about 5% (w / v). at least about 5% (w / v) to at leastabout 10% (w / v), at least about 10% (w / v) to at least about 15% (w / v), or at least about 15% (w / v) to at least about 20% (w / v) of nalmefene and / or a salt and / or solvate thereof.

[0176] In an aspect, a disclosed pharmaceutical formulation can comprise between at least about 1 mg and at least about 50 mg of setmelanotide and / or a salt and / or solvate thereof. In an aspect, a disclosed pharmaceutical formulation can comprise at least about 1 mg, at least about 2 mg, at least about 3 mg. at least about 4 mg, at least about 5 mg, at least about 6 mg. at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 16 mg, at least about 17 mg, at least about 18 mg, at least about 19 mg, at least about 20 mg, at least about 21 mg, at least about 22 mg. at least about 23 mg, at least about 24 mg, at least about 25 mg, at least about 26 mg, at least about 27 mg, at least about 28 mg, at least about 29 mg, at least about 30 mg, at least about 31 mg, at least about 32 mg, at least about 33 mg, at least about 34 mg, at least about 35 mg, at least about 36 mg, at least about 37 mg, at least about 38 mg, at least about 39 mg, at least about 40 mg. at least about 41 mg, at least about 42 mg, at least about 43 mg, at least about 44 mg, at least about 45 mg, at least about 46 mg. at least about 47 mg, at least about 48 mg, at least about 49 mg, or at least about 50 mg of setmelanotide and / or a salt and / or solvate thereof. In an aspect, a disclosed pharmaceutical formulation can comprise at least about 1 mg to least about 5 mg, at least about 5 mg to at least about 10 mg, at least about 10 mg to at least about 15 mg, at least about 15 mg to at least about 20 mg. at least about 20 mg to at least about 25 mg, at least about 25 mg to at least about 30 mg, at least about 30 mg to at least about 35 mg, at least about 35 mg to at least about 40 mg, at least about 40 mg to at least about 45 mg, or at least about 45 mg to at least about 50 mg of setmelanotide and / or a salt and / or solvate thereof.

[0177] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise between at least about 1 mg and at least about 50 mg of naloxone and / or a salt and / or solvate thereof. I In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg. at least about 14 mg, at least about 15 mg, at least about 16 mg, at least about 17 mg, at least about 18 mg, at least about 19 mg, at least about 20 mg, at least about 21 mg, at least about 22 mg, at least about 23 mg, at least about 24 mg, at least about 25 mg, at least about 26 mg, at least about 27 mg, at least about 28 mg. at least about 29 mg, at least about 30 mg, at least about 31 mg, at least about 32 mg, at least about 33 mg, at least about 34 mg, at least about 35 mg, at least about 36 mg, at least about 37 mg, at least about 38 mg, at least about 39 mg, at least about 40 mg, atleast about 41 mg, at least about 42 mg, at least about 43 mg, at least about 44 mg, at least about 45 mg, at least about 46 mg, at least about 47 mg, at least about 48 mg, at least about 49 mg, or at least about 50 mg of naloxone and / or a salt and / or solvate thereof.

[0178] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise at least about 1 mg to least about 5 mg, at least about 5 mg to at least about 10 mg, at least about 10 mg to at least about 15 mg, at least about 15 mg to at least about 20 mg, at least about 20 mg to at least about 25 mg, at least about 25 mg to at least about 30 mg, at least about 30 mg to at least about 35 mg, at least about 35 mg to at least about 40 mg, at least about 40 mg to at least about 45 mg, or at least about 45 mg to at least about 50 mg of naloxone and / or a salt and / or solvate thereof. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise between at least about 1 mg and at least about 50 mg of nalmefene and / or a salt and / or solvate thereof. I In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg. at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 16 mg, at least about 17 mg, at least about 18 mg, at least about 19 mg, at least about 20 mg, at least about 21 mg, at least about 22 mg, at least about 23 mg, at least about 24 mg, at least about 25 mg, at least about 26 mg, at least about 27 mg, at least about 28 mg, at least about 29 mg, at least about 30 mg, at least about 31 mg, at least about 32 mg, at least about 33 mg, at least about 34 mg, at least about 35 mg, at least about 36 mg, at least about 37 mg, at least about 38 mg, at least about 39 mg, at least about 40 mg, at least about 41 mg, at least about 42 mg, at least about 43 mg, at least about 44 mg, at least about 45 mg, at least about 46 mg, at least about 47 mg, at least about 48 mg. at least about 49 mg, or at least about 50 mg of nalmefene and / or a salt and / or solvate thereof.

[0179] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise n an aspect, a disclosed pharmaceutical formulation can comprise at least about 1 mg to least about 5 mg. at least about 5 mg to at least about 10 mg, at least about 10 mg to at least about 15 mg, at least about 15 mg to at least about 20 mg, at least about 20 mg to at least about 25 mg, at least about 25 mg to at least about 30 mg, at least about 30 mg to at least about 35 mg, at least about 35 mg to at least about 40 mg, at least about 40 mg to at least about 45 mg, or at least about 45 mg to at least about 50 mg of nalmefene and / or a salt and / or solvate thereof. In an aspect, a therapeutically effective amount of a disclosed pharmaceutical formulation can comprise at least about 25 nmol / kg, at least about 50 nmol / kg, at least about 75 nmol / kg, at least about 100 nmol / kg.at least about 125 nmol / kg, at least about 150 nmol / kg, at least about 175 nmol / kg, at least about 200 nmol / kg, at least about 225 nmol / kg, at least about 250 nmol / kg, at least about 275 nmol / kg, at least about 300 nmol / kg, at least about 325 nmol / kg, at least about 350 nmol / kg, at least about 375 nmol / kg, at least about 400 nmol / kg, at least about 425 nmol / kg, at least about 450 nmol / kg, at least about 475 nmol / kg, or at least about 500 nmol / kg of setmelanotide and / or a salt and / or solvate thereof.

[0180] In an aspect, a disclosed pharmaceutical formulation can be an aqueous solution. In an aspect, a dose of a disclosed aqueous solution can comprise between about 50 pL and about 500 pL. In an aspect, a dose of a disclosed aqueous solution can comprise between about 50 pL. about 100 pL, about 150 pL. about 200 pL, about 250 pL, about 300 pL. about 350 pL, about 400 pL, about 450 pL, about 500 pL, about 550 pL, about 600 pL, about 650 pL, about 700 pL, about 750 pL, about 800 pL, about 850 pL, about 900 pL, about 950 pL, or about 1000 pL.

[0181] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise one or more of an isotonicity agent, an acid, a preservative, a stabilizing agent, an absorption enhancer, and any combination thereof.

[0182] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise one or more tonicity agents. In an aspect, a disclosed tonicity agent can comprise dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine, or any combination thereof. In an aspect, a disclosed tonicity agent can comprise sodium chloride. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise about 0.2% (w / v) and about 1.2% (w / v) of a tonicity agent. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise about 0.2% (w / v), about 0.3% (w / v), about 0.4% (w / v). about 0.5% (w / v), about 0.6% (w / v), about 0.7% (w / v). about 0.8% (w / v), about 0.9% (w / v), about 1.0% (w / v), about 1.1% (w / v), or about 1.2% (w / v) of a tonicity agent. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise more than about 0.2% (w / v) of a tonicity agent. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise less than about 1.2% (w / v) of a tonicity agent. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise about 0. 1 mg and about 6 mg of a tonicity agent. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg. about 0.7 mg, about 0.8 mg. about 0.9 mg, about 1.0 mg. about 1.1 mg, about 1.2 mg, about 1.3 mg. about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg. about 2.7 mg, about 2.8 mg. about2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, or about 6.0 mg of a tonicity agent.

[0183] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise one or more absorption enhancers. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise absorption enhancer can be an alkylglycoside. In an aspect, alkylsaccharides are used in commercial food and personal care products and have been designated Generally Recognized as Safe (GRAS) substances for food applications. They 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 can increase absorption by increasing paracellular permeability, as indicated by a decrease in transepithelial electrical resistance; they may also increase. The effect can be short-lived.

[0184] In an aspect, a disclosed alkylsaccharide absorption enhancer can comprise dodecyl maltoside, tetradecyl maltoside, octyl maltoside, decyl maltoside, nonyl maltoside, undecyl maltoside, tridecyl maltoside, pentadecyl maltoside, hexadecyl maltoside, heptadecyl maltoside, octadecyl-a-maltoside. octadecyl-[3-D-maltoside, dodecyl glucoside, tetradecyl glucoside, octyl glucoside, decyl glucoside, nonyl glucoside, undecyl glucoside, tridecyl glucoside, pentadecyl glucoside, hexadecyl glucoside, heptadecyl glucoside, octadecyl-a-glucoside, and octadecyl-P-D- glucoside, dodecyl sucroside, tetradecyl sucroside, octyl sucroside, decyl sucroside, nonyl sucroside, undecyl sucroside. tridecyl sucroside, pentadecyl sucroside, hexadecyl sucroside, heptadecyl sucroside. octadecyl-a-sucroside, octadecyl-P-D-sucroside, or any combination thereof.

[0185] In an aspect, “saccharide” is inclusive of monosaccharides, oligosaccharides or polysaccharides in straight chain or ring forms, or a combination thereof to form a saccharide chain. In an aspect, oligosaccharides are saccharides having two or more monosaccharide residues. The saccharide can be chosen, for example, from any currently commercially available saccharide species or can be synthesized. In an aspect, some examples of the many possible saccharides to use include glucose, maltose, maltotriose, maltotetraose, sucrose, and trehalose.

[0186] In an aspect, a disclosed absorption enhancer can comprise aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramides, cetylpyridinium chloride, chitosan, cyclodextrins, deoxycholic acid, decanoyl carnitine, EDTA, glycocholic acid, glycodeoxycholicacid, glycofurol, glycosylated sphingosines, glycyrrhetinic acids, 2-hydroxypropyl-P- cyclodextrin, laureth-9, lauric acid, lauroyl carnitine, lauryl sulfate, lysophosphatidylchohne, menthol, poloxamer 407, poloxamer F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, polysorbate 80, propylene glycol, quillaia saponin, salicylic acid, P-sitosterol-P-D-glucoside, sucrose cocoate, taurocholic acid, taurodeoxy cholic acid, taurodihydrofusidic acid, and alkylsaccharides, such as dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, or any combination thereof.

[0187] In an aspect, a disclosed alkylsaccharide can be Intravail® (dodecyl maltoside). As known to the art, Intravail® is the alkyl saccharide 1-O-n-dodecyl-P-D-maltopyranoside (alternately referred to as lauryl-P-D-maltopyranoside, dodecyl maltopyranoside, and DDM; C24H66O11). In an aspect, a disclosed absorption enhancer can be Intravail®.

[0188] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise between about 0.05% and about 2.5% (w / v), between about 0.1% and about 0.5% (w / v), between about 0.15% and about 0.35% (w / v), between about 0.15% and about 0.2% (w / v), or about 0.2% to about 0.3% (w / v) Intravail®.

[0189] In an aspect, a disclosed absorption enhancer can comprise benzalkonium chloride.

[0190] In an aspect, a disclosed absorption enhancer can comprise between about 0.005% (w / v) to about 0.05% (w / v), betw een about 0.005% to about 3.0% of the absorption enhancer, between about 0.05% to about 3.0% of the absorption enhancer, or between about 0. 1% to about 0.5% of the absorption enhancer.

[0191] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise between about 0.1% to about 0.5%, about 0.5% to about 1.0%, about 1.0% to about 1.5%, about 1.5% to about 2.0%, about 2.0% to about 2.5%, about 2.5% to about 3.0%, about 3.0% to about 3.5%. about 3.5% to about 4.0%, about 4.0% to about 4.5%, or to about 4.5% to about 5.0% of the absorption enhancer.

[0192] In an aspect, a disclosed absorption enhancer can comprise benzalkonium chloride, chitosan, cyclodextrins, deoxycholic acid, dodecyl maltoside, tetradecyl maltoside, glycocholic acid, laureth-9, taurocholic acid, taurodihydrofusidic acid, or any combination thereof. In an aspect, the alkylsaccharide can comprise dodecyl maltoside, tetradecyl maltoside (TDM), and sucrose dodecanoate. In an aspect, a disclosed absorption enhancer can comprise about 0.05% (w / v) to about 2.5% (w / v) dodecyl maltoside or tetradecyl maltoside. In an aspect, a disclosed absorption enhancer can comprise about 0.05% (w / v) to about 0.25% (w / v). about 0.25% (w / v) to about 0.50% (w / v), about 0.50% (w / v) to about 0.75% (w / v), about 0.75% (w / v) to about 1.0% (w / v), about 1.0% (w / v) to about 1.25% (w / v), about 1.25% (w / v) to about 1.5% (w? / v), about1.5% (w / v) to about 1.75% (w / v), about 1.75% (w / v) to 2.0% (w / v). about 2.0% (w / v) to about 2.25% (w / v), or about 2.25% (w / v) to about 2.5% (w / v) dodecyl maltoside or tetradecyl maltoside.

[0193] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise one or more stabilizing agents. In an aspect, a disclosed stabilizing agent can comprise disodium edetate (EDTA). In an aspect, a disclosed stabilizing agent can be disodium edetate or edetate disodium.

[0194] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise one or more acids. In an aspect, a disclosed acid can be hydrochloric acid.

[0195] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise one or more preservatives. In an aspect, a disclosed preservative can comprise benzalkonium chloride, methylparaben, sodium benzoate, benzoic acid, phenyl ethyl alcohol, or any combination thereof.

[0196] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise one or more surfactants.

[0197] In an aspect, a disclosed surfactant can comprise polysorbate 80 NF, polyoxyethylene 20 sorbitan monolaurate, poly oxy ethylene (4) sorbitan monolaurate, poly oxy ethylene 20 sorbitan monopalmitate, poly oxy ethylene 20 sorbitan monostearate, poly oxy ethylene (4) sorbitan monostearate, poly oxy ethylene 20 sorbitan tristearate, poly oxy ethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitan monoisostearate, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trilaurate, sorbitan trioleate, sorbitan tristearate, and the like, and mixtures thereof.

[0198] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise one or more suspending agents. In an aspect, a disclosed suspending agent can comprise microcrystalline cellulose, carboxymethylcellulose sodium NF. polyacrylic acid, magnesium aluminum silicate, xanthan gum, or any combination thereof.

[0199] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise water. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise an aqueous solution. In an aspect, a disclosed aqueous solution can comprise about 10 pL, about 20 pL, about 30 pL, about 40 pL, about 50 pL, about 60 pL, about 70 pL, about 80 pL, about 90 pL, about 100 pL, about 100 pL, about 110 pL, about 120 pL, about 130 pL, about 140 pL, about 150 pL, about 160 pL, about 170 pL, about 180 pL, about 190 pL, about 200 pL, about 210 pL, about 220 pL, about 230 pL, about 240 pL, or about 250 pL.

[0200] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise water in an amount sufficient to achieve a final volume of at least about 20 pL, at leastabout 30 pL, at least about 40 pL, at least about 50 pL, at least about 60 pL, at least about 70 pL, at least about 80 pL, at least about 90 pL, at least about 100 pL, at least about 110 pL, at least about 120 pL, at least about 130 pL, at least about 140 pL, at least about 1 0 pL, at least about 160 pL, at least about 170 pL, at least about 180 pL, at least about 190 pL, at least about 200 pL, at least about 210 pL, at least about 220 pL, at least about 230 pL, at least about 240 pL, or at least about 250 pL.

[0201] In an aspect, water can be in an amount sufficient to total at least about 50 pL, at least about 100 pL, at least about 150 pL, at least about 200 pL, or at least about 250 pL.

[0202] Disclosed herein is a pharmaceutical formulation, comprising about 2% (w / v) to about 20% (w / v) setmelanotide and / or a salt and / or solvate thereof; between about 0.2% (w / v) to about 1.2% (w / v) of an isotonicity agent; between about 0.005% (w / v) to about 0.05% (w / v) of a preservative; between about 0. 1% (w / v) to about 0.5% (w / v) of a stabilizing agent; between about 0.1% (w / v) to about 0.5% (w / v) of an alky lsaccharide absorption enhancer; and water; wherein the pH of the formulation is between about 3.5 and about 5.5.

[0203] Disclosed herein is a pharmaceutical formulation, comprising about 2% (w / v) to about 20% (w / v) setmelanotide and / or a salt and / or solvate thereof; about 2% (w / v) to about 20% (w / v) naloxone and / or a salt and / or solvate thereof; between about 0.2% (w / v) to about 1.2% (w / v) of an isotonicity agent; between about 0.005% (w / v) to about 0.05% (w / v) of a preservative; between about 0.1% (w / v) to about 0.5% (w / v) of a stabilizing agent; between about 0.1% (w / v) to about 0.5% (w / v) of an alkylsaccharide absorption enhancer; and water; wherein the pH of the formulation is between about 3.5 and about 5.5.

[0204] Disclosed herein is a pharmaceutical formulation, comprising about 2% (w / v) to about 20% (w / v) setmelanotide and / or a salt and / or solvate thereof; about 2% (w / v) to about 20% (w / v) nalmefene and / or a salt and / or solvate thereof; between about 0.2% (w / v) to about 1.2% (w / v) of an isotonicity7agent; between about 0.005% (w / v) to about 0.05% (w / v) of a preservative; between about 0.1% (w / v) to about 0.5% (w / v) of a stabilizing agent; betw een about 0.1% (w / v) to about 0.5% (w / v) of an alkylsaccharide absorption enhancer; and water; wherein the pH of the formulation is between about 3.5 and about 5.5.

[0205] Disclosed herein is a pharmaceutical formulation, comprising about 2% (w / v) to about 20% (w / v) setmelanotide and / or a salt and / or solvate thereof; about 2% (w / v) to about 20% (w / v) naloxone and / or a salt and / or solvate thereof; about 2% (w / v) to about 20% (w / v) nalmefene and / or a salt and / or solvate thereof; between about 0.2% (w / v) to about 1.2% (w / v) of an isotonicity7agent; betw een about 0.005% (w / v) to about 0.05% (w / v) of a preservative; between about 0.1% (w / v) to about 0.5% (w / v) of a stabilizing agent; between about 0.1% (w / v) to about 0.5% (w / v)of an alkylsaccharide absorption enhancer; and water; wherein the pH of the formulation is between about 3.5 and about 5.5.

[0206] Disclosed herein is a pharmaceutical formulation, comprising at least about 1 mg to at least about 10 mg setmelanotide and / or a salt and / or solvate thereof; between about 0.2 mg and about 1.2 mg of an isotonicity agent; between about 0.005 mg and about 0.015 mg of preserv ative; between about 0.005 mg and about 0.015 mg of a cationic surfactant; between about 0.005 mg and about 0.015 mg of a permeation enhancer; between about 0.1 mg and about 0.5 mg of a stabilizing agent; and an amount of an acid sufficient to achieve a pH of 3.5 - pH 5.5.

[0207] Disclosed herein is a pharmaceutical formulation, comprising at least about 1 mg to at least about 10 mg setmelanotide and / or a salt and / or solvate thereof; at least about 1 mg to at least about 10 mg naloxone and / or a salt and / or solvate thereof; between about 0.2 mg and about 1.2 mg of an isotonicity agent; between about 0.005 mg and about 0.015 mg of preservative; between about 0.005 mg and about 0.015 mg of a cationic surfactant; between about 0.005 mg and about 0.015 mg of a permeation enhancer; between about 0. 1 mg and about 0.5 mg of a stabilizing agent; and an amount of an acid sufficient to achieve a pH of 3.5 - pH 5.5.

[0208] Disclosed herein is a pharmaceutical formulation, comprising at least about 1 mg to at least about 10 mg setmelanotide and / or a salt and / or solvate thereof; at least about 1 mg to at least about 10 mg nalmefene and / or a salt and / or solvate thereof; between about 0.2 mg and about 1.2 mg of an isotonicity agent; between about 0.005 mg and about 0.015 mg of preservative; between about 0.005 mg and about 0.015 mg of a cationic surfactant; between about 0.005 mg and about 0.015 mg of a permeation enhancer; between about 0. 1 mg and about 0.5 mg of a stabilizing agent; and an amount of an acid sufficient to achieve a pH of 3.5 - pH 5.5.

[0209] Disclosed herein is a pharmaceutical formulation, comprising at least about 1 mg to at least about 10 mg setmelanotide and / or a salt and / or solvate thereof; at least about 1 mg to at least about 10 mg nalmefene and / or a salt and / or solvate thereof; between about 0.2 mg and about 1.2 mg of an isotonicity agent; between about 0.005 mg and about 0.015 mg of preservative; between about 0.005 mg and about 0.015 mg of a cationic surfactant; between about 0.005 mg and about 0.015 mg of a permeation enhancer; between about 0. 1 mg and about 0.5 mg of a stabilizing agent; and an amount of an acid sufficient to achieve a pH of 3.5 - pH 5.5.

[0210] In an aspect, a therapeutically effective amount of a disclosed pharmaceutical formulation comprising setmelanotide can yield, when intranasally administered to a subject, an setmelanotide plasma concentration of at least about > 0.2 ng / mL within 2.5 minutes in the subject; or an setmelanotide plasma concentration of at least about > 1 ng / mL within 5 minutes in the subject;or an setmelanotide plasma concentration of at least about > 3 ng / mL within 10 minutes in the subject.

[0211] In an aspect, a therapeutically effective amount of a disclosed pharmaceutical formulation comprising setmelanotide can yield, when intranasally administered to a subject, an setmelanotide Tmax of less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, or less than about 15 minutes.

[0212] In an aspect, a therapeutically effective amount of a disclosed pharmaceutical formulation comprising setmelanotide can yield, when intranasally administered to a subject, a naloxone plasma concentration of at least about > 0.2 ng / mL within 2.5 minutes in the subj ect: or a naloxone plasma concentration of at least about > 1 ng / mL within 5 minutes in the subject; or a naloxone plasma concentration of at least about > 3 ng / mL within 10 minutes in the subject.

[0213] In an aspect, a therapeutically effective amount of a disclosed pharmaceutical formulation comprising setmelanotide can yield, when intranasally administered to a subject, a naloxone Tmax of less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, or less than about 15 minutes.

[0214] In an aspect, a therapeutically effective amount of a disclosed pharmaceutical formulation comprising setmelanotide can yield, when intranasally administered to a subject, a nalmefene plasma concentration of at least about > 0.2 ng / mL within 2.5 minutes in the subject; or a nalmefene plasma concentration of at least about > 1 ng / mL within 5 minutes in the subject; or a nalmefene plasma concentration of at least about > 3 ng / mL within 10 minutes in the subject.

[0215] In an aspect, a therapeutically effective amount of a disclosed pharmaceutical formulation comprising setmelanotide can yield, when intranasally administered to a subj ect, a nalmefene Tmax of less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, or less than about 15 minutes.

[0216] In an aspect, a therapeutically effective amount of a disclosed pharmaceutical formulation comprising setmelanotide can yield, when intranasally administered to a patient, (i) an setmelanotide Tmaxof less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, or less than about 15 minutes; (ii) a naloxone Tmaxof less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, or less than about 15 minutes; (iii) a nalmefene setmelanotide Tmaxof less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, or less than about 15 minutes; or (iv) any combination thereof.

[0217] In an aspect, a therapeutically effective amount of a disclosed pharmaceutical formulation comprising setmelanotide can yield, when intranasally administered to a subject, the plasma concentration versus time curve of setmelanotide in the subject has a Tmaxof between about 20and about 30 minutes; wherein the plasma concentration versus time curve of naloxone in the subject has a Tmaxof between about 20 and about 30 minutes; wherein the plasma concentration versus time curve of nalmefene in the subject has a Tmaxof between about 20 and about 30 minutes; or any combination thereof.

[0218] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD). In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD) in a clinical setting. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD) in an illicit use setting.

[0219] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD) without interrupting and / or affecting analgesia.

[0220] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD) in a clinical setting without interrupting and / or affecting analgesia.

[0221] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD) in an illicit use setting without interrupting and / or affecting analgesia.

[0222] In an aspect, a disclosed pharmaceutical formulation can be used to ease the subject’s transition from an intensive care unit (ICU) to a non-ICU in a clinical setting.

[0223] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat an opioid misuse and / or an opioid overdose.

[0224] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject suspected of experiencing an opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0225] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD) due to an opioid misuse and / or an opioid overdose.

[0226] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject suspected of experiencing an opioid misuse and / or an opioid overdose.

[0227] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to reduce and / or minimize and / or eliminate manifestations of anger, distress, aggression, and / or violence demonstrated by the subject following administration.

[0228] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject having an opioid dependence.

[0229] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject experiencing a depression of respiratory rate, a depression of minute ventilation, a depression of alveolar-arterial gas exchange, a decrease in respiratory responsiveness to hypoxia and hypercapnia, an increase in apnea duration and / or apnea frequency, an increase in hypoxemic events, cardiac arrest, and any combination thereof.

[0230] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject experiencing one or more symptoms associated with and / or related to an active opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject experiencing one or more symptoms associated with and / or related to a suspected active opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0231] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject experiencing (i) a loss of consciousness, (ii) constricted or pinpoint pupils, (iii) breathing difficulties (slowed, labored, and / or irregular breathing), (iv) respiratory arrest, (v) choking, gurgling, or snoring sounds, (vi) blue or purple lips or fingertips, (vii) a low of responsive to loud noises, shaking, or painful stimuli, or (viii) any combination thereof.

[0232] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject experiencing one or more symptoms associated with and / or related to an opioid misuse and / or an opioid overdose, wherein the one or more symptoms associated with and / or related to the illicit use of opioids.

[0233] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject experiencing one or more symptoms associated with and / or related to an active opioid overdose, wherein the one or more symptoms associated with and / or related to the accidental misuse of opioids during medical opioid therapy.

[0234] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat respiratory’ depression, central nervous system depression, cardiovascular depression, altered level consciousness, miotic pupils, hypoxemia, acute lung injury’, aspiration pneumonia, sedation, hypotension, unresponsiveness to stimulus, unconsciousness, stopped breathing, erratic or stopped pulse, choking or gurgling sounds, blue or purple fingernails or lips, slack or limp muscle tone, contracted pupils, vomiting, and any combination thereof.

[0235] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to minimize and / or reduce one or more symptoms of OIRD due to an opioid misuse and / or an opioid overdose. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to reverse and / or eliminate one or more symptoms of OIRD due to an opioid misuse and / or an opioid overdose. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject having a substance use disorder.

[0236] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject having alcohol use disorder, cocaine use disorder, cannabis use disorder, tobacco use disorder, methamphetamine use disorder, opioid use disorder, or any combination thereof.

[0237] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject having a substance use disorder comprising the abuse of opioids.

[0238] In an aspect, opioids can comprise heroin, codeine, fentanyl, hydrocodone (dihydrocodeinone), hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, or any combination thereof.

[0239] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject having at least one substance use withdrawal symptom. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to treat a subject having at least one physical symptom of withdrawal, at least psychological symptom of withdrawal, or any combination thereof.

[0240] In an aspect, a disclosed physical symptom of withdrawal can comprise tremors, insomnia, disturbed sleep, headache, sweating, nausea, vomiting, muscle pain, muscle stiffness, hypertension, irregular heart rate, elevated heart rate, heart palpitations, dizziness, shakiness, tremors, seizures, dehydration, shallow breathing, fatigue, loss of appetite, clammy skin, loss of color, or anu combination thereof.

[0241] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to reduce and / or eliminate at least one substance use withdrawal symptom in the subject.

[0242] In an aspect, a disclosed psychological symptom of withdrawal can comprise anxiety, irritability, difficulty concentrating, difficulty thinking clearly, mood swings, nightmares, depression, tension, panic attacks, short term memory loss, restlessness, a feeling of helplessness, stress-sensitivity, a heightened responsivity to substance-related cues, aberrant reward processing, a substance craving or a combination thereof. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used to reduce and / or eliminate at least one psychological symptom in the subject.

[0243] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be formulated for intravenous, intramuscular, sublingual, subcutaneous, intranasal, transnasal, oral, rectal or transdermal administration.

[0244] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can provide long-lasting relief of one or more indexes of OIRD.

[0245] In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can further comprise one or more additional therapeutic agents. In an aspect, a disclosed pharmaceutical formulation comprising setmelanotide can be used with one or more additional therapeutic agents.

[0246] In an aspect, a disclosed pharmaceutical formulation comprising can comprise (i) one or more active agents, (ii) biologically active agents, (iii) one or more pharmaceutically active agents, (iv) one or more immune-based therapeutic agents, (v) one or more clinically approved agents, or (vi) a combination thereof.

[0247] In an aspect, one or more disclosed pharmaceutical formulations comprising setmelanotide can be subjected to one or more validating and / or characterizing steps and / or protocols. For example, in an aspect, validating and / or characterizing one or more disclosed pharmaceutical formulations comprising setmelanotide can comprise measuring, ascertaining, and / or determining the purity and / or efficacy of the one or more disclosed pharmaceutical formulations.

[0248] In an aspect, a disclosed pharmaceutical formulation comprising SET can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, patient life expectancy can be increased at least about 5% or greater to at least about 100%, at least about 10% or greater to at least about 95% or greater, at least about 20% or greater to at least about 80% or greater, at least about 40% or greater to at least about 60% or greater compared to an untreated subject with the identical or near identical overdose and the identical or near identical predicted outcome.Liquid Sprays

[0249] Disclosed herein is a liquid spray comprising setmelanotide and one or more pharmaceutically acceptable carriers. Disclosed herein is a liquid spray comprising setmelanotide, naloxone, and one or more pharmaceutically acceptable carriers. Disclosed herein is a liquid spray comprising setmelanotide, nalmefene, and one or more pharmaceutically acceptable carriers. Disclosed herein is a liquid spray comprising setmelanotide and one or more opioid receptor antagonists, and one or more pharmaceutically acceptable carriers.

[0250] Disclosed herein is a liquid spray comprising setmelanotide, naloxone, and one or more opioid receptor antagonists, and one or more pharmaceutically acceptable carriers. Disclosed herein is a liquid spray comprising setmelanotide, nalmefene, and one or more opioid receptorantagonists, and one or more pharmaceutically acceptable carriers. Disclosed herein is a liquid spray comprising setmelanotide, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers. Disclosed herein is a liquid spray comprising setmelanotide, naloxone, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers. Disclosed herein is a liquid spray comprising setmelanotide, nalmefene, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers.

[0251] Disclosed herein is a liquid spray comprising setmelanotide, one or more opioid receptor antagonists, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers. Disclosed herein is a liquid spray comprising setmelanotide, naloxone, one or more additional therapeutic agents, one or more opioid receptor antagonists, and one or more pharmaceutically acceptable carriers. Disclosed herein is a liquid spray comprising setmelanotide, nalmefene, one or more opioid receptor antagonists, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers.

[0252] In an aspect, a disclosed liquid spray comprising setmelanotide is for intranasal administration and / or transnasal administration.

[0253] In an aspect, a disclosed liquid spray comprising setmelanotide does not contain sodium chloride, citric acid, benzyl alcohol, or benzalkonium chloride.

[0254] In an aspect, a disclosed liquid spray comprising setmelanotide can comprise a co-solvent. In an aspect, a co-solvent can be alcohol and / or a glycol. In an aspect, a disclosed alcohol can be ethanol (dehydrated alcohol) and a disclosed glycol can be propylene glycol.

[0255] In an aspect, a disclosed liquid spray comprising setmelanotide can have a pH from about 3.0 to about 6.0. In an aspect, a disclosed liquid sprays comprising setmelanotide can have a pH of about 4.5.

[0256] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject experiencing an opioid misuse and / or an opioid overdose. In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject suspected of experiencing an opioid overdose due to an opioid misuse and / or an opioid overdose. In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat an opioid misuse and / or an opioid overdose or a suspected opioid misuse and / or opioid overdose. In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD) due to an opioid misuse and / or an opioid overdose. In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject suspected of experiencing opioid-induced respiratory depression (OIRD) due to an opioid misuse and / or an opioid overdose.

[0257] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to reduce and / or minimize and / or eliminate manifestations of anger, distress, aggression, and / or violence demonstrated by the subject following administration.

[0258] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subj ect having an opioid dependence.

[0259] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject experiencing a depression of respiratory rate, a depression of minute ventilation, a depression of alveolar-arterial gas exchange, a decrease in respiratory responsiveness to hypoxia and hypercapnia, an increase in apnea duration and / or apnea frequency, an increase in hypoxemic events, cardiac arrest, and any combination thereof.

[0260] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject experiencing one or more symptoms associated with and / or related to an opioid misuse and / or an opioid overdose. In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject experiencing one or more symptoms associated with and / or related to a suspected active opioid misuse and / or an opioid overdose.

[0261] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject experiencing (i) a loss of consciousness, (ii) constricted or pinpoint pupils, (iii) breathing difficulties (slowed, labored, and / or irregular breathing), (iv) respiratory arrest, (v) choking, gurgling, or snoring sounds, (vi) blue or purple lips or fingertips, (vii) a low of responsive to loud noises, shaking, or painful stimuli, or (viii) any combination thereof.

[0262] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject experiencing one or more symptoms associated with and / or related to an opioid misuse and / or an opioid overdose, wherein the one or more symptoms associated with and / or related to the illicit use of opioids.

[0263] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject experiencing one or more symptoms associated with and / or related to an active opioid overdose, wherein the one or more symptoms associated with and / or related to the accidental misuse of opioids during medical opioid therapy.

[0264] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat respiratory depression, central nervous system depression, cardiovascular depression, altered level consciousness, miotic pupils, hypoxemia, acute lung injury', aspiration pneumonia, sedation, hypotension, unresponsiveness to stimulus, unconsciousness, stopped breathing, erratic or stopped pulse, choking or gurgling sounds, blue or purple fingernails or lips, slack or limp muscle tone, contracted pupils, vomiting, and any combination thereof.

[0265] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to minimize and / or reduce one or more symptoms of OIRD due to an opioid misuse and / or an opioid overdose. In an aspect, a disclosed liquid spray comprising setmelanotide can be used to reverse and / or eliminate one or more symptoms of OIRD due to an opioid misuse and / or an opioid overdose.

[0266] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject having a substance use disorder.

[0267] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject having alcohol use disorder, cocaine use disorder, cannabis use disorder, tobacco use disorder, methamphetamine use disorder, opioid use disorder, or any combination thereof.

[0268] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject having a substance use disorder comprising the abuse of opioids.

[0269] In an aspect, opioids can comprise heroin, codeine, fentanyl, hydrocodone (dihydrocodeinone), hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, or any combination thereof. In an aspect, opioids can comprise fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0270] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject having at least one substance use withdrawal symptom. In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject having at least one physical symptom of withdrawal, at least psychological symptom of withdrawal, or any combination thereof.

[0271] In an aspect, a disclosed physical symptom of withdrawal can comprise tremors, insomnia, disturbed sleep, headache, sweating, nausea, vomiting, muscle pain, muscle stiffness, hypertension, irregular heart rate, elevated heart rate, heart palpitations, dizziness, shakiness, tremors, seizures, dehydration, shallow breathing, fatigue, loss of appetite, clammy skin, loss of color, or anu combination thereof.

[0272] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to reduce and / or eliminate at least one substance use withdrawal symptom in the subject.

[0273] In an aspect, a disclosed psychological symptom of withdrawal can comprise anxiety, irritability, difficulty concentrating, difficulty thinking clearly, mood swings, nightmares, depression, tension, panic attacks, short term memory loss, restlessness, a feeling of helplessness, stress-sensitivity, a heightened responsivity to substance-related cues, aberrant reward processing, a substance craving or a combination thereof.

[0274] In an aspect, a disclosed liquid spray comprising setmelanotide can be used to reduce and / or eliminate at least one psychological symptom in the subject. In an aspect, a disclosed liquidspray comprising setmelanotide can be formulated for intravenous, intramuscular, sublingual, subcutaneous, intranasal, transnasal, oral, rectal, or transdermal administration.

[0275] In an aspect, a disclosed liquid spray comprising setmelanotide can provide long-lasting relief of one or more indexes of OIRD.

[0276] In an aspect, a disclosed liquid spray can improve and / or extend the survivability of the subject, can improve a subject's quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, patient life expectancy can be increased at least about 5% or greater to at least about 100%, at least about 10% or greater to at least about 95% or greater, at least about 20% or greater to at least about 80% or greater, at least about 40% or greater to at least about 60% or greater compared to an untreated subject with the identical or near identical overdose and the identical or near identical predicted outcome.

[0277] In an aspect a disclosed liquid spray comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory7depression (OIRD). In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory- depression (OIRD) in a clinical setting. In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD) in an illicit use setting. In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD) without interrupting and / or affecting analgesia. In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD) in a clinical setting without interrupting and / or affecting analgesia. In an aspect, a disclosed liquid spray comprising setmelanotide can be used to treat a subj ect experiencing opioid- induced respiratory depression (OIRD) in an illicit use setting without interrupting and / or affecting analgesia. In an aspect, a disclosed liquid spray comprising setmelanotide can be used to ease the subject’s transition from an intensive care unit (ICU) to anon-ICU in a clinical setting.Devices

[0278] Disclosed herein are nasal drug delivery- devices comprising a disclosed pharmaceutical formulation comprising SET. Disclosed herein are nasal drug delivery devices comprising a disclosed liquid spray.

[0279] In an aspect, a disclosed device adapted for nasal delivery- to a subject experiencing an opioid overdose. In an aspect, a disclosed device can be primed prior to use. In an aspect, a disclosed device can be actuated with one hand.

[0280] Nasal delivery is considered an attractive, safe, and easy-to-administer route for needle- free, systemic drug delivery, especially when rapid absorption and effect are desired. In addition.nasal delivery can help address issues related to poor bioavailability, slow absorption, drug degradation, and adverse events (AEs) in the gastrointestinal tract and avoids the first-pass metabolism in the liver.

[0281] In an aspect, a disclosed liquid nasal formulation can be an aqueous solution. In an aspect, a disclosed liquid nasal formulation can be a suspension or an emulsion. In an aspect, a disclosed liquid nasal formulation can comprise one or more antimicrobial preservatives.

[0282] In an aspect, a disclosed liquid nasal formulation can be delivered via a metered spray pump. In an aspect, a disclosed pump can deliver about 25 pL to about 200 pL per spray. In an aspect, a disclosed pump can deliver about 100 pL to about 150 pL per spray. In an aspect, a disclosed pump can off a high degree of reproducibility of an emitted dose. In an aspect, a disclosed pump can off a high degree of reproducibility of plume geometry. In an aspect, examples of standard metered spray pumps can include those offered by Aptar Pharma, Inc., such as the multi-dose “classic technology' platform” nasal spray devices.

[0283] In an aspect, a disclosed device can comprise a reservoir that can hold multiple doses of a disclosed 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 about 50 pL to about 1000 pL (e.g., about 50 pL, about 100 pL, about 150 pL, about 200 pL, about 250 pL, about 300 pL, about 350 pL, about 400 pL, about 450 pL, about 500 pL, about 550 pL, about 600 pL, about 650 pL, about 700 pL, about 750 pL, about 800 pL, about 850 pL, about 900 pL. about 950 pL, or about 1000 pL) of fluid per actuation to comprise a single dose.

[0284] In an aspect, a disclosed actuator can be configured to count doses, deliver gel formulations, deliver in an upside-down configuration, or any combination thereof. In an aspect, in traditional spray pump systems, antimicrobial preservatives can typically be required to maintain microbiological stability in liquid formulations. However, 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. In an aspect, a disclosed device can be 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.

[0285] In an aspect, 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. In an aspect, droplet size can be influenced by the actuation parameters of the device and the formulation. In an aspect, a disclosed median droplet size can be between about 30 pm to about 100 pm. In an aspect, if the droplets are too large (> about 120 pm), then deposition can takeplace mainly in the anterior parts of the nose. In an aspect, if the droplets are too small (< about 10 pm), then the droplets can possibly be inhaled and reach the lungs, which should be avoided because of safety reasons. In an aspect, 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 (e.g., photography, laser diffraction, and impaction systems (cascade impaction, NGI)).

[0286] In an aspect, plume geometry, droplet size and DSD can affect pharmacokinetic outcomes such as Cmax, Tmax, and linear dose proportionality. In an aspect, droplet size distribution can be controlled in terms of ranges for the DIO, D50, D90, span [(D90-D10) / D501, and percentage of droplets less than 10 mm. In an aspect, a disclosed liquid formulation can have a narrow DSD. In an aspect, a disclosed liquid formulation can have a D(v,50) of about 30 pm - about 70 pm and a D(v, 90) < 100 pm.

[0287] In an aspect, the percent of droplets less than 10 pm can be less than 10%. In an aspect, the percent of droplets less than 10 pm can be less than 5%. In an aspect, the percent of droplets less than 10 pm can be less than 2%. In an aspect, the percent of droplets less than 10 pm can be less than 1 %. In an aspect, a disclosed liquid formulation when dispensed by actuation from the device can 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”). In an aspect, a disclosed ovality ratio can be less than ±2.0. In an aspect, a disclosed ovality ratio can be less than ±1.5. In an aspect, a disclosed ovality ratio can be less than ±1.3. In an aspect, a disclosed ovality ratio can be less than ±1.2. In an aspect, a disclosed ovality ratio can be less than ±1.1. In an aspect, a disclosed ovality ratio can be about ±1.0. In an aspect, the 90% confidence interval for dose delivered per actuation can be ± about 2%. In an aspect, the 95% confidence interval for dose delivered per actuation can be ±about 2.5%.

[0288] In an aspect, intranasal administration of drugs in large volume, such as from syringes adapted with mucosal atomizer devices, has encountered difficulty due to the tendency of some of the formulation to drip back out of the nostril or down the nasopharynx.

[0289] In an aspect, a disclosed container closure system designs for inhalation spray drug products include both pre-metered and device-metered presentations using mechanical or power assistance and / or energy from patient inspiration for production of the spray plume. In an aspect, pre-metered presentations can 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. In an aspect, typical device-metered unitscan have a reservoir containing formulation sufficient for multiple doses that are delivered as metered sprays by the device itself when activated by the patient.

[0290] In an aspect, a disclosed subject is an opioid overdose subject or a suspected opioid overdose subject.

[0291] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject experiencing an opioid misuse and / or an opioid overdose. In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject suspected of experiencing an opioid misuse and / or an opioid overdose.

[0292] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat an opioid misuse and / or an opioid overdose.

[0293] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD) due to an opioid misuse and / or an opioid overdose.

[0294] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject suspected of experiencing opioid-induced respirator}' depression (OIRD) due to an opioid misuse and / or an opioid overdose.

[0295] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to reduce and / or minimize and / or eliminate manifestations of anger, distress, aggression, and / or violence demonstrated by the subject following administration.

[0296] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject having an opioid dependence.

[0297] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject experiencing a depression of respirator}’ rate, a depression of minute ventilation, a depression of alveolar-arterial gas exchange, a decrease inrespiratory responsiveness to hypoxia and hypercapnia, an increase in apnea duration and / or apnea frequency, an increase in hypoxemic events, cardiac arrest, and any combination thereof.

[0298] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject experiencing one or more symptoms associated with and / or related to an active opioid overdose due to an opioid misuse and / or an opioid overdose.

[0299] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject experiencing one or more symptoms associated with and / or related to a suspected active opioid overdose due to an opioid misuse and / or an opioid overdose.

[0300] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject experiencing (i) a loss of consciousness, (ii) constricted or pinpoint pupils, (hi) breathing difficulties (slowed, labored, and / or irregular breathing), (iv) respiratory arrest, (v) choking, gurgling, or snoring sounds, (vi) blue or purple lips or fingertips, (vii) a low of responsive to loud noises, shaking, or painful stimuli, or (viii) any combination thereof.

[0301] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject experiencing one or more symptoms associated with and / or related to an active opioid overdose due to an opioid misuse and / or an opioid overdose, wherein the one or more symptoms associated with and / or related to the illicit use of opioids.

[0302] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject experiencing one or more symptoms associated with and / or related to an active opioid overdose, wherein the one or more symptoms associated with and / or related to the accidental misuse of opioids during medical opioid therapy.

[0303] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat respiratory depression, central nervous system depression, cardiovascular depression, altered level consciousness, miotic pupils, hypoxemia, acute lung injury, aspiration pneumonia, sedation, hypotension, unresponsiveness to stimulus, unconsciousness, stopped breathing, erratic or stopped pulse, choking or gurgling sounds, blue orpurple fingernails or lips, slack or limp muscle tone, contracted pupils, vomiting, and any combination thereof.

[0304] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to minimize and / or reduce one or more symptoms of OIRD due to an opioid misuse and / or an opioid overdose.

[0305] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to reverse and / or eliminate one or more symptoms of OIRD due to an opioid misuse and / or an opioid overdose.

[0306] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject having a substance use disorder.

[0307] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject having alcohol use disorder, cocaine use disorder, cannabis use disorder, tobacco use disorder, methamphetamine use disorder, opioid use disorder, or any combination thereof.

[0308] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject having a substance use disorder comprising the abuse of opioids.

[0309] In an aspect, opioids can comprise heroin, codeine, fentanyl, hydrocodone (dihydrocodeinone), hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, or any combination thereof. In an aspect, opioids can comprise any opioid.

[0310] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject having at least one substance use withdrawal symptom. In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject having at least one physical symptom of withdrawal, at least psychological symptom of withdrawal, or any combination thereof.

[0311] In an aspect, a disclosed physical symptom of withdrawal can comprise tremors, insomnia, disturbed sleep, headache, sweating, nausea, vomiting, muscle pain, muscle stiffness.hypertension, irregular heart rate, elevated heart rate, heart palpitations, dizziness, shakiness, tremors, seizures, dehydration, shallow breathing, fatigue, loss of appetite, clammy skin, loss of color, or anu combination thereof.

[0312] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to reduce and / or eliminate at least one substance use withdrawal symptom in the subject.

[0313] In an aspect, a disclosed psychological symptom of withdrawal can comprise anxiety, irritability, difficulty concentrating, difficulty thinking clearly, mood swings, nightmares, depression, tension, panic attacks, short term memory loss, restlessness, a feeling of helplessness, stress-sensitivity, a heightened responsivity to substance-related cues, aberrant reward processing, a substance craving or a combination thereof.

[0314] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to reduce and / or eliminate at least one psychological symptom in the subj ect.

[0315] In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be formulated for intravenous, intramuscular, sublingual, subcutaneous, intranasal, transnasal, oral, rectal, or transdermal administration.

[0316] In an aspect, a disclosed device comprising a disclosed pharmaceutical formulation comprising setmelanotide can provide long-lasting relief of one or more indexes of OIRD.

[0317] In an aspect, a disclosed device can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, patient life expectancy can be increased at least about 5% or greater to at least about 100%, at least about 10% or greater to at least about 95% or greater, at least about 20% or greater to at least about 80% or greater, at least about 40% or greater to at least about 60% or greater compared to an untreated subj ect with the identical or near identical overdose and the identical or near identical predicted outcome.

[0318] I In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory’ depression (OIRD). In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprisingsetmelanotide can be used to treat a subject experiencing opioid-induced respiratory’ depression (OIRD) in a clinical setting. In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory’ depression (OIRD) in an illicit use setting. In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory’ depression (OIRD) without interrupting and / or affecting analgesia. In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory’ depression (OIRD) in a clinical setting without interrupting and / or affecting analgesia. In an aspect, a disclosed device comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD) in an illicit use setting without interrupting and / or affecting analgesia. In an aspect, a disclosed dey’ice comprising one or more disclosed pharmaceutical formulations comprising setmelanotide and / or one or more disclosed liquid sprays comprising setmelanotide can be used to ease the subject’s transition from an intensive care unit (ICU) to a non-ICU in a clinical setting.Kits

[0319] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivering setmelanotide, or any combination thereof. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivering setmelanotide, or any combination thereof and one or more additional therapeutic agents and / or pharmaceutical agents. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide. disclosed liquid sprays comprising setmelanotide, disclosed devices for delivering setmelanotide, or any combination thereof for use in a method of treating a subject in active overdose due to an opioid misuse and / or an opioid overdose. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery’ setmelanotide, or any combination thereof for use in a method of treating a subject suspected of having an active overdose due to opioid misuse and / or opioid overdose.

[0320] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject experiencing an opioid misuse and / or an opioid overdose. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject suspected of experiencing an opioid misuse and / or an opioid overdose.

[0321] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide. disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject experiencing opioid-induced respiratory depression (OIRD) due to opioid misuse and / or opioid overdose. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject suspected of experiencing opioid-induced respiratory depression (OTRD due to opioid misuse and / or opioid overdose.

[0322] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide. disclosed liquid sprays comprising setmelanotide, disclosed devices for deliver}' setmelanotide, or any combination thereof for use in a method of treating an opioid overdose due to opioid misuse and / or opioid overdose in a subject in need thereof. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery’ setmelanotide. or any combination thereof for use in a method of treating a suspected opioid misuse and / or opioid overdosein a subject in need thereof.

[0323] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide. or any combination thereof for use in a method of reducing aggression, anger, and / or violence associated with reversal of an opioid misuse and / or an opioid overdosein a subj ect in need thereof.

[0324] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject experiencing an opioid misuse and / or an opioid overdose.

[0325] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject suspected of experiencing an opioid misuse and / or an opioid overdose.

[0326] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide. disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject experiencing opioid-induced respiratory depression (OIRD) due to an opioid misuse and / or an opioid overdose. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating subject suspected of experiencing opioid-induced respiratory depression (OIRD) due to an opioid misuse and / or an opioid overdose.

[0327] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide. disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating an opioid misuse and / or an opioid overdosein a subject in need thereof. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a suspected opioid misuse and / or opioid overdosein a subject in need thereof.

[0328] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for deliver}' setmelanotide. or any combination thereof for use in a method of reducing aggression, anger, and / or violence associated with reversal of an opioid misuse and / or an opioid overdosein a subj ect in need thereof.

[0329] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide. disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject experiencing an opioid misuse and / or an opioid overdose.

[0330] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject suspected of experiencing an opioid misuse and / or an opioid overdose.

[0331] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject experiencing opioid-induced respiratory’ depression (OIRD) due to an opioid misuse and / or an opioid overdose. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject suspected of experiencing opioid-induced respiratory depression (OIRD) due to an opioid misuse and / or an opioid overdose.

[0332] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery' setmelanotide, or any combination thereof for use in a method of treating an opioid misuse and / or an opioid overdosein a subject in need thereof. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a suspected opioid overdose due to an opioid misuse and / or an opioid overdose in a subject in need thereof.

[0333] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide. disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of reducing aggression, anger, and / or violence associated with reversal of an opioid overdose due to an opioid misuse and / or an opioid overdose in a subject in need thereof.

[0334] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide. disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject experiencing an opioid misuse and / or an opioid overdose. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject suspected of experiencing an opioid misuse and / or an opioid overdose.

[0335] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject experiencing opioid-induced respiratory’ depression (OIRD) due to an opioid misuse and / or anopioid overdose. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject suspected of experiencing opioid-induced respiratory depression (OIRD) due to an opioid misuse and / or an opioid overdose.

[0336] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivety setmelanotide, or any combination thereof for use in a method of treating an opioid misuse and / or an opioid overdosein a subject in need thereof. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a suspected opioid misuse and / or suspected opioid overdosein a subject in need thereof.

[0337] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide. disclosed liquid sprays comprising setmelanotide, disclosed devices for deliver}7setmelanotide, or any combination thereof for use in amethod of reducing aggression, anger, and / or violence associated with reversal of an opioid misuse and / or an opioid overdosein a subj ect in need thereof.

[0338] In an aspect, opioids can comprise fentanyl mixed with and / or laced with and / or cut with another agent. In an aspect, a subject can be experiencing an opioid overdose due to fentanyl mixed with and / or laced with and / or cut with another agent.

[0339] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject experiencing an opioid misuse and / or an opioid overdose.

[0340] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject suspected of experiencing an opioid misuse and / or an opioid overdose.

[0341] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for deliver ’ setmelanotide, or any combination thereof for use in a method of treating a subject experiencing opioid-induced respiratory depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0342] Disclosed herein is a method of treating a subject, the method comprising administering to a subject suspected of experiencing opioid-induced respiratory depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0343] Disclosed herein is a method of treating an opioid overdose, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation. Disclosed herein is a method of treating a suspected opioid overdose, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0344] Disclosed herein is a method of reducing aggression, anger, and / or violence associated with reversal of an opioid misuse and / or an opioid overdose, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0345] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject experiencing an opioid overdose. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery' setmelanotide, or any combination thereof for use in a method of treating a subject suspected of experiencing an opioid misuse and / or an opioid overdose.

[0346] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery’ setmelanotide, or any combination thereof for use in a method of treating a subject experiencing opioid-induced respiratory depression (OIRD). Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject suspected of experiencing opioid- induced respiratory depression (OIRD).

[0347] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery' setmelanotide, or any combination thereof for use in a method of treating an opioid overdose in a subject in need thereof. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprisingsetmelanotide, disclosed devices for delivery’ setmelanotide. or any combination thereof for use in a method of treating a suspected opioid overdose in a subject in need thereof.

[0348] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of reducing aggression, anger, and / or violence associated with reversal of an opioid overdose in a subject in need thereof.

[0349] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery' setmelanotide, or any combination thereof for use in a method of treating a subject experiencing an opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0350] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject suspected of experiencing an opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0351] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery’ setmelanotide, or any combination thereof for use in a method of treating a subject experiencing opioid-induced respiratory depression (OIRD) in a subject in need thereof. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery’ setmelanotide, or any combination thereof for use in a method of treating a subject suspected of experiencing opioid-induced respiratory depression (OIRD) in a subject in need thereof.

[0352] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivers’ setmelanotide, or any combination thereof for use in a method of treating an opioid overdose in a subject in need thereof.

[0353] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery’ setmelanotide. or any combination thereof for use in a method of treating a suspected opioid overdose in a subject in need thereof. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprayscomprising setmelanotide. disclosed devices for delivery setmelanotide. or any combination thereof for use in a method of reducing aggression, anger, and / or violence associated with reversal of an opioid overdose in a subject in need thereof.

[0354] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject experiencing an opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery’ setmelanotide. or any combination thereof for use in a method of treating a subject suspected of experiencing an opioid overdose.

[0355] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery- setmelanotide, or any combination thereof for use in a method of treating a subject experiencing opioid-induced respiratory- depression (OIRD) due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents. Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery setmelanotide, or any combination thereof for use in a method of treating a subject suspected of experiencing opioid- induced respiratory- depression (OIRD) due to fentanyl or fentanyl mixed yvith and / or laced with and / or cut with one or more agents.

[0356] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery' setmelanotide, or any combination thereof for use in a method of treating an opioid overdose in a subject in need thereof.

[0357] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery- setmelanotide. or any combination thereof for use in a method of treating a suspected opioid overdose in a subject in need thereof.

[0358] Disclosed herein is a kit comprising one or more disclosed pharmaceutical formulations comprising setmelanotide, disclosed liquid sprays comprising setmelanotide, disclosed devices for delivery- setmelanotide, or any combination thereof for use in a method reducing aggression, anger, and / or violence associated yvith reversal of an opioid overdose in a subject in need thereof.

[0359] In an aspect, by using a disclosed kit, an overdose can be reversed.

[0360] In an aspect, a disclosed kit can be used to validate and / or characterize (i) one or more disclosed pharmaceutical formulations, and / or (ii) one or more disclosed or disclosed liquid sprays. In an aspect, validating and / or characterizing can comprise measuring, ascertaining, and / or determining the purity and / or efficacy of the one or more disclosed pharmaceutical formulations or one or more disclosed liquid sprays.

[0361] In an aspect, a disclosed kit can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD). In an aspect, a disclosed kit can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD) in a clinical setting. In an aspect, a disclosed kit can be used to treat a subject experiencing opioid-induced respiratory' depression (OIRD) in an illicit use setting. In an aspect, a disclosed kit can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD) without interrupting and / or affecting analgesia. In an aspect, a disclosed kit can be used to treat a subject experiencing opioid-induced respiratory' depression (OIRD) in a clinical setting without interrupting and / or affecting analgesia. In an aspect, a disclosed kit can be used to treat a subject experiencing opioid-induced respiratory depression (OIRD) in an illicit use setting without interrupting and / or affecting analgesia. In an aspect, a disclosed kit can be used to ease the subject’s transition from an intensive care unit (ICU) to a non-ICU in a clinical setting.

[0362] In an aspect, a disclosed kit can comprise at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose (such as, for example, treating a subject experiencing an opioid overdose or suspected of experiencing an opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents). Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0363] In an aspect, a disclosed kit for use in a disclosed method can comprise one or more containers holding one or more disclosed pharmaceutical formulations or one or more disclosed liquid sprays, disclosed opioid antagonists, disclosed pharmacological agents, or a combination thereof, and a label or package insert with instructions for use. In an aspect, suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The containers can be formed from a variety of materials such as glass or plastic. The container can hold one or more disclosed pharmaceutical formulations or one or more disclosed liquid sprays, disclosed opioid antagonists.disclosed pharmacological agents, or a combination thereof, and can have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The label or package insert can indicate one or more disclosed pharmaceutical formulations or one or more disclosed liquid sprays, disclosed opioid antagonists, disclosed pharmacological agents, or a combination thereof can be used for use in a disclosed method. A kit can comprise additional components necessary for administration such as, for example, other buffers, diluents, filters, needles, and syringes.

[0364] In an aspect, a disclosed kit can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, patient life expectancy can be increased at least about 5% or greater to at least about 100%, at least about 10% or greater to at least about 95% or greater, at least about 20% or greater to at least about 80% or greater, at least about 40% or greater to at least about 60% or greater compared to an untreated subj ect with the identical or near identical overdose and the identical or near identical predicted outcome.E. MethodsMethods of Treating a Subject

[0365] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing an opioid overdose a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0366] Disclosed herein is a method of treating a subject suspected of experiencing an opioid overdose, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0367] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0368] Disclosed herein is a method of treating a subject suspected of experiencing opioid- induced respiratory' depression (OIRD), the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0369] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) due to clinical administration of an opioid a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0370] Disclosed herein is a method of treating a subject suspected of experiencing opioid- induced respiratory depression (OIRD), the method comprising administering to a subject due toclinical administration of an opioid a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0371] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) due to opioid abuse or opioid misuse a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0372] Disclosed herein is a method of treating a subject suspected of experiencing opioid- induced respiratory depression (OIRD), the method comprising administering to a subject due to opioid abuse or opioid misuse a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0373] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing a morphine overdose a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0374] Disclosed herein is a method of treating a subject suspected of experiencing a morphine overdose, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0375] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing morphine-induced respiratory' depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0376] Disclosed herein is a method of treating a subject suspected of experiencing morphine- induced respiratory depression (OIRD), the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0377] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing a fentanyl overdose a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0378] Disclosed herein is a method of treating a subject suspected of experiencing a fentanyl overdose, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0379] Disclosed herein is a method of treating a subject, the method comprising administering to a subject experiencing fentanyl-induced respiratory depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0380] Disclosed herein is a method of treating a subject suspected of experiencing fentanyl- induced respiratory depression (OIRD), the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0381] In an aspect, an opioid can comprise fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents. In an aspect, a subject can be experiencing an opioid overdose due to clinical administration of an opioid, for example, for pain management. In an aspect, a subject can be experiencing an opioid overdose due to opioid abuse or opioid misuse.

[0382] In an aspect, a subject can be administering one or more opioids in a clinical setting, and following administration, the subject can experience one or more symptoms associated with and / or related to OIRD. In an aspect, the administering of a disclosed pharmaceutical formulation comprising SET can treat and / or reverse the one or more symptoms associated with and / or related to OIRD without interfering with and / or disrupting the analgesia provided to the subject by the one or more opioids.

[0383] In an aspect, a disclosed method can further comprise repeating the administering of a disclosed pharmaceutical formulation comprising SET. In an aspect of a disclosed method, administering can comprise intranasal administration, sublingual administration, intraperitoneal administration, intravenous administration, subcutaneous administration, or a combination thereof. In an aspect, a disclosed pharmaceutical formulation comprising SET can be administered via the same routes of administration. In an aspect, a disclosed pharmaceutical formulation comprising SET can be administered via the different routes of administration. In an aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can be administered subcutaneously. In an aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can be administered intranasally.

[0384] In an aspect, administering can comprise using a disclosed device adapted for intranasal delivery' of the pharmaceutical formulation. In an aspect, intranasal delivery' can comprise one actuation of the device into one or both nostrils of the subject. In an aspect, intranasal delivery’ can comprise one actuation into one nostril or both nostrils of the subject using a disclosed device.

[0385] In an aspect of a disclosed method, a subject can be experiencing an active opioid overdose due to fentanyl or fentanyl mixed yvith and / or laced yvith and / or cut yvith one or more agents. In an aspect of a disclosed method, a subject can be suspected of experiencing an active opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0386] In an aspect of a disclosed method, opioid-induced respiratory depression (OIRD) can comprise one or more of a depression of respiratory rate, a depression of minute ventilation, a depression of alveolar-arterial gas exchange, a decrease in respiratory’ responsiveness to hypoxia and hypercapnia, an increase in apnea duration and / or apnea frequency, an increase in hypoxemic events, cardiac arrest, and any combination thereof.

[0387] In an aspect of a disclosed method, following an administering step, one or more symptoms of opioid-induced respiratory depression (OIRD) can be improved and / or minimized. For example, in an aspect, following an administering step, a subject can experience an increase in respiratory rate, an increase in minute ventilation, an increase in alveolar-arterial gas exchange, an increase in respiratory responsiveness, a decrease in apnea duration and / or apnea frequency, a decrease in hypoxemic events, and any combination thereof.

[0388] In an aspect of a disclosed method, a subject can be experiencing one or more symptoms associated with and / or related to an active opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0389] In an aspect of a disclosed method, symptoms associated with and / or related to an active opioid overdose can comprise (i) a loss of consciousness, (ii) constricted or pinpoint pupils, (iii) breathing difficulties (slowed, labored, and / or irregular breathing), (iv) respiratory arrest, (v) choking, gurgling, or snoring sounds, (vi) blue or purple lips or fingertips, (vii) a low of responsive to loud noises, shaking, or painful stimuli, or (viii) any combination thereof.

[0390] In an aspect of a disclosed method, a subject can be exhibiting one or more symptoms associated with and / or related to the illicit use of opioids (e.g., fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents).

[0391] In an aspect of a disclosed method, a subject can be exhibiting one or more symptoms associated with and / or related to the accidental misuse of opioids (e g., morphine) during medical opioid therapy.

[0392] In an aspect of a disclosed method, following the administering step, a subject can be free from respiratory7depression for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, or at least about 6 hours following.

[0393] In an aspect of a disclosed method, an administering step can be performed on a subject in a lying, supine, or recovery position. In an aspect of a disclosed method, one or more disclosed symptoms can comprise respiratory' depression, central nervous system depression, cardiovascular depression, altered level consciousness, miotic pupils, hypoxemia, acute lung injury', aspiration pneumonia, sedation, hypotension, unresponsiveness to stimulus, unconsciousness, stopped breathing, erratic or stopped pulse, choking or gurgling sounds, blue or purple fingernails or lips, slack or limp muscle tone, contracted pupils, vomiting, and any combination thereof.

[0394] In an aspect of a disclosed method, following the administering step, one or more symptoms of OIRD can be minimized and / or reduced. In an aspect of a disclosed method, following the administering step, one or more symptoms of OIRD can be reversed and / or eliminated.

[0395] In an aspect of a disclosed method, the subject can have a substance use disorder. In an aspect of a disclosed method, a disclosed substance use disorder can comprise alcohol use disorder, cocaine use disorder, cannabis use disorder, tobacco use disorder, methamphetamine use disorder, opioid use disorder, or any combination thereof. In an aspect of a disclosed method, a disclosed substance use disorder can comprise abuse of opioids. In an aspect, a disclosed opioid can comprise heroin, codeine, fentanyl, hydrocodone (dihydrocodeinone). hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, or any combination thereof.

[0396] In an aspect, a disclosed method can further comprise administering to the subject one or more additional pharmacotherapeutic agents for opioid use disorder. In an aspect, a disclosed method can further comprise administering to the subject one or more additional pharmacotherapies for substance abuse. In an aspect, one or more disclosed additional pharmacotherapeutic agents can comprise buprenorphine, methadone, naltrexone, or any combination thereof. In an aspect, one or more disclosed additional pharmacotherapeutic agents can comprise naloxone, nalmefene, or any combination thereof. In an aspect, disclosed additional pharmacotherapy can comprise a gradually reducing regimen, a substitution therapy, or a medication assisted therapy. In an aspect, a disclosed method can further comprise administering to the subject one or more additional therapies. In an aspect, one or more disclosed additional therapies can comprise a behavioral therapy.

[0397] In an aspect, behavioral therapy can comprise counseling, a contingency management system, a mindfulness-based therapy, a cognitive-behavioral therapy, a digitally administered behavioral therapy or a virtual reality based behavioral therapy, or any combination thereof. In an aspect, counseling can be in person or via digital means. In an aspect, a disclosed method can reduce the amount behavioral therapy required compared behavioral therapy without the administration of the composition.

[0398] In an aspect, a disclosed substance use disorder can comprise abuse of an opioid, and wherein the substitution therapy comprises methadone or buprenorphine. In an aspect, a disclosed substance use disorder can comprise abuse of an opioid, and wherein the medication assisted treatment comprises naltrexone, disulfiram, acamprosate, or any combination thereof.

[0399] In an aspect, a disclosed substance use withdrawal symptom can comprise a symptom of withdrawal from opioids. In an aspect, a disclosed opioid can comprise heroin, codeine, fentanyl, hydrocodone (dihydrocodeinone), hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, or any combination thereof. In an aspect, a disclosed opioid can comprise fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0400] In an aspect, a disclosed substance use withdrawal symptom can comprise a physical symptom of withdrawal, a psychological symptom of withdrawal, or any combination thereof.

[0401] In an aspect, a disclosed physical symptom of withdrawal can comprise tremors, insomnia, disturbed sleep, headache, sweating, nausea, vomiting, muscle pain, muscle stiffness, hypertension, irregular heart rate, elevated heart rate, heart palpitations, dizziness, shakiness, tremors, seizures, dehydration, shallow breathing, fatigue, loss of appetite, clammy skin, loss of color, or any combination thereof.

[0402] In an aspect, a disclosed psychological symptom of withdrawal can comprise anxiety, irritability, difficulty concentrating, difficulty thinking clearly, mood swings, nightmares, depression, tension, panic attacks, short term memory loss, restlessness, a feeling of helplessness, stress-sensitivity, a heightened responsivity to substance-related cues, aberrant reward processing, a substance craving or a combination thereof.

[0403] In an aspect, a disclosed method can further comprise an additional pharmacotherapy for withdrawal. In an aspect, a disclosed additional pharmacotherapy can comprise a gradually- reducing regimen, a substitution therapy or a medication assisted treatment.

[0404] In an aspect, a disclosed method can further comprise a behavioral therapy. In an aspect, a disclosed behavioral therapy can comprise counseling, a contingency management system, a mindfulness-based therapy, a cognitive-behavioral therapy, a digitally administered behavioral therapy or a virtual reality based behavioral therapy.

[0405] In an aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can reduce or eliminate the at least one substance use withdrawal symptom in the subject. In an aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can reduce or eliminate the at least one psychological symptom in the subject.

[0406] In an aspect, a disclosed method can reduce a symptom of withdrawal or prevents a relapse of the substance use disorder in the subject. In an aspect, a disclosed method can reduce tolerance to a substance of the substance use disorder in the subject. In an aspect, a disclosed method can reduce dependence on a substance of the substance use disorder in the subject.

[0407] In an aspect, a disclosed method can improve adherence to a treatment for the substance use disorder in the subject. In an aspect, a disclosed method can reduce a preference for a substance or decreases liking for a substance. In an aspect, a disclosed method can increase abstinence from a substance.

[0408] In an aspect of a disclosed method, administering a disclosed pharmaceutical formulation comprising SET can comprise a single dose or multiple doses (such as 2. 3. 4, 5. 6. 7, 8, 9. 10. or more than 10 doses). In an aspect of a disclosed method, administering one or more disclosedpharmaceutical formulations comprising SET can comprise a single dose or multiple doses (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses). In an aspect of a disclosed method, administering a disclosed pharmaceutical formulation comprising SET can comprise a single dose or multiple doses (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses).

[0409] In an aspect, a disclosed method can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, patient life expectancy can be increased at least about 5% or greater to at least about 100%, at least about 10% or greater to at least about 95% or greater, at least about 20% or greater to at least about 80% or greater, at least about 40% or greater to at least about 60% or greater compared to an untreated subj ect with the identical or near identical overdose and the identical or near identical predicted outcome.

[0410] In an aspect, a disclosed method can further comprise monitoring the subject for adverse effects. In an aspect, in the absence of adverse effects, a disclosed method can further comprise continuing to treat the subject. In an aspect, continuing to treat the subject can comprise continuing to administer a disclosed pharmaceutical formulation comprising SET.

[0411] In an aspect, in the presence of adverse effects, a disclosed method can further comprise modifying one or more steps of the method. In an aspect, modifying one or more steps of a disclosed method can comprise modifying one or more administering steps. In an aspect, modifying one or more disclosed administering steps can comprise changing the amount of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administered to the subject, changing the frequency of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, changing the duration of a disclosed composition (i.e.. a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, changing the route of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, or any combination thereof. In an aspect, modifying one or more disclosed administering steps can comprise changing the amount a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administered to the subject, changing the frequency of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, changing the duration of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, changing the route of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray), or any combination thereof.

[0412] In an aspect, a disclosed method can further comprise providing additional respiratory’ support to the subject. In an aspect, a disclosed method can further comprise providing additional respiratory support to the subject such as, for example, supplemental oxygen or one or more additional pharmacological agents.

[0413] In an aspect, a subject can be ahuman patient. In an aspect a subject can be any age (e.g., geriatric, adult, young adult, teenager, tween, adolescent, child, toddler, baby, or infant), can be male or female, can be any nationality7, can be of any ethnicity, and / or can be of any race. In an aspect, a subject can be in active overdose. In an aspect, a subject can be suspected of having an active overdose. In an aspect, a subject can be in active overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents. In an aspect, a subject can be suspected of having an active overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0414] In an aspect, a disclosed method can comprise improving and / or enhancing the subject’s quality of life. In an aspect of a disclosed method, a disclosed improvement and / or enhancement (such as, for example, in the subject’s quality of life) can comprise a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of improvement when compared to a control subject (such as, for example, a subject that has not received a disclosed pharmaceutical formulation comprising SET).

[0415] In an aspect, a disclosed method can further comprise monitoring the subject following the administering step and / or the treating step to generate a compilation of biochemical and / or physiological and / or behavioral data. In an aspect, a disclosed compilation of data can be used to identify a trend or a pattern. In an aspect, a disclosed compilation of data can be used to guide and / or inform a skilled clinician in a decision-making process regarding treatment and / or testing. In an aspect, for example, a clinician can decide to change an aspect of the subject’s treatment and / or change the subject’s diagnosis or prognosis.

[0416] In an aspect, a disclosed method can further comprise monitoring the subject’s metabolic and / or physiologic improvement following the administering and / or treating step and / or following the administering and / or treating steps. In an aspect, a clinician can measure and / or determine the subject’s metabolic and / or physiologic status over time to identify one or more improvements and / or one or more dimini shments. In an aspect of a disclosed method, a clinician can use the subject’s metabolic and / or physiologic status and / or the trend of the subject’s metabolic and / or physiological status and / or trend to make a treatment decision and / or to modify an aspect of a disclosed method and / or to continue treating the subject and / or continue to administer one or moredisclosed pharmaceutical formulation comprising SET. In an aspect, metabolic and / or physiologic data can inform the clinician when make subsequent treatment decisions.

[0417] In an aspect, a disclosed method can further comprise repeating one or more disclosed steps of a disclosed method. In an aspect, a disclosed method can further comprise continuing to administer to the subject a therapeutically effective amount of one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or any combination thereof.

[0418] In an aspect, a disclosed method can further comprise generating and / or making one or more disclosed pharmaceutical formulations comprising SET. In an aspect, a disclosed method can further comprise validating and / or characterizing one or more disclosed pharmaceutical formulations SET. For example, in an aspect, validating and / or characterizing one or more disclosed pharmaceutical formulations thereof can comprise measuring, ascertaining, and / or determining the purity7and / or efficacy of the one or more disclosed pharmaceutical formulations comprising SET. In an aspect, a disclosed method can ease the subject’s transition from an intensive care unit (ICU) to a non-ICU in a clinical setting. In an aspect, a disclosed method can reduce an obese subject’s risk of developing OIRD. In an aspect, a disclosed method can provide longdasting relief of one or more indexes of OIRD.

[0419] In an aspect of a disclosed method, a disclosed therapeutically effective amount can comprise between about 0. 1 mg to about 5 mg of setmelanotide and / or a salt and / or solvate thereof. In an aspect, a disclosed therapeutically effective amount can comprise about 0. 1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg. about 2.0 mg, about 2.1 mg. about 2.2 mg, about 2.3 mg, about 2.4 mg. about 2.5 mg, about 2.6 mg. about 2.7 mg, about 2.8 mg. about2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg. about 4.7 mg, about 4.8 mg. about4.9 mg. or about 5.0 mg of setmelanotide and / or a salt and / or solvate thereof.Methods of Preventing and / or Minimizing Symptoms of OIRD

[0420] Disclosed herein is a method of preventing OIRD, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation comprising SET. wherein the subject has received one or more opioids for pain management, wherein the pharmaceutical formulation does not disrupt and / or diminish and / or affect theanalgesia provided to the subject by the one or more opioids, and wherein, following the administering step, the subject does not develop OIRD.

[0421] Disclosed herein is a method of preventing OIRD, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation, wherein the subject is receiving one or more opioids for pain management, wherein the pharmaceutical formulation comprising SET does not disrupt and / or diminish and / or affect the analgesia provided to the subject by the one or more opioids, and wherein, following the administering step, the subject does not develop OIRD.

[0422] Disclosed herein is a method of preventing OIRD, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation comprising SET, wherein the subject will receive one or more opioids for pain management, wherein the pharmaceutical formulation does not disrupt and / or diminish and / or affect the analgesia provided to the subject by the one or more opioids, and wherein, following the administering step, the subject does not develop OIRD.

[0423] Disclosed herein is a method of minimizing one or more symptoms of OIRD, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation comprising SET, wherein the subject has received one or more opioids for pain management, wherein the pharmaceutical formulation does not disrupt and / or diminish and / or affect the analgesia provided to the subject by the one or more opioids, and wherein, following the administering step, one or more symptoms of OIRD are reduced and / or minimized.

[0424] Disclosed herein is a method of minimizing one or more symptoms of OIRD, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation comprising SET. wherein the pharmaceutical formulation does not disrupt and / or diminish and / or affect the analgesia provided to the subject by the one or more opioids, and wherein, following the administering step, one or more symptoms of OIRD are reduced and / or minimized.

[0425] Disclosed herein is a method of minimizing one or more symptoms of OIRD, the method comprising administering to a subject a therapeutically effective amount of a disclosed pharmaceutical formulation comprising SET, wherein the pharmaceutical formulation does not disrupt and / or diminish and / or affect the analgesia provided to the subject by the one or more opioids, and wherein, following the administering step, one or more symptoms of OIRD are reduced and / or minimized.

[0426] In an aspect, a disclosed method can reduce aggression, anger, and / or violence associated with cessation of opioid use.

[0427] In an aspect, an opioid can comprise fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents. In an aspect, a subject can be experiencing an opioid overdose due to clinical administration of an opioid, for example, for pain management. In an aspect, a subject can be experiencing an opioid overdose due to opioid abuse or opioid misuse.

[0428] In an aspect, a subject can be administering one or more opioids in a clinical setting, and following administration, the subject can experience one or more symptoms associated with and / or related to OIRD. In an aspect, the administering of a disclosed pharmaceutical formulation comprising SET can treat and / or reverse the one or more symptoms associated with and / or related to OIRD without interfering with and / or disrupting the analgesia provided to the subject by the one or more opioids.

[0429] In an aspect, a disclosed method can further comprise repeating the administering of a disclosed pharmaceutical formulation comprising SET. In an aspect of a disclosed method, administering can comprise intranasal administration, sublingual administration, intraperitoneal administration, intravenous administration, subcutaneous administration, or a combination thereof. In an aspect, a disclosed pharmaceutical formulation comprising SET can be administered via the same routes of administration. In an aspect, a disclosed pharmaceutical formulation comprising SET can be administered via the different routes of administration. In an aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can be administered subcutaneously. In an aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can be administered intranasally.

[0430] In an aspect, administering can comprise using a disclosed device adapted for intranasal delivery of the pharmaceutical formulation. In an aspect, intranasal delivery can comprise one actuation of the device into one or both nostrils of the subject. In an aspect, intranasal deliver}' can comprise one actuation into one nostril or both nostrils of the subject using a disclosed device.

[0431] In an aspect of a disclosed method, a subject can be experiencing an active opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents. In an aspect of a disclosed method, a subject can be suspected of experiencing an active opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0432] In an aspect of a disclosed method, opioid-induced respiratory depression (OIRD) can comprise one or more of a depression of respiratory rate, a depression of minute ventilation, a depression of alveolar-arterial gas exchange, a decrease in respiratory responsiveness to hypoxiaand hypercapnia, an increase in apnea duration and / or apnea frequency, an increase in hypoxemic events, cardiac arrest, and any combination thereof.

[0433] In an aspect of a disclosed method, following an administering step, one or more symptoms of opioid-induced respiratory' depression (OIRD) can be improved and / or minimized. For example, in an aspect, following an administering step, a subject can experience an increase in respiratory rate, an increase in minute ventilation, an increase in alveolar-arterial gas exchange, an increase in respiratory responsiveness, a decrease in apnea duration and / or apnea frequency, a decrease in hypoxemic events, and any combination thereof.

[0434] In an aspect of a disclosed method, a subject can be experiencing one or more symptoms associated with and / or related to an active opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0435] In an aspect of a disclosed method, symptoms associated with and / or related to an active opioid overdose can comprise (i) a loss of consciousness, (ii) constricted or pinpoint pupils, (iii) breathing difficulties (slowed, labored, and / or irregular breathing), (iv) respiratory arrest, (v) choking, gurgling, or snoring sounds, (vi) blue or purple lips or fingertips, (vii) a low of responsive to loud noises, shaking, or painful stimuli, or (viii) any combination thereof.

[0436] In an aspect of a disclosed method, a subject can be exhibiting one or more symptoms associated with and / or related to the illicit use of opioids (e.g., fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents).

[0437] In an aspect of a disclosed method, a subject can be exhibiting one or more symptoms associated with and / or related to the accidental misuse of opioids (e.g., morphine) during medical opioid therapy.

[0438] In an aspect of a disclosed method, following the administering step, a subject can be free from respiratory depression for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, or at least about 6 hours following.

[0439] In an aspect of a disclosed method, an administering step can be performed on a subject in a lying, supine, or recovery' position. In an aspect of a disclosed method, one or more disclosed symptoms can comprise respiratory depression, central nervous system depression, cardiovascular depression, altered level consciousness, miotic pupils, hypoxemia, acute lung injury, aspiration pneumonia, sedation, hypotension, unresponsiveness to stimulus, unconsciousness, stopped breathing, erratic or stopped pulse, choking or gurgling sounds, blue or purple fingernails or lips, slack or limp muscle tone, contracted pupils, vomiting, and any combination thereof.

[0440] In an aspect of a disclosed method, following the administering step, one or more symptoms of OIRD can be minimized and / or reduced. In an aspect of a disclosed method.following the administering step, one or more symptoms of OIRD can be reversed and / or eliminated.

[0441] In an aspect of a disclosed method, the subject can have a substance use disorder. In an aspect of a disclosed method, a disclosed substance use disorder can comprise alcohol use disorder, cocaine use disorder, cannabis use disorder, tobacco use disorder, methamphetamine use disorder, opioid use disorder, or any combination thereof. In an aspect of a disclosed method, a disclosed substance use disorder can comprise abuse of opioids. In an aspect, a disclosed opioid can comprise heroin, codeine, fentanyl, hydrocodone (dihydrocodeinone), hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, or any combination thereof.

[0442] In an aspect, a disclosed method can further comprise administering to the subject one or more additional pharmacotherapeutic agents for opioid use disorder. In an aspect, a disclosed method can further comprise administering to the subject one or more additional pharmacotherapies for substance abuse. In an aspect, one or more disclosed additional pharmacotherapeutic agents can comprise buprenorphine, methadone, naltrexone, or any combination thereof. In an aspect, one or more disclosed additional pharmacotherapeutic agents can comprise naloxone, nalmefene, or any combination thereof. In an aspect, disclosed additional pharmacotherapy can comprise a gradually reducing regimen, a substitution therapy, or a medication assisted therapy. In an aspect, a disclosed method can further comprise administering to the subject one or more additional therapies. In an aspect, one or more disclosed additional therapies can comprise a behavioral therapy.

[0443] In an aspect, behavioral therapy can comprise counseling, a contingency management system, a mindfulness-based therapy, a cognitive-behavioral therapy, a digitally administered behavioral therapy or a virtual reality based behavioral therapy, or any combination thereof. In an aspect, counseling can be in person or via digital means. In an aspect, a disclosed method can reduce the amount behavioral therapy required compared behavioral therapy without the administration of the composition.

[0444] In an aspect, a disclosed substance use disorder can comprise abuse of an opioid, and wherein the substitution therapy comprises methadone or buprenorphine. In an aspect, a disclosed substance use disorder can comprise abuse of an opioid, and wherein the medication assisted treatment comprises naltrexone, disulfiram, acamprosate, or any combination thereof.

[0445] In an aspect, a disclosed substance use withdrawal symptom can comprise a symptom of withdrawal from opioids. In an aspect, a disclosed opioid can comprise heroin, codeine, fentanyl, hydrocodone (dihydrocodeinone). hydromorphone, meperidine, methadone, morphine,oxycodone, oxymorphone, or any combination thereof. In an aspect, a disclosed opioid can comprise fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0446] In an aspect, a disclosed substance use withdrawal symptom can comprise a physical symptom of withdrawal, a psychological symptom of withdrawal, or any combination thereof.

[0447] In an aspect, a disclosed physical symptom of withdrawal can comprise tremors, insomnia, disturbed sleep, headache, sweating, nausea, vomiting, muscle pain, muscle stiffness, hypertension, irregular heart rate, elevated heart rate, heart palpitations, dizziness, shakiness, tremors, seizures, dehydration, shallow breathing, fatigue, loss of appetite, clammy skin, loss of color, or any combination thereof.

[0448] In an aspect, a disclosed psychological symptom of withdrawal can comprise anxiety, irritability, difficulty concentrating, difficulty thinking clearly, mood swings, nightmares, depression, tension, panic attacks, short term memory loss, restlessness, a feeling of helplessness, stress-sensitivity7, a heightened responsivity7to substance-related cues, aberrant reward processing, a substance craving or a combination thereof.

[0449] In an aspect, a disclosed method can further comprise an additional pharmacotherapy for withdrawal. In an aspect, a disclosed additional pharmacotherapy can comprise a gradually reducing regimen, a substitution therapy or a medication assisted treatment.

[0450] In an aspect, a disclosed method can further comprise a behavioral therapy. In an aspect, a disclosed behavioral therapy can comprise counseling, a contingency management system, a mindfulness-based therapy, a cognitive-behavioral therapy, a digitally administered behavioral therapy or a virtual reality based behavioral therapy.

[0451] In an aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can reduce or eliminate the at least one substance use withdrawal symptom in the subject. In an aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can reduce or eliminate the at least one psychological symptom in the subject.

[0452] In an aspect, a disclosed method can reduce a symptom of w ithdraw al or prevents a relapse of the substance use disorder in the subject. In an aspect, a disclosed method can reduce tolerance to a substance of the substance use disorder in the subject. In an aspect, a disclosed method can reduce dependence on a substance of the substance use disorder in the subject.

[0453] In an aspect, a disclosed method can improve adherence to a treatment for the substance use disorder in the subject. In an aspect, a disclosed method can reduce a preference for a substance or decreases liking for a substance. In an aspect, a disclosed method can increase abstinence from a substance.

[0454] In an aspect of a disclosed method, administering a disclosed pharmaceutical formulation comprising SET can comprise a single dose or multiple doses (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses). In an aspect of a disclosed method, administering one or more disclosed pharmaceutical formulations comprising SET can comprise a single dose or multiple doses (such as 2, 3, 4, 5, 6, 7, 8. 9, 10, or more than 10 doses). In an aspect of a disclosed method, administering a disclosed pharmaceutical formulation comprising SET can comprise a single dose or multiple doses (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses).

[0455] In an aspect, a disclosed method can improve and / or extend the survivability of the subject, can improve a subject's quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, patient life expectancy can be increased at least about 5% or greater to at least about 100%, at least about 10% or greater to at least about 95% or greater, at least about 20% or greater to at least about 80% or greater, at least about 40% or greater to at least about 60% or greater compared to an untreated subj ect with the identical or near identical overdose and the identical or near identical predicted outcome.

[0456] In an aspect, a disclosed method can further comprise monitoring the subject for adverse effects. In an aspect, in the absence of adverse effects, a disclosed method can further comprise continuing to treat the subject. In an aspect, continuing to treat the subject can comprise continuing to administer a disclosed pharmaceutical formulation comprising SET.

[0457] In an aspect, in the presence of adverse effects, a disclosed method can further comprise modifying one or more steps of the method. In an aspect, modifying one or more steps of a disclosed method can comprise modifying one or more administering steps. In an aspect, modifying one or more disclosed administering steps can comprise changing the amount of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administered to the subject, changing the frequency of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, changing the duration of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, changing the route of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, or any combination thereof. In an aspect, modifying one or more disclosed administering steps can comprise changing the amount a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administered to the subject, changing the frequency of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, changing the duration of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or adisclosed liquid spray) administration, changing the route of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray), or any combination thereof.

[0458] In an aspect, a disclosed method can further comprise providing additional respiratory' support to the subject. In an aspect, a disclosed method can further comprise providing additional respiratory support to the subject such as, for example, supplemental oxygen or one or more additional pharmacological agents.

[0459] In an aspect, a subject can be ahuman patient. In an aspect a subject can be any age (e.g., geriatric, adult, young adult, teenager, tween, adolescent, child, toddler, baby, or infant), can be male or female, can be any nationality, can be of any ethnicity, and / or can be of any race. In an aspect, a subject can be in active overdose. In an aspect, a subject can be suspected of having an active overdose. In an aspect, a subject can be in active overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents. In an aspect, a subject can be suspected of having an active overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0460] In an aspect, a disclosed method can comprise improving and / or enhancing the subject’s quality of life. In an aspect of a disclosed method, a disclosed improvement and / or enhancement (such as, for example, in the subject's quality' of life) can comprise a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of improvement when compared to a control subject (such as, for example, a subject that has not received a disclosed pharmaceutical formulation comprising SET).

[0461] In an aspect, a disclosed method can further comprise monitoring the subject following the administering step and / or the treating step to generate a compilation of biochemical and / or physiological and / or behavioral data. In an aspect, a disclosed compilation of data can be used to identify a trend or a pattern. In an aspect, a disclosed compilation of data can be used to guide and / or inform a skilled clinician in a decision-making process regarding treatment and / or testing. In an aspect, for example, a clinician can decide to change an aspect of the subject’s treatment and / or change the subject’s diagnosis or prognosis.

[0462] In an aspect, a disclosed method can further comprise monitoring the subject’s metabolic and / or physiologic improvement following the administering and / or treating step and / or following the administering and / or treating steps. In an aspect, a clinician can measure and / or determine the subject’s metabolic and / or physiologic status over time to identify one or more improvements and / or one or more diminishments. In an aspect of a disclosed method, a clinician can use the subject’s metabolic and / or physiologic status and / or the trend of the subject’s metabolic and / orphysiological status and / or trend to make a treatment decision and / or to modify an aspect of a disclosed method and / or to continue treating the subject and / or continue to administer one or more disclosed pharmaceutical formulation comprising SET. In an aspect, metabolic and / or physiologic data can inform the clinician when make subsequent treatment decisions.

[0463] In an aspect, a disclosed method can further comprise repeating one or more disclosed steps of a disclosed method. In an aspect, a disclosed method can further comprise continuing to administer to the subject a therapeutically effective amount of one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or any combination thereof.

[0464] In an aspect, a disclosed method can further comprise generating and / or making one or more disclosed pharmaceutical formulations comprising SET. In an aspect, a disclosed method can further comprise validating and / or characterizing one or more disclosed pharmaceutical formulations SET. For example, in an aspect, validating and / or characterizing one or more disclosed pharmaceutical formulations thereof can comprise measuring, ascertaining, and / or determining the purity and / or efficacy of the one or more disclosed pharmaceutical formulations comprising SET. In an aspect, a disclosed method can ease the subject’s transition from an intensive care unit (ICU) to a non-ICU in a clinical setting. In an aspect, a disclosed method can reduce an obese subject’s risk of developing OIRD. In an aspect, a disclosed method can provide longdasting relief of one or more indexes of OIRD.

[0465] In an aspect of a disclosed method, a disclosed therapeutically effective amount can comprise between about 0. 1 mg to about 5 mg of setmelanotide and / or a salt and / or solvate thereof. In an aspect, a disclosed therapeutically effective amount can comprise about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg. about 0.5 mg, about 0.6 mg. about 0.7 mgsabout 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg. about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg. about 3.8 mg, about 3.9 mg. about 4.0 mg, about 4.1 mg. about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about4.9 mg, or about 5.0 mg of setmelanotide and / or a salt and / or solvate thereof.Methods of Treating an Opioid Overdose

[0466] Disclosed herein is a method of treating an opioid overdose, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0467] Disclosed herein is a method of treating a suspected opioid overdose, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0468] Disclosed herein is a method of treating an opioid overdose, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0469] Disclosed herein is a method of treating a suspected opioid overdose, the method comprising administering to a subject suspected of experiencing opioid-induced respirator}' depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0470] Disclosed herein is a method of treating an opioid overdose, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) due to clinical administration of an opioid a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0471] Disclosed herein is a method of treating a suspected opioid overdose, the method comprising administering to a subject suspected of experiencing opioid-induced respirators’ depression (OIRD) due to clinical administration of an opioid a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0472] Disclosed herein is a method of treating an opioid overdose, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) due to opioid abuse or opioid misuse a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0473] Disclosed herein is a method of treating a suspected opioid overdose, the method comprising administering to a subject suspected of experiencing opioid-induced respiratory’ depression (OIRD) due to opioid abuse or opioid misuse a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0474] In an aspect, an opioid can comprise fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents. In an aspect, a subject can be experiencing an opioid overdose due to clinical administration of an opioid, for example, for pain management. In an aspect, a subject can be experiencing an opioid overdose due to opioid abuse or opioid misuse.

[0475] In an aspect, a subject can be administering one or more opioids in a clinical setting, and following administration, the subject can experience one or more symptoms associated with and / or related to OIRD. In an aspect, the administering of a disclosed pharmaceutical formulation comprising SET can treat and / or reverse the one or more symptoms associated with and / or relatedto OIRD without interfering with and / or disrupting the analgesia provided to the subject by the one or more opioids.

[0476] In an aspect, a disclosed method can further comprise repeating the administering of a disclosed pharmaceutical formulation comprising SET. In an aspect of a disclosed method, administering can comprise intranasal administration, sublingual administration, intraperitoneal administration, intravenous administration, subcutaneous administration, or a combination thereof. In an aspect, a disclosed pharmaceutical formulation comprising SET can be administered via the same routes of administration. In an aspect, a disclosed pharmaceutical formulation comprising SET can be administered via the different routes of administration. In an aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can be administered subcutaneously. In an aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can be administered intranasally.

[0477] In an aspect, administering can comprise using a disclosed device adapted for intranasal delivery of the pharmaceutical formulation. In an aspect, intranasal delivery can comprise one actuation of the device into one or both nostrils of the subject. In an aspect, intranasal delivers’ can comprise one actuation into one nostril or both nostrils of the subject using a disclosed device.

[0478] In an aspect of a disclosed method, a subject can be experiencing an active opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents. In an aspect of a disclosed method, a subject can be suspected of experiencing an active opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0479] In an aspect of a disclosed method, opioid-induced respiratory depression (OIRD) can comprise one or more of a depression of respiratory rate, a depression of minute ventilation, a depression of alveolar-arterial gas exchange, a decrease in respiratory responsiveness to hypoxia and hypercapnia, an increase in apnea duration and / or apnea frequency, an increase in hypoxemic events, cardiac arrest, and any combination thereof.

[0480] In an aspect of a disclosed method, following an administering step, one or more symptoms of opioid-induced respiratory depression (OIRD) can be improved and / or minimized. For example, in an aspect, following an administering step, a subject can experience an increase in respiratory rate, an increase in minute ventilation, an increase in alveolar-arterial gas exchange, an increase in respiratory responsiveness, a decrease in apnea duration and / or apnea frequency, a decrease in hypoxemic events, and any combination thereof.

[0481] In an aspect of a disclosed method, a subject can be experiencing one or more symptoms associated with and / or related to an active opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0482] In an aspect of a disclosed method, symptoms associated with and / or related to an active opioid overdose can comprise (i) a loss of consciousness, (ii) constricted or pinpoint pupils, (iii) breathing difficulties (slowed, labored, and / or irregular breathing), (iv) respiratory arrest, (v) choking, gurgling, or snoring sounds, (vi) blue or purple lips or fingertips, (vii) a low' of responsive to loud noises, shaking, or painful stimuli, or (viii) any combination thereof.

[0483] In an aspect of a disclosed method, a subject can be exhibiting one or more symptoms associated with and / or related to the illicit use of opioids (e.g., fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents).

[0484] In an aspect of a disclosed method, a subject can be exhibiting one or more symptoms associated with and / or related to the accidental misuse of opioids (e.g., morphine) during medical opioid therapy.

[0485] In an aspect of a disclosed method, following the administering step, a subject can be free from respiratory depression for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, or at least about 6 hours following.

[0486] In an aspect of a disclosed method, an administering step can be performed on a subject in a lying, supine, or recovery position. In an aspect of a disclosed method, one or more disclosed symptoms can comprise respiratory depression, central nervous system depression, cardiovascular depression, altered level consciousness, miotic pupils, hypoxemia, acute lung injury, aspiration pneumonia, sedation, hypotension, unresponsiveness to stimulus, unconsciousness, stopped breathing, erratic or stopped pulse, choking or gurgling sounds, blue or purple fingernails or lips, slack or limp muscle tone, contracted pupils, vomiting, and any combination thereof.

[0487] In an aspect of a disclosed method, following the administering step, one or more symptoms of OIRD can be minimized and / or reduced. In an aspect of a disclosed method, following the administering step, one or more symptoms of OIRD can be reversed and / or eliminated.

[0488] In an aspect of a disclosed method, the subject can have a substance use disorder. In an aspect of a disclosed method, a disclosed substance use disorder can comprise alcohol use disorder, cocaine use disorder, cannabis use disorder, tobacco use disorder, methamphetamine use disorder, opioid use disorder, or any combination thereof. In an aspect of a disclosed method, a disclosed substance use disorder can comprise abuse of opioids. In an aspect, a disclosed opioidcan comprise heroin, codeine, fentanyl, hydrocodone (dihydrocodeinone). hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, or any combination thereof.

[0489] In an aspect, a disclosed method can further comprise administering to the subject one or more additional pharmacotherapeutic agents for opioid use disorder. In an aspect, a disclosed method can further comprise administering to the subject one or more additional pharmacotherapies for substance abuse. In an aspect, one or more disclosed additional pharmacotherapeutic agents can comprise buprenorphine, methadone, naltrexone, or any combination thereof. In an aspect, one or more disclosed additional pharmacotherapeutic agents can comprise naloxone, nalmefene, or any combination thereof. In an aspect, disclosed additional pharmacotherapy can comprise a gradually reducing regimen, a substitution therapy, or a medication assisted therapy. In an aspect, a disclosed method can further comprise administering to the subject one or more additional therapies. In an aspect, one or more disclosed additional therapies can comprise a behavioral therapy.

[0490] In an aspect, behavioral therapy can comprise counseling, a contingency management system, a mindfulness-based therapy, a cognitive-behavioral therapy, a digitally administered behavioral therapy or a virtual reality based behavioral therapy, or any combination thereof. In an aspect, counseling can be in person or via digital means. In an aspect, a disclosed method can reduce the amount behavioral therapy required compared behavioral therapy without the administration of the composition.

[0491] In an aspect, a disclosed substance use disorder can comprise abuse of an opioid, and wherein the substitution therapy comprises methadone or buprenorphine. In an aspect, a disclosed substance use disorder can comprise abuse of an opioid, and wherein the medication assisted treatment comprises naltrexone, disulfiram, acamprosate, or any combination thereof.

[0492] In an aspect, a disclosed substance use withdrawal symptom can comprise a symptom of withdrawal from opioids. In an aspect, a disclosed opioid can comprise heroin, codeine, fentanyl, hydrocodone (dihydrocodeinone), hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, or any combination thereof. In an aspect, a disclosed opioid can comprise fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0493] In an aspect, a disclosed substance use withdrawal symptom can comprise a physical symptom of withdrawal, a psychological symptom of withdrawal, or any combination thereof.

[0494] In an aspect, a disclosed physical symptom of withdrawal can comprise tremors, insomnia, disturbed sleep, headache, sweating, nausea, vomiting, muscle pain, muscle stiffness, hypertension, irregular heart rate, elevated heart rate, heart palpitations, dizziness, shakiness,tremors, seizures, dehydration, shallow breathing, fatigue, loss of appetite, clammy skin, loss of color, or any combination thereof.

[0495] In an aspect, a disclosed psychological symptom of withdrawal can comprise anxiety, irritability , difficulty concentrating, difficulty' thinking clearly, mood swings, nightmares, depression, tension, panic attacks, short term memory loss, restlessness, a feeling of helplessness, stress-sensitivity, a heightened responsivity to substance-related cues, aberrant reward processing, a substance craving or a combination thereof.

[0496] In an aspect, a disclosed method can further comprise an additional pharmacotherapy for withdrawal. In an aspect, a disclosed additional pharmacotherapy can comprise a gradually reducing regimen, a substitution therapy or a medication assisted treatment.

[0497] In an aspect, a disclosed method can further comprise a behavioral therapy. In an aspect, a disclosed behavioral therapy can comprise counseling, a contingency management system, a mindfulness-based therapy, a cognitive-behavioral therapy, a digitally administered behavioral therapy or a virtual reality based behavioral therapy.

[0498] In an aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can reduce or eliminate the at least one substance use withdrawal symptom in the subject. In an aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can reduce or eliminate the at least one psychological symptom in the subject.

[0499] In an aspect, a disclosed method can reduce a symptom of withdrawal or prevents a relapse of the substance use disorder in the subject. In an aspect, a disclosed method can reduce tolerance to a substance of the substance use disorder in the subject. In an aspect, a disclosed method can reduce dependence on a substance of the substance use disorder in the subject.

[0500] In an aspect, a disclosed method can improve adherence to a treatment for the substance use disorder in the subject. In an aspect, a disclosed method can reduce a preference for a substance or decreases liking for a substance. In an aspect, a disclosed method can increase abstinence from a substance.

[0501] In an aspect of a disclosed method, administering a disclosed pharmaceutical formulation comprising SET can comprise a single dose or multiple doses (such as 2, 3, 4, 5, 6. 7, 8, 9. 10, or more than 10 doses). In an aspect of a disclosed method, administering one or more disclosed pharmaceutical formulations comprising SET can comprise a single dose or multiple doses (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses). In an aspect of a disclosed method, administering a disclosed pharmaceutical formulation comprising SET can comprise a single dose or multiple doses (such as 2. 3, 4, 5. 6. 7, 8, 9. 10. or more than 10 doses).

[0502] In an aspect, a disclosed method can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, patient life expectancy can be increased at least about 5% or greater to at least about 100%, at least about 10% or greater to at least about 95% or greater, at least about 20% or greater to at least about 80% or greater, at least about 40% or greater to at least about 60% or greater compared to an untreated subj ect with the identical or near identical overdose and the identical or near identical predicted outcome.

[0503] In an aspect, a disclosed method can further comprise monitoring the subject for adverse effects. In an aspect, in the absence of adverse effects, a disclosed method can further comprise continuing to treat the subject. In an aspect, continuing to treat the subject can comprise continuing to administer a disclosed pharmaceutical formulation comprising SET.

[0504] In an aspect, in the presence of adverse effects, a disclosed method can further comprise modifying one or more steps of the method. In an aspect, modifying one or more steps of a disclosed method can comprise modifying one or more administering steps. In an aspect, modifying one or more disclosed administering steps can comprise changing the amount of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administered to the subject, changing the frequency of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, changing the duration of a disclosed composition (i.e.. a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, changing the route of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, or any combination thereof. In an aspect, modifying one or more disclosed administering steps can comprise changing the amount a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administered to the subject, changing the frequency of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, changing the duration of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, changing the route of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray), or any combination thereof.

[0505] In an aspect, a disclosed method can further comprise providing additional respiratory support to the subject. In an aspect, a disclosed method can further comprise providing additional respiratory support to the subject such as, for example, supplemental oxygen or one or more additional pharmacological agents.

[0506] In an aspect, a subject can be a human patient. In an aspect a subject can be any age (e.g., geriatric, adult, young adult, teenager, tween, adolescent, child, toddler, baby, or infant), can be male or female, can be any nationality, can be of any ethnicity, and / or can be of any race. In an aspect, a subject can be in active overdose. In an aspect, a subject can be suspected of having an active overdose. In an aspect, a subject can be in active overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents. In an aspect, a subject can be suspected of having an active overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0507] In an aspect, a disclosed method can comprise improving and / or enhancing the subject’s quality of life. In an aspect of a disclosed method, a disclosed improvement and / or enhancement (such as, for example, in the subject’s quality of life) can comprise a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of improvement when compared to a control subject (such as, for example, a subject that has not received a disclosed pharmaceutical formulation comprising SET).

[0508] In an aspect, a disclosed method can further comprise monitoring the subject following the administering step and / or the treating step to generate a compilation of biochemical and / or physiological and / or behavioral data. In an aspect, a disclosed compilation of data can be used to identify a trend or a pattern. In an aspect, a disclosed compilation of data can be used to guide and / or inform a skilled clinician in a decision-making process regarding treatment and / or testing. In an aspect, for example, a clinician can decide to change an aspect of the subject’s treatment and / or change the subject’s diagnosis or prognosis.

[0509] In an aspect, a disclosed method can further comprise monitoring the subject’s metabolic and / or physiologic improvement following the administering and / or treating step and / or following the administering and / or treating steps. In an aspect, a clinician can measure and / or determine the subject’s metabolic and / or physiologic status over time to identify one or more improvements and / or one or more dimini shments. In an aspect of a disclosed method, a clinician can use the subject’s metabolic and / or physiologic status and / or the trend of the subject’s metabolic and / or physiological status and / or trend to make a treatment decision and / or to modify an aspect of a disclosed method and / or to continue treating the subject and / or continue to administer one or more disclosed pharmaceutical formulation comprising SET. In an aspect, metabolic and / or physiologic data can inform the clinician when make subsequent treatment decisions.

[0510] In an aspect, a disclosed method can further comprise repeating one or more disclosed steps of a disclosed method. In an aspect, a disclosed method can further comprise continuing to administer to the subject a therapeutically effective amount of one or more disclosedpharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or any combination thereof.

[0511] In an aspect, a disclosed method can further comprise generating and / or making one or more disclosed pharmaceutical formulations comprising SET. In an aspect, a disclosed method can further comprise validating and / or characterizing one or more disclosed pharmaceutical formulations SET. For example, in an aspect, validating and / or characterizing one or more disclosed pharmaceutical formulations thereof can comprise measuring, ascertaining, and / or determining the purity and / or efficacy of the one or more disclosed pharmaceutical formulations comprising SET. In an aspect, a disclosed method can ease the subject’s transition from an intensive care unit (ICU) to a non-ICU in a clinical setting. In an aspect, a disclosed method can reduce an obese subject’s risk of developing OIRD. In an aspect, a disclosed method can provide long-lasting relief of one or more indexes of OIRD.

[0512] In an aspect of a disclosed method, a disclosed therapeutically effective amount can comprise between about 0. 1 mg to about 5 mg of setmelanotide and / or a salt and / or solvate thereof. In an aspect, a disclosed therapeutically effective amount can comprise about 0. 1 mg. about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg. about 2.7 mg, about 2.8 mg. about2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about4.9 mg. or about 5.0 mg of setmelanotide and / or a salt and / or solvate thereof.Methods of Reducing Aggression, Anger, and Violence associated with Reversal of Opioid Overdose

[0513] Disclosed herein is a method of reducing aggression, anger, and / or violence associated with reversal of an opioid overdose, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0514] Disclosed herein is a method of reducing aggression, anger, and / or violence associated with reversal of an opioid overdose due to clinical administration of an opioid, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0515] Disclosed herein is a method of reducing aggression, anger, and / or violence associated with reversal of an opioid overdose due to opioid abuse or opioid misuse, the method comprisingadministering to a subject in need thereof a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0516] Disclosed herein is a method of reducing aggression, anger, and / or violence associated with reversal of an opioid overdose, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0517] Disclosed herein is a method of reducing aggression, anger, and / or violence associated with reversal of an opioid overdose due to clinical administration of an opioid, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0518] Disclosed herein is a method of reducing aggression, anger, and / or violence associated with reversal of an opioid overdose due to opioid abuse or opioid misuse, the method comprising administering to a subject experiencing opioid-induced respiratory depression (OIRD) a therapeutically effective amount of a disclosed pharmaceutical formulation.

[0519] In an aspect, an opioid can comprise fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents. In an aspect, a subject can be experiencing an opioid overdose due to clinical administration of an opioid, for example, for pain management. In an aspect, a subject can be experiencing an opioid overdose due to opioid abuse or opioid misuse.

[0520] In an aspect, a subject can be administering one or more opioids in a clinical setting, and following administration, the subject can experience one or more symptoms associated with and / or related to OIRD. In an aspect, the administering of a disclosed pharmaceutical formulation comprising SET can treat and / or reverse the one or more symptoms associated with and / or related to OIRD without interfering with and / or disrupting the analgesia provided to the subject by the one or more opioids.

[0521] In an aspect, a disclosed method can further comprise repeating the administering of a disclosed pharmaceutical formulation comprising SET. In an aspect of a disclosed method, administering can comprise intranasal administration, sublingual administration, intraperitoneal administration, intravenous administration, subcutaneous administration, or a combination thereof. In an aspect, a disclosed pharmaceutical formulation comprising SET can be administered via the same routes of administration. In an aspect, a disclosed pharmaceutical formulation comprising SET can be administered via the different routes of administration. In an aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can be administered subcutaneously. In an aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can be administered intranasally.

[0522] In an aspect, administering can comprise using a disclosed device adapted for intranasal delivery of the pharmaceutical formulation. In an aspect, intranasal delivery can comprise one actuation of the device into one or both nostrils of the subject. In an aspect, intranasal deliver}' can comprise one actuation into one nostril or both nostrils of the subject using a disclosed device.

[0523] In an aspect of a disclosed method, a subject can be experiencing an active opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents. In an aspect of a disclosed method, a subject can be suspected of experiencing an active opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0524] In an aspect of a disclosed method, opioid-induced respiratory depression (OIRD) can comprise one or more of a depression of respiratory rate, a depression of minute ventilation, a depression of alveolar-arterial gas exchange, a decrease in respiratory responsiveness to hypoxia and hypercapnia, an increase in apnea duration and / or apnea frequency, an increase in hypoxemic events, cardiac arrest, and any combination thereof.

[0525] In an aspect of a disclosed method, following an administering step, one or more symptoms of opioid-induced respiratory depression (OIRD) can be improved and / or minimized. For example, in an aspect, following an administering step, a subject can experience an increase in respiratory rate, an increase in minute ventilation, an increase in alveolar-arterial gas exchange, an increase in respiratory responsiveness, a decrease in apnea duration and / or apnea frequency, a decrease in hypoxemic events, and any combination thereof.

[0526] In an aspect of a disclosed method, a subject can be experiencing one or more symptoms associated with and / or related to an active opioid overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0527] In an aspect of a disclosed method, symptoms associated with and / or related to an active opioid overdose can comprise (i) a loss of consciousness, (ii) constricted or pinpoint pupils, (iii) breathing difficulties (slowed, labored, and / or irregular breathing), (iv) respiratory' arrest, (v) choking, gurgling, or snoring sounds, (vi) blue or purple lips or fingertips, (vii) a low of responsive to loud noises, shaking, or painful stimuli, or (viii) any combination thereof.

[0528] In an aspect of a disclosed method, a subject can be exhibiting one or more symptoms associated with and / or related to the illicit use of opioids (e.g., fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents).

[0529] In an aspect of a disclosed method, a subject can be exhibiting one or more symptoms associated with and / or related to the accidental misuse of opioids (e.g., morphine) during medical opioid therapy.

[0530] In an aspect of a disclosed method, following the administering step, a subject can be free from respiratory depression for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, or at least about 6 hours following.

[0531] In an aspect of a disclosed method, an administering step can be performed on a subject in a lying, supine, or recovery position. In an aspect of a disclosed method, one or more disclosed symptoms can comprise respiratory depression, central nervous system depression, cardiovascular depression, altered level consciousness, miotic pupils, hypoxemia, acute lung injury, aspiration pneumonia, sedation, hypotension, unresponsiveness to stimulus, unconsciousness, stopped breathing, erratic or stopped pulse, choking or gurgling sounds, blue or purple fingernails or lips, slack or limp muscle tone, contracted pupils, vomiting, and any combination thereof.

[0532] In an aspect of a disclosed method, following the administering step, one or more symptoms of OIRD can be minimized and / or reduced. In an aspect of a disclosed method, following the administering step, one or more symptoms of OIRD can be reversed and / or eliminated.

[0533] In an aspect of a disclosed method, the subject can have a substance use disorder. In an aspect of a disclosed method, a disclosed substance use disorder can comprise alcohol use disorder, cocaine use disorder, cannabis use disorder, tobacco use disorder, methamphetamine use disorder, opioid use disorder, or any combination thereof. In an aspect of a disclosed method, a disclosed substance use disorder can comprise abuse of opioids. In an aspect, a disclosed opioid can comprise heroin, codeine, fentanyl, hydrocodone (dihydrocodeinone), hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, or any combination thereof.

[0534] In an aspect, a disclosed method can further comprise administering to the subject one or more additional pharmacotherapeutic agents for opioid use disorder. In an aspect, a disclosed method can further comprise administering to the subject one or more additional pharmacotherapies for substance abuse. In an aspect, one or more disclosed additional pharmacotherapeutic agents can comprise buprenorphine, methadone, naltrexone, or any combination thereof. In an aspect, one or more disclosed additional pharmacotherapeutic agents can comprise naloxone, nalmefene, or any combination thereof. In an aspect, disclosed additional pharmacotherapy can comprise a gradually reducing regimen, a substitution therapy, or a medication assisted therapy. In an aspect, a disclosed method can further comprise administering to the subject one or more additional therapies. In an aspect, one or more disclosed additional therapies can comprise a behavioral therapy.

[0535] In an aspect, behavioral therapy can compnse counseling, a contingency management system, a mindfulness-based therapy, a cognitive-behavioral therapy, a digitally administeredbehavioral therapy or a virtual reality based behavioral therapy, or any combination thereof. In an aspect, counseling can be in person or via digital means. In an aspect, a disclosed method can reduce the amount behavioral therapy required compared behavioral therapy without the administration of the composition.

[0536] In an aspect, a disclosed substance use disorder can comprise abuse of an opioid, and wherein the substitution therapy comprises methadone or buprenorphine. In an aspect, a disclosed substance use disorder can comprise abuse of an opioid, and wherein the medication assisted treatment comprises naltrexone, disulfiram, acamprosate, or any combination thereof.

[0537] In an aspect, a disclosed substance use withdrawal symptom can comprise a symptom of withdrawal from opioids. In an aspect, a disclosed opioid can comprise heroin, codeine, fentanyl, hydrocodone (dihydrocodeinone), hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, or any combination thereof. In an aspect, a disclosed opioid can comprise fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0538] In an aspect, a disclosed substance use withdrawal symptom can comprise a physical symptom of withdrawal, a psychological symptom of withdrawal, or any combination thereof.

[0539] In an aspect, a disclosed physical symptom of withdrawal can comprise tremors, insomnia, disturbed sleep, headache, sweating, nausea, vomiting, muscle pain, muscle stiffness, hypertension, irregular heart rate, elevated heart rate, heart palpitations, dizziness, shakiness, tremors, seizures, dehydration, shallow breathing, fatigue, loss of appetite, clammy skin, loss of color, or any combination thereof.

[0540] In an aspect, a disclosed psychological symptom of withdrawal can comprise anxiety, irritability, difficulty concentrating, difficulty thinking clearly, mood swings, nightmares, depression, tension, panic attacks, short term memory loss, restlessness, a feeling of helplessness, stress-sensitivity, a heightened responsivity to substance-related cues, aberrant reward processing, a substance craving or a combination thereof.

[0541] In an aspect, a disclosed method can further comprise an additional pharmacotherapy for withdrawal. In an aspect, a disclosed additional pharmacotherapy can comprise a gradually reducing regimen, a substitution therapy or a medication assisted treatment.

[0542] In an aspect, a disclosed method can further comprise a behavioral therapy. In an aspect, a disclosed behavioral therapy can comprise counseling, a contingency management system, a mindfulness-based therapy, a cognitive-behavioral therapy, a digitally administered behavioral therapy or a virtual reality based behavioral therapy.

[0543] In an aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can reduce or eliminate the at least one substance use withdrawal symptom in the subject. Inan aspect of a disclosed method, a disclosed pharmaceutical formulation comprising SET can reduce or eliminate the at least one psychological symptom in the subject.

[0544] In an aspect, a disclosed method can reduce a symptom of withdrawal or prevents a relapse of the substance use disorder in the subject. In an aspect, a disclosed method can reduce tolerance to a substance of the substance use disorder in the subject. In an aspect, a disclosed method can reduce dependence on a substance of the substance use disorder in the subject.

[0545] In an aspect, a disclosed method can improve adherence to a treatment for the substance use disorder in the subject. In an aspect, a disclosed method can reduce a preference for a substance or decreases liking for a substance. In an aspect, a disclosed method can increase abstinence from a substance.

[0546] In an aspect of a disclosed method, administering a disclosed pharmaceutical formulation comprising SET can comprise a single dose or multiple doses (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses). In an aspect of a disclosed method, administering one or more disclosed pharmaceutical formulations comprising SET can comprise a single dose or multiple doses (such as 2. 3, 4. 5, 6. 7, 8. 9, 10, or more than 10 doses). In an aspect of a disclosed method, administering a disclosed pharmaceutical formulation comprising SET can comprise a single dose or multiple doses (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses).

[0547] In an aspect, a disclosed method can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, patient life expectancy can be increased at least about 5% or greater to at least about 100%, at least about 10% or greater to at least about 95% or greater, at least about 20% or greater to at least about 80% or greater, at least about 40% or greater to at least about 60% or greater compared to an untreated subj ect with the identical or near identical overdose and the identical or near identical predicted outcome.

[0548] In an aspect, a disclosed method can further comprise monitoring the subject for adverse effects. In an aspect, in the absence of adverse effects, a disclosed method can further comprise continuing to treat the subject. In an aspect, continuing to treat the subject can comprise continuing to administer a disclosed pharmaceutical formulation comprising SET.

[0549] In an aspect, in the presence of adverse effects, a disclosed method can further comprise modifying one or more steps of the method. In an aspect, modifying one or more steps of a disclosed method can comprise modifying one or more administering steps. In an aspect, modifying one or more disclosed administering steps can comprise changing the amount of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administered to the subject, changing the frequency of a disclosed composition (i.e..a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, changing the duration of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, changing the route of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, or any combination thereof. In an aspect, modifying one or more disclosed administering steps can comprise changing the amount a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administered to the subject, changing the frequency of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, changing the duration of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray) administration, changing the route of a disclosed composition (i.e., a disclosed pharmaceutical formulation comprising SET or a disclosed liquid spray), or any combination thereof.

[0550] In an aspect, a disclosed method can further comprise providing additional respiratory support to the subject. In an aspect, a disclosed method can further comprise providing additional respiratory support to the subject such as, for example, supplemental oxygen or one or more additional pharmacological agents.

[0551] In an aspect, a subject can be ahuman patient. In an aspect a subject can be any age (e.g., geriatric, adult, young adult, teenager, tween, adolescent, child, toddler, baby, or infant), can be male or female, can be any nationality, can be of any ethnicity, and / or can be of any race. In an aspect, a subject can be in active overdose. In an aspect, a subject can be suspected of having an active overdose. In an aspect, a subject can be in active overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents. In an aspect, a subject can be suspected of having an active overdose due to fentanyl or fentanyl mixed with and / or laced with and / or cut with one or more agents.

[0552] In an aspect, a disclosed method can comprise improving and / or enhancing the subject’s quality of life. In an aspect of a disclosed method, a disclosed improvement and / or enhancement (such as, for example, in the subject’s quality of life) can comprise a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of improvement when compared to a control subject (such as, for example, a subject that has not received a disclosed pharmaceutical formulation comprising SET).

[0553] In an aspect, a disclosed method can further comprise monitoring the subject following the administering step and / or the treating step to generate a compilation of biochemical and / or physiological and / or behavioral data. In an aspect, a disclosed compilation of data can be used toidentify a trend or a pattern. In an aspect, a disclosed compilation of data can be used to guide and / or inform a skilled clinician in a decision-making process regarding treatment and / or testing. In an aspect, for example, a clinician can decide to change an aspect of the subject’s treatment and / or change the subject’s diagnosis or prognosis.

[0554] In an aspect, a disclosed method can further comprise monitoring the subject’s metabolic and / or physiologic improvement following the administering and / or treating step and / or following the administering and / or treating steps. In an aspect, a clinician can measure and / or determine the subject’s metabolic and / or physiologic status over time to identify one or more improvements and / or one or more dimini shments. In an aspect of a disclosed method, a clinician can use the subject’s metabolic and / or physiologic status and / or the trend of the subject’s metabolic and / or physiological status and / or trend to make a treatment decision and / or to modify an aspect of a disclosed method and / or to continue treating the subject and / or continue to administer one or more disclosed pharmaceutical formulation comprising SET. In an aspect, metabolic and / or physiologic data can inform the clinician when make subsequent treatment decisions.

[0555] In an aspect, a disclosed method can further comprise repeating one or more disclosed steps of a disclosed method. In an aspect, a disclosed method can further comprise continuing to administer to the subject a therapeutically effective amount of one or more disclosed pharmaceutical formulations comprising SET, one or more disclosed liquid sprays, one or more disclosed devices, or any combination thereof.

[0556] In an aspect, a disclosed method can further comprise generating and / or making one or more disclosed pharmaceutical formulations comprising SET. In an aspect, a disclosed method can further comprise validating and / or characterizing one or more disclosed pharmaceutical formulations SET. For example, in an aspect, validating and / or characterizing one or more disclosed pharmaceutical formulations thereof can comprise measuring, ascertaining, and / or determining the purity and / or efficacy of the one or more disclosed pharmaceutical formulations comprising SET. In an aspect, a disclosed method can ease the subject’s transition from an intensive care unit (ICU) to a non-ICU in a clinical setting. In an aspect, a disclosed method can reduce an obese subject’s risk of developing OIRD. In an aspect, a disclosed method can provide long-lasting relief of one or more indexes of OIRD.

[0557] In an aspect of a disclosed method, a disclosed therapeutically effective amount can comprise between about 0. 1 mg to about 5 mg of setmelanotide and / or a salt and / or solvate thereof. In an aspect, a disclosed therapeutically effective amount can comprise about 0.1 mg. about 0.2 mg, about 0.3 mg, about 0.4 mg. about 0.5 mg, about 0.6 mg. about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg.about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg. about 2.0 mg, about 2.1 mg. about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg. about 4.7 mg, about 4.8 mg. about4.9 mg. or about 5.0 mg of setmelanotide and / or a salt and / or solvate thereof.VI. EXAMPLES

[0558] The Examples that follow are illustrative of specific aspects of the invention, and various uses thereof. The Examples set forth for explanatory' purposes only and are not to be taken as limiting the invention.

[0559] Opioid addiction and misuse are a serious national crisis that affects public health, as well as social and economic welfare. The opioid crisis has been greatly exacerbated by (i) the increased availability' of synthetic opioids (such as fentanyl) and (ii) the increased prescribing of opioid pain relievers. According to the CDC / NCHS National Vital Statistics System, opioid overdose kills 130 people in the United States every day.

[0560] The primary cause of death associated with opioids is opioid-induced respiratory' depression (OIRD). Naloxone is a competitive antagonist of the p-opioid receptor (MOR) and other opioid receptors, has a rapid onset, and is highly effective in acutely reversing OIRD. But, to reverse long-acting synthetic opioids, re-dosing of naloxone is required. As a recently approved MOR antagonist, nalmefene is long-acting (Britch SC, et al. (2022) Psychopharmacology (Berl). 239(7):2063-2081). However, both naloxone and nalmefene induce acute withdrawal and reverse analgesia (Britch SC, et al. (2022)). The adverse effects of MOR antagonists limit their use for OIRD prevention. This limitation affects vulnerable OIRD populations including, for example, (i) patients receiving high doses of opioids for pain and (ii) patients with opioid use disorder (OUD) with self-escalating opioid doses. Consequently, alternative non-opioid receptor antagonist-based approaches to OIRD treatment and prevention are urgently needed.

[0561] Several classes of respiratory stimulants have been queried, but the effects on OIRD were modest. But. as described herein, the treatment of OIRD focuses on FDA-approved agents shown to stimulate breathing in sleep disorders. Specifically, leptin stimulates breathing by increasing the hypercapnic ventilatory' response (HCVR) and treats hypoventilation in obese animals (Amorim M, et al. (2023) Cell Rep. 42(12): 113512-113512). Leptin also prevents OIRD and decreases opioid mortality in a mouse model (Freire C, et al. (2020) Am J Respir Cell Mol Biol. 63(4):502-509). However, leptin resistance often limits leptin as a pharmacotherapy. Leptin upregulates pro-opiomelanocortin (POMC), which is a pre-hormone post-transcriptionallyprocessed into several peptides, including a-melanocyte stimulating hormone (a-MSH), a ligand for the melanocortin 4 receptor. The melanocortin 4 receptor (MC4R) agonist setmelanotide (SET) has been approved by the FDA for treatment of genetic forms of obesity (Amorim M, et al. (2023); Freire C, et al. (2020); Collet T-H, et al. (2017) Mol Metab 6(10): 1321-1329; Ayers KL, et al. (2018) Endocrinol Metab. 103(7):2601-26012). Now, as disclosed herein, the exciting preliminary data generated in mice shows that (1) SET effectively treated both sleep disordered breathing (SDB) and OIRD by increasing respiratory rate and decreasing (by at least 3x) the number of apneas without affecting analgesia. The mechanism behind this exciting data centers on MC4R agonists via activation of brainstem respiratory neurons.Example 1 SET Treated Morphine Opioid-Induced Respiratory Depression in Mice

[0562] SET or placebo vehicle (VEH) were administered 15 minutes AFTER morphine to examine whether SET can treat OIRD and rescue breathing. C57BL / 6J male mice, 18-20 weeks of age (n = 8) were housed at a 12 hr. hght / dark cycle (7 am - 7 pm lights on) and fed ad libitum. The animals were acclimated to the barometric plethysmography chamber for three consecutive days (1 hr. / day) and were treated with IP morphine (10 mg / kg). Then, 15 min later, the animals were treated with either SET (1 mg / kg IP) or vehicle VEH (IP) in a random order. Immediately after SET / VEH injection, respiratory recordings were collected for 2 hrs. in the whole-body chamber after acclimation. One week later, the experiment was repeated in a cross-over manner. One week after the respirator}7experiments, nociception was investigated by the tail-flick test as previously described (Clement K, et al. (2020) Lancet Diabetes Endocrinol. 8(12):960-970; Wang W, et al. (2009) J Pain. 10(8): 836-843; Glovak Z. et al. (2017) Neurosci Lett. 660:29-33). Mice were immobilized (25-30 sec) in an acrylic tube and the distal 1 / 3 of the tail was immersed in water at 50±l °C. Nociceptive latency was recorded the moment a tail flick was observed. A maximum 15 second immersion was used to avoid tissue damage. Mice subsequently received IP morphine (10 mg / kg) followed by VEH or SET (1 mg / kg, IP) 15 min. later. Then, a week later, the experiment w as repeated with the other condition. (VEH. then SET or SET, then VEH).

[0563] In mice with OIRD, SET reduced by 3-fold the apnea index - from 67 ± 7 to 22 ± 4 events per hour (p < 0.001, FIG. 1), and decreased apnea duration as compared to the VEH treatment. SET increased respiratory rate from 102 ± 4.5 to 130 ± 5.6 breaths per minute (p < 0.05) (FIG. 1). SET did not affect opioid analgesia (FIG. 2). Therefore, SET treated morphine OIRD in mice without decreasing analgesia.Example 2 SET Treated Fentanyl OIRD in Adult Male C57BL / 6J Mice

[0564] To examine whether SET can treat OIRD and rescue breathing, SET or VEH was administered 15 minutes AFTER fentanyl administration. The dose of SET was selected based on the work described in Example 1 while the dose of fentanyl was based on previous publications (Burgraff NJ, et al. (2023). J Physiol. 601(20):4625-4642; Haouzi P, et al. (2021) J Neurophysiol. 125(4): 1396-1407; Fechtner L, et al. (2015) Respir Physiol Neurobiol. 215:20-29).

[0565] Specifically, C57BL / 6J male mice 16-18 wks. of age were housed at a 12 hr. light / dark cycle (7 am - 7 pm lights on) and fed ad libitum (n = 8). These mice were acclimated to the barometric plethysmography chamber for three consecutive days (1 hr. / day). Then, the animals were treated with IP fentanyl (0.5 mg / kg IP) and then 15 min later with either SET (1 mg / kg IP) or vehicle VEH (IP) in a random order. Immediately after the SET or VEH injection, respiratory’ recordings were performed in the whole-body chamber for 2 hrs. One week later, the experiment was repeated in a cross-over manner. Those mice that received SET now received VEH, and those mice that received VEH now received SET.

[0566] As expected, fentanyl induced OIRD increased the apnea rate and decreased respiratory- rate. Fentanyl decreased respiratory rate from 147 ± 5 to 109 ± 4 breaths per minute. In fentanyl- treated mice, SET increased respiratory rate to 136 ± 9 breaths per minute (p < 0.01 ) (FIG. 3). In mice with OIRD, SET reduced the apnea index by nearly 3-fold (from 179 ± 30 per hour to 60 ± 9 per hour, p < 0.001, FIG. 3) and did not change the apnea duration. These data demonstrated that SET treated fentanyl OIRD in mice.Example 3 SET Treated Fentanyl OIRD in Rats

[0567] To further explore translational relevance of these findings, the effect of SET on OIRD in another rodent model (rats) was examined. Adult male Sprague Dawley rats were acclimated to a plethysmography system for 2 hr. on 4 consecutive days. On day 5, rats were randomized to vehicle vs. SET (1 mg / kg IP). Fentanyl (0.5 mg / kg IP) was administered followed by vehicle or SET 10-15 min later. Two rats died prior to vehicle / SET treatment. SET (n = 6) increased respiratory rate (134 ± 13 vs. 94 ± 5 breaths / min in the vehicle group, n = 8, p < 0.01). increased tidal volume, more than doubled minute ventilation (297 ± 44 vs 134 ± 12 mL / min, p < 0.01) (FIG. 4), and decreased the apnea index (FIG. 5). The data showed that SET treated fentanyl- induced OIRD in rats.Summary of Examples

[0568] These results indicate that setmelanotide can mitigate opioid-induced respiratory' depression in both an emergency setting and in a clinical setting. Building on the information disclosed herein, SET’s effectiveness could pave the way for improved interventions and betteroutcomes in combating the detrimental effects of the opioid crisis and the growing need to manage OIRD in clinical settings.

[0569] In conclusion, a novel paradigm was developed for OIRD treatment. SET (a powerful respiratory stimulant) was effective for drug overdoses caused by ultra-potent synthetic (UPS) opioids (which can cause a mass casualty event). SET reversed OIRD independently of opioid receptor antagonism, and, therefore, it did not reduce analgesia and did not induce opioid withdrawal. SET can also be helpful when opioids are combined with highly toxic non-opioid drugs, such as xylazine. Finally, SET can be considered for treating hypoventilation syndromes caused by non-drug related suppression of brain respiratory control centers, such as sleep- disordered breathing or congenital hypoventilation syndromes.

Claims

VII. CLAIMSWhat is claimed is:

1. A pharmaceutical formulation for treating an opioid overdose, comprising: setmelanotide and one or more pharmaceutically acceptable carriers.

2. The pharmaceutical formulation of Claim 1. further comprising one or more opioid antagonists.

3. The pharmaceutical formulation of Claim 2. wherein the opioid antagonists comprise naloxone, nalmefene, or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical formulation of any one of Claims 1 - 3, further comprising one or more of an isotonicity agent, an acid, a preservative, a stabilizing agent, an absorption enhancer, and any combination thereof.

5. A liquid spray, comprising: the pharmaceutical formulation of any one of Claims 1 - 4.

6. A device, comprising: the liquid spray of Claim 5.

7. The device of Claim 6, wherein the device is configured for nasal administration.

8. A method of treating a subject, the method comprising: administering to a subject experiencing an opioid overdose a therapeutically effective amount of the pharmaceutical formulation of any one of Claims 1 - 4.

9. The method of Claim 8, wherein the opioid overdose is due to absorption and / or ingestion of fentanyl.

10. The method of Claim 8 or Claim 9, wherein the subject is experiencing one or more indexes of opioid-induced respiratory depression (OIRD).

11. The method of Claim 10, wherein the one or more indexes of OIRD comprise decreased and / or reduced respiratory rate, tidal volume, minute ventilation, or any combination thereof.

12. The method of Claim 10, wherein the subject is experiencing apnea.

13. The method of Claim 10, wherein the subject is in cardiac arrest and / or respiratory arrest.

14. The method of Claim 13, wherein, following the administering step, the subject is resuscitated.

15. The method of Claim 14, wherein, following resuscitation, the subject does not demonstrate anger, aggression, combativeness, and / or hostility.

16. The method of Claim 11, wherein, following the administering step, the respiratory rate, tidal volume, minute ventilation, or any combination thereof is increased and / or improved.

17. The method of any one of Claims 8 - 16, wherein administering comprises intranasal administration.

18. The method of any one of Claims 8 - 17, further comprising repeating the administering step.

19. The method of any one of Claims 8 - 18. wherein a therapeutically effective amount of the pharmaceutical formulation comprises at least about 1 IU to about 10 IU of setmelanotide.

20. The method of any one of Claims 8 - 19, further comprising administering to the subject one or more additional therapeutic agents.

21. A method of treating a subject, the method comprising: administering to a subject a therapeutically effective amount of the pharmaceutical formulation of any one of Claims 1 - 4, wherein the subject has received or is receiving one or more opioids for pain management, wherein the pharmaceutical formulation does not disrupt and / or diminish and / or affect the analgesia provided to the subject by the one or more opioids, and wherein, following the administering step, one or more indexes of opioid-induced respiratory depression (OIRD) are reduced and / or prevented.

22. The method of Claim 21, wherein the one or more indexes of OIRD comprise decreased and / or reduced respiratory' rate, tidal volume, minute ventilation, or any combination thereof.

23. The method of Claim 21, wherein, following the administering step, the respiratory rate, tidal volume, minute ventilation, or any combination thereof of subject is increased and / or improved.

24. The method of any one of Claims 21 - 24, wherein administering comprises subcutaneous administration.

25. The method of any one of Claims 21 - 24, wherein a therapeutically effective amount of the pharmaceutical formulation comprises at least about 1 IU to about 10 IU of setmelanotide.

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