R-ketamine administration method

Abstract

The present disclosure provides a method for treating or ameliorating depressive symptoms in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising R(-)-ketamine or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 477,439, filed December 28, 2022, and U.S. Provisional Patent Application No. 63 / 582,273, filed September 13, 2023, the contents of each of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Racemic ketamine and the S(+)-ketamine isomer have been implicated in the treatment of many diseases and disorders affecting cognitive or neurological function, including depression, bipolar disorder, post-traumatic stress disorder, obsessive-compulsive disorder, substance use disorders, Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies. However, while racemic ketamine is widely used as an approved parenteral anesthetic, its approval for treating such disorders is limited due to concerns about side effects and its potential for abuse. Similarly, approval of the S(+)-ketamine isomer for depression through administration of esketamine (Spravato) is limited to use in a clinic under the supervision of a medical professional.

[0003] Thus, there is a need for additional ketamine-like agents that provide symptomatic efficacy while reducing the side effects seen with racemic ketamine and S(+)-ketamine, and that have a convenient route of administration to allow for use outside of controlled clinical settings. Thus, the present disclosure addresses this unmet need. Summary of the Invention

[0004] The present disclosure provides methods for treating or ameliorating depressive symptoms in a subject, the methods comprising administering to the subject a therapeutically effective amount of a composition comprising R(-)-ketamine or a pharmaceutically acceptable salt thereof, wherein the composition is substantially free of S(+)-ketamine or a pharmaceutically acceptable salt thereof, and the therapeutically effective amount comprises a maximum plasma concentration (Cmax) of R(-)-ketamine of at least 250 ng / mL.

[0005] In some embodiments of the methods of the present disclosure, the depressive symptoms are symptoms of a mood disorder in the subject. In some embodiments, the mood disorder comprises depression, and optionally, the depression is treatment-resistant depression or major depressive disorder. In some embodiments, the mood disorder comprises bipolar disorder, post-traumatic stress disorder, obsessive-compulsive disorder, autism spectrum disorder, schizophrenia, or dementia. In some embodiments, the depressive symptoms are associated with a substance use disorder in the subject.

[0006] The present disclosure provides methods for treating a disease or disorder in a subject, the methods comprising administering to the subject a therapeutically effective amount of a composition comprising R(-)-ketamine or a pharmaceutically acceptable salt thereof, wherein the composition is substantially free of S(+)-ketamine or a pharmaceutically acceptable salt thereof, and the therapeutically effective amount comprises a maximum plasma concentration (Cmax) of R(-)-ketamine of at least 250 ng / mL.

[0007] In some embodiments of the disclosed methods, Cmax is 250 to 1000 ng / mL, hi some embodiments, Cmax is 250 to 800 ng / mL.

[0008] In some embodiments of the methods of the present disclosure, depressive symptoms are assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) subject score, and the MADRS subject score is reduced by administration of the composition. In some embodiments, the MADRS subject score is reduced by about 2 to about 20 by administration of the composition. In some embodiments, the MADRS subject score is reduced by about 2 to about 20 when measured about 24 hours, about 7 days, or about 14 days after initiation of administration of the composition. In some embodiments, the MADRS subject score is reduced by about 2 to about 20 after initiation of administration of the composition.

[0009] In some embodiments of the disclosed methods, the therapeutically effective dose of the composition comprises about 50 mg to about 300 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the composition comprises about 50 mg to about 150 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments of the disclosed methods, the composition comprises R(-)-ketamine hydrochloride.

[0011] In some embodiments of the disclosed methods, the composition is administered intravenously or subcutaneously to a subject. In some embodiments, intravenous administration comprises intravenous infusion. In some embodiments, the composition is administered by intravenous infusion over a period of about 10 minutes to about 1.5 hours. In some embodiments, the composition is administered once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once per week, once every two weeks, once every ten days, or once per month. In some embodiments, the method has a dosing schedule including (a) an initial period in which the composition is administered once every 1, 2, 3, or 4 days, and (b) a maintenance period in which the composition is administered less frequently than the initial period. In some embodiments, the composition is administered once per week, twice per week, once every two weeks, once every ten days, or once per month during the maintenance period.

[0012] In some embodiments of the disclosed methods, the composition further comprises a pharmaceutically acceptable carrier.

[0013] In some embodiments of the disclosed methods, a therapeutically effective amount of a composition comprising R(-)-ketamine does not cause significant dissociation, derealization, or sedation in a subject. In some embodiments, a therapeutically effective amount of the composition increases a subject's systolic blood pressure by less than 40 mmHg, optionally less than 10 mmHg, measured within 14 days of administration. In some embodiments, a therapeutically effective amount of the composition increases a subject's diastolic blood pressure by less than 25 mmHg, optionally less than 10 mmHg, measured within 14 days of administration. In some embodiments, administration of a therapeutically effective amount of the composition results in fewer side effects or adverse events than administration of a therapeutically effective amount of S(+)-ketamine or racemic ketamine.

[0014] In some embodiments of the methods of the present disclosure, the disease or disorder is a neurodegenerative disease or disorder, a neurodevelopmental disorder, an inflammatory disease, or a bone disease. In some embodiments, the neurodegenerative disease or disorder includes Parkinson's disease, Parkinsonism, Huntington's disease, acanthocytic chorea, spinocerebellar degeneration, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, spinal-bulbar muscular atrophy, syringomyelia, neuroacanthocytosis, an eating disorder, Alzheimer's disease, dementia with Lewy bodies, basal ganglia degeneration, multiple sclerosis, traumatic brain injury, cerebral infarction, or cardiovascular disease. In some embodiments, the neurodevelopmental disorder includes schizophrenia, autism spectrum disorder, attention-deficit / hyperactivity disorder, or a learning disability. In some embodiments, inflammatory diseases include ulcerative colitis, Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, insulin-dependent diabetes mellitus, Addison's disease, Goodpasture's syndrome, IgA nephropathy, interstitial nephritis, Sjogren's syndrome, autoimmune pancreatitis, psoriasis, atopic dermatitis, pneumonia, chronic bronchitis, bronchial asthma, systemic lupus erythematosus (SLE), scleroderma, or delirium, and bone diseases include osteoporosis, osteolytic bone metastasis, and Paget's disease of bone.

[0015] The present disclosure provides a composition for use in treating or ameliorating depressive symptoms in a subject, or treating a disease or disorder in a subject, the use comprising administering to the subject a therapeutically effective amount of a composition comprising R(-)-ketamine or a pharmaceutically acceptable salt thereof, wherein the composition is substantially free of S(+)-ketamine or a pharmaceutically acceptable salt thereof, and the therapeutically effective amount comprises a maximum plasma concentration (Cmax) of R(-)-ketamine of at least 250 ng / mL.

[0016] The present disclosure provides a composition for use in the manufacture of a medicament for treating or ameliorating depressive symptoms in a subject, or for treating a disease or disorder in a subject, the use comprising administering to the subject a therapeutically effective amount of a composition comprising R(-)-ketamine or a pharmaceutically acceptable salt thereof, wherein the composition is substantially free of S(+)-ketamine or a pharmaceutically acceptable salt thereof, and the therapeutically effective amount comprises a maximum plasma concentration (Cmax) of R(-)-ketamine of at least 250 ng / mL. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 shows a plot of the arithmetic mean (+ / - SD, standard deviation) plasma concentration time for R(-)-ketamine on a linear scale.

[0018] [Figure 2] FIG. 1 shows a plot of the arithmetic mean (+ / -SD) plasma concentration time for R(-)-ketamine on a semi-log scale.

[0019] [Figure 3] FIG. 1 shows arithmetic mean (+ / - SD, standard deviation) plasma concentration time plot for norketamine on a linear scale.

[0020] [Figure 4] FIG. 1 shows arithmetic mean (+ / - SD) plasma concentration time plots for norketamine on a semi-log scale.

[0021] [Figure 5] FIG. 1 shows arithmetic mean (+ / - SD, standard deviation) plasma concentration time plot for 6-hydroxynorketamine on a linear scale.

[0022] [Figure 6] FIG. 1 shows arithmetic mean (+ / - SD) plasma concentration time plots for 6-hydroxynorketamine on a semi-log scale.

[0023] [Figure 7] FIG. 1 shows arithmetic mean (+ / - SD, standard deviation) plasma concentration time plot for dehydronorketamine on a linear scale.

[0024] [Figure 8] FIG. 1 shows arithmetic mean (+ / - SD) plasma concentration time plots for dehydronorketamine on a semi-log scale.

[0025] [Figure 9A] A table summarizing the plasma parameters of R(-)-ketamine in the six cohorts administered R(-)-ketamine at the indicated doses is shown. Abbreviations: CV% = coefficient of variation, DN = dose-normalized, N = number of subjects, SD = standard deviation, PK = pharmacokinetics. Tmax is expressed as median (range). The clinical site confirmed that the source documents contained no documentation describing any irregularities in the sample collection process, and the bioanalytical laboratory confirmed that the raw data were accurate. [Figure 9B] A table summarizing the plasma parameters of R(-)-ketamine in the six cohorts administered R(-)-ketamine at the indicated doses is shown. Abbreviations: CV% = coefficient of variation, DN = dose-normalized, N = number of subjects, SD = standard deviation, PK = pharmacokinetics. Tmax is expressed as median (range). The clinical site confirmed that the source documents contained no documentation describing any irregularities in the sample collection process, and the bioanalytical laboratory confirmed that the raw data were accurate.

[0026] [Figure 10A]A table summarizing plasma parameters of norketamine in six cohorts receiving R(-)-ketamine at the indicated doses is shown. Abbreviations: CV% = coefficient of variation, DN = dose-normalized, N = number of subjects, SD = standard deviation. Tmax is expressed as median (range). [Figure 10B] A table summarizing plasma parameters of norketamine in six cohorts receiving R(-)-ketamine at the indicated doses is shown. Abbreviations: CV% = coefficient of variation, DN = dose-normalized, N = number of subjects, SD = standard deviation. Tmax is expressed as median (range).

[0027] [Figure 11A] A table summarizing plasma parameters of 6-hydroxynorketamine in six cohorts receiving R(-)-ketamine at the indicated doses is shown. Abbreviations: CV% = coefficient of variation, DN = dose-normalized, N = number of subjects, SD = standard deviation. Tmax is expressed as median (range). [Figure 11B] A table summarizing plasma parameters of 6-hydroxynorketamine in six cohorts receiving R(-)-ketamine at the indicated doses is shown. Abbreviations: CV% = coefficient of variation, DN = dose-normalized, N = number of subjects, SD = standard deviation. Tmax is expressed as median (range).

[0028] [Figure 12A] A table summarizing plasma parameters of dehydronorketamine in six cohorts receiving R(-)-ketamine at the indicated doses is shown. Abbreviations: CV% = coefficient of variation, DN = dose-normalized, N = number of subjects, SD = standard deviation. Tmax is expressed as median (range). [Figure 12B] A table summarizing plasma parameters of dehydronorketamine in six cohorts receiving R(-)-ketamine at the indicated doses is shown. Abbreviations: CV% = coefficient of variation, DN = dose-normalized, N = number of subjects, SD = standard deviation. Tmax is expressed as median (range).

[0029] [Figure 13]1 is a table outlining the dose proportionality of R(-)-ketamine and its metabolites. Abbreviations: N = number of subjects, CI = confidence interval.

[0030] [Figure 14] 1 is a table summarizing the PK parameters of plasma R(-) ketamine following subcutaneous injection at the indicated doses.

[0031] [Figure 15] 1 is a table summarizing the PK parameters of plasma R(-) ketamine following intravenous injection at the indicated doses. DETAILED DESCRIPTION OF THE INVENTION

[0032] The World Health Organization reports that depression is the leading cause of mental disability and job loss worldwide, affecting more than 300 million people (NPL 26). Severe cases can lead to suicide, which has become the third leading cause of death in the United States, with incidence rates increasing by 30% over the past decade (NPLs 27, 28). The prevalence of treatment-resistant depression (TRD), generally defined as treatment failure after adequately attempting at least two antidepressant regimens, remains very high. A European multicenter study found that 51% of depressed patients recruited from specialist referral centers met these criteria (NPL 29). Furthermore, TRD is a major contributor to much of the cost and disability associated with depression (NPL 30). Finally, it should be noted that many patients with major depressive disorder (MDD) continue to experience residual symptoms without meeting a formal diagnosis of TRD, thereby adding to the unmet medical burden.

[0033] Existing treatments for TRD involve the administration of compositions containing ketamine, a compound approved for use as a parenteral anesthetic in the United States (US) in 1970. Since then, it has been widely used in both adult and pediatric populations. Ketamine is available as two stereoisomers, R(-)-ketamine and S(+)-ketamine, the latter of which was approved for the treatment of TRD in adults in the US and later approved in the European Union (EU) in 2019 as the isolated stereoisomer in an intranasal formulation (Spravato™). However, this product has been shown to have a limited therapeutic index, particularly with regard to dissociative side effects, including illusions, time and space distortion, derealization, and depersonalization. Furthermore, in human abuse potential studies, scores for "current drug liking" and "relapse" were similar to those of racemic ketamine, a known drug of abuse, and higher than placebo at both the maximum indicated antidepressant dose and 1.3 times this dose (Non-Patent Document 1). Based in part on these findings, administration of Spravato is restricted to a doctor's office and under the supervision of a medical professional.

[0034] Both R(-)-ketamine and S(+)-ketamine (and by extension, racemic ketamine) have complex pharmacology, and receptor binding studies have revealed significant affinity for several receptors and ion channels, including glutamatergic, cholinergic, sigma, opioid, and hyperpolarization-activated cyclic nucleotide-gated channels. R(-)-ketamine and S(+)-ketamine are primarily regarded as noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor, with S(+)-ketamine having approximately four times greater binding affinity for the phencyclidine site of this receptor than R(-)-ketamine. Such pharmacological activity is thought to be a major driver of the adverse psychotomimetic properties seen with ketamine, suggesting that S(+)-ketamine primarily mediates these effects. However, data suggest that such NMDA receptor activity is not the sole driver of antidepressant effects. In fact, studies in non-clinical depression models in rodents using subanesthetic doses (10 mg / kg) suggest that R(-)-ketamine has longer-acting and more potent effects than S(+)-ketamine, despite its lower affinity for NMDA receptors (Non-Patent Documents 2, 3, 5, 7, 9, 11, 12, 13, 14, 15, 16, 17, 18). Furthermore, at doses (20 mg / kg) that were effective in rodent depression models, R(-)-ketamine did not induce conditioned place preference, a non-clinical study that may suggest a clinical risk for substance abuse (Non-Patent Documents 2, 7). However, it should be noted that R(-)-ketamine induced conditioned place preference in rodents at higher doses (40 mg / kg) (Non-Patent Document 19). Non-clinical studies suggest that R(-)-ketamine is less likely to cause dissociative and psychotomimetic effects at therapeutic doses and has a lower potential for misuse compared to S(+)-ketamine or racemic ketamine (Non-Patent Documents 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0035] Both nonclinical and preliminary clinical studies suggest that R(-)-ketamine may have a more favorable safety profile compared with S(+)-ketamine, with a reduced incidence of adverse events (AEs) (e.g., dissociation, cognitive impairment, and psychotomimetic effects). Based on nonclinical studies, R(-)-ketamine may also have a lower abuse potential than S(+)-ketamine. Overall, available data support the concept of R(-)-ketamine's use as a potentially better-tolerated, rapidly acting antidepressant compared with ketamine and S(+)-ketamine, which may support its use outside of controlled clinical settings. Racemic ketamine has been widely used worldwide as an approved parenteral anesthetic for nearly 50 years; however, it has not been approved for the treatment of thyroid dysfunction (TRD) due to concerns about repeated dosing, abuse liability, and potential AEs associated with its intravenous (IV) administration route. Thus, there is a need for additional ketamine-like agents that reduce the side effects seen with ketamine and S(+)-ketamine, while providing efficacy against depressive symptoms and with a convenient route of administration that allows for use outside of a controlled clinic environment.

[0036] definition The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the same.

[0037] The singular forms "a," "an," and "the" refer to one or more referenced items unless the context clearly dictates otherwise. The term "or" refers to any single element or combination of two or more of the listed alternative elements unless the context clearly dictates otherwise. As used herein, "comprises" means "includes." Thus, "comprising A or B" means "including A, B, or A and B," without excluding additional elements. All references cited herein, including patents and patent applications, are incorporated by reference in their entirety unless otherwise stated.

[0038] Unless otherwise indicated, all numbers expressing amounts of ingredients, molecular weights, percentages, temperatures, times, and the like used in the specification and claims should be understood as being modified by the term "about." Thus, unless otherwise expressly or implicitly indicated, the numerical parameters recited are approximations that may depend on the desired properties sought and / or the limits of detection under standard testing conditions / methods. When directly and explicitly distinguishing the embodiments from the discussed prior art, the numbers of the embodiments are not approximations unless the word "about" is explicitly recited.

[0039] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0040] "Administration" refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, subcutaneous administration, intrathecal administration, or implantation of a sustained release device, e.g., a mini-osmotic pump, into a subject.

[0041] "Peak plasma concentration" or "Cmax" refers to the highest concentration of a drug in plasma after a dose of the drug is administered to a subject. Methods for measuring drug concentrations are known to those skilled in the art and include, among others, liquid chromatography and tandem mass spectrometry.

[0042] "Area under the curve" or "AUC" is the integral of the concentration of a drug in plasma as a function of time. The AUC is calculated for the entire time for which data are available, e.g., until the drug is no longer detectable (AUC 0-inf ), or for a specific shortened time frame, e.g., 24 hours after administration (AUC 0-24 ) can be determined.

[0043] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. The contents of International Publication Nos. WO2015 / 037248, published on March 19, 2015, WO2019 / 213551, published on November 7, 2019, WO2018 / 079693, published on May 3, 2018, WO2019 / 065900, published on April 4, 2019, WO2019 / 160057, published on August 22, 2019, WO2020 / 138491, published on July 2, 2020, WO2023 / 064363, published on April 20, 2023, and WO2023 / 178039, published on September 21, 2023, are incorporated herein by reference in their entireties.

[0044] How to Treat Depression The present disclosure relates to a method for treating or ameliorating depressive symptoms in a subject. The method includes administering to the subject a therapeutically effective amount of a composition comprising R(-)-ketamine or a pharmaceutically acceptable salt thereof.

[0045] A therapeutically effective amount can be an amount that results in a maximum plasma concentration (Cmax) of R(-)-ketamine of at least 250 ng / mL in a subject after administration. In some embodiments, a therapeutically effective amount of R(-)-ketamine includes an amount of R(-)-ketamine that results in a Cmax of at least 100 ng / mL, at least 150 ng / mL, at least 200 ng / mL, at least 250 ng / mL, at least 300 ng / mL, at least 350 ng / mL, at least 400 ng / mL, at least 400 ng / mL, at least 500 ng / mL, at least 600 ng / mL, at least 700 ng / mL, at least 800 ng / mL, at least 900 ng / mL, or at least 1000 ng / mL after administration to a subject. In some embodiments, a therapeutically effective amount of R(-)-ketamine includes an amount of R(-)-ketamine that results in a Cmax of at least 200 ng / mL after administration to a subject. In some embodiments, a therapeutically effective amount of R(-)-ketamine comprises an amount of R(-)-ketamine that results in a Cmax of at least 300 ng / mL after administration to a subject. In some embodiments, a therapeutically effective amount of R(-)-ketamine comprises an amount of R(-)-ketamine that results in a Cmax of at least 400 ng / mL after administration to a subject. In some embodiments, a therapeutically effective amount of R(-)-ketamine comprises an amount of R(-)-ketamine that results in a Cmax of at least 500 ng / mL after administration to a subject. In some embodiments, a therapeutically effective amount of R(-)-ketamine comprises an amount of R(-)-ketamine that results in a Cmax of at least 600 ng / mL after administration to a subject. In some embodiments, a therapeutically effective amount of R(-)-ketamine comprises an amount of R(-)-ketamine that results in a Cmax of at least 700 ng / mL after administration to a subject. In some embodiments, a therapeutically effective amount of R(-)-ketamine comprises an amount of R(-)-ketamine that results in a Cmax of at least 800 ng / mL after administration to a subject. In some embodiments, a therapeutically effective amount of R(-)-ketamine comprises an amount of R(-)-ketamine that results in a Cmax of at least 900 ng / mL after administration to a subject.

[0046] In some embodiments, a therapeutically effective amount of R(-)-ketamine comprises an amount of R(-)-ketamine that results in a Cmax of 100-1000 ng / mL after administration to a subject. In some embodiments, a therapeutically effective amount of R(-)-ketamine comprises an amount of R(-)-ketamine that results in a Cmax of 200-900 ng / mL after administration to a subject. In some embodiments, a therapeutically effective amount of R(-)-ketamine comprises an amount of R(-)-ketamine that results in a Cmax of 250-900 ng / mL after administration to a subject. In some embodiments, a therapeutically effective amount of R(-)-ketamine comprises an amount of R(-)-ketamine that results in a Cmax of 2500-800 ng / mL after administration to a subject. In some embodiments, a therapeutically effective amount of R(-)-ketamine comprises an amount of R(-)-ketamine that results in a Cmax of 300-800 ng / mL after administration to a subject. In some embodiments, a therapeutically effective amount of R(-)-ketamine includes an amount of R(-)-ketamine that results in a Cmax of 400-800 ng / mL after administration to a subject. In some embodiments, a therapeutically effective amount of R(-)-ketamine includes an amount of R(-)-ketamine that results in a Cmax of 300-1000 ng / mL after administration to a subject. In some embodiments, a therapeutically effective amount of R(-)-ketamine includes an amount of R(-)-ketamine that results in a Cmax of 300-900 ng / mL after administration to a subject.

[0047] A therapeutically effective amount can be an amount that results in an AUC of 400 to 3000 after administration. In some embodiments, a therapeutically effective amount of R(-)-ketamine includes an amount of R-(-)-ketamine that results in an AUC of about 1500 to about 4000, about 1000 to about 3500, about 500 to about 2500, about 500 to about 2000, about 500 to about 1900, about 500 to about 1800, about 600 to about 1850, or about 600 to about 1750. In some embodiments, a therapeutically effective amount of R-(-)-ketamine includes an amount of R-(-)-ketamine that results in an AUC of about 500 to about 2500. In some embodiments, a therapeutically effective amount of R-(-)-ketamine includes an amount of R-(-)-ketamine that results in an AUC of about 500 to about 2000. In some embodiments, a therapeutically effective amount of R-(-)-ketamine includes an amount of R-(-)-ketamine that provides an AUC of about 500 to about 1900. In some embodiments, a therapeutically effective amount of R-(-)-ketamine includes an amount of R-(-)-ketamine that provides an AUC of about 600 to about 2000. In some embodiments, the AUC is determined by the AUC 0-inf In some embodiments, the AUC is the truncated AUC (AUC 0-24h ) is included.

[0048] Depressive symptoms can be assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) subject score. The MADRS is a 10-item diagnostic questionnaire administered by a clinician to measure the severity of depressive episodes in subjects with mood disorders. MADRS score ranges include 0-6 (normal, i.e., no symptoms), 7-19 (mild depression), 20-34 (moderate depression), and 34 or higher (severe depression). In some embodiments, the MADRS subject score is reduced by administration of the composition.

[0049] In some embodiments, the MADRS subject score decreases by about 2 to about 20, or about 3 to about 16, or about 4 to about 12, or about 5 to about 8 as a result of administering the composition. In some embodiments, the MADRS subject score decreases by about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 as a result of administering the composition.

[0050] In some embodiments, the MADRS subject score decreases about 12 hours to about 96 hours, or about 12 hours to about 72 hours, or about 12 hours to about 48 hours, or about 12 hours to about 24 hours after initiation of administration of the composition. In some embodiments, the MADRS subject score decreases about 6, 12, 18, 24, 36, 48, 60, 72, 84, or 96 hours after initiation of administration of the composition. In some embodiments, the MADRS score decreases by about 2 to about 20 when measured about 24 hours, about 7 days, about 10 days, about 14 days, or about 21 days after initiation of administration of the composition.

[0051] In some embodiments, the MADRS subject score is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiation of administration of the composition. In some embodiments, the MADRS subject score is reduced by at least 10% when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiation of administration of the composition. In some embodiments, the MADRS subject score is reduced by at least 20% when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiation of administration of the composition. In some embodiments, the MADRS subject score is reduced by at least 30% when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiation of administration of the composition. In some embodiments, the MADRS subject score is reduced by at least 40% when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiating administration of the composition. In some embodiments, the MADRS subject score is reduced by at least 50% when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiating administration of the composition. In some embodiments, the MADRS subject score is reduced by at least 60% when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiating administration of the composition. In some embodiments, the MADRS subject score is reduced by at least 70% when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiating administration of the composition. In some embodiments, the MADRS subject score is reduced by at least 80% when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiating administration of the composition. In some embodiments, the MADRS subject score is reduced by at least 90% when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiation of administration of the composition.

[0052] In some embodiments, the MADRS subject score is 14, 15, 16, 17, 18, 19, 20, 21, or 22 or less when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiation of administration of the composition. In some embodiments, the MADRS subject score is 18 or less when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiation of administration of the composition. In some embodiments, the MADRS subject score is 17 or less when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiation of administration of the composition. In some embodiments, the MADRS subject score is 16 or less when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiation of administration of the composition. In some embodiments, the MADRS subject score is 14 or less when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiation of administration of the composition. In some embodiments, the MADRS subject score is 12 or less when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiating administration of the composition. In some embodiments, the MADRS subject score is 10 or less when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiating administration of the composition. In some embodiments, the MADRS subject score is 8 or less when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiating administration of the composition. In some embodiments, the MADRS subject score is 6 or less when measured about 2 hours, about 4 hours, about 7 days, or about 14 days after initiating administration of the composition.

[0053] R(-)-Ketamine In a study using a mouse model of depression, R(-)-ketamine demonstrated a more potent and longer-lasting antidepressant effect on depression-like symptoms compared with S(+)-ketamine. In a study using a mouse social defeat stress model, R(-)-ketamine demonstrated a more potent and longer-lasting antidepressant effect compared with S(+)-ketamine. Furthermore, administration of S(+)-ketamine induced side effects such as hyperactivity, prepulse inhibition deficits, and drug dependence, whereas administration of R(-)-ketamine did not. Because R(-)-ketamine has a lower affinity for the NMDA receptor compared with S(+)-ketamine, R(-)-ketamine is thought to have fewer psychotomimetic side effects and negligible drug dependence. Therefore, R(-)-ketamine or its pharmaceutically acceptable salts have rapid and sustained antidepressant effects with fewer side effects than S(+)-ketamine.

[0054] In some embodiments, a composition comprising R(-)-ketamine or a pharmaceutically acceptable salt thereof is substantially free of S(+)-ketamine or a pharmaceutically acceptable salt thereof. R(-)-ketamine or a pharmaceutically acceptable salt thereof can be considered substantially free of S(+)-ketamine if the amount of S(+)-ketamine is such that when the composition is administered to a subject, side effects associated with S(+)-ketamine are substantially reduced or absent. Exemplary side effects include, but are not limited to, psychotomimetic effects such as changes in perception, mood, thought, or mental state, for example, anhedonia or negative affect. Additional side effects include somnolence, dizziness, headache, speech and speech disorders, paresthesia, balance disorders, hypoesthesia, lethargy, memory impairment, sedation, sensory disturbances, delayed speech, derealization, confusion, aversion, teeth grinding, dissociation, euphoria, speech omissions, and altered time perception.

[0055] In some embodiments, the composition comprising R(-)-ketamine or a pharmaceutically acceptable salt thereof contains less than about 5% S(+)-ketamine or a pharmaceutically acceptable salt thereof, less than about 4% S(+)-ketamine or a pharmaceutically acceptable salt thereof, less than about 3% S(+)-ketamine or a pharmaceutically acceptable salt thereof, less than about 2% S(+)-ketamine or a pharmaceutically acceptable salt thereof, less than about 1% S(+)-ketamine or a pharmaceutically acceptable salt thereof, less than about 0.9% S(+)-ketamine or a pharmaceutically acceptable salt thereof, less than about 0.8% S(+)-ketamine or a pharmaceutically acceptable salt thereof, less than about 0.7% S(+)-ketamine or or a pharmaceutically acceptable salt thereof, less than about 0.6% S(+)-ketamine or a pharmaceutically acceptable salt thereof, less than about 0.5% S(+)-ketamine or a pharmaceutically acceptable salt thereof, less than about 0.4% S(+)-ketamine or a pharmaceutically acceptable salt thereof, less than about 0.3% S(+)-ketamine or a pharmaceutically acceptable salt thereof, less than about 0.2% S(+)-ketamine or a pharmaceutically acceptable salt thereof, less than about 0.1% S(+)-ketamine or a pharmaceutically acceptable salt thereof, less than about 0.005% S(+)-ketamine or a pharmaceutically acceptable salt thereof, or less than about 0.001% S(+)-ketamine or a pharmaceutically acceptable salt thereof.

[0056] R(-)-ketamine may be a free base, a pharmaceutically acceptable salt thereof, or both. The pharmaceutically acceptable salt is preferably a pharmaceutically acceptable acid addition salt, more preferably a hydrochloride salt. The chemical structure of R(-)-ketamine hydrochloride is represented by the following formula (I): [ka]

[0057] R(-)-ketamine or a pharmaceutically acceptable salt thereof can be modified to produce a derivative, for example, by replacing a chlorine atom as a substituent with another halogen atom and / or replacing a methyl group as a substituent with another alkyl group. Examples of halogens include fluorine, chlorine, bromine, iodine, astatine, and tennessine. As a result, a compound with a more preferable effect may be obtained. In addition, the compound of the present invention can be converted to a stable isotope. 13 C. 2 When labeled with an isotope such as 3H(D), for example, it is possible to measure the pharmacokinetics and quantitatively measure the affinity to NMDA receptors in the brain.

[0058] In some embodiments, the composition contains about 5 to 1000 mg, or about 5 to 500 mg, or about 10 to 300 mg, or about 20 to 200 mg, or about 10 to 100 mg, or about 30 to 60 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains about 30 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains about 60 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the therapeutically effective dose of the composition comprises about 50 mg to 1000 mg, about 50 mg to 500 mg, about 50 mg to 400 mg, about 50 mg to 300 mg, about 50 mg to 250 mg, about 50 mg to 200 mg, about 50 mg to 150 mg, about 50 mg to 100 mg, about 50 mg to 300 mg, about 50 mg to 250 mg, about 50 mg to 200 mg, about 50 mg to 150 mg, about 50 mg to 100 mg, about 100 mg to 300 mg, about 100 mg to 250 mg, about 100 mg to 200 mg, about 100 mg to 150 mg, about 150 mg to 300 mg, about 150 mg to 250 mg, or about 150 mg to 200 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a therapeutically effective dose of the composition comprises about 50 mg to about 200 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a therapeutically effective dose of the composition comprises about 50 mg to about 150 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a therapeutically effective dose of the composition comprises about 100 mg to about 200 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the therapeutically effective dose of the composition is 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, In some embodiments, the therapeutically effective dose of the composition comprises 60 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the composition comprises 80 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the composition comprises 90 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the composition comprises 100 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the composition comprises 120 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the composition comprises 150 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the composition comprises 200 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the composition comprises 250 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the composition comprises 300 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the composition comprises 350 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective dose of the composition comprises 400 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof.In some embodiments, the therapeutically effective dose of the composition comprises 450 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof, hi some embodiments, the therapeutically effective dose of the composition comprises 500 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the composition comprises R(-)-ketamine hydrochloride. In some embodiments, the composition comprises about 5 to 1000 mg, or about 5 to 500 mg, or about 10 to 300 mg, or about 20 to 200 mg, or about 10 to 100 mg, or about 30 to 60 mg of R(-)-ketamine hydrochloride. In some embodiments, the composition comprises about 30 mg of R(-)-ketamine hydrochloride. In some embodiments, the composition comprises about 60 mg of R(-)-ketamine hydrochloride.

[0062] Administration The compositions of the present disclosure can be administered orally or parenterally. Examples of parenteral administration include intravenous, intramuscular, and subcutaneous injections. Examples include transmucosal administration, such as nasal administration using sprays or aerosols, oral administration, rectal administration using suppositories, and transdermal or sublingual administration using patches, liniments, gels, and the like. For oral administration, known dosage forms can be used, including tablets, capsules, coated tablets, lozenges, or liquids such as solutions or suspensions. In some embodiments, the compositions may be administered intravenously or subcutaneously.

[0063] In some embodiments, a composition comprising R(-)-ketamine or a pharmaceutically acceptable salt thereof is administered by intravenous infusion, intravenous injection, subcutaneous infusion, or subcutaneous injection. In some embodiments, the R(-)-ketamine composition is administered by intravenous infusion. In some embodiments, the R(-)-ketamine composition is administered by subcutaneous injection.

[0064] In some embodiments, the R(-)-ketamine hydrochloride composition is administered by intravenous infusion, intravenous injection, subcutaneous infusion, or subcutaneous injection. In some embodiments, the R(-)-ketamine hydrochloride composition is administered by intravenous infusion. In some embodiments, the R(-)-ketamine hydrochloride composition is administered by subcutaneous injection. In some embodiments, the R(-)-ketamine hydrochloride composition in sterile water is administered by intravenous infusion, intravenous injection, subcutaneous infusion, or subcutaneous injection. In some embodiments, the R(-)-ketamine hydrochloride composition in sterile water is administered by intravenous infusion. In some embodiments, the R(-)-ketamine hydrochloride composition in sterile water is administered by subcutaneous injection.

[0065] The compositions of the present disclosure may be administered by intravenous infusion. In some embodiments, the compositions may be administered over a time period of about 10 minutes to about 3 hours. In some embodiments, the compositions may be administered over a time period of about 20 minutes, about 40 minutes, or about 1 hour. In some embodiments, a composition of R(-)-ketamine or a pharmaceutically acceptable salt thereof is administered over a time period of 5 minutes to 10 hours, or 10 minutes to 3 hours, or 20 minutes to 1 hour. In some embodiments, a composition of R(-)-ketamine hydrochloride is administered over a time period of 5 minutes to 10 hours, or 10 minutes to 3 hours, or 20 minutes to 1 hour. In some embodiments, a composition of R(-)-ketamine hydrochloride in sterile water is administered over a time period of 5 minutes to 10 hours, or 10 minutes to 3 hours, or 20 minutes to 1 hour. In some embodiments, a composition of R(-)-ketamine or a pharmaceutically acceptable salt thereof is administered over a period of about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, or 3 hours. In some embodiments, a composition of R(-)-ketamine hydrochloride is administered over a period of about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, or 3 hours. In some embodiments, a composition of R(-)-ketamine hydrochloride in sterile water is administered over a period of about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, or 3 hours.

[0066] In some embodiments, a composition comprising R(-)-ketamine or a pharmaceutically acceptable salt thereof is administered by inhalation. For example, a composition comprising R(-)-ketamine or a pharmaceutically acceptable salt thereof can be administered intranasally in the form of an aerosol.

[0067] The compositions of the present disclosure may be administered once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every ten days, or once a month. In some embodiments, the R(-)-ketamine or pharmaceutically acceptable salt thereof composition is administered once daily. In some embodiments, the R(-)-ketamine or pharmaceutically acceptable salt thereof composition is administered twice daily. In some embodiments, the R(-)-ketamine or pharmaceutically acceptable salt thereof composition is administered two to five times daily. In some embodiments, the R(-)-ketamine or pharmaceutically acceptable salt thereof composition is administered once every two days. In some embodiments, the R(-)-ketamine or pharmaceutically acceptable salt thereof composition is administered once every three days. In some embodiments, the R(-)-ketamine or pharmaceutically acceptable salt thereof composition is administered once every four days. In some embodiments, the R(-)-ketamine or pharmaceutically acceptable salt thereof composition is administered once a week. In some embodiments, the R(-)-ketamine or pharmaceutically acceptable salt thereof composition is administered twice a week. In some embodiments, the R(-)-ketamine or pharmaceutically acceptable salt thereof composition is administered once every 10 days. In some embodiments, the R(-)-ketamine or pharmaceutically acceptable salt thereof composition is administered once every two weeks. In some embodiments, the R(-)-ketamine or pharmaceutically acceptable salt thereof composition is administered 2 to 5 times a week. In some embodiments, the R(-)-ketamine or pharmaceutically acceptable salt thereof composition is administered once a month. In some embodiments, the R(-)-ketamine or pharmaceutically acceptable salt thereof composition is administered twice a month. In some embodiments, the R(-)-ketamine or pharmaceutically acceptable salt thereof composition is administered 2 to 5 times a month.

[0068] The compositions of the present disclosure can be administered according to a dosing schedule that includes an initial period in which the composition is administered at a higher concentration and / or more frequently, followed by a maintenance period in which the composition is administered at a lower dose and / or less frequently. In some embodiments, the dosing schedule includes (a) an initial period in which the composition is administered once every 1, 2, 3, or 4 days, and (b) a maintenance period in which the composition is administered less frequently than the initial period. In some embodiments, the composition is administered once per week, twice per week, once every 2 weeks, once every 10 days, or once per month during the maintenance period.

[0069] As used herein, a "therapeutically effective amount" refers to an amount of an R(-)-ketamine composition sufficient to treat or ameliorate depressive symptoms in a subject, as described herein. For example, a therapeutically effective amount of an R(-)-ketamine composition can reduce the MADRS subject score by about 2 to about 20, or about 3 to about 16, or about 4 to about 12, or about 5 to about 8 in a subject with depressive symptoms.

[0070] In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's systolic blood pressure by less than 40 mmHg, less than 30 mmHg, less than 20 mmHg, or less than 10 mmHg. In some embodiments, the change in systolic blood pressure is measured within 1 hour, 5 hours, 1 day, 7 days, or 14 days of administration.

[0071] In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's systolic blood pressure by less than 40 mmHg, less than 30 mmHg, less than 20 mmHg, or less than 10 mmHg, when measured within 14 days of administration. In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's systolic blood pressure by less than 40 mmHg, when measured within 14 days of administration. In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's systolic blood pressure by less than 30 mmHg, when measured within 14 days of administration. In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's systolic blood pressure by less than 20 mmHg, when measured within 14 days of administration. In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's systolic blood pressure by less than 10 mmHg, when measured within 14 days of administration. In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's systolic blood pressure by less than 3 mmHg when measured within 14 days of administration. In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's systolic blood pressure by less than 40 mmHg when measured within 14 days of administration.

[0072] In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's diastolic blood pressure by less than 35 mmHg, less than 30 mmHg, less than 25 mmHg, less than 20 mmHg, less than 15 mmHg, less than 10 mmHg, or less than 50 mmHg. In some embodiments, the change in diastolic blood pressure is measured within 1 hour, 5 hours, 1 day, 7 days, or 14 days of administration.

[0073] In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's diastolic blood pressure by less than 40 mmHg, less than 30 mmHg, less than 20 mmHg, or less than 10 mmHg, when measured within 14 days of administration. In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's diastolic blood pressure by less than 40 mmHg, when measured within 14 days of administration. In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's diastolic blood pressure by less than 30 mmHg, when measured within 14 days of administration. In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's diastolic blood pressure by less than 20 mmHg, when measured within 14 days of administration. In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's diastolic blood pressure by less than 10 mmHg, when measured within 14 days of administration. In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's diastolic blood pressure by less than 3 mmHg when measured within 14 days of administration. In some embodiments, a therapeutically effective amount of an R(-)-ketamine composition increases a subject's diastolic blood pressure by less than 40 mmHg when measured within 14 days of administration.

[0074] In some embodiments, administration of a therapeutically effective amount of an R(-)-ketamine composition results in fewer side effects or adverse events than administration of a therapeutically effective amount of S(+)-ketamine or racemic ketamine. In some embodiments, administration of a therapeutically effective amount of an R(-)-ketamine composition results in fewer side effects or adverse events than administration of a similar amount of S(+)-ketamine or racemic ketamine.

[0075] Pharmaceutical preparations The present disclosure also relates to a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and R(-)-ketamine or a pharmaceutically acceptable salt thereof, or a composition comprising R(-)-ketamine or a pharmaceutically acceptable salt thereof, as disclosed herein. In some embodiments, the pharmaceutical formulation comprises a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical formulation comprises a pharmaceutically acceptable carrier and R(-)-ketamine hydrochloride. Examples of pharmaceutically acceptable carriers include, for example, antioxidants, stabilizers, preservatives, flavoring agents, coloring agents, dissolution aids, solubilizers, surfactants, emulsifiers, antifoaming agents, viscosity modifiers, gelling agents, absorption enhancers, dispersants, excipients, and pH adjusters.

[0076] In some embodiments, the pharmaceutical formulations of the present disclosure comprise a pH adjusting or buffering agent. Suitable buffers are known to those skilled in the art and include succinate buffers, tartrate buffers, maleate buffers, fumarate buffers, citrate buffers, and acetate buffers, among others.

[0077] In some embodiments, pharmaceutical formulations can be prepared as dosage forms. In some embodiments, pharmaceutical formulations for administration by infusion or injection can be prepared in the form of a solution or suspension. In some embodiments, pharmaceutical formulations for transmucosal administration, such as nasal or oral administration, can be prepared in the form of a powder, drop, or aerosol. In some embodiments, pharmaceutical formulations for rectal administration can be prepared in the form of a semi-solid preparation, such as a cream or suppository. In some embodiments, pharmaceutical formulations for sublingual administration can be prepared in the form of a fast-dissolving strip or tablet. Each formulation can be prepared by any one of the methods known to those skilled in the art of pharmacy, for example, as disclosed in Remington's Pharmaceutical Sciences (Mack Publishing Company, Easton, PA, 1970).

[0078] The exact dosage and administration regimen of the compositions and pharmaceutical formulations disclosed herein can be adjusted depending on the amount required for an individual therapeutic target, the treatment method, the disease, the degree of need, and the like. The dosage can be determined specifically depending on the patient's age, weight, general health, sex, diet, administration time, administration method, excretion rate, drug combination, medical condition, and other factors. When administering a composition or pharmaceutical formulation to an individual with a substance use disorder exhibiting symptoms such as anxiety, irritability, impaired concentration, impaired thinking, mood swings, nightmares, depression, tension, panic attacks, short-term memory loss, agitation, helplessness, stress sensitivity, increased responsiveness to substance-related cues, abnormal reward processing, or substance craving, it is preferable that the active ingredient contained in the composition or pharmaceutical formulation be limited to an amount effective to alleviate the symptoms of the substance use disorder. R(-)-ketamine or a pharmaceutically acceptable salt thereof can be used safely because it has fewer side effects than S(+)-ketamine and racemic ketamine. The daily dose varies depending on the patient's condition, body weight, type of compound, route of administration, and the like.

[0079] Subcutaneous Formulation and Administration In some embodiments, the formulations may include pre-filled syringes, syringes, vials, injectable powders for reconstitution, injectable concentrates (ready to dilute) or solutions (ready to use) that are diluted prior to delivery.

[0080] In some embodiments, any of the salts or salt forms described in International Publication No. WO2023 / 064363 are contemplated in each aspect and / or embodiment described herein, which is incorporated by reference in its entirety.

[0081] In some embodiments, the formulation may be an aqueous isotonic solution or suspension.

[0082] For subcutaneous use, a sterile solution may be used. In some embodiments, the total concentration of solutes is adjusted to render the formulation isotonic.

[0083] In some embodiments, the subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 60 mg / mL to about 150 mg / mL.

[0084] In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 70 mg / mL to about 150 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 80 mg / mL to about 150 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 90 mg / mL to about 150 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 100 mg / mL to about 150 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 110 mg / mL to about 150 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 120 mg / mL to about 150 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 130 mg / mL to about 150 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 140 mg / mL to about 150 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 60 mg / mL to about 140 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 70 mg / mL to about 140 mg / mL. In some embodiments, the subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 80 mg / mL to about 140 mg / mL. In some embodiments, the subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 90 mg / mL to about 140 mg / mL. In some embodiments, the subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 100 mg / mL to about 140 mg / mL. In some embodiments, the subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 110 mg / mL to about 140 mg / mL.In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 120 mg / mL to about 140 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 130 mg / mL to about 140 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 60 mg / mL to about 130 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 70 mg / mL to about 130 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 80 mg / mL to about 130 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 90 mg / mL to about 130 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 100 mg / mL to about 130 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 110 mg / mL to about 130 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 120 mg / mL to about 130 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 60 mg / mL to about 120 mg / mL. In some embodiments, the subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 70 mg / mL to about 120 mg / mL. In some embodiments, the subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 80 mg / mL to about 120 mg / mL. In some embodiments, the subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 90 mg / mL to about 120 mg / mL. In some embodiments, the subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 100 mg / mL to about 120 mg / mL.In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 110 mg / mL to about 120 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 60 mg / mL to about 110 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 70 mg / mL to about 110 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 80 mg / mL to about 110 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 90 mg / mL to about 110 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 100 mg / mL to about 110 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 60 mg / mL to about 100 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 70 mg / mL to about 100 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 80 mg / mL to about 100 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 90 mg / mL to about 100 mg / mL. In some embodiments, the subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 60 mg / mL to about 90 mg / mL. In some embodiments, the subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 70 mg / mL to about 90 mg / mL. In some embodiments, the subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 80 mg / mL to about 90 mg / mL. In some embodiments, the subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 60 mg / mL to about 80 mg / mL.In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 70 mg / mL to about 80 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 60 mg / mL to about 70 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 95 mg / mL to about 110 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 90 mg / mL to about 105 mg / mL. In some embodiments, a subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 95 mg / mL to about 105 mg / mL. In some embodiments, the subcutaneous injection formulation containing R(-)-ketamine contains R(-)-ketamine at a concentration of about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 mg / mL, or about 110 mg / mL.

[0085] In some embodiments, the subcutaneous injection formulation comprising R(-)-ketamine contains R(-)-ketamine at a concentration of about 60 mg / mL. In some embodiments, the subcutaneous injection formulation comprising R(-)-ketamine contains R(-)-ketamine at a concentration of about 65 mg / mL. In some embodiments, the subcutaneous injection formulation comprising R(-)-ketamine contains R(-)-ketamine at a concentration of about 70 mg / mL. In some embodiments, the subcutaneous injection formulation comprising R(-)-ketamine contains R(-)-ketamine at a concentration of about 75 mg / mL. In some embodiments, the subcutaneous injection formulation comprising R(-)-ketamine contains R(-)-ketamine at a concentration of about 80 mg / mL. In some embodiments, the subcutaneous injection formulation comprising R(-)-ketamine contains R(-)-ketamine at a concentration of about 85 mg / mL. In some embodiments, the subcutaneous injection formulation comprising R(-)-ketamine contains R(-)-ketamine at a concentration of about 90 mg / mL. In some embodiments, the subcutaneous injection formulation comprising R(-)-ketamine contains R(-)-ketamine at a concentration of about 95 mg / mL. In some embodiments, the subcutaneous injection formulation comprising R(-)-ketamine contains R(-)-ketamine at a concentration of about 100 mg / mL. In some embodiments, the subcutaneous injection formulation comprising R(-)-ketamine contains R(-)-ketamine at a concentration of about 105 mg / mL. In some embodiments, the subcutaneous injection formulation comprising R(-)-ketamine contains R(-)-ketamine at a concentration of about 110 mg / mL.

[0086] In some embodiments, the formulation contains substantially pure R(-)-ketamine. In some embodiments, the formulation is substantially free of S-ketamine. In some embodiments, more than 90%, more than 95%, more than 96%, more than 97%, more than 98%, or more than 99% of the ketamine is R(-)-ketamine. Alternatively, or in addition, R(-)-ketamine substantially free of S-ketamine refers to R(-)-ketamine in which the S-ketamine is below the limit of detection using conventional methods in the art. Further alternatively, R(-)-ketamine substantially free of S-ketamine refers to R(-)-ketamine in which the amount of S-ketamine is such that side effects associated with S(+)-ketamine are substantially reduced or absent when the composition is administered to a subject. Exemplary side effects include, but are not limited to, psychotomimetic effects such as changes in perception, mood, thinking, or mental state, for example, anhedonia or negative affect. Further side effects include somnolence, dizziness, headache, dysphonia, paresthesia, imbalance, hypoesthesia, lethargy, memory impairment, sedation, sensory disturbances, delayed speech, derealization, confusion, aversion, teeth grinding, dissociation, euphoria, speech loss, and altered time perception.

[0087] In some embodiments, greater than 90% of the ketamine is R(-)-ketamine. In some embodiments, greater than 95% of the ketamine is R(-)-ketamine. In some embodiments, greater than 96% of the ketamine is R(-)-ketamine. In some embodiments, greater than 97% of the ketamine is R(-)-ketamine. In some embodiments, greater than 98% of the ketamine is R(-)-ketamine. In some embodiments, greater than 99% of the ketamine is R(-)-ketamine. In some embodiments, greater than 99.5% of the ketamine is R(-)-ketamine. In some embodiments, greater than 99.9% of the ketamine is R(-)-ketamine.

[0088] In some embodiments, the formulation is a liquid formulation for subcutaneous administration comprising R(-)-ketamine. In some embodiments, the formulation is a liquid formulation for subcutaneous administration comprising non-ionized R(-)-ketamine (i.e., free base). In some embodiments, the formulation is a liquid formulation for subcutaneous administration comprising R(-)-ketamine in a mixture of ionized and non-ionized (free base) forms. In some embodiments, the formulation is a liquid formulation for subcutaneous administration comprising R(-)-ketamine in ionized form. In some embodiments, the formulation is a liquid formulation for subcutaneous administration comprising R(-)-ketamine in salt form.

[0089] In some embodiments, the pH of an injectable formulation of the present disclosure can be adjusted to a suitable pH. In some embodiments, the pH of the formulation is adjusted using a weak base. In some embodiments, the pH of the formulation is adjusted using a dilute base. In some embodiments, the pH of the formulation is adjusted using a strong base. In some embodiments, the pH of the formulation is adjusted using a weak dilute base. In some embodiments, the pH of the formulation is adjusted using a strong dilute base. In some embodiments, the pH of the formulation is adjusted using NaOH. In some embodiments, the pH of the formulation is adjusted using KOH. In some embodiments, the pH of the formulation is adjusted using 1N NaOH. In some embodiments, the pH of the formulation is adjusted using 1N KOH. In some embodiments, the pH of the formulation is adjusted using 0.5N NaOH. In some embodiments, the pH of the formulation is adjusted using 0.5N KOH.

[0090] In some embodiments, the pH of the formulation is adjusted using a weak acid. In some embodiments, the pH of the formulation is adjusted using a dilute acid. In some embodiments, the pH of the formulation is adjusted using a strong acid. In some embodiments, the pH of the formulation is adjusted using a weak dilute acid. In some embodiments, the pH of the formulation is adjusted using a strong dilute acid.

[0091] In some embodiments, the method further comprises adjusting the pH of the pharmaceutical composition. In some embodiments, only minimal adjustment of the pH is necessary. In some embodiments, the pH is adjusted with a strong base. In some embodiments, the pH is adjusted with sodium hydroxide, potassium hydroxide, barium hydroxide, cesium hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, lithium hydroxide, or rubidium hydroxide.

[0092] In some embodiments, the pH is adjusted with sodium hydroxide. In some embodiments, the pH is adjusted to a desired pH. In some embodiments, the formulation is adjusted to a pH of about 5.0. In some embodiments, the formulation is adjusted to a pH of about 5.1. In some embodiments, the formulation is adjusted to a pH of about 5.2. In some embodiments, the formulation is adjusted to a pH of about 5.3. In some embodiments, the formulation is adjusted to a pH of about 5.4. In some embodiments, the formulation is adjusted to a pH of about 5.5. In some embodiments, the formulation is adjusted to a pH of about 5.6. In some embodiments, the formulation is adjusted to a pH of about 5.70. In some embodiments, the formulation is adjusted to a pH of about 5.71. In some embodiments, the formulation is adjusted to a pH of about 5.72. In some embodiments, the formulation is adjusted to a pH of about 5.73. In some embodiments, the formulation is adjusted to a pH of about 5.74. In some embodiments, the formulation is adjusted to a pH of about 5.75. In some embodiments, the formulation is adjusted to a pH of about 5.76. In some embodiments, the formulation is adjusted to a pH of about 5.77. In some embodiments, the formulation is adjusted to a pH of about 5.78. In some embodiments, the formulation is adjusted to a pH of about 5.79. In some embodiments, the formulation is adjusted to a pH of about 5.8. In some embodiments, the formulation is adjusted to a pH of about 5.9. In some embodiments, the formulation is adjusted to a pH of about 6.0. In some embodiments, the formulation is adjusted to a pH of 5.0-6.0.

[0093] In some embodiments, the pH of the formulation is about 5.0 to about 6.0. In some embodiments, the pH of the formulation is about 5.1 to about 6.0. In some embodiments, the pH of the formulation is about 5.2 to about 6.0. In some embodiments, the pH of the formulation is about 5.3 to about 6.0. In some embodiments, the pH of the formulation is about 5.4 to about 6.0. In some embodiments, the pH of the formulation is about 5.5 to about 6.0. In some embodiments, the pH of the formulation is about 5.6 to about 6.0. In some embodiments, the pH of the formulation is about 5.7 to about 6.0. In some embodiments, the pH of the formulation is about 5.8 to about 6.0. In some embodiments, the pH of the formulation is about 5.9 to about 6.0.

[0094] In some embodiments, the pH of the formulation is about 5.0 to about 5.9. In some embodiments, the pH of the formulation is about 5.1 to about 5.9. In some embodiments, the pH of the formulation is about 5.2 to about 5.9. In some embodiments, the pH of the formulation is about 5.3 to about 5.9. In some embodiments, the pH of the formulation is about 5.4 to about 5.9. In some embodiments, the pH of the formulation is about 5.5 to about 5.9. In some embodiments, the pH of the formulation is about 5.6 to about 5.9. In some embodiments, the pH of the formulation is about 5.7 to about 5.9. In some embodiments, the pH of the formulation is about 5.8 to about 5.9.

[0095] In some embodiments, the pH of the formulation is about 5.0 to about 5.8. In some embodiments, the pH of the formulation is about 5.1 to about 5.8. In some embodiments, the pH of the formulation is about 5.2 to about 5.8. In some embodiments, the pH of the formulation is about 5.3 to about 5.8. In some embodiments, the pH of the formulation is about 5.4 to about 5.8. In some embodiments, the pH of the formulation is about 5.5 to about 5.8. In some embodiments, the pH of the formulation is about 5.6 to about 5.8. In some embodiments, the pH of the formulation is about 5.7 to about 5.8.

[0096] In some embodiments, the pH of the formulation is about 5.0 to about 5.7. In some embodiments, the pH of the formulation is about 5.1 to about 5.7. In some embodiments, the pH of the formulation is about 5.2 to about 5.7. In some embodiments, the pH of the formulation is about 5.3 to about 5.7. In some embodiments, the pH of the formulation is about 5.4 to about 5.7. In some embodiments, the pH of the formulation is about 5.5 to about 5.7. In some embodiments, the pH of the formulation is about 5.6 to about 5.7.

[0097] In some embodiments, the pH of the formulation is about 5.0 to about 5.6. In some embodiments, the pH of the formulation is about 5.1 to about 5.6. In some embodiments, the pH of the formulation is about 5.2 to about 5.6. In some embodiments, the pH of the formulation is about 5.3 to about 5.6. In some embodiments, the pH of the formulation is about 5.4 to about 5.6. In some embodiments, the pH of the formulation is about 5.5 to about 5.6.

[0098] In some embodiments, the pH of the formulation is about 5.0 to about 5.5. In some embodiments, the pH of the formulation is about 5.1 to about 5.5. In some embodiments, the pH of the formulation is about 5.2 to about 5.5. In some embodiments, the pH of the formulation is about 5.3 to about 5.5. In some embodiments, the pH of the formulation is about 5.4 to about 5.5.

[0099] In some embodiments, the pH of the formulation is about 5.0 to about 5.4. In some embodiments, the pH of the formulation is about 5.1 to about 5.4. In some embodiments, the pH of the formulation is about 5.2 to about 5.4. In some embodiments, the pH of the formulation is about 5.3 to about 5.4.

[0100] In some embodiments, the pH of the formulation is about 5.0 to about 5.3. In some embodiments, the pH of the formulation is about 5.1 to about 5.3. In some embodiments, the pH of the formulation is about 5.2 to about 5.3.

[0101] In some embodiments, the pH of the formulation is about 5.0 to about 5.2, In some embodiments, the pH of the formulation is about 5.1 to about 5.2.

[0102] In some embodiments, the pH of the formulation is about 5.0 to about 5.1.

[0103] In some embodiments, the pH of the formulation is about 5.0. In some embodiments, the pH of the formulation is about 5.1. In some embodiments, the pH of the formulation is about 5.2. In some embodiments, the pH of the formulation is about 5.3. In some embodiments, the pH of the formulation is about 5.4. In some embodiments, the pH of the formulation is about 5.5. In some embodiments, the pH of the formulation is about 5.6. In some embodiments, the pH of the formulation is about 5.70. In some embodiments, the pH of the formulation is about 5.71. In some embodiments, the pH of the formulation is about 5.72. In some embodiments, the pH of the formulation is about 5.73. In some embodiments, the pH of the formulation is about 5.74. In some embodiments, the pH of the formulation is about 5.75. In some embodiments, the pH of the formulation is about 5.76. In some embodiments, the pH of the formulation is about 5.77. In some embodiments, the pH of the formulation is about 5.78. In some embodiments, the pH of the formulation is about 5.79. In some embodiments, the pH of the formulation is about 5.8. In some embodiments, the pH of the formulation is about 5.9. In some embodiments, the pH of the formulation is about 6.0.

[0104] In some embodiments, the R(-)-ketamine formulation does not include a cyclodextrin. In some embodiments, the R(-)-ketamine formulation does not include a cyclodextrin or a cyclodextrin derivative.

[0105] In those embodiments in which the composition is administered by injection, the injectable composition may be supplied in a variety of delivery forms, for example, in ampoules, pre-filled syringes, auto-injectors with or without needles, as small dose injections, or in multi-dose containers with added preservatives.

[0106] In some embodiments of the present disclosure, the parenteral composition is formulated as a subcutaneous injection.

[0107] Each of the injectable formulations (eg, subcutaneous injection formulations) of the present disclosure also includes water, which may be present as saline, to further dilute the formulation to a suitable volume suitable for injection.

[0108] Suitable volumes of the R(-)-ketamine formulations of the present disclosure for use in an injection device (e.g., for subcutaneous administration) range from about 0.1 mL to about 10 mL, including, for example, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 2.0 mL, 3.0 mL, 4.0 mL, 5.0 mL, 6.0 mL, 7.0 mL, 8.0 mL, 9.0 mL, 10.0 mL, and all volumes therebetween.

[0109] In some embodiments, the formulation has an osmolality of about 150 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 175 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 200 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 225 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 250 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 275 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 300 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 325 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 350 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 375 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 400 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 300 mOsm / kg to about 450 mOsm / kg. In some embodiments, the formulation has an osmolality of about 475 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 500 mOsm / kg to about 850 mOsm / kg.

[0110] In some embodiments, the formulation has an osmolality of at least about 150 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 175 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 200 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 225 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 250 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 275 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 300 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 325 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 350 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 375 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 400 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 425 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 450 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 475 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 500 mOsm / kg.

[0111] In some embodiments, the formulation has an osmolality of less than about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 825 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 800 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 775 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 750 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 725 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 700 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 675 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 650 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 625 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 600 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 575 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 550 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 525 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 500 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 450 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 400 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 350 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 300 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 250 mOsm / kg.

[0112] In some embodiments, the formulation has an osmolality of about 300 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 300 mOsm / kg to about 350 mOsm / kg, about 300 mOsm / kg to about 400 mOsm / kg, about 300 mOsm / kg to about 450 mOsm / kg, about 300 mOsm / kg to about 500 mOsm / kg, about 300 mOsm / kg to about 550 mOsm / kg, about 300 mOsm / kg to about 600 mOsm / kg, about 300 mOsm / kg to about 650 mOsm / kg, about 300 mOsm / kg to about 700 mOsm / kg, or about 300 mOsm / kg to about 750 mOsm / kg. g, about 300mOsm / kg to about 800mOsm / kg, about 300mOsm / kg to about 850mOsm / kg, about 350mOsm / kg to about 400mOsm / kg, about 350mOsm / kg to about 450mOsm / kg, about 350mOsm / kg to about 500mO sm / kg, about 350mOsm / kg to about 550mOsm / kg, about 350mOsm / kg to about 600mOsm / kg, about 350mOsm / kg to about 650mOsm / kg, about 350mOsm / kg to about 700mOsm / kg, about 350mOsm / kg to about 75 0mOsm / kg, about 350mOsm / kg to about 800mOsm / kg, about 350mOsm / kg to about 850mOsm / kg, about 400mOsm / kg to about 450mOsm / kg, about 400mOsm / kg to about 500mOsm / kg, about 400mOsm / kg ~550mOsm / kg, approximately 400mOsm / kg~approximately 600mOsm / kg, approximately 400mOsm / kg~approximately 650mOsm / kg, approximately 400mOsm / kg~approximately 700mOsm / kg, approximately 400mOsm / kg~approximately 750mOsm / kg, approximately 400mOs m / kg~about 800mOsm / kg, about 400mOsm / kg~about 850mOsm / kg, about 450mOsm / kg~about 500mOsm / kg, about 450mOsm / kg~about 550mOsm / kg, about 450mOsm / kg~about 600mOsm / kg, about 45 0mOsm / kg to about 650mOsm / kg, about 450mOsm / kg to about 700mOsm / kg, about 450mOsm / kg to about 750mOsm / kg, about 450mOsm / kg to about 800mOsm / kg, about 450mOsm / kg to about 850mOsm / kg,Approx. 500mOsm / kg~Approx. 550mOsm / kg, Approx. 500mOsm / kg~Approx. 600mOsm / kg, Approx. 500mOsm / kg~Approx. 650mOsm / kg, Approx. 500mOsm / kg~Approx. 700mOsm / kg, about 500mOsm / kg to about 750mOsm / kg, about 500mOsm / kg to about 800mOsm / kg, about 500mOsm / kg to about 850mOsm / kg, about 5 50mOsm / kg~Approx. 600mOsm / kg, Approx. 550mOsm / kg~Approx. 650mOsm / kg, Approx. 550mOsm / kg~Approx. 700mOsm / kg, Approx. 550mOsm / kg~Approx. 75 0mOsm / kg, approximately 550mOsm / kg to approximately 800mOsm / kg, approximately 550mOsm / kg to approximately 850mOsm / kg, approximately 600mOsm / kg to approximately 650mOsm / kg, approximately 600m Osm / kg ~ approx. 700mOsm / kg, approx. 600mOsm / kg ~ approx. 750mOsm / kg, approx. 600mOsm / kg ~ approx. 800mOsm / kg, approx. 600mOsm / kg ~ approx. 850mO sm / kg, about 650mOsm / kg to about 700mOsm / kg, about 650mOsm / kg to about 750mOsm / kg, about 650mOsm / kg to about 800mOsm / kg, about 650mOsm The osmolality is about 700 mOsm / kg to about 850 mOsm / kg, about 700 mOsm / kg to about 750 mOsm / kg, about 700 mOsm / kg to about 800 mOsm / kg, about 700 mOsm / kg to about 850 mOsm / kg, about 750 mOsm / kg to about 800 mOsm / kg, about 750 mOsm / kg to about 850 mOsm / kg, and about 800 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 300 mOsm / kg, about 350 mOsm / kg, about 400 mOsm / kg, about 450 mOsm / kg, about 500 mOsm / kg, about 550 mOsm / kg, about 600 mOsm / kg, about 650 mOsm / kg, about 700 mOsm / kg, about 750 mOsm / kg, about 800 mOsm / kg, or about 850 mOsm / kg. In some embodiments, the formulation provides a saturation of at least about 300 mOsm / kg, about 350 mOsm / kg, about 400 mOsm / kg, about 450 mOsm / kg, about 500 mOsm / kg, about 550 mOsm / kg, about 600 mOsm / kg, about 650 mOsm / kg, about 700 mOsm / kg, about 750 mOsm / kg,or about 800 mOsm / kg. In some embodiments, the formulation has an osmolality of up to about 350 mOsm / kg, about 400 mOsm / kg, about 450 mOsm / kg, about 500 mOsm / kg, about 550 mOsm / kg, about 600 mOsm / kg, about 650 mOsm / kg, about 700 mOsm / kg, about 750 mOsm / kg, about 800 mOsm / kg, or about 850 mOsm / kg.

[0113] In some embodiments, the formulation is isotonic.

[0114] In some embodiments, the formulation has an osmolality of about 500 mOsm / kg.

[0115] stability In some embodiments, the formulation remains stable for more than about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.

[0116] In some embodiments, the formulation remains stable for more than about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, about 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months.

[0117] In some embodiments, the concentration of R(-)-ketamine in the formulation is stable for more than about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.

[0118] In some embodiments, the concentration of R(-)-ketamine in the formulation is stable for more than about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, about 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months.

[0119] In some embodiments, the impurities in the formulation remain stable for more than about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.

[0120] In some embodiments, impurities in the formulation remain stable for more than about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, about 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months.

[0121] In some embodiments, the osmolality in the formulation is stable for more than about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.

[0122] In some embodiments, the osmolality in the formulation is stable for more than about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, about 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months.

[0123] In some embodiments, the pH of the formulation is stable for more than about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks.

[0124] In some embodiments, the pH of the formulation is stable for more than about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, about 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months.

[0125] In some embodiments, the formulation is stable in the presence of light, in some embodiments, the formulation is stable in the presence of heat, in some embodiments, the formulation is stable at room temperature.

[0126] In some embodiments, the term stable means that the percentage, volume, or concentration of impurities, pH, R(-)-ketamine, osmolality, etc. does not change by more than about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% from the original percentage, volume, or concentration.

[0127] Carrier Fluid In some embodiments, the R(-)-ketamine subcutaneous formulation comprises a carrier liquid. In some embodiments, the R(-)-ketamine subcutaneous formulation comprises a carrier liquid, wherein the carrier fluid is water. In some embodiments, the R(-)-ketamine subcutaneous formulation comprises a carrier liquid, wherein the carrier fluid is water for injection (WFI). In some embodiments, the R(-)-ketamine subcutaneous formulation comprises a carrier liquid, wherein the carrier fluid is a buffer.

[0128] In some embodiments, the R(-)-ketamine subcutaneous formulation comprises water for injection. In some embodiments, the R(-)-ketamine subcutaneous formulation comprises water for injection and a buffer. In some embodiments, the R(-)-ketamine subcutaneous formulation comprises a buffer.

[0129] In some embodiments, the R(-)-ketamine subcutaneous formulation comprises a succinate buffer. In some embodiments, the R(-)-ketamine subcutaneous formulation comprises a tartrate buffer. In some embodiments, the R(-)-ketamine subcutaneous formulation comprises a maleate buffer. In some embodiments, the R(-)-ketamine subcutaneous formulation comprises a fumarate buffer. In some embodiments, the R(-)-ketamine subcutaneous formulation comprises a citrate buffer. In some embodiments, the R(-)-ketamine subcutaneous formulation comprises an acetate buffer. In some embodiments, the R(-)-ketamine subcutaneous formulation comprises water for injection and a maleate buffer. In some embodiments, the R(-)-ketamine subcutaneous formulation comprises water for injection and a fumarate buffer. In some embodiments, the R(-)-ketamine subcutaneous formulation comprises water for injection and a citrate buffer. In some embodiments, the R(-)-ketamine subcutaneous formulation comprises water for injection and an acetate buffer.

[0130] Formulation preparation process In some embodiments, R(-)-ketamine or a pharmaceutically acceptable salt thereof is added to water for injection, and the pH is slowly adjusted using a dilute base to achieve a final concentration of R(-)-ketamine of about 60 mg / mL to about 110 mg / mL. In some embodiments, the R(-)-ketamine used in preparing the formulation is selected from any of the salts or salt forms described in International Application No. PCT / US2022 / 046412. In some embodiments, a specific amount of R(-)-ketamine, an R(-)-ketamine salt, or an R(-)-ketamine salt form is added to obtain the free base equivalent disclosed herein.

[0131] In some embodiments, the pH of the R(-)-ketamine formulation is increased using an inorganic base. In some embodiments, the pH of the R(-)-ketamine formulation is increased using an inorganic base at a concentration of 1 N. In some embodiments, the pH of the R(-)-ketamine formulation is increased using an inorganic base at a concentration of 0.5 N. In some embodiments, the pH of the R(-)-ketamine formulation is increased using an inorganic base at a concentration of 0.15 N. In some embodiments, the pH of the R(-)-ketamine formulation is titrated.

[0132] In some embodiments, the preparation process for a subcutaneous formulation comprising R(-)-ketamine discussed herein facilitates increasing the solubility of R(-)-ketamine. In some embodiments, the pH is adjusted slowly. In some embodiments, the pH is adjusted slowly with a dilute acid or a dilute base. In some embodiments, the pH is adjusted to minimize local fluctuations in pH. In some embodiments, the pH is adjusted to minimize small changes in pH in the solution. In some embodiments, the pH is adjusted slowly using a dilute acid or a dilute base to minimize small changes in pH in the solution. In some embodiments, the pH is adjusted slowly using a dilute acid or a dilute base to minimize small changes in pH in the solution, thereby improving the solubility of R(-)-ketamine in the formulation.

[0133] Injectable compositions of the present disclosure can be prepared by those skilled in the art using standard methods and conventional techniques appropriate for the desired formulation. Formulations for intramuscular or subcutaneous administration of the present disclosure can be filled and / or stored in suitable containers, such as syringes, ampoules, and vials, including sealed vials such as vials with syringe-pierceable septa or Sure-Seal caps. In some embodiments, the formulations are pre-filled into disposable syringes for patient self-administration, with or without an auto-injector. Each container can contain a desired dose of R(-)-ketamine or a pharmaceutically acceptable salt thereof.

[0134] To further minimize oxidative degradation of the active ingredient, the container may be filled with an inert gas, such as nitrogen and / or carbon dioxide, or otherwise oxygen-free. It is further contemplated that the container may be enclosed in a sealed package from which oxygen has been excluded. This may be achieved by vacuum packaging or by replacing oxygen with a blanket or purge of nitrogen, carbon dioxide, or other oxygen-free inert gas. After the seal is sealed, the packaging material itself should be relatively impermeable to oxygen diffusion. Additionally, the package should be opaque to ordinary light, as light can induce degradation of R(-)-ketamine. Standard methods for sealing and packaging the various containers described herein are known in the art and can be used in conjunction with packaging and / or storing the dosage forms of the present disclosure.

[0135] In some embodiments, the R(-)-ketamine formulation is contained in a "unit dosage form." The phrase "unit dosage form" refers to physically discrete units, each unit containing a predetermined amount of R(-)-ketamine sufficient to obtain a desired effect. It is understood that the parameters of the unit dosage form depend on the concentration of R(-)-ketamine in the formulation and the effect to be obtained.

[0136] R(-)-Ketamine formulation in maleate buffer R(-)-ketamine formulations at various pH values ​​were prepared in maleate buffer.

[0137] Maleate Buffer Ingredients: Maleic acid, C4H4O4, mw 116.07 ·NaOH, 1N aqueous solution Distilled water

[0138] Maleate buffer (100 mL at 20 mM) is prepared, for example, by adding 0.232 g maleic acid, 2 mL NaOH, and adding HO to 100 mL. R(-)-ketamine formulation (40 mg / mL) in 20 mM maleate buffer at pH 5.0 and R(-)-ketamine formulation (40 mg / mL) in 20 mM maleate buffer at pH 5.7

[0139] A formulation is prepared, for example, by adding 40 mg / ml of R(-)-ketamine free base equivalent (46 mg / ml of R(-)-ketamine hydrochloride) in 20 mM maleic acid buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M). R(-)-ketamine formulation (80 mg / mL) in 20 mM maleate buffer at pH 5.0 and R(-)-ketamine formulation (80 mg / mL) in 20 mM maleate buffer at pH 5.7

[0140] A formulation is prepared, for example, by adding 80 mg / ml of R(-)-ketamine free base equivalent (92 mg / ml of R(-)-ketamine hydrochloride) in 20 mM maleate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or equivalent to a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0141] R(-)-Ketamine formulation in fumarate buffer R(-)-ketamine formulations at various pH values ​​were prepared in fumarate buffer.

[0142] Fumarate buffer ingredients: Fumaric acid, C4H4O4, mw 116.07 ·NaOH, 1N aqueous solution Distilled water

[0143] Fumarate buffer (100 mL at 20 mM) is prepared, for example, by adding 0.232 g of fumaric acid, 2 mL of NaOH, and adding H2O to 100 mL. R(-)-ketamine formulation (40 mg / mL) in 20 mM fumarate buffer at pH 5.0 and R(-)-ketamine formulation (40 mg / mL) in 20 mM fumarate buffer at pH 5.7

[0144] A formulation is prepared, for example, by adding 40 mg / ml of R(-)-ketamine free base equivalent (46 mg / ml of R(-)-ketamine hydrochloride) in 20 mM fumarate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M). R(-)-ketamine formulation (80 mg / mL) in 20 mM fumarate buffer at pH 5.0 and R(-)-ketamine formulation (80 mg / mL) in 20 mM fumarate buffer at pH 5.7

[0145] A formulation is prepared, for example, by adding 80 mg / ml of R(-)-ketamine free base equivalent (92 mg / ml of R(-)-ketamine hydrochloride) in 20 mM fumarate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0146] R(-)-Ketamine formulation in citrate buffer R(-)-ketamine formulations at various pH values ​​were prepared in citrate buffer, and the citrate buffer was adjusted accordingly.

[0147] Prepare 1 liter of 20 mM citrate buffer, pH 5 [Table 1] 1. Prepare 800 mL of distilled water in a suitable container. 2. Add 3.42 g of sodium citrate dihydrate to the solution. 3. Add 1.608g of citric acid to the solution. 4. Adjust the solution to the final desired pH using HCl or NaOH 5. Add distilled water to bring the volume to 1 L.

[0148] Prepare 1 liter of pH 5.7 citrate buffer [Table 2] 1. Prepare 800 mL of distilled water in a suitable container. 2. Add 4.424 g of sodium citrate dihydrate to the solution. 3. Add 0.953 g of citric acid to the solution. 4. Adjust the solution to the final desired pH using HCl or NaOH 5. Add distilled water to bring the volume to 1 L.

[0149] R(-)-ketamine formulation (40 mg / mL) in 20 mM citrate buffer at pH 5.0 and R(-)-ketamine formulation (40 mg / mL) in 20 mM citrate buffer at pH 5.7 A formulation is prepared, for example, by adding 40 mg / ml of R(-)-ketamine free base equivalent (46 mg / ml of R(-)-ketamine hydrochloride) in 20 mM citrate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0150] R(-)-ketamine formulation (80 mg / mL) in 20 mM citrate buffer at pH 5.0 and R(-)-ketamine formulation (80 mg / mL) in 20 mM citrate buffer at pH 5.7 A formulation is prepared, for example, by adding 80 mg / ml of R(-)-ketamine free base equivalent (92 mg / ml of R(-)-ketamine hydrochloride) in 20 mM citrate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0151] R(-)-Ketamine formulation in succinate buffer R(-)-ketamine formulations at various pH values ​​were prepared in succinate buffer.

[0152] Succinate buffer components: Succinic acid, C4H4O4, mw 118.09 ·NaOH, 1N aqueous solution Distilled water

[0153] Fumarate buffer (100 mL at 20 mM) is prepared, for example, by adding 0.236 g succinic acid, 2 mL NaOH, and adding H2O to 100 mL. R(-)-ketamine formulation (40 mg / mL) in 20 mM succinate buffer at pH 5.0 and R(-)-ketamine formulation (40 mg / mL) in 20 mM succinate buffer at pH 5.7

[0154] A formulation is prepared, for example, by adding 40 mg / ml of R(-)-ketamine free base equivalent (46 mg / ml of R(-)-ketamine hydrochloride) in 20 mM succinate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0155] R(-)-ketamine formulation (80 mg / mL) in 20 mM succinate buffer at pH 5.0 and R(-)-ketamine formulation (80 mg / mL) in 20 mM succinate buffer at pH 5.7 A formulation is prepared, for example, by adding 80 mg / ml of R(-)-ketamine free base equivalent (92 mg / ml of R(-)-ketamine hydrochloride) in 20 mM succinate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or equivalent to a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0156] R(-)-Ketamine formulation in tartrate buffer R(-)-ketamine formulations at various pH values ​​were prepared in tartrate buffer.

[0157] Tartrate buffer ingredients: ·Tartaric acid, C4H6O6, mw150.09 Sodium tartrate dihydrate, mw 230.08 ·NaOH, 1N aqueous solution Distilled water

[0158] Tartrate buffer (1 L at 5 mM) is prepared, for example, by adding 0.75 g of tartaric acid, 2 mL of NaOH, and adding HO to 1 L. Tartrate buffer (1 L at 15 mM) is prepared, for example, by adding 3.452 g of sodium tartrate dihydrate, 2 mL of dilute acid, and adding HO to 1 L. Tartrate buffer (1 L at 20 mM) is prepared, for example, by adding 4.6 g of sodium tartrate dihydrate, 2 mL of dilute acid, and adding HO to 1 L.

[0159] R(-)-ketamine formulation (40 mg / mL) in 20 mM tartrate buffer at pH 5.0 and R(-)-ketamine formulation (40 mg / mL) in 20 mM tartrate buffer at pH 5.7 A formulation is prepared, for example, by adding 40 mg / ml of R(-)-ketamine free base equivalent (46 mg / ml of R(-)-ketamine hydrochloride) in 20 mM tartrate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0160] R(-)-ketamine formulation (80 mg / mL) in 20 mM tartrate buffer at pH 5.0 and R(-)-ketamine formulation (80 mg / mL) in 20 mM tartrate buffer at pH 5.7 A formulation is prepared, for example, by adding 80 mg / ml of R(-)-ketamine free base equivalent (92 mg / ml of R(-)-ketamine hydrochloride) in 20 mM tartrate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0161] Methods for treating diseases and disorders The methods disclosed herein can be used to treat a variety of diseases and disorders. In some cases, the disease or disorder is associated with depressive symptoms, and the methods of administering R(-)-ketamine compositions described herein can be used to treat depressive symptoms.

[0162] In some embodiments, the depressive symptoms are symptoms of a mood disorder in the subject. Exemplary mood disorders include depression, e.g., treatment-resistant depression or major depressive disorder. Further exemplary mood disorders include bipolar disorder, post-traumatic stress disorder, obsessive-compulsive disorder, autism spectrum disorder, schizophrenia, or dementia. Additional diseases or disorders, such as neurodegenerative diseases or disorders, neurodevelopmental disorders, and inflammatory or bone diseases, are also contemplated within the scope of the present disclosure. Exemplary diseases that can be treated using the R(-)-ketamine compositions and methods of using the same disclosed herein are described in International Publication Nos. WO / 2015 / 037248, WO2019 / 213551, WO2019 / 065900, WO2019 / 160057, and WO20200138491, the contents of each of which are incorporated herein by reference.

[0163] In some embodiments, the neurodegenerative disease or disorder includes Parkinson's disease, Parkinsonism, Huntington's disease, acanthocytic chorea, spinocerebellar degeneration, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, spinal-bulbar muscular atrophy, syringomyelia, neuroacanthocytosis, eating disorders, Alzheimer's disease, dementia with Lewy bodies, basal ganglia degeneration, multiple sclerosis, traumatic brain injury, cerebral infarction, or cardiovascular disease.

[0164] In some embodiments, the neurodevelopmental disorder includes schizophrenia, autism spectrum disorder, attention-deficit / hyperactivity disorder, or a learning disability.

[0165] In some embodiments, inflammatory diseases include ulcerative colitis, Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, insulin-dependent diabetes mellitus, Addison's disease, Goodpasture's syndrome, IgA nephropathy, interstitial nephritis, Sjogren's syndrome, autoimmune pancreatitis, psoriasis, atopic dermatitis, pneumonia, chronic bronchitis, bronchial asthma, systemic lupus erythematosus (SLE), scleroderma, or delirium, and bone diseases include osteoporosis, osteolytic bone metastasis, and Paget's disease of bone.

[0166] Mood disorders In some embodiments, the methods disclosed herein further include treating a mood disorder in a subject. As used herein, "mood disorder" refers to a mental health disorder accompanied by severe changes in mood. Exemplary mood disorders include, but are not limited to, treatment-resistant depression (TRD), major depressive disorder, bipolar disorder, dementia, low motivation, anxiety, insomnia, loss of appetite, obsessive-compulsive disorder, post-traumatic stress disorder, persistent depressive disorder, cyclothymic disorder, and seasonal affective disorder. Symptoms of mood disorders include, but are not limited to, anhedonia or negative affect, depressed mood, low motivation, anxiety, insomnia, loss of appetite, impulsivity, and stress sensitivity. In some embodiments, the methods disclosed herein include treating or ameliorating TRD. TRD can be defined as a depressive disorder that does not respond to treatment with two or more antidepressant regimens.

[0167] Treatment of substance abuse with R(-)-ketamine Racemic ketamine has been shown to have the potential to help alleviate withdrawal symptoms in patients following chronic opioid use (Non-Patent Document 38), and data from animal models suggest that racemic ketamine may be useful for attenuating addiction-related phenomena of drug tolerance and dependence for both opiates and ethanol (Non-Patent Documents 39, 40, 41). However, racemic ketamine also has many associated issues that make it a difficult choice for administration to patients, as described elsewhere herein. Racemic ketamine is also known to be potentially addictive, making it a difficult option for the treatment of substance use disorders (Non-Patent Documents 42, 43, 44). Furthermore, administration of racemic ketamine is associated with central nervous system damage, especially after long-term use (Non-Patent Document 45). Therefore, safer alternatives to racemic ketamine are needed.

[0168] The inventors of the present disclosure have conducted research demonstrating that R(-)-ketamine provides superior treatment for substance use disorders, such as opioid and alcohol use disorders, when compared with S(+)-ketamine and racemic ketamine. For example, in a mouse model of morphine addiction, R(-)-ketamine significantly attenuated the addictive properties of morphine when co-administered to mice, and R(-)-ketamine administered to rats significantly ameliorated morphine-induced withdrawal symptoms. R(-)-ketamine also reduced the effects of alcohol tolerance in rats. Surprisingly, R(-)-ketamine and its metabolite R-hydroxynorketamine, unlike S(+)-ketamine, did not exhibit side effects of anhedonia or negative affect in rats.

[0169] substance of abuse Drug abuse is related to their ability to produce certain subjective effects (e.g., euphoria) in humans. Many substances exist that can lead to substance use disorders in subjects. As used herein, the term "drug" refers to any substance that can cause addiction or dependence upon continued use. Both legal and illegal (illicit) substances can lead to substance use disorders. Drugs included within this term include alcohol, marijuana, synthetic cannabinoids, opioids, stimulants, barbiturates, benzodiazepines, dextromethorphan (DXM), sleeping pills, khat, synthetic cathinones, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), phencyclidine (PCP), lysergic acid diethylamide (LSD), psilocybin, inhalants, rohypnol, gamma-hydroxybutyric acid (GHB), N,N-dimethyltryptamine (DMT), ayahuasca, mescaline, salvia, and nicotine. However, all substances that can cause addiction or dependence are contemplated as falling within the scope of the present invention.

[0170] Most substances fall into three major categories: stimulants, depressants, and hallucinogens or dissociative substances. In some embodiments, particularly but not limited to, those in which the substance is a complex plant product such as marijuana, the substance may have more than one active ingredient and be classified into more than one of the three categories. In some embodiments, the substance may have a single active ingredient with multiple effects and may therefore be classified into more than one of the three categories. In some embodiments, the substance may be classified into a single category as a stimulant, a depressant, or a hallucinogen or dissociative substance.

[0171] The substances of the present disclosure may be naturally occurring, for example, purified from plant, animal, or fungal sources (e.g., marijuana, tobacco), synthetic (e.g., synthetic cathinones, LSD), or a combination thereof. The substances of the present disclosure may also be synthetic versions of substances originally purified from nature. An exemplary, but non-limiting, list of substances of the present disclosure is provided in Table 1. All substances and all biological mechanisms capable of inducing substance use disorders in a subject are contemplated as being within the scope of the present invention.

[0172] [Table 3-1] [Table 3-2] [Table 3-3]

[0173] Treatment of substance use disorders In some embodiments, the disclosed methods further include treating a substance use disorder in a subject. Substance use disorders are characterized by progressive, uncontrollable substance use that persists despite negative consequences (e.g., social, economic, and / or medical consequences). Substance use disorders feature a transition from well-controlled substance use to uncontrolled, destructive use. This transition may be sudden or gradual in nature. Substance use disorders are characterized by addiction or dependence on a substance. When a subject is dependent on or addicted to a substance, this means that there is a physical, physiological, or psychological response and / or interaction between the substance and the subject that results in the subject exhibiting or having a compulsive or obsessive use of the substance without any perceived purpose or need to treat the disorder. Rather, the goal is to achieve a desired effect and / or avoid withdrawal symptoms, as defined below, that occur when the substance is discontinued or reduced. Substance use disorders are sometimes referred to as "substance abuse," where the substance or substances to which the subject is addicted or dependent are "abused," such as opioid abuse or alcohol abuse.

[0174] In some embodiments, the substance use disorder includes abuse of alcohol, marijuana, synthetic cannabinoids, opioids, stimulants, barbiturates, benzodiazepines, dextromethorphan (DXM), sleeping pills, khat, synthetic cathinones, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), phencyclidine (PCP), lysergic acid diethylamide (LSD), psilocybin, inhalants, rohypnol, gamma-hydroxybutyric acid (GHB), N,N-dimethyltryptamine (DMT), ayahuasca, mescaline, salvia, or nicotine.

[0175] In some embodiments, the opioid comprises heroin, codeine, fentanyl, hydrocodone (dihydrocodeinone), hydromorphone, meperidine, methadone, morphine, oxycodone, or oxymorphone. In some embodiments, the stimulant comprises amphetamine, amphetamine sulfate, methamphetamine, dextroamphetamine, levoamphetamine, lisdexamphetamine, atomoxetine, methylphenidate, dexmethylphenidate, oxymetazoline, pseudoephedrine, phenylephrine, or a combination thereof. In some embodiments, the benzodiazepine comprises aprazolam, chlorodiazepoxide, diazepam, lorazepam, or triazolam. In some embodiments, the barbiturate comprises phenobarbital, pentobarbital, methohexital, secobarbital, butabarbital, or butalbital. In some embodiments, the hypnotic comprises eszopiclone, zaleplon, or zolpidem.

[0176] In some embodiments, a therapeutically effective amount of a composition comprising R(-)-ketamine does not induce anhedonia or negative affect in a subject. Anhedonia and negative affect are symptoms associated with substance use disorders of the present disclosure. As used herein, anhedonia, a clinical feature of mood disorders such as depression and bipolar disorder, refers to a reduced or lost ability to experience pleasure. Negative affect refers to the prevalence of negative moods and emotions in a subject that are contrary to well-being. Anhedonia and negative affect are believed to be important factors involved in both relapse and the transition from recreational to excessive substance use. Without wishing to be bound by theory, anhedonia and negative affect are thought to originate from dopaminergic mesolimbic and mesocortical reward circuits. Surprisingly, the R(-)-ketamine compositions and methods of the present disclosure do not induce anhedonia or negative affect. Because subjects experience anhedonia and negative affect both while abusing substances in substance use disorders and while attempting to stop substance abuse, treatments that do not themselves cause or exacerbate anhedonia or negative affect are preferred and are more effective treatments for substance use disorders.

[0177] In some embodiments, the substance use disorder comprises opioid abuse, hi some embodiments, the substance use disorder comprises alcohol abuse.

[0178] In some embodiments, administration of the composition reduces symptoms of withdrawal or prevents relapse of a substance use disorder in a subject. In some embodiments, administration of the composition reduces tolerance to a substance of a substance use disorder in a subject. In some embodiments, administration of the composition reduces dependence on a substance of a substance use disorder in a subject. In some embodiments, administration of the composition improves compliance with treatment for a substance use disorder in a subject. In some embodiments, administration of the composition reduces liking for or decreases liking for a substance of a substance use disorder in a subject. In some embodiments, administration of the composition improves withdrawal from a substance of a substance use disorder in a subject.

[0179] In some embodiments, the method further comprises treating at least one withdrawal symptom of substance use in a subject. Withdrawal occurs when a subject who has become accustomed to a relatively stable level of a substance is suddenly deprived of that substance. Withdrawal symptoms can be physical or mental in nature, or a combination thereof. Specific withdrawal symptoms can depend on the substance being withdrawn, the amount and duration of substance use, and the individual. The onset of withdrawal symptoms can be immediate or delayed.

[0180] In some embodiments, the at least one substance use withdrawal symptom comprises a symptom of withdrawal from an opioid, hi some embodiments, the at least one substance use withdrawal symptom comprises a symptom of withdrawal from alcohol.

[0181] In some embodiments, the at least one substance use withdrawal symptom comprises a physical symptom of withdrawal, a psychiatric symptom of withdrawal, or a combination thereof. In some embodiments, the physical symptom of withdrawal comprises tremors, insomnia, sleep disturbances, headache, sweating, nausea, vomiting, muscle pain, muscle stiffness, high blood pressure, irregular heartbeat, increased heart rate, palpitations, dizziness, tremors, tremors, seizures, dehydration, shallow breathing, fatigue, loss of appetite, dull skin, pale complexion, or a combination thereof. In some embodiments, the psychiatric symptom of withdrawal comprises anxiety, irritability, difficulty concentrating, difficulty thinking, mood swings, nightmares, depression, tension, panic attacks, short-term memory loss, agitation, helplessness, stress sensitivity, increased responsiveness to substance-associated cues, abnormal reward information processing, substance craving, or a combination thereof.

[0182] In some embodiments, the method further comprises treating psychiatric symptoms associated with substance use disorder in the subject. Symptoms of substance use disorder depend on the substance used, the duration and amount of use, and the subject. These symptoms can be physical or mental in nature, or a combination thereof. Physical symptoms of substance use include, but are not limited to, tremors, insomnia, sleep disturbances, headaches, sweating, nausea, vomiting, muscle pain, muscle stiffness, high blood pressure, irregular heartbeat, increased heart rate, palpitations, dizziness, tremors, seizures, dehydration, shallow breathing, fatigue, loss of appetite, dull skin, poor complexion, or a combination thereof. Psychiatric symptoms of substance use include, but are not limited to, anxiety, irritability, difficulty concentrating, impaired thinking, mood swings, nightmares, depression, tension, panic attacks, short-term memory loss, agitation, helplessness, stress sensitivity, increased responsiveness to substance-related cues, abnormal reward information processing, cravings, or a combination thereof.

[0183] In some embodiments, the psychiatric symptoms include psychiatric symptoms of a mood disorder comorbid with a substance use disorder, hi some embodiments, the mood disorder includes major depressive disorder, bipolar disorder, post-traumatic stress disorder, obsessive-compulsive disorder, or dementia.

[0184] In some embodiments, psychiatric symptoms include anxiety, irritability, difficulty concentrating, difficulty thinking, mood swings, nightmares, depression, tension, panic attacks, short-term memory loss, agitation, helplessness, stress sensitivity, increased responsiveness to substance-associated cues, abnormal reward processing, substance craving, or a combination thereof.

[0185] In some embodiments, the composition is administered prior to the onset of at least one psychiatric symptom in the subject. In some embodiments, the composition is administered simultaneously with the onset of at least one psychiatric symptom in the subject. In some embodiments, the composition is administered after the onset of at least one psychiatric symptom in the subject. In some embodiments, the composition reduces or eliminates at least one psychiatric symptom in the subject.

[0186] Adverse events As used herein, the term "adverse event" refers to any undesired medical occurrence occurring in a subject and temporally associated with the use of the methods described herein. For example, an adverse event (AE) can be any undesired or unintended sign (e.g., an abnormal laboratory finding), symptom, or disease (new or worsening temporally associated with the use of the methods described herein). In some embodiments, an AE can be an abnormal clinical test result (hematology, clinical chemistry, or urinalysis) or other safety assessment (e.g., ECG, radiology scan, vital sign measurement), a worsening of a chronic or intermittent pre-existing condition, a new condition detected or diagnosed after the use of the methods described herein, a sign, symptom, or clinical sequelae of a suspected drug-drug interaction, or a sign, symptom, or clinical sequelae of a suspected overdose of any of the compositions or concomitant medications described herein. As used herein, the term "serious adverse event" refers to any undesirable medical event at any dose that a) results in death, b) is life-threatening, c) requires hospitalization or an extension of an existing hospitalization, d) results in permanent disability / incapacity, or e) is a congenital anomaly / birth defect. In some embodiments, use of the methods described herein occurs in the absence of adverse events and serious adverse events. In some embodiments, the methods described herein reduce adverse events compared to a comparable method of administering S(+)-ketamine or racemic ketamine.

[0187] Kits and manufactured products In another aspect, the present specification provides kits containing the R(-)-ketamine compositions of the embodiments described herein. In some embodiments, the kits further include packaging for the R(-)-ketamine composition and instructions for use.

[0188] In this description, many example configurations, methods, parameters, and the like are set forth. However, it should be recognized that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of example embodiments. The above-described embodiments of the inventive subject matter may be beneficial alone or in combination with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting embodiments of the present disclosure are provided below. As will be apparent to one of ordinary skill in the art upon reading this disclosure, each of the embodiments may be used or combined with any of the preceding or following embodiments. This is intended to provide support for all such combinations of embodiments, and is not limited to the combinations of embodiments expressly provided. [Example]

[0189] Example 1: Safety and Efficacy of R(-)-Ketamine in Human Subjects A. Clinical Trial Overview This disclosure is a proof-of-concept study to evaluate efficacy and safety, providing evidence that R(-)-ketamine can be developed as a rapidly acting antidepressant for the potential treatment of treatment-resistant depression (TRD). To date, there has been one clinical trial evaluating the safety of R(-)-ketamine. The primary objective of this study was to identify a tolerable dose of R(-)-ketamine in healthy subjects and compare this dose with the safety profile of 15 mg of S(+)-ketamine, a dose that demonstrated potent antidepressant effects in a published study of TRD patients (Non-Patent Document 36). A dose range using single, ascending doses of R(-)-ketamine demonstrated that doses of 150 mg or less of R(-)-ketamine have an acceptable safety profile as a single 40-minute IV infusion. A comparison of the safety of dose levels of R(-)-ketamine with 15 mg of S(+)-ketamine identified 60 mg of R(-)-ketamine as the dose level most similar to 15 mg of S(+)-ketamine in terms of safety profile. The 30 mg and 60 mg doses of R(-)-ketamine were associated with fewer transient increases in mean systemic blood pressure, less sedation, fewer psychiatric or psychotic and dissociative effects, and fewer episodes of altered consciousness than the 100 mg or 150 mg doses of R(-)-ketamine.

[0190] The 30 mg and 60 mg doses used in this clinical trial were selected based on the results of a Phase 1 single ascending dose study in healthy volunteers (see Example 2 below). Due to its four-fold lower affinity for the receptor, R(-)-ketamine is hypothesized to have fewer N-methyl-D-aspartate receptor (NMDAR)-related side effects, such as psychotomimetic effects and dissociation, compared with racemic ketamine or S(+)-ketamine. R(-)-ketamine has 15-fold higher affinity for sigma receptors compared with S(+)-ketamine. Therefore, ketamine's sigma-related side effects may be largely caused by R(-)-ketamine. This effect of R(-)-ketamine may be involved in the hallucinogenic effects of racemic ketamine and may also be responsible for the lowered seizure threshold seen with racemic ketamine.

[0191] Adverse events (AEs) reported in limited academic clinical trials evaluating subanesthetic doses of R(-)-ketamine in healthy volunteers at up to 1 mg / kg IV bolus or short-term infusion, or 1.8 mg / kg intramuscularly, included transient increases in blood pressure, changes in affect, illusions, sedation, impaired proprioception and sensation, impaired concentration and primary memory, blurred vision, auditory changes, and dizziness. Overall, R(-)-ketamine was reported to produce less pronounced psychotomimetic and dissociative-like effects than S(+)-ketamine (Non-Patent Documents 20, 21, 22, 23, 24, 25). Results from an open-label pilot study of a single IV infusion of R(-)-ketamine (0.5 mg / kg) administered to seven subjects with TRD suggested that R(-)-ketamine may provide a rapid onset and sustained antidepressant effect with a favorable safety profile (Non-Patent Document 35).

[0192] Ketamine has been reported to be used as a drug of abuse. Dependence and tolerance to ketamine can occur after long-term administration. Although R(-)-ketamine may have abuse potential, non-clinical data suggest that R(-)-ketamine has a lower abuse potential than racemic ketamine or S(+)-ketamine due to its pharmacological properties, such as lower affinity for NMDAR and lack of effect on the dopamine pathway (Non-Patent Documents 4, 30, 31, 32). The abuse and dependence potential of R(-)-ketamine in humans is unknown and has not yet been studied.

[0193] Several in vitro studies have been conducted to examine the in vitro drug metabolism and pharmacokinetics of R(-)-ketamine. Multiple cytochrome P450 (CYP) isoforms, primarily CYP2B6, CYP3A4 / 5, and CYP2C19, are involved in the metabolism of R(-)-ketamine. R(-)-ketamine is considered an inhibitor of CYP2B6 and CYP2C19 and an inducer of CYP1A2, CYP2B6, and CYP3A4. Drug-drug interactions with CYP2B6 and CYP3A4 substrates are possible. The clinical impact of these drug-drug interactions (DDIs) is thought to be minimal.

[0194] B. Study Design The investigational medicinal product (IMP), R(-)-ketamine hydrochloride in sterile water for intravenous injection, was studied as a home treatment for TRD. The International Union of Pure and Applied Chemistry (IUPAC) name for IMP is (2R)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one. Subjects received either a 30 mg or 60 mg dose of the solution or a placebo. IMP or placebo was administered as a single IV infusion over 40 minutes via an electronic infusion pump on Day 1. Each subject participated in the study for a maximum of 29 days, including a screening period, three clinic visits, and two follow-up visits. 101 subjects were enrolled at approximately 20 study sites in the EU and the US.

[0195] This was a double-blind, randomized, placebo-controlled, multicenter trial consisting of three phases: screening (up to 2 weeks [days -15 to -2]), in-clinic treatment (days -1 to -2, including double-blind treatment [day 1]), and post-treatment follow-up (days 8 and 15, 7 and 14 days after infusion, respectively). The trial consisted of three groups: placebo, R(-)-ketamine solution (30 mg), and R(-)-ketamine solution (60 mg). A total of 101 adult subjects with TRD were randomly assigned to the three arms of the trial in a blinded manner, in cohorts of 33 to 35 subjects per group.

[0196] Subjects were randomized within 14 days of screening (Visit 1). Subjects were admitted to the clinic the evening before administration of study treatment (Day -1, Visit 2) and underwent baseline testing to ensure continued study eligibility. Study treatment was administered by IV infusion over 40 minutes the following morning (Day 1, Visit 2). Subjects were closely monitored for safety, beginning immediately prior to administration.

[0197] In addition, subject alertness, mood, and other psychological parameters were assessed using clinician- and subject-completed scales and questionnaires. Subjects were discharged no sooner than 24 hours after infusion and after the final in-clinic assessment was completed (Day 2, Visit 2). Subjects were asked to return to the clinic approximately 6 days (Day 8, Visit 3) and 13 days (Day 15, Visit 4) after discharge to assess the safety and tolerability of the study treatment and to determine the durability of antidepressant effect.

[0198] The study population included adult men and women, aged 18 to 65 years, who met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) diagnostic criteria for major depressive disorder (MDD) without psychotic features as confirmed by the Mini-Instrumental Interview for Mental Disorders (MINI). Based on published data from racemic ketamine, R(-)-ketamine may have the potential for adverse fetal effects when administered to pregnant women. Therefore, female subjects of childbearing potential should be appropriately protected from pregnancy, and pregnant women should not be enrolled.

[0199] Primary Objectives and Estimand To determine the efficacy of two doses of intravenous (IV) R(-)-ketamine hydrochloride (30 mg and 60 mg), these doses were administered as an IV infusion over 40 minutes. These doses were within the range shown to be well tolerated in Phase 1 studies in healthy volunteers. Two doses of IV R(-)-ketamine hydrochloride (30 mg and 60 mg) were compared with placebo to determine the most effective dose for improving depressive symptoms in subjects with TRD, as assessed by the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score up to 24 hours after the start of the R(-)-ketamine hydrochloride infusion. The 10-item clinician-administered MADRS was designed to measure the overall severity of depressive symptoms in subjects with MDD. The MADRS scale has been validated, reliable, and recognized by health regulatory agencies as a primary measure of efficacy in major depression.

[0200] The primary estimand was defined as follows: Population: Subjects with TRD in the Full Analysis Set (FAS) who will be analyzed according to their randomized treatment. The analysis set includes all randomized subjects who received any amount of study treatment and have at least one available post-baseline assessment.

[0201] Variable: Change in total MADRS score from baseline 24 hours after initiation of infusion.

[0202] Intercurrent Events (ICE): Events in which a subject did not receive the full treatment infusion were considered intercurrent events. Intercurrent events were handled with a policy of using all measurements regardless of their occurrence. No imputation was performed in the primary efficacy analysis.

[0203] Population-level summary: Difference in mean change from baseline between each R(-)-ketamine group vs. placebo.

[0204] Additional methodologies will be identified in the Statistical Analysis Plan (SAP) for sensitivity and supplementary analyses to assess the robustness of the results. These sensitivity or supplementary analyses will explore different methods for handling intercurrent events and different assumptions about missing data.

[0205] Secondary objectives and estimand: To assess the proportion of subjects who demonstrated a response (defined as a 50% or greater improvement in MADRS total score from baseline).

[0206] To assess the proportion of subjects who achieved remission (defined as a MADRS total score of 10 or less).

[0207] To characterize change on the Hamilton Rating Scale for Depression (HAM-D). The HAM-D is a multi-item questionnaire designed to provide an index of depression in adults and used as a guide to assess recovery. This questionnaire is designed to assess the severity of depression by examining mood, guilt, suicidal ideation, insomnia, agitation or inhibitions, anxiety, weight loss, and somatic symptoms.

[0208] Generalized Anxiety Disorder 7-Item (GAD-7). The GAD-7 is a self-administered 7-item scale used to diagnose anxiety and has the sensitivity and specificity to screen for panic, social anxiety, and post-traumatic stress disorder.

[0209] Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I). The CGI-S and CGI-I scales can assess the minimal clinically important difference using an anchor-based approach calculated from the clinician's and subject's overall impressions.

[0210] Brief Inventory of Depressive Symptoms Scale-16 Items (QIDS-SR-16). The QIDS-SR-16 is a 16-item self-report measure of depression that has very similar sensitivity to the Inventory of Depressive Symptomatology Self-Report-30 Items and the Hamilton Depression Rating Scale-24 Items in detecting changes in depressive symptoms.

[0211] European Quality-5 Dimensions-3 Levels (EQ-5D-3L). The EQ-5D is a widely accepted, self-contained instrument for assessing health-related quality of life in the domains of mobility, ability to care for one's own needs, carrying out usual activities, pain / discomfort, and anxiety / depression.

[0212] To determine the safety and tolerability of two doses of IV administered R(-)-ketamine compared to placebo in subjects with TRD.

[0213] All secondary efficacy estimands were defined using the same populations, ICE strategies, and population-level summaries (mean or percentage differences between each randomized treatment and placebo, as appropriate) as described above. The estimand variables were as follows: The MADRS total score was assessed 2 and 4 hours after the start of the infusion, and on days 7 and 14 (days 8 and 15, respectively). Note that sleep and appetite items were not assessed for the 2- and 4-hour recall periods.

[0214] Percentage of subjects achieving a 50% or greater improvement in the MADRS total score at 24 hours, 7 days, and 14 days (days 8 and 15, respectively) after the start of the infusion.

[0215] Percentage of subjects with a MADRS total score of 10 or less at 24 hours, 7 days, and 14 days after initiation of infusion (days 8 and 15, respectively).

[0216] Changes in HAM-D on days 8 and 15 after the start of infusion.

[0217] Change from baseline in GAD-7 at each visit.

[0218] Change from baseline in CGI-S and CGI-I (calculated from pre-dose CGI-S) at each visit.

[0219] Change from baseline in QIDS-SR-16 at each visit.

[0220] Change from baseline in EQ-5D-3L at each visit.

[0221] Safety will be assessed by vital signs, 12-lead electrocardiogram (ECG), oxygen saturation (SpO2), clinical laboratory parameters, AEs, modified observer assessment of alertness / sedation (MOAA / S), clinician-administered dissociative states scale (CADSS), brief psychiatric symptom rating scale-revised 4 components (BPRS+), 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC), and Columbia-Suicide Severity Rating Scale (C-SSRS).

[0222] Selection Criteria Subjects were eligible to participate in the study only if all of the following criteria were met: Ability to provide signed informed consent, including compliance with the requirements and restrictions set out in the Informed Consent Form (ICF) and this protocol.

[0223] A man or woman who is between the ages of 18 and 65 at the time of signing the ICF.

[0224] Weight ≥ 50 kg, body mass index (BMI) ≥ 18 and ≤ 35.

[0225] Have a diagnosis of recurrent major depressive disorder (MDD) without psychotic features according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), as confirmed by the Mini-Interview for Mental Disorders (MINI).

[0226] A HAM-D total score >20 at screening and baseline (day -1).

[0227] In the current depressive episode, there has been an inadequate response to at least two antidepressants, each administered at an adequate dose for at least 6 weeks as defined by the Massachusetts General Hospital Depressant Response Questionnaire (MGH-ATRQ).

[0228] Subjects must be on stable oral antidepressant therapy with no change in dose for at least 30 days prior to screening (missing a dose during that period, or a reasonable number of missed doses at the investigator's discretion, will not exclude subjects).

[0229] Male subjects must be medically sterile for at least 6 months prior to screening, or agree to use highly effective contraception during the treatment period and for at least 3 months after the last dose of study treatment, and must refrain from donating sperm during this period. If a man with an OCBP is included, his partner must also use highly effective contraception.

[0230] Female subjects are eligible to participate if they are not pregnant, not lactating, and meet at least one of the following conditions: Non-pregnant women. Subjects are OCBPs who agree to follow highly effective contraceptive guidance for highly effective contraception during the treatment period and for at least 3 months after the last dose of study treatment and to refrain from donating eggs during this period.

[0231] Medically stable based on physical examination, medical history, vital signs, and 12-lead ECG performed at screening. If abnormalities are present, the subject may be included only if the investigator determines that the abnormality is not clinically significant. This decision must be recorded on the subject's source documentation and must be initialed and dated by the investigator.

[0232] Exclusion criteria Subjects will be excluded from the study if any of the following criteria apply: History of, or current signs and symptoms of, any disease or condition that may make participation not in the subject's best interest (e.g., compromising health) or that may interfere with, limit, or confound protocol-specified evaluations.

[0233] History of moderate or severe head trauma (e.g., loss of consciousness for more than 15 minutes) or other neurological disorder (including a diagnosis of epilepsy or a history of seizures within the last 6 months), neurodegenerative disorder (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease), or any systemic medical illness that, in the opinion of the investigator, is likely to interfere with the conduct of the trial or confound the trial evaluations. A history of childhood febrile convulsions is not excluded.

[0234] Have a current (active) primary DSM-V diagnosis of MDD with psychotic features, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, anorexia nervosa, or bulimia nervosa. Comorbid anxiety or panic disorder that does not dominate clinical symptoms is permitted.

[0235] Have a current or previous DSM-V diagnosis of a primary psychotic disorder (e.g., schizophrenia), bipolar or related disorder (as confirmed by MINI), intellectual disability or autism spectrum disorder, or borderline personality disorder.

[0236] Any serious disease or disorder (e.g., cardiovascular, pulmonary, gastrointestinal, hepatic, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical disorder) that, in the opinion of the investigator, may put the subject at risk from participation in the trial, affect the outcome of the trial, or affect the subject's ability to participate in the trial.

[0237] At screening, subjects may have uncontrolled hypertension (systolic blood pressure [SBP] >160 mmHg or diastolic blood pressure [DBP] >90 mmHg) despite medication or any history of hypertensive crisis. Abnormal blood pressure values ​​at screening may be repeated once after 10-15 minutes of relaxation to determine subject eligibility.

[0238] Have clinically relevant ECG abnormalities at screening or baseline (Day -1), including, but not limited to, the following: QT interval corrected according to the Fridericia formula, (QTcF) interval >450 msec for male subjects and >470 msec for female subjects; evidence of second- and third-degree atrioventricular block, complete left bundle branch block (LBBB), or complete right bundle branch block (RBBB); new ischemic features; arrhythmias (excluding premature atrial contractions [PACs] and premature ventricular contractions [PVCs]); or a medical history of risk factors or family history of long QT syndrome, including hypokalemia.

[0239] Subjects with a known history of or positive serology for human immunodeficiency virus (HIV), positive hepatitis B surface antigen, and / or confirmed current hepatitis C infection (positive hepatitis C virus [HCV] antibody confirmed by reflex HCV ribonucleic acid [RNA] test). Subjects with a history of hepatitis B vaccination but no history of hepatitis B will be allowed to enroll.

[0240] History of malignancy within 5 years prior to screening (exceptions are squamous cell and basal cell carcinoma of the skin and cervical intraepithelial neoplasia, or malignancies considered to have minimal risk of recurrence).

[0241] Have homicidal ideation / intent according to the investigator's clinical judgment, or have suicidal ideation with some intent to act within the month prior to the start of screening according to the investigator's clinical judgment or based on the C-SSRS corresponding to a "yes" response on item 4 (active suicidal ideation with some intent to act, without a specific plan) or item 5 (active suicidal ideation with a specific plan and intent), or have a history of suicidal behavior within the past year prior to the start of the screening / prospective observation phase.

[0242] Have undergone major surgery (e.g., requiring general or local anesthesia) within 4 weeks prior to screening, or have not fully recovered from surgery or planned surgery during the period in which the subject is expected to participate in the clinical trial.

[0243] Moderately impaired liver function at screening, defined as serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2x the upper limit of normal (ULN) or total bilirubin (TBL) >2x the ULN.

[0244] Have received any unauthorized therapy, including: Received a known strong inhibitor of hepatic cytochrome P450 (CYP) 2B6 or CYP3A, active within 1 week or within 5 half-lives of the drug, whichever is longer, prior to the first dose of study drug on Day 1; Received unauthorized antipsychotic treatment within the past 30 days prior to screening, except that subjects receiving stable doses of quetiapine, aripiprazole, brexpiprazole, or olanzapine prescribed as adjunctive treatment for depression (without psychosis) may be included in the study; Have had any change in type or dose of psychotropic medication within the past 30 days prior to screening; Have received treatment with a monoamine oxidase inhibitor (MAOI) currently or within the past 30 days prior to screening; Oral contraceptive doses must not contain more than 30 micrograms of ethinyl estradiol per day.

[0245] Have started psychotherapy (e.g., cognitive behavioral therapy, interpersonal psychotherapy, psychodynamic psychotherapy other than psychoeducation, or acupuncture) within the past 90 days prior to screening. Patients planning to start individual or group therapy during the study are also ineligible.

[0246] Have received electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve stimulation, deep brain stimulation, or other brain stimulation therapy within the past 4 weeks, or are currently using it as acute or maintenance treatment for depression.

[0247] Received any investigational drug (IP) within 30 days or 5 half-lives prior to administration of R(-)-ketamine.

[0248] Have a history of substance abuse (drugs or alcohol) or dependence (excluding nicotine or caffeine) within the past 6 months prior to the screening visit.

[0249] Have a positive urine drug screen or a positive alcohol screen for ketamine, opiates, cocaine, barbiturates, and / or amphetamine / methamphetamine at screening or day -1.

[0250] Subjects who test positive at screening due to prescribed opiates or amphetamines may be allowed to continue in the screening phase if the prohibited medication is discontinued at least 1 week or 5 half-lives, whichever is longer, before the first dose of study medication. Retesting will not be permitted for positive test results due to non-prescribed use of drugs of abuse.

[0251] had a history of prior non-response to ketamine, R(-)-ketamine, or S(+)-ketamine, or had received 8 or more doses of ketamine, R(-)-ketamine, or S(+)-ketamine in their lifetime;

[0252] Have a history of intolerance to ketamine, R(-)-ketamine, or S(+)-ketamine.

[0253] History of ketamine, R(-)-ketamine, S(+)-ketamine, or phencyclidine abuse.

[0254] Subjects must not consume grapefruit, grapefruit juice, or Seville orange-related products for 72 hours prior to IP administration and throughout the study.

[0255] Have clinically relevant long-term COVID-19 symptoms. Have current signs or symptoms of COVID-19.

[0256] COVID-19 vaccination is acceptable as long as it is administered at least 30 days before administration of the investigational drug, and vaccination will not be permitted during the course of the trial.

[0257] Abbreviation 5D-ASC 5-Dimensional Altered States of Consciousness Rating Scale AE Adverse Event ALT alanine aminotransferase AST aspartate aminotransferase BMI Body Mass Index BPRS+ Brief Psychiatric Rating Scale-Revised 4 Components CADSS Clinician-Administered Dissociative Status Scale CFR Code of Federal Regulations CGI-I Clinical Global Impression-Improvement CGI-S Clinical Global Impression-Severity CI confidence interval COVID-19 Coronavirus Disease 2019 CRF Case Report Form CRO Contract Research Organization C-SSRS Columbia-Suicide Severity Rating Scale CYP cytochrome P450 DBP Diastolic Blood Pressure DSM-V Diagnostic and Statistical Manual of Mental Disorders, 5th Edition ECG electrocardiogram EDC Electronic Data Capture End of EoI injection EQ-5D-3L European Quality-5 Dimensions-3 Levels EU European Union EudraCT European Union Drug Regulating Authorities Clinical Trials (database) FAS full analysis set GAD-7 Generalized Anxiety Disorder 7-item scale GCP Good Clinical Practice GGT gamma-glutamyltransferase HAM-D Hamilton Depression Rating Scale HCV Hepatitis C virus HIV human immunodeficiency virus ICE Intercurrent Event ICF Informed Consent Form ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IEC Independent Ethics Committee IMP Investigational Drug IRB Independent Review Board IUPAC International Union of Pure and Applied Chemistry IV (intravenous) IWRS Interactive Web Response System LBBB Left bundle branch block LS Least Squares LDH lactate dehydrogenase MADRS Montgomery-Asberg Depression Rating Scale MAOI monoamine oxidase inhibitors MAR Missing at Random MDD Major depressive disorder MedDRA International Medical Terminology, Version 23.0 or later MGH-ATRQ Massachusetts General Hospital Antidepressant Therapy Response Questionnaire MINI Mini Mental Health Interview MMRM Mixed-effects Model for Repeated Measures Data MoAA / S Modified Observer Assessment of Arousal / Sedation n Number of subjects NMDA N-methyl-D-aspartate NMDAR N-methyl-D-aspartate receptor NPL non-patent literature OCBP Women of childbearing potential PAC Premature atrial contraction PK Pharmacokinetics PTL patent literature PVC Premature Ventricular Contractions QIDS-SR-14 Brief Depressive Symptoms Scale - 14 items QIDS-SR-16 Brief Depressive Symptoms Scale - 16 items QTc corrected QT interval QTcF: QT interval corrected according to Fridericia's formula RBBB right bundle branch block SAE serious adverse event SAP Statistical Analysis Plan SBP systolic blood pressure SD standard deviation SpO2 oxygen saturation TBL Total bilirubin TEAE Treatment-emergent adverse events TRD Treatment-Resistant Depression UNL Upper limit of standard value US VAS visual analogue scale

[0258] C. Action Schedule As shown in Tables 2, 3, and 4, study activities included Visit 1 for screening between Days -15 and -2, Visit 2 for baseline assessment on Day -1, in-clinic medication administration on Day 1, and discharge on Day 2, Visit 3 for follow-up on Day 8 (±1 day), and Visit 15 (±1 day). a The study included four follow-up visits.

[0259] [Table 4]

[0260] [Table 5]

[0261] [Table 6] Notes applicable to Tables 2, 3 and 4.

[0262] a. Subjects who discontinue the study early will complete the assessments and procedures at Visit 4 as part of their early termination procedures.

[0263] b. All post-dose time points are relative to the start of the infusion, except for the 40 minute (EoI) time point, which must occur 40 minutes after the start of the infusion or at the end of the infusion if the infusion lasts longer than 40 minutes.

[0264] c. When actions at a given time point overlap, consideration must be given to ensuring that the following order of actions is maintained: efficacy measures (if more than one efficacy measure is assessed at a time point, the order of assessment must be MADRS, CGI-I and CGI-S, QIDS-SR-14 / 16, HAM-D, GAD-7, and EQ5D-3L), 12-lead ECG, vital signs and pulse oximetry, safety measures (order: MOAA / S, CADSS, and BPRS+), observation for AEs, concomitant medication review, physical examination, and clinical laboratory assessments (including urine pregnancy test and drug / alcohol screen).

[0265] d. Evaluations and procedures should be initiated as soon as possible after EoI.

[0266] e. Check eligibility.

[0267] f. Evaluate clinical hematology and chemistry panels (non-fasting blood sample required, but both fasting and non-fasting samples are acceptable).

[0268] g. Collect prior to clinical laboratory evaluation. If possible, perform ECG in supine position 5 minutes later.

[0269] h. Collect before clinical laboratory assessment. Vital signs include SBP / DBP, heart rate, respiratory rate, and temperature (tympanic / temporal). Blood pressure and pulse measurements must be taken after the subject has been at rest in a supine or semi-supine position for at least 5 minutes. Blood pressure should be recorded using the same arm and position (supine or semi-supine), if possible, throughout the trial. Three consecutive blood pressure readings should be recorded with at least 1 minute between readings, and the average of the three blood pressure readings should be recorded on the CRF. Abnormal blood pressure values ​​at screening may be repeated again after 10-15 minutes of relaxation to determine the subject's eligibility.

[0270] i. Urine drug screens will be performed by the facility's laboratory and will include alcohol, ketamine, opiates, cocaine, barbiturates, and / or amphetamines / methamphetamines. Benzodiazepines will be allowed up to 6 hours before the start of the infusion and as rescue medication if needed.

[0271] j.HAM-D, MADRS, CGI-S, CGI-I, GAD-7, and EQ-5D-3L must be assessed by a separate investigator not involved in safety assessments to avoid functional unblinding.

[0272] The k.MADRS has three versions: a 7-day recall, a 24-hour recall, and a 2-hour recall. In the 2-hour and 4-hour recalls, sleep and appetite items were not assessed, and pre-administration scores for these items obtained on the same day were carried forward.

[0273] l. The QIDS-SR-14 with a 24-hour recall period will be used at the Visit 2 Day 2 assessment for the recall period.

[0274] m. Note: The pre-dose CGI-S will be used as the basis for calculating the CGI-I at Visit 2.

[0275] n. Note: The C-SSRS may be assessed by either efficacy or safety assessors.

[0276] Clinical trial treatment compliance Deviations from the prescribed dose, timing, and mode of administration were recorded on the appropriate CRF. Noncompliance was defined as receiving less than a complete infusion or deviation from the 40-minute infusion time. All medications or vaccines (including over-the-counter or prescription medications, vitamins, and / or herbal supplements) received by subjects at enrollment (within 30 days prior to the screening visit) or during the study were recorded on the CRF. The following medications were prohibited for the duration of the study, beginning 1 week (or 5 half-lives, whichever is longer) prior to baseline (Day -1): Receiving a known strong inhibitor of hepatic cytochrome P450 (CYP) 2B6 or CYP3A activity within 1 week or 5 half-lives of the drug, whichever is longer, prior to the first dose of study drug on Day 1. Treatment with an unapproved antipsychotic within the past 30 days prior to screening, except that subjects receiving a stable dose of quetiapine, aripiprazole, brexpiprazole, or olanzapine prescribed as adjunctive treatment for depression (without psychosis) may be included in the study. Any change in type or dose of psychotropic medication within the past 30 days prior to screening. Treatment with a monoamine oxidase inhibitor (MAOI) currently or within the past 30 days prior to screening. The following medications were restricted for the duration of the study, starting from the screening visit through completion of assessments at Visit 4 (Day 15) or the discontinuation visit: The daily dose of benzodiazepine receptor agonists was limited to 2 mg / day or less of lorazepam or equivalent. Benzodiazepines were prohibited within 6 hours prior to administration. Short-acting benzodiazepines, excluding clobazam, may be used as rescue medication to treat intolerable hallucinations / dissociative effects or any other symptoms, at the investigator's discretion. Rescue medications may be used for other symptoms, including anxiety / agitation, nausea / vomiting, dissociation, and blood pressure / hypertension, per the investigator's discretion. Oral contraceptive doses must not contain more than 30 micrograms of ethinyl estradiol per day. If applicable, the potential impact of these medications on efficacy endpoints will be considered during evaluation of the evaluable period. Changes in IMP dose will not be permitted during the study.

[0277] D. Clinical Trial Assessments and Procedures The investigator or his / her qualified designee completed sponsor-specified training for each assessment measure (as needed) before completing any assessment measures and, if necessary, obtained evidence of any additional training before site activity. To maintain blinded study status, staff members completing efficacy measures did not administer any safety measures for any subject, except for the C-SSRS or adverse event assessments. Similarly, staff members completing safety measures did not administer any efficacy measures for any subject. To ensure consistency, the same staff member (when possible) completed questionnaires for each subject throughout the study. All post-administration time points in the behavioral schedule (Section C) were relative to the start of the infusion, except for the 40-minute time point (end of infusion [EoI]). EoI procedures were performed 40 minutes after the start of the infusion or at the end of the infusion if the infusion continued beyond 40 minutes. EoI procedures included a 12-lead ECG, vital signs, pulse oximetry, CADSS, and BPRS+. MOAA / S continued at 20-minute intervals from the start of the infusion, and observations for AEs continued from pre-dose through 4 hours post-dose. For EoI, a ±2-minute time window was allowed after a total time of 40 minutes. However, assessments and procedures began as soon as possible after EoI. Study procedures and their timing are summarized in the behavioral schedule.

[0278] No exemptions or exceptions to the protocol were permitted. Compliance with the study design requirements, including those specified in the Schedule of Actions, was essential and necessary for the conduct of the study. All screening assessments were completed and reviewed to confirm that potential subjects met all eligibility criteria. The investigator maintained a screening log, recording details of all subjects screened and, if necessary, confirming eligibility or recording the reason for screening failure. Procedures performed as part of a subject's routine clinical management (e.g., blood counts) and obtained before signature of the ICF may be utilized for screening or baseline purposes, provided the procedures met the criteria specified in the protocol and were performed within the timeframe defined in the Schedule of Actions.

[0279] Screening and / or baseline procedures include obtaining informed consent, verifying that the subject met all eligibility criteria, recording the subject's demographic information, conducting a physical examination (including recording the subject's height, weight, and BMI), recording the subject's medical history, screening for HIV, Hepatitis B, and Hepatitis C, recording the subject's previous and concomitant medications, and, for OCBP subjects, administering a serum pregnancy test at screening and a urine pregnancy test at baseline, and conducting clinical laboratory assessments. The study included conducting a 12-lead ECG, vital signs, pulse oximetry, performing a urine alcohol and drug screen (including, at a minimum, ketamine, opiates, cocaine, barbiturates, and / or amphetamine / methamphetamine), reviewing AEs, administering the MGH-ATRQ, HAM-D, MADRS, and C-SSRS, and administering the MINI version 7.0.2 to assess the 17 most common psychiatric disorders in DSM-III-R, DSM-IV, DSM-V, and ICD-10. The MINI is designed as a brief structured diagnostic interview to fill the need for a short yet precise psychiatric structured interview for multicenter clinical trials and epidemiological studies, and for use as a first step in outcome tracking in non-investigational clinical settings. The MINI is a structured interview in which patients are asked to answer questions with a "yes" or "no" (e.g., "Have you ever felt depressed or down, sad, empty, or hopeless for most of the day, almost every day, over the course of two weeks?"). The MINI is designed to map to diagnoses defined by DSM-5 (37).

[0280] D.1 Effectiveness Evaluation Efficacy assessments were conducted at the time points listed in the behavioral schedule in Section C.

[0281] D.1.1 Montgomery-Asberg Depression Rating Scale The 10-item MADRS was administered by study staff to measure the overall severity of depressive symptoms. MADRS total scores were assessed at screening and baseline (pre-dose on Day 1). The primary efficacy endpoint of improvement in MADRS total score was assessed 24 hours after the start of study treatment infusion, before discharge on Day 2 at Visit 2. MADRS total scores were also assessed 2 hours, 4 hours, 7 days (Day 8), and 14 days (Day 15) after the start of infusion to assess the secondary efficacy endpoints of response (defined as a 50% or greater improvement in MADRS total score from pre-dose) and remission (defined as a MADRS total score of 10 or less) in improving depressive symptoms in subjects. While the MADRS is typically used with a 7-day recall period, versions of the MADRS including 2- and 24-hour recall periods were used in this study. (For the 2- and 4-hour periods, sleep and appetite items were assessed, and pre-dose scores for these items obtained on the same day were carried forward.)

[0282] D.1.2 Hamilton Depression Rating Scale The Hamilton Depression Rating Scale is a 17-item questionnaire designed to assess subjects' levels of depression before, during, and after treatment. This survey is used as a guide to assess recovery and is based on a clinician's interview with the subject. The HAM-D assesses the severity of depression by examining mood, guilt, suicidal ideation, insomnia, agitation or inhibitions, anxiety, weight loss, and somatic symptoms. Scoring takes approximately 15 minutes. Raters indicate the number of each symptom, ranging from 0 (absent) to 4 (extreme symptoms). During this trial, questionnaires were completed at screening, baseline, pre-dose on Day 1, discharge on Day 2, and both follow-up visits.

[0283] D.1.3 Brief Depressive Symptoms Scale - Self-Administered Participants completed the QIDS-SR-16, a sensitive measure for detecting changes in depression symptoms. The 16 items correlate with nine DSM-V symptom criteria domains, including: sleep disturbances—early, middle, and late insomnia or hypersomnia (Questions 1–4), feeling unwell (Question 5), appetite / weight loss / gain (Questions 6–9), concentration (Question 10), self-criticism (Question 11), suicidal ideation (Question 12), interest (Question 13), energy / fatigue (Question 14), and psychomotor agitation / retardation (Questions 15 and 16). While the QIDS-SR-16 is typically administered with a 7-day recall period, a 24-hour recall period for the QIDS-SR-14 was administered on Day 2. For the 24-hour recall period, weight and appetite items were assessed using pre-administration scores for these items obtained before administration on Day 1. A version of the QIDS-SR-16 item was used at pre-dose on Day 1 and at follow-up on Days 8 and 15.

[0284] D.1.4 Generalized Anxiety Disorder 7-Item Scale The GAD-7 is a self-report questionnaire for screening and measuring the severity of generalized anxiety disorder. It has sensitivity and specificity for screening for panic, social anxiety, and post-traumatic stress disorder. The GAD-7 consists of seven items that measure the severity of various symptoms of GAD according to reported response categories with assigned points. Scores on all seven items are summed to obtain a total score that provides an assessment of anxiety.

[0285] D.1.5 Clinical global impression The CGI rating scales measure symptom severity, treatment response, and treatment effectiveness in clinical trials of patients with psychiatric disorders. The questionnaires require study staff to compare subjects with typical patients in the clinician's experience. The CGI-S assesses the minimal clinically important difference in treatment with respect to the severity of depressive symptoms. The CGI-I assesses the minimal clinically important difference in treatment with respect to the improvement of depressive symptoms.

[0286] D.1.6 European Quality-5 Dimensions-3 Levels The EQ-5D-3L (Questionnaire for Assessing Health-Related Quality of Life in the Domains of Mobility, Ability to Take Care of Oneself, Performing Usual Activities, Pain / Discomfort, and Anxiety / Depression) is essentially a two-page questionnaire consisting of the EQ-5D descriptor system and a visual analog scale (VAS). The descriptor system is composed of five dimensions: Mobility, Ability to Take Care of Oneself, Performing Usual Activities, Pain / Discomfort, and Anxiety / Depression. Each dimension has three levels: no problems, some problems, and extreme problems. Subjects are asked to indicate their health status by marking the box corresponding to the most appropriate statement in each of the five dimensions. The VAS records the subject's self-rated health on a vertical VAS, with endpoints labeled "Best Imaginable Health State" and "Worst Imaginable Health State." This information was used as a quantitative measure of health outcomes.

[0287] D.2 Safety Assessment The planned timing of all safety assessments is shown in the action schedule in Section C.

[0288] D.2.1 Physical Examination A complete physical examination included, at a minimum, evaluation of the cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight were also measured and recorded, and BMI was calculated and recorded at screening.

[0289] D.2.2 Vital signs Tympanic or temporal temperature, heart rate, blood pressure (SBP / DBP), respiratory rate, and SpO2 were assessed. Blood pressure and pulse measurements were assessed with fully automated equipment while the subject was in the supine or semi-supine position. Manual techniques were used only when automated equipment was unavailable. Blood pressure and pulse measurements were preceded by subjects resting for at least 5 minutes in a quiet environment free of distractions (e.g., television, cell phone). Abnormal blood pressure values ​​at screening may be repeated after 5 minutes of relaxation to determine subject eligibility. When possible, blood pressure was recorded using the same arm and position (supine or semi-supine) throughout the trial. Vital signs (taken before blood collection for clinical testing) consisted of one pulse and three blood pressure measurements (three consecutive blood pressure readings recorded at least 1 minute apart). The average of the three blood pressure readings was recorded on the CRF. Peripheral capillary oxygen saturation (SpO2) was measured continuously from before dosing until 4 hours after dosing using a pulse oximeter. The pulse oximeter was clipped to the subject's finger or toe, and a light was transmitted through the finger or toe, and measurements were taken on the contralateral side.

[0290] D.2.3 Review of concomitant medications Concomitant medications were recorded at the time points indicated in Section C and throughout the study until the second follow-up visit.

[0291] D.2.4 Electrocardiogram A 12-lead ECG was obtained as outlined in the Schedule of Actions (see Section C) using an ECG device that automatically calculates heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals. If abnormal, the ECG was repeated. All ECGs were centrally reviewed by an independent cardiologist blinded to treatment assignment, although central review of the baseline (Day -1) ECG was not required before dosing on Day 1.

[0292] D.2.5 Laboratory Evaluation of Clinical Safety See Section H for a list of laboratory tests performed and the Action Schedule (Section C) for timing and frequency. The investigator reviewed laboratory reports, documented this review, and recorded all clinically relevant changes occurring during the study in the AE section of the CRF. Laboratory reports were submitted with the source documentation. Clinically significant abnormal laboratory findings are those not related to the underlying disease unless judged by the investigator to be more severe than expected for the subject's condition. All laboratory tests with values ​​considered to be clinically significant abnormalities during participation in the study or within 15 days after the last dose of study treatment were repeated until the values ​​returned to normal or baseline or were no longer considered clinically significant by the investigator or medical monitor. If such values ​​did not return to normal / baseline within a time period judged reasonable by the investigator, the etiology was identified and the sponsor notified. All protocol-required laboratory evaluations, as defined in Section H, were performed in accordance with the Clinical Laboratory Manual and Action Schedule. If a laboratory value from a non-protocol-specified clinical laboratory evaluation performed in the site laboratory required a change in subject management or was deemed clinically significant by the investigator (e.g., SAE, AE, or dose modification), the result was recorded on the CRF.

[0293] D.2.6 Modified observer assessment of alertness / sedation The MOAA / S was intended to determine whether and to what extent R(-)-ketamine caused the side effect of sedation. Sedation was assessed by study staff using the MOAA / S. Observers recorded subject alertness before administration, every 20 minutes for the first 2 hours after administration, and at 4 and 6 hours after the start of the infusion.

[0294] D.2.7 Clinician-rated Dissociative Status Scale The CADSS was designed to assess the wakefulness or dissociative state of subjects administered R(-)-ketamine. Clinical trial staff assessed the degree of dissociation by administering the CADSS questionnaire before administration, 40 minutes after administration (EoI), 2 hours, and 4 hours after administration.

[0295] D.2.8 Brief Psychiatric Rating Scale-Revised 4 Components The BPRS+ is one of the oldest and most widely used rating scales for measuring psychotic symptoms and was used by clinical trial staff to measure psychiatric symptoms, including depression, anxiety, hallucinations, and abnormal behavior. Only the four-item positive symptom subscale (consisting of suspiciousness, hallucinations, abnormal thought content, and conceptual disorganization) was used in the study to assess treatment-emergent psychotic symptoms. Questionnaires were administered pre-dose, 40 minutes post-dose (EoI), and 2 and 4 hours post-dose.

[0296] D.2.9 5-Dimensional Altered States of Consciousness Rating Scale The quality of all acute psychological effects of R(-)-ketamine infusion was assessed using the 5D-ASC, a retrospectively assessed questionnaire measuring the subjective experience of altered states of consciousness, containing 94 items formatted as a visual analog scale. The test was conducted 6 hours after the start of R(-)-ketamine infusion.

[0297] D.2.10 Suicide risk monitoring R(-)-ketamine is being investigated as an antidepressant / central nervous system active investigational treatment. There is concern that these types of treatments may be associated with an increased risk of suicidal ideation or behavior when given to some subjects with MDD, although other studies have shown that ketamine may be associated with a reduction in suicidal ideation or behavior. Therefore, the sponsor believes it is important to monitor suicidal ideation and behavior during the trial, as well as any suicidal ideation or behavior that emerges under treatment. The definition of suicidal behavior events used in this scale is based on that used in the Columbia-Suicide History Form. Questions are asked about suicidal behavior, suicidal ideation, and ideation intensity. At screening (Visit 1), questions relate to life experiences. Questions at all subsequent visits (see Section C, Behavior Schedule) relate to the last assessment (since the previous visit). The adult C-SSRS was used for all subjects. The C-SSRS was administered to subjects at screening, baseline, and 24 hours after infusion of the study treatment and prior to discharge from the clinic. The C-SSRS was administered to subjects at Follow-Up Visit 3 (Day 8) and Visit 4 (Day 15). The C-SSRS was assessed by either efficacy or safety assessors.

[0298] D.3 Adverse Events Definitions of AEs and SAEs can be found in Section F. AEs were reported by the subject (or by the caregiver, representative, or legally authorized representative of the subject, as appropriate). The investigator and any designee were responsible for detecting, documenting, and recording events that met the definition of an AE or SAE, and remained responsible for following up on AEs that were serious, considered related to the study treatment or procedures, or that caused the subject to discontinue the study.

[0299] D.3.1 Duration and Frequency of Adverse Event and Serious Adverse Event Information Collection All AEs were collected at the times specified in the Action Schedule (Section C) from the time of ICF signing through the second follow-up visit (Day 15). Medical events that began before the start of study treatment but after informed consent was obtained were recorded in the Medical History / Current Conditions section of the CRF, not in the AE section. All SAEs were recorded and reported to the sponsor or designee within 24 hours as described in Section F. The investigator submitted all updated SAE data to the sponsor or designee within 24 hours of its availability. The investigator was under no obligation to actively seek AEs or SAE information after the end of study participation. However, if the investigator becomes aware of any SAE, including death, at any time after a subject has withdrawn from the study and believes the event is reasonably related to study treatment or participation, the investigator must promptly notify the sponsor or designee. Methods for recording, assessing, and evaluating the causality of AEs and SAEs, as well as procedures for completing and submitting SAE reports, are provided in Section F.

[0300] D.3.2 Methods for detecting AEs and SAEs Care was taken to avoid bias in detecting AEs and / or SAEs. Open-ended, non-leading verbal questioning of subjects was the preferred method for inquiring about the occurrence of AEs.

[0301] D.3.3 Follow-up of Adverse Events and Serious Adverse Events After the first AE / SAE report, investigators were asked to actively follow each subject at subsequent visits / contacts. All SAEs were followed until resolution, stabilization, the event was otherwise explained, or the subject was lost to follow-up. Further information regarding follow-up procedures is provided in Section F.

[0302] D.3.4 Regulatory reporting requirements for serious adverse events Prompt notification of SAEs by the investigator to the sponsor or designee was essential to fulfill legal and ethical obligations for the safety of subjects and the investigational treatment under clinical trial. Investigators who receive an Investigator's Safety Report from the sponsor describing an SAE or other specific safety information (e.g., a summary or list of SAEs) review it, then file it with the Investigator's Brochure and notify the IEC / IRB as appropriate according to local requirements.

[0303] D.3.5 Pregnancy Details of all pregnancies in female subjects and, if necessary, female partners of male subjects were collected after the start of study treatment and up until the second follow-up visit. When a pregnancy was reported, the investigator notified the sponsor within 24 hours of learning of the pregnancy. Information regarding the status of the mother and child was forwarded to the sponsor. Generally, follow-up was within 6-8 weeks after the estimated delivery date. All terminations of pregnancy were reported regardless of fetal status (presence or absence of abnormalities) or procedural indications. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) were considered SAEs.

[0304] D.3.6 COVID-19 If a subject tested positive for COVID-19, this was recorded as an AE of either "symptomatic COVID-19 illness" or "asymptomatic COVID-19 illness." COVID-19 symptoms, signs, and sequelae were reported as AEs according to the Definitions and Procedures for Recording, Evaluation, Follow-up, and Reporting (Section F). Medications for the prevention or treatment of COVID-19 were entered as concomitant medications. (See the EDC Completion Guidelines for further details.)

[0305] D.4 Treatment of overdose Overdoses were unlikely during this study because all treatments were administered in a clinic setting using infusion pumps. However, if study treatment was administered in less than 40 minutes due to pump error, the investigator would closely monitor the subject for all AEs / SAEs and laboratory abnormalities for at least 24 hours, obtain plasma samples for pharmacokinetic (PK) analysis as soon as possible, record the time from the start of the study treatment infusion (determined on a case-by-case basis) if requested by the medical monitor, record the amount of the overdose as well as the time of the overdose on the CRF, and contact the medical monitor immediately, as follows:

[0306] E. Statistical considerations The primary efficacy analysis was intended to demonstrate the superiority of at least one treatment dose of injectable R(-)-ketamine solution (30 mg or 60 mg) over placebo based on the change in MADRS total score from pre-dose to 24 hours after dosing. For the primary analysis, a sample size of 101 randomized subjects (33:35:33) provided 80% power to detect an 8-point difference between each injectable R(-)-ketamine solution and placebo in the mean change from baseline MADRS total score at 24 hours after dosing using a two-tailed t-test with an α of 0.05 and assuming a common standard deviation of 11.

[0307] All statistical analyses, including summary tables and data listings, were performed using SAS® software (version 9.4 or higher). Continuous endpoints were summarized using descriptive statistics (number of subjects [n], mean, standard deviation [SD], median, minimum, and maximum). Categorical endpoints were summarized using frequency counts and percentages. All individual subject data are presented in the listings.

[0308] The Full Analysis Set (FAS) consisted of all randomized subjects who received at least one dose of study treatment and had at least one available post-baseline assessment. This population was used as the basis for efficacy analyses. Subjects were analyzed according to randomized treatment. The safety analysis set consisted of all randomized subjects who received any study treatment, even partial doses. This population was used for compilation of all safety information, including subject disposition, demographic characteristics and baseline data, as well as incidence of AEs. Subjects were analyzed according to the treatment actually received.

[0309] Primary endpoint Changes from baseline in MADRS scores were summarized separately for each treatment group at each visit. The relevant baseline score was obtained as the last corresponding measurement before the first dose of IMP in the treatment period (i.e., Visit 2, pre-dose). The primary endpoint of change from baseline MADRS total score 24 hours after the start of infusion was assessed using a mixed-effects model for repeated measures (MMRM) analysis using only observed cases. The MMRM model included fixed effects for treatment group, region, visit, study center, and treatment group by visit interaction, with subject as the random effect and baseline score as the covariate. An unstructured covariance matrix was used to estimate the within-subject variance-covariance structure across time points. If convergence was not achieved, alternative covariance structures were specified in SAP. Objective criteria for assessing normality assumptions and proposed alternative analyses were specified in SAP. From this analysis, least squares (LS) mean estimates for each treatment group at each visit were presented separately, along with standard errors and 95% confidence intervals (CIs). Additionally, estimates of the treatment difference at each visit were presented, along with the standard error of the difference and 95% CI. The primary comparison for the MADRS was the estimate of the treatment difference at 24 hours after initiation of the infusion.

[0310] Secondary endpoints Changes from baseline to day 14 in MADRS, HAM-D, GAD-7, and QIDS-SR scores were analyzed using a model approach similar to that used for the MADRS. Observed values ​​and changes from baseline for continuous secondary endpoints were summarized descriptively by treatment group. Continuous secondary efficacy endpoints assessed at more than one post-baseline visit were analyzed using MMRM analysis. The MMRM model included fixed effects for treatment group, region, visit, study center, and treatment group by visit interaction, with subject as a random effect and baseline score as a covariate. From this analysis, LS mean estimates for each treatment group at each visit were presented separately, along with standard errors and 95% CIs. Additionally, estimates of the treatment difference at each visit were presented, along with standard errors of the difference and 95% CIs. Numerical values ​​for CGI-S and CGI-I assessments were analyzed separately using a model approach similar to that used for the MADRS. For the CGI-S, baseline score was included as a covariate. Values ​​for both the original categorical scale and the transformed numeric scale (including change from baseline on the CGI-S numeric scale) at each visit were summarized using standard summary statistics. Binary exploratory endpoints were analyzed separately, and odds ratios, 95% CIs, and p-values ​​are presented. Full details of the efficacy analyses and any further supplementary analyses deemed appropriate are provided in the SAP.

[0311] F. Adverse Events and Serious Adverse Events Definition of AE An AE is any untoward medical occurrence in a patient or subject that is temporally associated with the use of an investigational treatment, whether or not considered related to the investigational treatment. Thus, an AE can be any untoward and unintended sign (including abnormal laboratory findings), symptom, or disease (new or worsening) that is temporally associated with the use of the investigational treatment.

[0312] Events that meet the definition of AE All abnormal clinical laboratory results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiology scan, vital sign measurements), including those that worsen from baseline, that are considered clinically significant (i.e., not related to progression of the underlying disease) in the medical and scientific judgment of the investigator.

[0313] A worsening of existing chronic or intermittent symptoms, including an increase in either the frequency and / or intensity of symptoms.

[0314] New symptoms that may have been present before the start of the study but are detected or diagnosed after administration of the study treatment.

[0315] Signs, symptoms, or clinical sequelae of a suspected drug-drug interaction.

[0316] Signs, symptoms, or clinical sequelae of suspected overdose of either the investigational treatment or concomitant medication. An overdose itself is not reportable as an AE / SAE unless it is an intentional overdose taken with suicidal / self-harming intent. Such overdoses must be reported regardless of sequelae.

[0317] "Lack of efficacy" or "failure of expected pharmacological action" itself is not reported as an AE or SAE. Such instances are captured in the efficacy evaluation. However, signs, symptoms, and / or clinical sequelae resulting from lack of efficacy are reported as AEs or SAEs if they meet the definition of an AE or SAE.

[0318] Events that do not meet the definition of AE Any clinically significant abnormal laboratory finding or other abnormal safety assessment related to the underlying disease, unless judged by the investigator to be more severe than expected for the subject's condition. The disease / disorder being investigated or the expected progression, signs, or symptoms of the disease / disorder being investigated, unless it is more severe than expected for the subject's condition. Medical or surgical procedures (e.g., endoscopy, appendectomy): conditions leading to the procedure are AEs. Situations in which no untoward medical events occurred (social and / or convenience admission to hospital, including planned admission for this study). Expected day-to-day fluctuations of a pre-existing disease or condition that was present or detected at the start of the study that do not worsen.

[0319] Definition of SAE If an event is not an AE according to the above definition, it cannot be an SAE, even if the serious condition is met (e.g., hospitalization for signs / symptoms of the disease under investigation). A serious adverse event (SAE), at any dose, is any untoward medical occurrence that a) results in death, b) is life-threatening, c) requires hospitalization or an extension of an existing hospitalization, d) results in permanent disability / incapacity, or e) is a congenital anomaly / birth defect. The term "life-threatening" in the definition of "serious" refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event that hypothetically might have caused death if it had been more severe. Generally, hospitalization means that the subject is confined to a hospital or emergency room (usually including at least an overnight stay) for observation and / or treatment that would not be appropriate in a physician's office or outpatient setting. Complications occurring during hospitalization are AEs. An event is serious if the complication prolongs hospitalization or other serious criteria are met. An AE should be considered serious if there is any doubt as to whether "hospitalization" occurred or was necessary. Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE, nor is a planned hospitalization for this study considered an AE. The term disability means substantial disruption of a person's ability to perform normal life functions. This definition is not intended to include experiences of relatively minor medical significance that may interfere with or interfere with daily life functions but do not result in substantial disruption, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle).

[0320] Other situations related to SAE Medical or scientific judgment must be used in determining whether reporting an SAE is appropriate in other situations, such as a significant medical event that is not immediately life-threatening or likely to result in death or hospitalization, but which may endanger the subject or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above. These events should generally be considered serious. Examples of such events include invasive or malignant cancer, intensive care in the emergency room or at home for allergic bronchospasm, cachexia, or seizures that do not result in hospitalization, or the development of drug dependence or abuse.

[0321] AE and SAE records When an AE / SAE occurs, it is the investigator's responsibility to review all documentation related to the event (e.g., hospital progress notes, laboratory reports, and diagnostic reports). The investigator then records all relevant AE / SAE information on the CRF. Each event must be recorded separately. The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and / or other clinical information. Whenever possible, the diagnosis (not individual signs / symptoms) will be recorded as the AE / SAE.

[0322] Strength evaluation The investigator will provide an intensity rating for each AE and SAE reported during the study and assign it to one of the following categories: Mild: An event that is easily tolerated by the subject, causes minimal discomfort, and does not interfere with daily activities.

[0323] Moderate: An event that causes sufficient discomfort to interfere with normal daily activities.

[0324] Severe: An event that makes normal daily activities impossible. AEs rated as severe should not be confused with SAEs. Severity is a category used to rate the intensity of the event; both AEs and SAEs can be rated as severe.

[0325] An event is defined as "serious" if it meets at least one of the predefined outcomes as described in the SAE definition, and not if it is rated as severe.

[0326] Causal assessment The investigator is obligated to assess the relationship between the investigational treatment and each occurrence of each AE / SAE. AEs must be characterized as unrelated, unlikely related, possibly related, probably related, or clearly related. "Clearly related" suggests that the AE has a reasonable temporal relationship to the administration of the investigational treatment and that no obvious potential alternative etiology exists. "Probably related" conveys that a relationship cannot be ruled out, but that there are facts, evidence, and / or arguments suggesting a causal relationship. "Possibly related" suggests that the relationship between the AE and the investigational treatment is unclear, but the AE is not reasonably supported by other conditions. "Unlikely related" suggests that only a distant relationship exists between the investigational treatment and the AE. Other conditions, including chronic illness, progression or development of a disease state, or response to concomitant therapy, appear to explain the reported AE. "Unrelated" is used when there is no reasonable possibility that the investigational treatment caused the AE.

[0327] The investigator will use clinical judgment to determine the relationship. Alternative causes, such as underlying diseases, concomitant therapies, and other risk factors, as well as the temporal relationship of the event to the administration of the investigational treatment, will be considered and investigated. The investigator will also consult the IB and / or product information for marketed products during his / her evaluation. For each AE / SAE, the investigator must document in the medical note that he / she has reviewed the AE / SAE and provided a causality assessment. There may be situations in which an SAE occurs and the investigator has minimal information to include in the initial report to safety management. However, it is critical that the investigator always conduct a causality assessment for all events before initially communicating SAE data to safety management. The investigator may change his / her causality opinion in light of follow-up information and communicate an SAE follow-up report with an updated causality assessment. The causality assessment is one of the criteria used when determining regulatory reporting requirements.

[0328] AE and SAE follow-up The investigator is obligated to perform or arrange for the conduct of supplementary measurements and / or evaluations as medically indicated or as requested by safety management to elucidate as completely as possible the nature and / or causality of the AE or SAE. This may include additional clinical tests or investigations, histopathological examination, or consultation with other medical professionals. If a subject dies during participation in the trial or during the recognized follow-up period, the investigator will provide safety management with a copy of all post-mortem findings, including histopathology. New or updated information will be recorded on the originally completed CRF. The investigator will submit updated SAE data to the sponsor or designee within 24 hours of receiving the information.

[0329] Adverse events will be coded using the Medical Dictionary for Oversight Activities (MedDRA, version 23.0 or higher). Treatment-emergent adverse events (TEAEs) are AEs that developed or worsened after the start of study treatment. AE summaries are primarily based on TEAEs. The number and percentage of subjects with TEAEs will be summarized by treatment group, system organ class, and preferred term for all TEAEs, treatment-related TEAEs, SAEs, serious TEAEs, severe TEAEs, TEAEs of special interest, and all TEAEs leading to study drug discontinuation. All TEAEs will be further summarized by maximum severity and causality. TEAEs of special interest will be identified in the SAP. All AEs will be presented in a subject-specific list. Serious AEs, severe AEs, and AEs leading to study discontinuation or death will be presented in separate lists.

[0330] G. Permitted and Prohibited Concomitant Medications A list of permitted and prohibited concomitant medications throughout the study is shown in Table 5. Permitted temporary or continuous use of concomitant medications is indicated by a "Y" (yes). Prohibited temporary or continuous use of concomitant medications is indicated by an "N" (no).

[0331] [Table 7]

[0332] H. Clinical Examination Pregnancy Testing: Serum testing was performed at screening to confirm a positive urine test. Site-specific urine pregnancy testing was performed at both follow-up visits. Hepatitis B and C Screening: Hepatitis B surface antigen and hepatitis C virus (HCV antibody) testing are required. Tests detailed in Table 6 will be performed by the site's laboratory. Urine drug screening may also be performed on-site. Protocol-specific requirements for subject inclusion or exclusion are detailed in Section B herein. Additional testing may be performed at any time during the trial as determined necessary by the investigator or required by local regulations. The investigator documented their review of each laboratory's safety reports. Results of tests / analytes that could potentially unblind the trial were reported to the trial center or other blinded personnel until the trial was unblinded.

[0333] [Table 8]

[0334] I. Demographic and Baseline Characteristics of Study Subjects The demographic and baseline characteristics of the study subjects are shown in Table 7 below.

[0335] [Table 9-1] [Table 9-2] 1 Multiple choices may have been reported for each subject. Note: HAM-D = Hamilton Depression Rating Scale, MADRS = Montgomery-Asberg Depression Rating Scale.

[0336] Table 8 provides a summary of subject disposition at study initiation and the number of subjects who discontinued early, were lost to follow-up, or withdrew.

[0337] [Table 10] Percentages are based on the number of randomized subjects.

[0338] H. Results The results of the trial are shown in the table below.

[0339] Tables 9, 10, and 11 show the MADRS results described in Section D.1.1. Analytical methods are described in Section E.

[0340] [Table 11-1] [Table 11-2]

[0341] In Table 9, the total score is calculated as the sum of the scores across all 10 items. Each item is scored from 0 to 6, so the total score ranges from 0 to 60. Higher scores indicate more severe depression.

[0342] 1 The baseline value is defined as the last non-missing value before administration of study drug.

[0343] [Table 12] CI = confidence interval, SE = standard error.

[0344] Analyses in Table 10 were performed using mixed models for repeated measures data (MMRM) with treatment group, analysis visit, region, and treatment group by visit interaction as fixed effects. Baseline values ​​are included as covariates. An unstructured covariance matrix is ​​used to model within-subject variance-covariance error. The total score is calculated as the sum of scores across all 10 items. Each item is scored from 0 to 6, so the total score ranges from 0 to 60. Higher scores indicate more severe depression.

[0345] [Table 13]

[0346] In Table 11, the total score is calculated as the sum of the scores across all 10 items. Each item is scored from 0 to 6, so the total score ranges from 0 to 60. Higher scores indicate more severe depression. Responder status was defined as subjects who experienced at least a 50% reduction in the MADRS total score at the corresponding time point. The analysis was based on logistic regression with fixed effects of treatment group, analysis visit, region, and treatment group by visit interaction. Baseline values ​​were included as covariates. MADRS scores showed a trend toward a positive response in response to R(-)-ketamine at later time points at the higher 60 mg dose, with a difference of approximately 2 points observed at day 15. This difference from placebo was not statistically significant. The observed effect may have been low due to the single administration and may have been greater with repeated administration.

[0347] Tables 13-18 show summaries of vital signs and pulse oximetry at the indicated time points and R(-)-ketamine doses. In these tables, baseline values ​​are defined as the last non-missing value before administration of study drug.

[0348] [Table 14-1] [Table 14-2] [Table 14-3]

[0349] [Table 15-1] [Table 15-2] [Table 15-3]

[0350] [Table 16-1] [Table 16-2] [Table 16-3]

[0351] [Table 17-1] [Table 17-2] [Table 17-3]

[0352] [Table 18-1] [Table 18-2] [Table 18-3]

[0353] [Table 19-1] [Table 19-2]

[0354] Adverse events that occurred during the study are summarized in Tables 19 to 24. There were no serious adverse events (SAEs).

[0355] [Table 20]

[0356] In Table 19, frequency is the number of subjects who experienced at least one adverse event in that category. Subjects experiencing two or more adverse events in each category are counted only once for that category. Adverse events that are possibly, probably, definitely, or have an unknown relationship to the study drug are considered "related" for analysis. All treatment-emergent adverse events that are not graded are assumed to be "severe." Subjects who experience multiple treatment-emergent adverse events are counted only once at the maximum severity.

[0357] [Table 21]

[0358] [Table 22]

[0359] [Table 23-1] [Table 23-2]

[0360] In Table 22, adverse events were coded using the MedDRA Dictionary v24.0. Frequency is the number of subjects who experienced at least one AE in that category. Subjects experiencing two or more adverse events in each category were counted only once for that category.

[0361] [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4]

[0362] The MOAA / S scale used in Table 23 is a 6-point scale assessing patient responsiveness, with higher scores indicating greater responsiveness.

[0363] 1 The baseline value is defined as the last non-missing value before administration of study drug.

[0364] [Table 25]

[0365] In Table 24, the CADSS assesses the alertness or dissociation state of subjects receiving PCN101, with higher scores indicating greater severity. 1 Baseline values ​​are defined as the last non-missing value before study drug administration.

[0366] Example 2: Pharmacokinetics (PK) of R(-)-ketamine in human subjects This was a single-center, phase 1, randomized, placebo-controlled, double-blind, single-dose study. Part of the study was an ascending-dose, randomized, placebo-controlled, double-blind safety and tolerability study of a single intravenous (IV) infusion of R(-)-ketamine or placebo (saline) administered over 40 minutes to healthy subjects. A total of up to 48 healthy subjects were enrolled in six consecutive cohorts of eight subjects each. The pharmacokinetic (PK) population consisted of 36 subjects, with 12 additional subjects receiving placebo. Subjects receiving all or part of the infusion of the study drug and C max , T max or AUC 0-tAll subjects with sufficient evaluable concentration-time data to allow determination of at least one PK parameter were included in the PK population. Subjects were healthy male or female subjects aged 18 to 65 years. Within each cohort, subjects were randomized 3:1 between active drug and placebo. Six subjects received R(-)-ketamine and two received placebo. Each cohort began with a sentinel dose of two subjects, who were randomized 1:1 to either the R(-)-ketamine or placebo cohort. After safety review, the full cohort was enrolled. Cohort 1 received 5 mg of R(-)-ketamine, followed by Cohort 2 at 15 mg, Cohort 3 at 30 mg, Cohort 4 at 60 mg, Cohort 5 at 100 mg, and Cohort 6 at 150 mg. Dose escalation continued until an acceptable tolerated dose (ATD) was confirmed or the 150 mg cohort was completed. In addition to safety and tolerability data, the study also evaluated dose-related PK of each 40-minute IV infusion of R(-)-ketamine.

[0367] To evaluate the pharmacokinetics of R(-)-ketamine, blood was collected from subjects for PK analysis at the following sampling times: pre-dose (-30 min), 5, 10, and 15 min [±1 min], 30 min [±5 min], 40 min [just before the completion of the infusion], 1, 1.5, 2, and 3 hours [±5 min], 4 and 8 hours [±10 min], 12 and 24 hours [±15 min]).

[0368] The following plasma PK parameters of R(-)-ketamine and its metabolites (norketamine, 6-hydroxynorketamine, and dehydronorketamine) were evaluated. ·Maximum plasma concentration (Cmax), Time to Cmax (Tmax), ·Area under the plasma concentration curve (AUC 0-t , AUC 0-∞ ) ·Excretion rate constant (λz), Half-life (t 1 / 2) Clearance (CL, PR(-)-ketamine only), Volume of distribution (Vz, R(-)-ketamine only), and Metabolite-to-parent compound ratios (area under the curve [AUC] and C max ).

[0369] Dose proportionality was assessed visually and statistically using the calculated Cmax and AUC values. Statistical analysis was performed according to the statistical analysis plan. Continuous variables: Descriptive statistics included the number of non-missing values ​​(n), arithmetic mean, standard deviation (SD), median, minimum, and maximum. The minimum and maximum values ​​were expressed with the same decimal precision as the original data, and the arithmetic mean, SD, and median were expressed with one more decimal than the original data for certain variables. The appropriate precision of derived variables was determined based on the precision of the data on which they were derived, and statistics were presented according to the rules described above. For PK concentration data, the number of non-missing values, the number of values ​​below the lower limit of quantitation (BLQ), arithmetic mean, SD, median, minimum, maximum, coefficient of variation (CV%), geometric mean, and geometric CV (geo CV%) values ​​were presented. For PK parameter data, the number of non-missing values, arithmetic mean, SD, median, minimum, maximum, CV%, geometric mean, and geometric CV (geo CV%) values ​​are shown.

[0370] The assigned blinded study drug was administered intravenously (morning, Day 1) over 40 minutes. Blood samples for plasma PK analysis were taken at 5, 10, 15, 30, 40, 60, and 90 minutes after the infusion and at 2, 3, 4, 8, and 12 hours after the start of the infusion.

[0371] Table 25 shows the doses administered to each cohort.

[0372] [Table 26]

[0373] Plasma concentrations of R(-)-ketamine and its metabolites, norketamine, 6-hydroxynorketamine, and dehydronorketamine, were measured using a suitable validated analytical method with a limit of quantitation (LOQ) of 1 ng / mL. The results are shown in Figures 1–8.

[0374] R(-)-Ketamine Plasma concentrations of R(-)-ketamine are shown in Figures 1 and 2. Selected PK parameters of R(-)-ketamine by cohort are tabulated in Figures 9A and 9B. Analysis of plasma concentrations following IV infusion administration (40-minute duration) of 5, 15, 30, 60, 100, or 150 mg of R(-)-ketamine demonstrated that R(-)-ketamine concentrations were quantifiable in all subjects at the earliest time point (5 minutes), with a median plasma Tmax of 40 minutes (range: 15 to 40 minutes), regardless of dose level. Overall, across all cohorts, plasma exposure of R(-)-ketamine, as indicated by Cmax and AUC (AUC0-t, AUC0-24h, AUC0-inf), increased with increasing administered dose.

[0375] The arithmetic mean Cmax (CV%) increased from 33.9 ng / mL (27.9%) after a 5 mg IV dose to 780 ng / mL (15.9%) after a 150 mg IV dose, representing a 23-fold increase in Cmax for a 30-fold increase in dose. The arithmetic mean AUC0-24h (CV%) was 63.5 hr after a 5 mg IV dose of R(-)-ketamine. * ng / mL (15.4%) at 1720 hours after IV administration of 150 mg of R(-)-ketamine * The arithmetic mean AUC0-t (CV%) increased from 0.05 to 0.05 ng / mL (15.1%), representing a 27.1-fold increase in AUC0-24h for a 30-fold increase in dose. The arithmetic mean AUC0-t (CV%) was 0.05 to 0.05 ng / mL (15.1%) after IV administration of 5 mg of R(-)-ketamine. * ng / mL (16.8%) at 1720 hours after IV administration of 150 mg of R(-)-ketamine * The arithmetic mean AUC0-inf (CV%) increased 64.0 hr after IV administration of 5 mg R(-)-ketamine. * ng / mL (15.3%) at 1820 hours after IV administration of 150 mg of R(-)-ketamine *The dose-proportionality of R(-)-ketamine increased from 5 mg to 150 mg (16.1%), demonstrating a 28.4-fold increase in AUC0-inf with a 30-fold increase in dose. Assessment of dose-proportionality of R(-)-ketamine from 5 mg to 150 mg using power modeling and graphical evaluation revealed that the pharmacokinetics of R(-)-ketamine increased approximately dose-proportionally for Cmax, AUC0-t, AUC0-24h, and AUC0-inf. Overall, interindividual variability of R(-)-ketamine was low to moderate for Cmax, AUC0-t, AUC0-24h, and AUC0-inf, with CV% values ​​ranging from 15.9% to 51.6%, 13.3% to 25.1%, 13.3% to 25.1%, and 13.7% to 22.6%, respectively. After peak R(-)-ketamine plasma concentrations were achieved following IV administration, a monophasic decline was observed, with arithmetic mean t range (CV%) of 3.06 to 7.21 hours (21.9% to 53.3%) across all dose cohorts from 5 mg to 150 mg. Overall, plasma R(-)-ketamine arithmetic mean (CV%) CL and Vz were fairly consistent across R(-)-ketamine cohorts from 5 mg to 150 mg, ranging from 76.8 to 97.5 L / hr (13.7% to 22.6%) and 345 to 921 L (20.0% to 50.2%), respectively.

[0376] Norketamine Plasma concentrations of norketamine are shown in Figures 3-4. Selected norketamine PK parameters for the R(-)-ketamine cohorts are tabulated in Figures 10A-10B, by cohort. Analysis of norketamine plasma concentrations following IV infusions (40-minute duration) of 5 mg, 15 mg, 30 mg, 60 mg, 100 mg, or 150 mg of R(-)-ketamine revealed that, regardless of R(-)-ketamine dose level, norketamine concentrations were quantifiable in all subjects at the earliest time point (10-15 minutes) and approximately plasma T max The median time to C was 1 hour (range: 40 minutes to 2.00 hours). Overall, across all cohorts, max and AUC(AUC 0-t , AUC 0-24h , AUC 0-infPlasma exposure of norketamine, as indicated by ), increased with increasing R(-)-ketamine dose.

[0377] Norketamine arithmetic mean C max The CV% increased from 11.4 ng / mL (17.3%) after 5 mg IV R(-)-ketamine to 360 ng / mL (12.1%) after 150 mg IV R(-)-ketamine, representing a 31.6-fold increase in norketamine Cmax for a 30.0-fold increase in R(-)-ketamine dose. Arithmetic mean AUC of norketamine 0-24h (CV%) was 79.6 hours after IV administration of 5 mg of R(-)-ketamine. * ng / mL (23.1%) at 3140 hours after IV administration of 150 mg of R(-)-ketamine * ng / mL (21.0%), and the AUC of norketamine increased with a 30-fold increase in R(-)-ketamine dose. 0-24h The arithmetic mean AUC of norketamine was 39.4-fold increased. 0-t (CV%) was 78.0 hours after IV administration of 5 mg. * ng / mL (26.5%) at 3140 hr after 150 mg IV administration * The arithmetic mean AUC of norketamine increased to 21.0% (21.0%), representing a 40.3-fold increase in AUC0-t for a 30-fold increase in dose. 0-inf (CV%) was 79.1 hours after IV administration of 5 mg. * ng / mL (15.2%) to 3530 hr after 150 mg IV administration * ng / mL (22.1%) with a 30-fold increase in dose, and the AUC 0-inf The dose proportionality of norketamine to 5 mg to 150 mg of R(-)-ketamine using a power model and graphical evaluation showed that the pharmacokinetics of norketamine were significantly higher than that of C max , AUC 0-t , AUC 0-24h , and AUC 0-inf Overall, the interindividual variability of norketamine was max , AUC 0-t , AUC0-24h , and AUC 0-inf The CV% values ​​ranged from 12.1% to 28.4%, 14.2% to 26.5%, 14.2% to 23.1%, and 12.7% to 24.7%, respectively. After peak plasma concentrations were achieved, a monophasic decline in norketamine was observed, with arithmetic mean t values ​​across all dose cohorts of R(-)-ketamine from 5 mg to 150 mg. 1 / 2 The range (CV%) of was 6.70 to 8.05 hours (11.0% to 26.7%).

[0378] 6-hydroxynorketamine Plasma concentrations of 6-hydroxynorketamine are shown in Figures 5-6. Selected PK data for 6-hydroxynorketamine in the R(-)-ketamine cohort Parameters are tabulated in Figures 11A-11B for each cohort. Analysis of plasma concentrations following IV infusions (40 minutes duration) of 5 mg, 15 mg, 30 mg, 60 mg, 100 mg, or 150 mg of R(-)-ketamine revealed that, regardless of dose level, 6-hydroxynorketamine concentrations were quantifiable in all subjects at the earliest time point (10-15 minutes) and approximately plasma T max The median range of C was demonstrated to be 4.00–8.00 hours. Overall, across all cohorts, max and AUC(AUC 0-t and AUC 0-24h Plasma exposure of 6-hydroxynorketamine, as indicated by ), increased with R(-)-ketamine dose.

[0379] Arithmetic mean C of 6-hydroxynorketamine max The CV% of 6-hydroxynorketamine increased from 5.98 ng / mL (21.3%) after 5 mg IV R(-)-ketamine to 165 ng / mL (14.8%) after 150 mg IV R(-)-ketamine, a 30.0-fold increase in R(-)-ketamine dose. max The arithmetic mean AUC of 6-hydroxynorketamine was 27.6-fold increased. 0-24hand AUC0-t (CV%) at 110 hours after IV administration of 5 mg of R(-)-ketamine * ng / mL (14.3%) to 3000 hr after IV administration of 150 mg R(-)-ketamine * ng / mL (12.8%) with a 30-fold increase in the R(-)-ketamine dose. 0-24h and AUC 0-t The dose proportionality of 6-hydroxynorketamine to R(-)-ketamine from 5 mg to 150 mg using a power model and graphical evaluation showed that the pharmacokinetics of 6-hydroxynorketamine was max , AUC 0-t , and AUC 0-24h Overall, the interindividual variability of 6-hydroxynorketamine was max and AUC 0-t , or AUC 0-24h The CV% values ​​were in the range of 14.8% to 46.0% and 12.8% to 46.0%, respectively.

[0380] Dehydronorketamine Plasma concentrations of dehydronorketamine are shown in Figures 7-8. Selected PK parameters for dehydronorketamine in the R(-)-ketamine cohorts are tabulated in Figures 12A-12B, by cohort. Analysis of plasma concentrations following IV infusion administration (40-minute duration) of R(-)-ketamine at doses of 5 mg, 15 mg, 30 mg, 60 mg, 100 mg, or 150 mg revealed that, regardless of dose level, dehydronorketamine concentrations were quantifiable in all subjects at the earliest time points (15 minutes to 1.50 hours) and were consistent with the approximate plasma T max The median range of C was 1.50 to 3.02 hours. Overall, across all cohorts, max and AUC (AUC0-t, AUC 0-24h , AUC 0-inf The plasma exposure of dehydronorketamine, as indicated by ), increased with increasing R(-)-ketamine dose.

[0381] The arithmetic mean Cmax (CV%) of dehydronorketamine increased from 198 pg / mL (14.9%) after 5 mg IV R(-)-ketamine to 35,600 pg / mL (33.0%) after 150 mg IV R(-)-ketamine, a 30-fold increase in the R(-)-ketamine dose. max The arithmetic mean AUC of dehydronorketamine was 179.8-fold increased. 0-24h (CV%) was measured at 2500 hours after IV administration of 5 mg of R(-)-ketamine. * pg / mL (11.1%) to 424,000 hr after IV administration of 150 mg of R(-)-ketamine * pg / mL (26.7%), and the AUC of dehydronorketamine increased with a 30-fold increase in the R(-)-ketamine dose. 0-24h This showed a 169.6-fold increase.

[0382] Arithmetic mean AUC of dehydronorketamine 0-t (CV%) was 1370 hours after IV administration of 5 mg. * pg / mL (26.5%) to 424,000 hr after IV administration of 150 mg of R(-)-ketamine * pg / mL (26.7%), and the AUC of dehydronorketamine increased with a 30-fold increase in the R(-)-ketamine dose. 0-t The arithmetic mean AUC of dehydronorketamine was 309.5-fold increased. 0-inf (CV%) was 16300 hr after IV administration of 15 mg of R(-)-ketamine. * pg / mL (51.5%) to 576,000 hr after IV administration of 150 mg of R(-)-ketamine * pg / mL (25.6%), and the AUC of dehydronorketamine increased with a 10-fold increase in the R(-)-ketamine dose. 0-inf showed a 35.3-fold increase.

[0383] Assessment of dose proportionality of dehydronorketamine to R(-)-ketamine from 5 mg to 150 mg using power model and graphical evaluation showed that the pharmacokinetics of dehydronorketamine were max , AUC 0-t , AUC0-24h , and AUC 0-inf Overall, the interindividual variability of dehydronorketamine was greater than that of C max , AUC0-t, AUC 0-24h , and AUC 0-inf The CV% values ​​ranged from 14.9% to 40.9%, 24.2% to 32.4%, 11.1% to 32.4%, and 1.5% to 51.5%, respectively. After peak plasma concentrations were obtained, the arithmetic mean t 1 / 2 The range (CV%) of CI was 7.41 to 9.32 hours (2.1% to 10.6%) across all dose cohorts of 15 mg to 60 mg and 150 mg.

[0384] PK parameter ratios for metabolites versus parent compound (M / P) The overall arithmetic mean (geometric CV%) ratios of norketamine / R(-)-ketamine based on Cmax, AUC0-t, AUC0-24h, and AUC0-inf across all dose cohorts of R(-)-ketamine from 5 mg to 150 mg ranged from 0.264 to 0.448 (21.7% to 32.8%), 1.05 to 1.76 (8.7% to 33.0%), and 1.14 to 1.88 (11.5% to 28.0%), respectively. The overall arithmetic mean (geometric CV%) ratios of 6-hydroxynorketamine / R(-)-ketamine based on Cmax, AUC0-t, and AUC0-24h across all dose cohorts of R(-)-ketamine from 5 mg to 150 mg ranged from 0.151 to 0.251 (22.5% to 90.0%), 1.54 to 2.22 (23.8% to 63.3%), and 1.54 to 2.22 (23.8% to 63.3%), respectively. The overall arithmetic mean (geometric CV%) ratios of dehydronorketamine / R(-)-ketamine based on Cmax, AUC0-t, AUC0-24h, and AUC0-inf across all dose cohorts of R(-)-ketamine from 5 mg to 150 mg ranged from 0.00581 to 0.0437 (19.3% to 56.8%), 0.0223 to 0.233 (24.5% to 35.0%), 0.0512 to 0.233 (17.0% to 33.1%), and 0.0585 to 0.27 (17.0% to 39.7%), respectively.

[0385] Summary of dose proportionality of plasma PK parameters The linearity of increasing exposure with increasing administered dose was evaluated for the C values ​​of R(-)-ketamine and its metabolites (norketamine, 6-hydroxynorketamine, and dehydronorketamine). max and AUC were evaluated. max , AUC 0-t , AUC 0-24h , and AUC 0-infDose proportionality, as measured by , was assessed using a power model (using natural log-transformed PK parameter values ​​and natural log-transformed doses) and graphical assessment (using scatter plots and power model regression plots of dose-normalized PK parameter values ​​and treatment doses). The power model was used to estimate the slope parameter and 90% confidence interval for the slope. A summary of dose proportionality assessments for R(-)-ketamine, norketamine, 6-hydroxynorketamine, and dehydronorketamine is shown in the table in Figure 13.

[0386] Across the dose range of R(-)-ketamine (5 mg, 15 mg, 30 mg, 60 mg, 100 mg, and 150 mg), increasing R(-)-ketamine exposure was observed at C max , AUC 0-t , AUC 0-24h , and AUC 0-inf The effect was dose-proportional with slope estimates (β1) and 90% CI of 0.92 (0.85-0.99), 1.00 (0.96-1.05), 0.97 (0.93-1.02), and 0.99 (0.95-1.03), respectively. Graphical assessment also demonstrated a significant decrease in R(-)-ketamine exposure (C) across the dose range. max , AUC 0-t , AUC 0-24h , and AUC 0-inf ) was dose-proportional.

[0387] Across the R(-)-ketamine dose range (5 mg, 15 mg, 30 mg, 60 mg, 100 mg, and 150 mg), increases in norketamine exposure were observed. max , AUC 0-t , AUC 0-24h , and AUC 0-inf The effect was dose-proportional for 100 mg / kg / day, with slope estimates (β) and 90% CI of 1.04 (0.99-1.09), 1.12 (1.05-1.19), 1.11 (1.05-1.18), and 1.14 (1.07-1.22), respectively. Graphical assessment also demonstrated a significant decrease in norketamine exposure (C) across the dose range. max , AUC 0-t , AUC 0-24h , and AUC 0-inf) was dose-proportional.

[0388] Across the R(-)-ketamine dose range (5 mg, 15 mg, 30 mg, 60 mg, 100 mg, and 150 mg), increased 6-hydroxynorketamine exposure was observed at C max , AUC 0-t , AUC 0-24h , and AUC 0-inf The effect was dose-proportional for 6-hydroxynorketamine, with a slope estimate (β) and 90% CI of 0.97 (0.9-1.04), 0.97 (0.9-1.03), and 0.97 (0.9-1.03), respectively. Graphical assessment also demonstrated that the exposure (C max , AUC 0-t , AUC 0-24h Across the dose range of R(-)-ketamine (5 mg, 15 mg, 30 mg, 60 mg, 100 mg, and 150 mg), the increase in dehydronorketamine exposure was max , AUC 0-t , AUC 0-24h , and AUC 0-inf The dose-proportional response was greater than dose-proportional for 1.28 (1.15-1.42), 1.45 (1.32-1.58), 1.31 (1.17-1.46), and 1.61 (1.26-1.95), respectively. However, based on graphical evaluation, the exposure of dehydronorketamine across the dose range (C max , AUC 0-t , AUC 0-24h , and AUC 0-inf ) suggest that overall exposure was approximately dose-proportional, except at the highest dose (150 mg), where dose-proportionality was exceeded. Note that due to small sample sizes and interindividual variability, these data are only suggestive.

[0389] Pharmacokinetic considerations PK analysis of R(-)-ketamine plasma concentrations after IV infusion demonstrated that R(-)-ketamine concentrations were quantifiable in all subjects 5 minutes after the start of the infusion, regardless of dose level, with a median plasma Tmax ranging from 15 to 40 minutes. was also quantifiable within 15 minutes of initiating the infusion. Norketamine was quantifiable in all subjects within 10-15 minutes and demonstrated plasma T max The median range was 40 minutes to 2.00 hours. 6-hydroxynorketamine was quantifiable in all subjects within 10-15 minutes, and plasma T max The median range was 4.00 to 8.00 hours. Dehydronorketamine was quantifiable in all subjects between 15 minutes and 1.50 hours, and plasma T max The median range was 1.50 to 3.00 hours.

[0390] For R(-)-ketamine doses of 5 mg to 150 mg (a 30-fold increase in the R(-)-ketamine dose), the arithmetic mean C for R(-)-ketamine, norketamine, 6-hydroxynorketamine, and dehydronorketamine was max The arithmetic mean AUC values ​​for R(-)-ketamine, norketamine, 6-hydroxynorketamine, and dehydronorketamine increased by 23.0-fold (33.9 ng / mL compared with 780 ng / mL), 31.6-fold (11.4 ng / mL compared with 360 ng / mL), 27.6-fold (5.98 ng / mL compared with 165 ng / mL), and 179.8-fold (198 pg / mL compared with 35600 pg / mL). For doses of 5 mg to 150 mg of R(-)-ketamine (a 30-fold increase in the R(-)-ketamine dose), the arithmetic mean AUC values ​​for R(-)-ketamine, norketamine, 6-hydroxynorketamine, and dehydronorketamine, respectively, were 0~24hr is 27.1 times (1720hr * ng / mL compared to 63.5hr * ng / mL), 39.4 times (3140hr * ng / mL compared to 79.6hr * ng / mL), 27.3 times (3000hr * ng / mL compared to 110hr* ng / mL), and 169.6 times (424000hr * pg / mL compared to 2500hr * pg / mL). The arithmetic mean AUC of R(-)-ketamine, norketamine, 6-hydroxynorketamine, and dehydronorketamine increased with R(-)-ketamine 1 (a 30-fold increase in the dose of R(-)-ketamine 1). 0-t is 29.9 times (1720hr * ng / mL compared to 57.5hr * ng / mL), 40.3 times (3140hr * ng / mL compared to 78.0hr * ng / mL), 27.3 times (3000hr * ng / mL compared to 110hr * ng / mL), and 309.5 times (424000hr * pg / mL compared to 1370hr * pg / mL) increased.

[0391] Overall, based on statistical analysis, plasma exposure of R(-)-ketamine and two metabolites (norketamine and 6-hydroxynorketamine) was significantly higher than C max and AUC(AUC 0-t , AUC 0-24h , AUC 0-inf ) which increased with the dose administered across all dose cohorts. Based on graphical evaluation, the exposure of dehydronorketamine across the dose range (C max , AUC 0-t , AUC 0-24h , and AUC 0-inf ) suggest that overall exposure was approximately dose-proportional, except for the highest dose of R(-)-ketamine (150 mg), which was greater than dose-proportional. Note that these data are only suggestive, given the small sample size, interindividual variability, and the fact that dehydronorketamine was not stable in the samples.

[0392] Overall, the inter-individual variability was C max, AUC 0-t , AUC 0-24h , and AUC 0-inf The geometric CV% values ​​ranged from 13.3% to 30.3%, 12.1% to 28.4%, 12.8% to 46.0%, and 11.1% to 51.5% for R(-)-ketamine, norketamine, 6-hydroxynorketamine, and dehydronorketamine, respectively.

[0393] Overall, the arithmetic mean (CV%) CL and Vz of plasma R(-)-ketamine were fairly consistent across all dose cohorts, ranging from 76.8 to 97.5 L / hr (13.7% to 22.6%) and 345 to 921 L (20.0% to 50.2%), respectively. After peak plasma concentrations were achieved, a monophasic decline was observed, with arithmetic mean t 1 / 2 The ranges across all dose cohorts were 3.06 to 7.21 hours for R(-)-ketamine, 6.70 to 8.05 hours for norketamine, and 7.41 to 9.32 hours for dehydronorketamine. 1 / 2 was NC for 6-hydroxynorketamine due to insufficient concentration data in the elimination phase.

[0394] Overall, the arithmetic mean (CV%) ratios of Cmax metabolites to parent (R(-)-ketamine) were higher for norketamine and lower for dehydronorketamine, ranging from 0.00581 to 0.448 (19.3% to 90.0%) across all R(-)-ketamine dose cohorts. Overall, the arithmetic mean (CV%) AUC0-t and AUC 0-24h The metabolite-to-parent (R(-)-ketamine) ratios were higher for 6-hydroxynorketamine and lower for dehydronorketamine across all dose cohorts, ranging from 0.0223 to 2.22 (8.7% to 63.3%) and 0.0512 to 2.22 (8.7% to 63.3%), respectively. Overall, the arithmetic mean (CV%) AUC 0-infMetabolite-to-parent compound (R(-)-ketamine) ratios were higher for norketamine compared with dehydronorketamine across all dose cohorts, ranging from 0.0585 to 1.88 (17.0% to 28.0%).

[0395] The pharmacokinetics of IV administration of R(-)-ketamine (5 mg, 15 mg, 30 mg, 60 mg, 100 mg, and 150 mg) in healthy human subjects showed the following: Across all R(-)-ketamine dose cohorts, R(-)-ketamine, norketamine, 6-hydroxynorketamine, and dehydronorketamine reached peak plasma concentrations after IV administration (infused over 40 minutes), with median Tmax ranges of approximately 15 to 40 minutes, 40 minutes to 2 hours, 4 hours to 8 hours, and 1.5 hours to 3 hours, respectively.

[0396] After IV administration of R(-)-ketamine, Cmax and AUC(AUC 0-t , AUC 0-24h , AUC 0-inf The rate and extent of systemic exposure of R(-)-ketamine and its metabolites (norketamine, 6-hydroxynorketamine, and dehydronorketamine), as measured by MRI, appeared to be approximately dose-proportional over a 30-fold dose range of R(-)-ketamine (5 mg to 150 mg).

[0397] The terminal half-lives (t 1 / 2 ) estimates were low to moderate across all dose cohorts, ranging from 3.0 to 9.5 hours.

[0398] The clearance and final volume of distribution of R(-)-ketamine ranged from 76.8 to 97.5 L / hr and 345 to 921 L, respectively, and were comparable across all dose cohorts.

[0399] Across all dose cohorts, norketamine had a relatively higher Cmax (0.448) and a significantly higher AUC (AUC) of 6-hydroxynorketamine compared to other metabolites at metabolite-to-parent (R(-)-ketamine) ratios. 0-t :2.22 and AUC 0-24h :2.22) was relatively high.

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Claims

1. 1. A method for treating or ameliorating depressive symptoms in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising R(-)-ketamine or a pharmaceutically acceptable salt thereof; wherein the composition is substantially free of S(+)-ketamine or a pharmaceutically acceptable salt thereof; and The method, wherein the therapeutically effective amount comprises a maximum plasma concentration (Cmax) of R(-)-ketamine of at least 250 ng / mL.

2. 2. The method of claim 1, wherein the Cmax is 250 to 1000 ng / mL.

3. 2. The method of claim 1, wherein the Cmax is 250 to 800 ng / mL.

4. The depressive symptoms are assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) subject score; and 10. The method of claim 1, wherein the MADRS subject score is reduced by administration of the composition.

5. 5. The method of claim 4, wherein the MADRS subject score is reduced by about 2 to about 20 upon administration of the composition.

6. 5. The method of claim 4, wherein the MADRS subject score is reduced by about 2 to about 20 when measured about 24 hours, about 7 days, or about 14 days after initiation of administration of the composition.

7. 5. The method of claim 4, wherein the MADRS subject score is reduced by about 2 to about 20 after initiation of administration of the composition.

8. 10. The method of claim 1, wherein the therapeutically effective dose of the composition comprises about 50 mg to about 150 mg of R(-)-ketamine or a pharmaceutically acceptable salt thereof.

9. 2. The method of claim 1, wherein the composition comprises R(-)-ketamine hydrochloride.

10. 10. The method of claim 1, wherein the composition is administered intravenously or subcutaneously.

11. 11. The method of claim 10, wherein the intravenous administration comprises intravenous infusion.

12. 12. The method of claim 11, wherein the composition is administered over a period of about 10 minutes to about 1.5 hours.

13. 10. The method of claim 1, wherein the composition is administered once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, once every two weeks, once every ten days, or once every month.

14. below (a) an initial period during which the composition is administered once every 1, 2, 3, or 4 days; 10. The method of claim 1, comprising a dosing schedule comprising: (b) a maintenance period during which the composition is administered less frequently than during said initial period.

15. 15. The method of claim 14, wherein the composition is administered once a week, twice a week, once every two weeks, once every 10 days, or once a month during the maintenance period.

16. The method of claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier.

17. 10. The method of claim 1, wherein the depressive symptoms are symptoms of a mood disorder in the subject.

18. 18. The method of claim 17, wherein the mood disorder comprises depression, and optionally, the depression is treatment-resistant depression or major depressive disorder.

19. 18. The method of claim 17, wherein the mood disorder comprises bipolar disorder, post-traumatic stress disorder, obsessive-compulsive disorder, autism spectrum disorder, schizophrenia, or dementia.

20. 10. The method of claim 1, wherein the depressive symptoms are associated with a substance use disorder in the subject.

21. 2. The method of claim 1, wherein the therapeutically effective amount of the composition comprising R(-)-ketamine does not cause significant dissociation, derealization, or sedation in the subject.

22. 10. The method of claim 1, wherein the therapeutically effective amount of the composition increases the systolic blood pressure of the subject by less than 40 mmHg, optionally less than 10 mmHg, measured within 14 days of administration.

23. 10. The method of claim 1, wherein the therapeutically effective amount of the composition increases the diastolic blood pressure of the subject by less than 25 mmHg, optionally less than 10 mmHg, measured within 14 days of administration.

24. 2. The method of claim 1, wherein administration of the therapeutically effective amount of the composition results in fewer side effects or adverse events than administration of a therapeutically effective amount of S(+)-ketamine or racemic ketamine.

25. 1. A method for treating a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising R(-)-ketamine or a pharmaceutically acceptable salt thereof; wherein the composition is substantially free of S(+)-ketamine or a pharmaceutically acceptable salt thereof; and The method, wherein the therapeutically effective amount comprises a maximum plasma concentration (Cmax) of R(-)-ketamine of at least 250 ng / mL.

26. 26. The method of claim 25, wherein the Cmax is 250 to 1000 ng / mL.

27. 26. The method of claim 25, wherein the Cmax is 250 to 800 ng / mL.

28. 26. The method of claim 25, wherein the composition comprises R(-)-ketamine hydrochloride.

29. 26. The method of claim 25, wherein the composition is administered intravenously or subcutaneously.

30. 30. The method of claim 29, wherein the intravenous administration comprises intravenous infusion.

31. 31. The method of claim 30, wherein the composition is administered over a period of about 10 minutes to about 1.5 hours.

32. 26. The method of claim 25, wherein the composition is administered once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, once every two weeks, once every ten days, or once every month.

33. below (a) an initial period during which the composition is administered once every 1, 2, 3, or 4 days; 26. The method of claim 25, comprising a dosing schedule comprising: (b) a maintenance period during which the composition is administered less frequently than during said initial period.

34. 34. The method of claim 33, wherein the composition is administered once a week, twice a week, once every two weeks, once every 10 days, or once a month during the maintenance period.

35. 26. The method of claim 25, wherein the composition further comprises a pharmaceutically acceptable carrier.

36. 26. The method of claim 25, wherein the disease or disorder is a neurodegenerative disease or disorder, a neurodevelopmental disorder, an inflammatory disease, or a bone disease.

37. 37. The method of claim 36, wherein the neurodegenerative disease or disorder comprises Parkinson's disease, Parkinsonism, Huntington's disease, acanthocytic chorea, spinocerebellar degeneration, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, spinal-bulbar muscular atrophy, syringomyelia, neuroacanthocytosis, eating disorders, Alzheimer's disease, dementia with Lewy bodies, basal ganglia degeneration, multiple sclerosis, traumatic brain injury, cerebral infarction, or cardiovascular disease.

38. 37. The method of claim 36, wherein the neurodevelopmental disorder comprises schizophrenia, autism spectrum disorder, attention-deficit / hyperactivity disorder, or a learning disability.

39. 37. The method of claim 36, wherein the inflammatory disease comprises ulcerative colitis, Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, insulin-dependent diabetes mellitus, Addison's disease, Goodpasture's syndrome, IgA nephropathy, interstitial nephritis, Sjogren's syndrome, autoimmune pancreatitis, psoriasis, atopic dermatitis, pneumonia, chronic bronchitis, bronchial asthma, systemic lupus erythematosus (SLE), scleroderma, or delirium, and the bone disease comprises osteoporosis, osteolytic bone metastasis, and Paget's disease of bone.

40. 26. The method of claim 25, wherein the therapeutically effective amount of the composition comprising R(-)-ketamine does not cause significant dissociation, derealization, or sedation in the subject.

41. 26. The method of claim 25, wherein the therapeutically effective amount of the composition increases the systolic blood pressure of the subject by less than 40 mmHg, optionally less than 10 mmHg, measured within 14 days of administration.

42. 26. The method of claim 25, wherein the therapeutically effective amount of the composition increases the diastolic blood pressure of the subject by less than 25 mmHg, optionally less than 10 mmHg, measured within 14 days of administration.

43. 26. The method of claim 25, wherein administration of the therapeutically effective amount of the composition results in fewer side effects or adverse events than administration of a therapeutically effective amount of S(+)-ketamine or racemic ketamine.

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