Treatment or prevention of depressive disorders with combination therapy

Abstract

Provided herein are compositions and methods for treating a disease or disorder using a therapeutically effective amount of an N-methyl-D-aspartate (NMDA) receptor modulator and a therapeutically effective amount of a target of rapamycin (mTOR) inhibitor.

Description

[Technical Field]

[0001] cross reference

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 386,340, filed December 7, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] N-methyl-D-aspartate (NMDA) receptors are involved in various nervous system disorders, including neurodegenerative disorders, mood disorders, and neurodevelopmental disorders. NMDA receptor modulators are classified as rapid-acting antidepressants (RAADs) due to their rapid antidepressant effects compared to slow-acting antidepressants (SAADs). NMDA receptor modulators have brought about a paradigm shift in thinking regarding the pharmacological treatment of depression and other mood disorders. In some cases, coadministration of an NMDA receptor modulator and a rapamycin target protein (mTOR) inhibitor can extend the effects of the NMDA receptor modulator through mTOR inhibition. In certain cases, mTOR inhibitors can prolong the clinical effects of the NMDA receptor modulator. In other cases, mTOR inhibitors can reduce the abuse liability of the NMDA receptor modulator. Currently, coadministration of an NMDA receptor modulator and an mTOR inhibitor can be performed by sequential administration of the NMDA receptor modulator and the mTOR inhibitor in any order and with any interval between their separate administrations. Thus, there is an unmet need for the development of pharmaceutical compositions containing both an NMDA receptor modulator and an mTOR inhibitor that are effectively and conveniently co-administered to improve compliance and potentially reduce the abuse liability associated with NMDA receptor modulators. Summary of the Invention [Means for solving the problem]

[0003]

[0003] In some aspects, the present disclosure provides a solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator and a target of rapamycin (mTOR) inhibitor. In some embodiments, the mTOR inhibitor binds to a domain of mTOR and inhibits mTOR activity. In some embodiments, the NMDA receptor modulator binds to a component of the NMDA receptor and activates or inhibits the NMDA receptor. In certain aspects, the present disclosure provides a solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator at a concentration of about 0.04 milligrams per milliliter (mg / mL) to about 150 mg / mL and an mTOR inhibitor at a concentration of about 0.02 mg / mL to about 10 mg / mL. In certain aspects, the present disclosure provides a solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator and an mTOR inhibitor, wherein the NMDA receptor modulator and the mTOR inhibitor have a weight ratio of greater than about 1:1. In some aspects, the present disclosure also provides a solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator at a concentration of about 0.01 mg / mL to about 1.0 mg / mL and an mTOR inhibitor at a concentration of about 0.5 micrograms / milliliter (μg / mL) to about 100 μg / mL. In some embodiments, the solution comprises about 0.9% (w / v) sodium chloride in water or about 5% (w / v) dextrose in water. In some embodiments, the NMDA receptor modulator and the mTOR inhibitor have a weight ratio greater than about 1:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 600:1 to about 5:1. In some embodiments, the solution further comprises polyethylene glycol (PEG), polysorbate, or both. In some embodiments, the solution comprises a polysorbate, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the solution comprises PEG, wherein the PEG has an average molecular weight of about 300 to about 600, and optionally is PEG 400.In some embodiments, the solution comprises polysorbate 80 and PEG 400. In some aspects, the present disclosure also provides a solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator, an mTOR inhibitor, and polysorbate or PEG 400.

[0004] In some embodiments, the solution further comprises an excipient selected from the group consisting of an aqueous vehicle, a water-miscible vehicle, a non-aqueous vehicle, a preservative, a solubility enhancer, a stabilizer, an antioxidant, a buffer, an emulsifier, a suspending agent, a complexing agent, a sequestering or chelating agent, a thickening agent, an osmotic / tonicity agent, an antifoaming / defoaming agent, an osmotic agent, a polymer, a spreading agent, a wetting agent, and a pH adjuster. In some embodiments, the solution further comprises an excipient selected from the group consisting of water, ethanol, propylene glycol, polyethylene glycol (PEG), a polysorbate, citric acid, and DL-α-tocopherol. In some embodiments, the solution comprises water. In some embodiments, the solution comprises a polysorbate. In some embodiments, the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the solution comprises PEG. In some embodiments, the PEG has an average molecular weight of about 300 to about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the solution comprises ethanol. In some embodiments, the ethanol is absolute ethanol.

[0005] In some embodiments, the concentration of polysorbate ranges from about 10% w / w to about 50% w / w. In some embodiments, the concentration of PEG ranges from about 0.1% w / w to about 30% w / w. In some embodiments, the concentration of ethanol ranges from about 10% w / w to about 50% w / w. In some embodiments, the concentration of water ranges from about 0.1% w / w to about 30% w / w.

[0006] In some embodiments, the solution further comprises 38.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, 10% (w / w) water, or any combination thereof. In some embodiments, the solution further comprises 33.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, or 15% (w / w) water. In some embodiments, the solution further comprises 28.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, or 20% (w / w) water. In some embodiments, the solution further comprises 23.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, or 25% (w / w) water. In some embodiments, the solution further comprises 18.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, or 30% (w / w) water.

[0007] In some embodiments, the weight ratio of the N-methyl-D-aspartate receptor modulator to the mTOR inhibitor is greater than the weight of the mTOR inhibitor. In some embodiments, the weight ratio of the N-methyl-D-aspartate receptor modulator to the mTOR inhibitor is greater than about 1:1. In some embodiments, the weight ratio of the N-methyl-D-aspartate receptor modulator to the mTOR inhibitor is in the range of about 1000:1 to about 2:1. In some embodiments, the weight ratio of the N-methyl-D-aspartate receptor modulator to the mTOR inhibitor is in the range of about 600:1 to about 5:1. In some embodiments, the weight ratio of the N-methyl-D-aspartate receptor modulator to the mTOR inhibitor is in the range of about 1000:1 to about 10:1.

[0008]

[0008] The present disclosure provides a solution comprising an NMDA receptor modulator that binds to a component of the NMDA receptor and activates or inhibits the NMDA receptor, and an mTOR inhibitor. In some embodiments, the mTOR inhibitor binds to a domain of mTOR and inhibits mTOR activity, and the excipient is selected from the group consisting of water, polysorbate 80, PEG 400, propylene glycol, and absolute ethanol.

[0009]

[0009] The present disclosure also provides a solution comprising an NMDA receptor modulator that binds to a component of the NMDA receptor and activates or inhibits the NMDA receptor, and an mTOR target of rapamycin (mTOR) inhibitor. In some embodiments, the mTOR inhibitor binds to a domain of mTOR and inhibits mTOR activity, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is greater than about 1:1, and the excipient is selected from the group consisting of water, polysorbate 80, PEG 400, and absolute ethanol. In some embodiments, the weight of the N-methyl-D-aspartate receptor modulator is greater than the weight of the mTOR inhibitor. In some embodiments, the solution further comprises citric acid or DL-alpha-tocopherol.

[0010]

[0010] In certain aspects, the present disclosure provides a solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator and an excipient. In some embodiments, the NMDA receptor modulator binds to a component of the NMDA receptor and activates or inhibits the NMDA receptor. In some embodiments, the excipient is selected from the group consisting of ethanol, propylene glycol, polyethylene glycol (PEG), and polysorbate. In some embodiments, the excipient further comprises an aqueous vehicle, a water-miscible vehicle, a non-aqueous vehicle, a preservative, a solubility enhancer, a stabilizer, an antioxidant, a buffer, an emulsifier, a suspending agent, a complexing agent, a sequestering or chelating agent, a thickening agent, an osmotic / tonicity agent, an antifoaming / defoaming agent, an osmotic agent, a polymer, a spreading agent, a wetting agent, and a pH adjuster. In some embodiments, the excipient is selected from the group consisting of water, ethanol, propylene glycol, polyethylene glycol (PEG), polysorbate, citric acid, and DL-alpha-tocopherol. In some embodiments, the solution comprises water. In some embodiments, the solution comprises a polysorbate. In some embodiments, the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the solution comprises PEG. In some embodiments, the PEG has an average molecular weight of about 300 to about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the solution comprises ethanol. In some embodiments, the ethanol is absolute ethanol.

[0011] In some embodiments, the concentration of polysorbate ranges from about 10% w / w to about 50% w / w. In some embodiments, the concentration of PEG ranges from about 0.1% w / w to about 30% w / w. In some embodiments, the concentration of ethanol ranges from about 10% w / w to about 50% w / w. In some embodiments, the concentration of water ranges from about 0.1% w / w to about 30% w / w.

[0012] In some embodiments, the solution comprises 38.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, 10% (w / w) water, or any combination thereof. In some embodiments, the solution comprises 33.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, or 15% (w / w) water. In some embodiments, the solution comprises 28.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, or 20% (w / w) water. In some embodiments, the solution comprises 23.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, or 25% (w / w) water. In some embodiments, the solution comprises 18.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, or 30% (w / w) water.

[0013]

[0013] The present disclosure also provides compositions comprising an N-methyl-D-aspartate (NMDA) receptor modulator and a target of rapamycin (mTOR) inhibitor. In some embodiments, the NMDA receptor modulator binds to a component of the NMDA receptor and activates or inhibits the NMDA receptor. In some embodiments, the mTOR inhibitor binds to a domain of mTOR and inhibits mTOR activity.

[0014] In some embodiments, the weight ratio of the N-methyl-D-aspartate receptor modulator is greater than the weight of the mTOR inhibitor. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is greater than about 1:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 1000:1 to about 2:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 800:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 600:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 500:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 300:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 1000:1 to about 10:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 30:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 50:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 100:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 200:1.

[0015] In some embodiments, the composition further comprises an excipient. In some embodiments, the excipient is selected from the group consisting of aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, preservatives, solubility enhancers, stabilizers, antioxidants, buffers, emulsifiers, suspending agents, complexing agents, sequestering or chelating agents, thickening agents, osmotic / tonicity agents, antifoaming / defoaming agents, penetrating agents, polymers, spreading agents, wetting agents, and pH adjusters. In some embodiments, the excipient is selected from the group consisting of water, ethanol, propylene glycol, polyethylene glycol (PEG), polysorbates, citric acid, and DL-alpha-tocopherol.

[0016] In some embodiments, the NMDA receptor modulator is ketamine, R-ketamine, S-ketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, dextromethorphan, a fixed-dose combination of dextromethorphan and quinidine, a fixed-dose combination of dextromethorphan and bupropion, GM-1020, besonprodil, eliprodil, ifenprodil, lisrenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro8-4304, traxoprodil (CP-101,606), BMT-108908, omfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP37849, 1-aminocyclopropanecarboxylic acid, traxoprodil, Ro25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxyzine, tiletamine, neramexane, etoxadrol, dexoxadrol le, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delsemin, dextralorphan, dextrorphan, diphenidine, eticcyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7-Dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnalone sulfate (3α5βS), UBP608, UBP618, UBP551, UBP512, HA- 966, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salts, solvates, enantiomers, tautomers, stereoisomers, and geometric isomers thereof, or any mixtures thereof. In some embodiments, the NMDA receptor modulator comprises ketamine, any salts, solvates, enantiomers, tautomers, stereoisomers, and geometric isomers thereof, or any mixtures thereof. In some embodiments, the ketamine is ketamine HCl.

[0017] In some embodiments, the mTOR inhibitor is BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), KU-0063794, PI-103 (mTOR inhibitor V, PI3-K inhibitor V, PI-103 (CAS371935-74-9)), tolquinib (PP242), tacrolimus (FK-506, Fujimycin), ridaforolimus (AP23573, MK-8669 , deforolimus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), Torin-1 (DNA-PK inhibitor VI, PI3-K inhibitor XVIII, mTOR inhibitor XI, Torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE390), GS K1059615, WYE-354 (mTOR inhibitor II), gedatolicib (PF-05212384, PKI-587), AZD-2014 (bistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (A TRi), GDC-0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound401, GNE-477, vimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC223), clemastine (HS-592) fumarate, nitazoxanide (NSC697855), 4EGI-1, ABTL-0812, astragaloside IV,In some embodiments, the mTOR inhibitor is selected from the group consisting of samotricisib (LY3023414), chrysophanic acid, and zotarolimus (ABT-578), any salts, solvates, enantiomers, tautomers, diastereomers, stereoisomers, and geometric isomers thereof, and any mixtures thereof. In some embodiments, the mTOR inhibitor comprises rapamycin (sirolimus, AY22989, ABI-009) or temsirolimus (CCI-779).

[0018] In some embodiments, the solution further comprises an excipient selected from the group consisting of water, ethanol, propylene glycol, polypropylene glycol, citric acid, and DL-alpha-tocopherol. In some embodiments, the concentration of ethanol ranges from about 10% w / w to about 50% w / w, from about 0.1% w / w to about 30% w / w, or from about 5% w / w to about 50% w / w. In some embodiments, the concentration of polysorbate ranges from about 5% w / w to about 50% w / w. In some embodiments, the concentration of PEG ranges from about 0.1% w / w to about 30% w / w. In some embodiments, the solution comprises about 23.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 6% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution comprises about 20.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 9% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution comprises about 17.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 12% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution comprises about 14.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 15% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution comprises about 11.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 18% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution does not comprise citric acid or DL-alpha-tocopherol.

[0019] In some embodiments, the solution contains about 20 mg to about 150 mg, about 30 mg to about 140 mg, about 40 mg to about 120 mg, about 50 mg to about 100 mg, or about 60 mg to about 80 mg of an NMDA receptor modulator. In some embodiments, the solution contains about 0.05 mg to about 2.0 mg, about 0.1 mg to about 1.8 mg, about 0.2 mg to about 1.5 mg, about 0.4 mg to about 1.2 mg, or about 0.8 mg to about 1.0 mg of an mTOR inhibitor.

[0020] In some embodiments, the solution is stable at temperatures up to about 60° C. for at least about 1 week.

[0021] In additional embodiments, the present disclosure provides a method for treating or preventing a disease in a subject in need thereof, comprising administering a solution or composition disclosed herein to the subject. In some embodiments, administration is via intramuscular, intravenous, subcutaneous, oral, inhalation, or intranasal routes. In some embodiments, the solution or composition is administered once daily, twice daily, three times daily, four times daily, or five times daily. In some embodiments, the solution or composition is administered once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, or seven times weekly. In some embodiments, the solution or composition is administered once monthly, twice monthly, three times monthly, four times monthly, five times monthly, six times monthly, seven times monthly, eight times monthly, nine times monthly, or ten times monthly.

[0021]

[0022] In some embodiments, the disease is selected from the group consisting of major depressive disorder (MDD), major depressive episode in bipolar disorder (bipolar depression), persistent depressive disorder (dysthymia), major mood dysregulation disorder, major depressive disorder (including major depressive episode), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, depressive disorder due to other medical illness, other specified depressive disorder, unspecified depressive disorder, anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, addictive disorder, bipolar disorder type I, bipolar disorder type II, generalized anxiety disorder, social anxiety disorder (social phobia), specific phobia, panic disorder, agoraphobia, separation anxiety disorder, selective mutism, substance-induced anxiety disorder, medication-induced anxiety disorder, anxiety disorder due to other medical illness, borderline personality disorder, treatment-resistant depression, unspecified anxiety disorder, chronic pain, and any combination thereof. In some embodiments, the disease, disorder, or condition is a mood disorder, optionally a depressive disorder. In some embodiments, the treatment or prevention is by adjunctive therapy.

[0022]

[0023] Provided herein is a method for treating or preventing a depressive disorder in a subject, the method comprising administering a solution comprising an NMDA receptor modulator that binds to a component of the NMDA receptor and activates or inhibits the NMDA receptor, and an mTOR target of rapamycin (mTOR) inhibitor that binds to a domain of mTOR and inhibits mTOR activity, wherein the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is greater than about 1:1, and the solution comprises an excipient selected from the group consisting of water, polysorbate 80, PEG 400, propylene glycol, and absolute ethanol. In some embodiments, the present disclosure provides a method for treating or preventing a disease, disorder, or condition in a subject in need thereof, the method comprising mixing a first solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator with a second solution comprising an mTOR target of rapamycin (mTOR) inhibitor, thereby producing a solution comprising both the NMDA receptor modulator and the mTOR inhibitor, and administering the solution to the subject within about 4, 6, or 24 hours after the solution is produced.

[0023]

[0024] In some embodiments, the weight of the N-methyl-D-aspartate receptor modulator is greater than the weight of the mTOR inhibitor. In some embodiments, the solution further comprises citric acid or DL-alpha-tocopherol.

[0024]

[0025] The present disclosure also provides a method for preparing a solution, the method comprising: mixing 1) a solution of an N-methyl-D-aspartate (NMDA) receptor modulator that binds to a component of the NMDA receptor and activates or inhibits the NMDA receptor; and 2) a solution of an mTOR inhibitor that binds to a domain of mTOR and inhibits mTOR activity. In some embodiments, the present disclosure provides a method for preparing a solution, the method comprising: mixing (i) a first solution containing the N-methyl-D-aspartate (NMDA) receptor modulator and (ii) a second solution containing a target of rapamycin (mTOR) inhibitor, thereby producing a solution containing both the NMDA receptor modulator and the mTOR inhibitor, wherein the volume ratio of the first solution to the second solution is about 3:2.

[0025]

[0026] In some embodiments, the NMDA receptor modulator solution further comprises an excipient selected from the group consisting of an aqueous vehicle, a water-miscible vehicle, a non-aqueous vehicle, a preservative, a solubility enhancer, a stabilizer, an antioxidant, a buffer, an emulsifier, a suspending agent, a complexing agent, a sequestering or chelating agent, a thickening agent, an osmotic / tonicity agent, an antifoaming / defoaming agent, an osmotic agent, a polymer, a spreading agent, a wetting agent, and a pH adjuster. In some embodiments, the NMDA receptor modulator solution further comprises an excipient selected from the group consisting of water, ethanol, propylene glycol, polyethylene glycol (PEG), a polysorbate, citric acid, and DL-alpha-tocopherol. In some embodiments, the NMDA receptor modulator solution comprises water. In some embodiments, the NMDA receptor modulator solution comprises a polysorbate. In some embodiments, the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the NMDA receptor modulator solution comprises PEG. In some embodiments, the PEG has an average molecular weight of about 300 to about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the NMDA receptor modulator solution comprises ethanol. In some embodiments, the ethanol is absolute ethanol.

[0026]

[0027] In some embodiments, the concentration of polysorbate ranges from about 10% w / w to about 50% w / w. In some embodiments, the concentration of PEG ranges from about 0.1% w / w to about 30% w / w. In some embodiments, the concentration of ethanol ranges from about 10% w / w to about 50% w / w. In some embodiments, the concentration of water ranges from about 0.1% w / w to about 30% w / w.

[0027]

[0028] In some embodiments, the solution comprises 38.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, 10% (w / w) water, or any combination thereof. In some embodiments, the solution comprises 33.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, or 15% (w / w) water. In some embodiments, the solution comprises 28.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, or 20% (w / w) water. In some embodiments, the solution comprises 23.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, or 25% (w / w) water. In some embodiments, the solution comprises 18.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, or 30% (w / w) water.

[0028]

[0029] In some embodiments, the weight of the N-methyl-D-aspartate receptor modulator is greater than the weight of the mTOR inhibitor. In some embodiments, the weight ratio of the N-methyl-D-aspartate receptor modulator to the mTOR inhibitor is greater than about 1:1. In some embodiments, the method further comprises adding a diluent. In some embodiments, the diluent comprises saline containing water and sodium chloride (NaCl). In some embodiments, the concentration of NaCl ranges from about 0.5 milligrams per milliliter (mg / ml) to about 20 mg / ml. In some embodiments, the solution comprises about 0.9% (w / v) sodium chloride in water or about 5% (w / v) dextrose in water. In some embodiments, the solution of the mTOR inhibitor comprises an excipient selected from the group consisting of anhydrous alcohol, DL-alpha-tocopherol, propylene glycol, and anhydrous citric acid. In some embodiments, the anhydrous alcohol comprises ethyl alcohol.

[0029]

[0030] In some embodiments, the concentration of anhydrous alcohol in the solution of the mTOR inhibitor ranges from about 10% w / w to about 50% w / w. In some embodiments, the concentration of DL-alpha-tocopherol in the solution of the mTOR inhibitor ranges from about 0.01% w / w to about 1.0% w / w. In some embodiments, the concentration of propylene glycol in the solution of the mTOR inhibitor ranges from about 20% w / w to about 70% w / w. In some embodiments, the concentration of anhydrous citric acid in the solution of the mTOR inhibitor ranges from about 0.001% w / w to about 0.01% w / w.

[0030]

[0031] In some embodiments, the NMDA receptor modulator is selected from the group consisting of ketamine, R-ketamine, S-ketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, dextromethorphan, a fixed-dose combination of dextromethorphan and quinidine, a fixed-dose combination of dextromethorphan and bupropion, GM-1020, besonprodil, eliprodil, ifenprodil, lislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro8-4304, traxoprodil (CP-101,606), BMT-108908, omfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP37849, 1-aminocyclopropanecarboxylic acid, traxoprodil, Ro25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxyzine, tiletamine, neramexane, etoxadrol, dexoxadrol le, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delsemin, dextralorphan, dextrorphan, diphenidine, eticcyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7-Dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnalone sulfate (3α5βS), UBP608, UBP618, UBP551, UBP512, HA- 966, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salts, solvates, enantiomers, tautomers, stereoisomers, and geometric isomers thereof, or any mixtures thereof. In some embodiments, the NMDA modulator comprises ketamine, any salts, solvates, enantiomers, tautomers, stereoisomers, and geometric isomers thereof, or any mixtures thereof. In some embodiments, the ketamine is ketamine HCl.

[0031]

[0032] In some embodiments, the mTOR inhibitor is BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), KU-0063794, PI-103 (mTOR inhibitor V, PI3-K inhibitor V, PI-103 (CAS371935-74-9)), tolquinib (PP242), tacrolimus (FK-506, Fujimycin), ridaforolimus (AP23573, MK-8669, deforomicin), or rituximab (PP242). Limus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), Torin-1 (DNA-PK inhibitor VI, PI3-K inhibitor XVIII, mTOR inhibitor XI, Torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE390), GSK10 59615, WYE-354 (mTOR inhibitor II), gedatolisib (PF-05212384, PKI-587), AZD-2014 (bistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (AT Ri), GDC-0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound401, GNE-477, vimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC223), clemastine (HS-592) fumarate, nitazoxanide (NSC697855), 4EGI-1, ABTL-0812, astragaloside IV,In some embodiments, the mTOR inhibitor is selected from the group consisting of samotricisib (LY3023414), chrysophanic acid, and zotarolimus (ABT-578), any salts, solvates, enantiomers, tautomers, diastereomers, stereoisomers, and geometric isomers thereof, and any mixtures thereof. In some embodiments, the mTOR inhibitor comprises rapamycin (sirolimus, AY22989, ABI-009) or temsirolimus (CCI-779).

[0032]

[0033] In some embodiments, the solution is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or seven times per week. In some embodiments, the NMDA receptor modulator is administered at a dose of about 0.1 mg / kg to about 1 mg / kg. In some embodiments, the NMDA receptor modulator is administered at a dose of about 0.3 mg / kg to about 0.7 mg / kg. In some embodiments, the NMDA receptor modulator is administered at a dose of about 30 mg to about 90 mg. In some embodiments, the NMDA receptor modulator is administered at a dose of about 30 mg to about 60 mg. In some embodiments, the mTOR inhibitor is administered at a dose of about 1 μg / kg to about 100 μg / kg. In some embodiments, the mTOR inhibitor is administered at a dose of about 2.5 μg / kg to about 30 μg / kg. In some embodiments, the mTOR inhibitor is administered at a dose of about 3 μg / kg to about 25 μg / kg. In some embodiments, the mTOR inhibitor is administered at a dose of about 1 μg / kg to about 40 μg / kg. In some embodiments, the mTOR inhibitor is administered at a dose of about 20 μg / kg to about 50 μg / kg. In some embodiments, the mTOR inhibitor is administered at a dose of about 1 μg / kg to about 70 μg / kg. In some embodiments, the mTOR inhibitor is administered at a dose of about 5 μg / kg to about 60 μg / kg. In some embodiments, the mTOR inhibitor is administered at a dose of about 0.1 mg / kg to about 4 mg / kg.

[0033]

[0034] The present disclosure also provides a kit for preparing the solution or composition disclosed herein for administration to a subject in need of administration.In some embodiments, the kit comprises a first container that contains an NMDA receptor modulator and a second container that contains an mTOR inhibitor.In some embodiments, the solution or composition disclosed herein from the first container and the second container are mixed before administration.

[0034]

[0035] In certain embodiments, the present disclosure provides a kit comprising (i) a first container containing a first solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator at a concentration of about 5 mg / mL to about 200 mg / mL, and (ii) a second container containing a second solution comprising an mTOR inhibitor at a concentration of about 0.1 mg / mL to about 25 mg / mL. In certain embodiments, the present disclosure also provides a kit comprising (i) a first container containing a first solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator, and (ii) a second container containing a second solution comprising an mTOR inhibitor, wherein the volume ratio of the first solution to the second solution is about 1.2:1 to about 3:1.

[0035]

[0036] In some embodiments, the volume ratio of the first solution to the second solution is about 3:2, about 2.2:1.2, about 2.4:1.2, or about 2.5:1.2. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is greater than about 1:1. In some embodiments, the first container further comprises water, ethanol, polyethylene glycol (PEG), polysorbate, or any combination thereof. In some embodiments, the first container comprises polysorbate, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, and optionally is polysorbate 80. In some embodiments, the first container comprises PEG, wherein the PEG has an average molecular weight of about 300 to about 600, and optionally is PEG 400. In some embodiments, the second container further comprises ethanol, DL-alpha-tocopherol, propylene glycol, citric acid, or any combination thereof. In some embodiments, the second container further comprises ethanol, propylene glycol, or any combination thereof.

[0036]

[0037] In certain aspects, the present disclosure provides a kit comprising: (i) a first container housing a first composition comprising an N-methyl-D-aspartate (NMDA) receptor modulator; and (ii) a second container housing a second composition comprising an mTOR (target of rapamycin) inhibitor, wherein the NMDA receptor modulator and the mTOR inhibitor have a weight ratio of greater than about 1:1. In some embodiments, the first composition is a solution. In some embodiments, the solution further comprises water, ethanol, polyethylene glycol (PEG), polysorbate, or any combination thereof. In some embodiments, the first composition is a solid. In some embodiments, the solid is a powder. In some embodiments, the solid is dissolved in a diluent.

[0037]

[0038] In some aspects, the present disclosure also provides kits comprising: (i) a first container housing a first composition comprising an N-methyl-D-aspartate (NMDA) receptor modulator, (ii) a second container housing a second composition comprising an mTOR inhibitor, and (iii) a diluent comprising polysorbate, PEG 400, or both. In some embodiments, the NMDA receptor modulator and the mTOR inhibitor have a weight ratio of greater than about 1:1.

[0038]

[0039] In some embodiments, the first solution or composition further comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 10% (w / w) water, or any combination thereof. In some embodiments, the first solution or composition further comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 15% (w / w) water, or any combination thereof. In some embodiments, the first solution or composition further comprises about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 20% (w / w) water, or any combination thereof. In some embodiments, the first solution or composition further comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 25% (w / w) water, or any combination thereof. In some embodiments, the first solution or composition further comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 30% (w / w) water, or any combination thereof. In some embodiments, the second solution or composition further comprises about 39.5% (w / v) absolute ethanol, about 0.075% (w / v) DL-alpha-tocopherol, about 50.3% (w / v) propylene glycol, about 0.0025% (w / v) anhydrous citric acid, or any combination thereof. In some embodiments, the second solution or composition further comprises about 39.5% (w / v) absolute ethanol, about 50.3% (w / v) propylene glycol, or any combination thereof.

[0039]

[0040] In some embodiments, the first solution or first composition is stable at room temperature for at least about 1 week, 1 month, 3 months, 6 months, or 1 year. In some embodiments, the first solution or first composition is stable at a temperature below about 60° C. for at least about 1 week. In some embodiments, the second solution or second composition is stable at room temperature for at least about 1 week, 1 month, 3 months, 6 months, or 1 year. In some embodiments, the second solution or second composition is stable at a temperature below about 60° C. for at least about 1 week. In some embodiments, the second solution or second composition does not comprise citric acid or DL-alpha-tocopherol.

[0040]

[0041] In a further aspect, the present disclosure provides a dual-chamber syringe for preparing a solution or composition disclosed herein for administration to a subject in need thereof. In some embodiments, the dual chamber comprises a first chamber containing an NMDA receptor modulator and a second chamber containing an mTOR inhibitor. In some embodiments, the solution or composition disclosed herein from the first chamber and the second chamber are mixed prior to administration. The present disclosure also relates to a dual-compartment device for preparing a solution or composition for administration to a subject in need thereof. In some embodiments, the dual-compartment device comprises a first compartment containing an NMDA receptor modulator and a second compartment containing an mTOR inhibitor. In some embodiments, the solution or composition from the first compartment and the second compartment are mixed prior to administration. In some embodiments, the dual-compartment device is a dual-compartment nasal inhaler.

[0041]

[0042] In some embodiments, the present disclosure provides a solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator, polysorbate, or PEG 400. In some embodiments, the present disclosure provides a solution comprising an mTOR inhibitor, wherein the concentration of the mTOR inhibitor is about 0.05 mg / mL to about 10 mg / mL, about 0.2 mg / mL to about 8 mg / mL, about 0.5 mg / mL to about 6 mg / mL, about 1 mg / mL to about 4 mg / mL, or about 2 mg / mL to about 3 mg / mL.

[0042]

[0043] In additional aspects, the present disclosure provides a solution comprising water, ethanol, polyethylene glycol (PEG), polysorbate, or any combination thereof. In some embodiments, the solution comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 10% (w / w) water, or any combination thereof. In some embodiments, the solution comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 15% (w / w) water, or any combination thereof. In some embodiments, the solution comprises about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 20% (w / w) water, or any combination thereof. In some embodiments, the solution comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 25% (w / w) water, or any combination thereof. In some embodiments, the solution comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 30% (w / w) water, or any combination thereof.

[0043]

[0044] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the present disclosure. Accordingly, the drawings and description should be regarded as illustrative in nature and not restrictive.

[0044] Incorporation by Reference

[0045] 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.

[0045]

[0046] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings. [Brief explanation of the drawings]

[0046] [Figure 1]

[0047] FIG. 1 shows the stability profile of samples with t of 2 weeks at 50° C. according to some embodiments of the present disclosure. [Figure 2]

[0048] 1A-1C illustrate the appearance of a two-vial kit before and after mixing, according to some embodiments of the present disclosure. [Figure 3]

[0049] FIG. 1 illustrates the appearance of saline before and after adding a formulated API, according to some embodiments of the present disclosure. [Figure 4]

[0050] FIG. 1 shows the appearance of diluents and the solubility of samples in Diluents A, B, and C, according to some embodiments of the present disclosure. [Figure 5]

[0051] FIG. 1 shows the appearance of diluents and the solubility of samples in diluents D and E, according to some embodiments of the present disclosure. [Figure 6]

[0052] FIG. 1 shows the appearance of diluents and the solubility of samples in diluents F and G, according to some embodiments of the present disclosure. [Figure 7]

[0053] FIG. 1 shows the solubility of ketamine HCl as a function of water composition, according to some embodiments of the present disclosure. [Figure 8]

[0054] FIG. 1 shows an overview of a sirolimus solubility assay, according to some embodiments of the present disclosure. [Figure 9]

[0055] FIG. 1 shows an appearance of a ketamine HCl solubility assay, according to some embodiments of the present disclosure. [Figure 10]

[0056] FIG. 1 shows an appearance of a ketamine HCl solubility assay, according to some embodiments of the present disclosure. [Figure 11]

[0057] FIG. 1 shows an overview of a sirolimus solubility assay, according to some embodiments of the present disclosure. [Figure 12]

[0058] FIG. 1 shows an overview of a combined solubility assay, according to some embodiments of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0047] Concurrent therapy

[0059] N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors that function in synaptic transmission, plasticity, and cognition. NMDA receptors are involved in various nervous system disorders, including neurodegenerative, mood, and neurodevelopmental disorders. NMDA receptor modulators are classified as rapid-acting antidepressants (RAADs) due to their rapid antidepressant effects compared to slow-acting antidepressants (SAADs). Among various NMDA receptor modulators, esketamine (Spravato) has been approved by the US FDA for prescription to patients with treatment-resistant depression and those at risk for suicide. However, the effects of ketamine and other NMDA receptor modulators are transient, lasting approximately 7 days. Furthermore, prototype NMDA receptor modulators can induce transient psychotomimetic and dissociative effects, produce hemodynamic instability, and may cause nausea and vomiting, which are associated with significant abuse liability. The target of rapamycin (mTOR) is a threonine and serine protein kinase involved in regulating cell growth and proliferation. mTOR is known as the target of the immunosuppressant rapamycin. Rapamycin is the prototypic first-generation mTOR inhibitor.

[0048]

[0060] According to some embodiments of the present disclosure, an NMDA receptor modulator and an mTOR inhibitor can be co-administered to a subject in need of treatment for a mood disorder (e.g., depression) to prolong the effect of the NMDA receptor modulator through mTOR inhibition. In certain cases, the mTOR inhibitor prolongs the clinical effect of the NMDA receptor modulator. In other embodiments, the mTOR inhibitor reduces the abuse liability of the NMDA receptor modulator. In some cases, administering a single dose of the mTOR inhibitor 2 hours before a single ketamine injection increases the duration of the benefit provided by ketamine from several days to at least two weeks. In some cases, a single dose of the mTOR inhibitor at an mTOR-blocking dose blocks the antidepressant effect of the NMDA receptor modulator.

[0049] Solution-based co-formulations

[0061] In one aspect, a solution is provided herein that includes an N-methyl-D-aspartate (NMDA) receptor modulator and an mTOR (mTOR) inhibitor.In some embodiments, the NMDA receptor modulator binds to a component of the NMDA receptor and activates or inhibits the NMDA receptor.In some embodiments, the mTOR inhibitor binds to a domain of mTOR and inhibits the activity of mTOR.

[0050]

[0062] In some embodiments, the NMDA receptor modulator is selected from the group consisting of ketamine, R-ketamine, S-ketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, dextromethorphan, a fixed-dose combination of dextromethorphan and quinidine, a fixed-dose combination of dextromethorphan and bupropion, GM-1020, besonprodil, eliprodil, ifenprodil, lislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro8-4304, traxoprodil (CP-101,606), BMT-108908, omfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP37849, 1-aminocyclopropanecarboxylic acid, traxoprodil, Ro25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxyzine, tiletamine, neramexane, etoxadrol, dexoxadrol le, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delsemin, dextralorphan, dextrorphan, diphenidine, eticcyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7-Dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnalone sulfate (3α5βS), UBP608, UBP618, UBP551, UBP512, HA-9 66, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, and NYX-783, and any salts, solvates, enantiomers, tautomers, stereoisomers, and geometric isomers thereof, and any mixtures thereof. In some embodiments, the NMDP receptor modulator is an NMDA receptor channel blocker, such as, but not limited to, ketamine (R / S-ketamine, R-ketamine), memantine, a fixed-dose combination of dextromethorphan and quinidine, a fixed-dose combination of dextromethorphan and bupropion, or GM-1020. In some embodiments, the NMDP receptor modulator is an NR2B NAM / GluN2B NAM, such as, but not limited to, besonprodil, eliprodil, ifenprodil, lislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, traxoprodil (CP-101,606), BMT-108908, omfasprodil, radiprodil, NP10679, or GluN2B NAM. In some embodiments, the NMDA receptor modulator is a fixed-dose combination of dextromethorphan hydrobromide and quinidine sulfate. In some embodiments, the NMDA receptor modulator is a fixed-dose combination of dextromethorphan and quinidine, comprising 20 mg of dextromethorphan hydrobromide and 10 mg of quinidine sulfate. In some embodiments, the NMDA receptor modulator is a fixed-dose combination of dextromethorphan and bupropion. In some embodiments, the fixed-dose combination of dextromethorphan and bupropion comprises 45 mg of dextromethorphan and 105 mg of bupropion.

[0051]

[0063] In some embodiments, the NMDA receptor modulator comprises ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any mixture thereof. In some embodiments, the ketamine is ketamine HCl.

[0052]

[0064] In some embodiments, the mTOR inhibitor is BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), KU-0063794, PI-103 (mTOR inhibitor V, PI3-K inhibitor V, PI-103-CAS371935-74-9), tolquinib (PP242), tacrolimus (FK-506, Fujimycin), ridaforolimus (AP23573, MK-8669, deforolimus). Mus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), Torin-1 (DNA-PK inhibitor VI, PI3-K inhibitor XVIII, mTOR inhibitor XI, Torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE390), GSK105 9615, WYE-354 (mTOR inhibitor II), gedatolisib (PF-05212384, PKI-587), AZD-2014 (bistusertib), Torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATR i), GDC-0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound401, GNE-477, vimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC223), clemastine (HS-592) fumarate, nitazoxanide (NSC697855), 4EGI-1, ABTL-0812, astragaloside IV,The mTOR inhibitor may comprise samotricisib (LY3023414), chrysophanic acid, or zotarolimus (ABT-578), or a salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some embodiments, the mTOR inhibitor comprises sirolimus, temsirolimus, or everolimus. In some embodiments, the mTOR inhibitor comprises a natural product derived from food or drink, such as, but not limited to, curcumin, resveratrol, epigallocatechin gallate (EGCG), genistein, 3,3-diindolylmethane (DIM), or caffeine.

[0053]

[0065] In some embodiments, the mTOR inhibitor comprises rapamycin (sirolimus, AY22989, ABI-009) or temsirolimus (CCI-779).

[0066] In some embodiments, the solution is generated by mixing a first solution or composition comprising an NMDA receptor modulator with a second solution or composition comprising an mTOR inhibitor. In some embodiments, the solution is generated by mixing a first solution or composition comprising ketamine HCl with a second solution or composition comprising temsirolimus.

[0054]

[0067] In some embodiments, the first solution or composition comprises an NMDA receptor modulator at a concentration of about 1 milligram per milliliter (mg / mL) to 200 mg / mL. In some embodiments, the first solution or composition comprises an NMDA receptor modulator at a concentration of at least about 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, or 100 mg / mL. mL, 110 mg / mL, 115 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, 150 mg / mL, 155 mg / mL, 160 mg / mL, 165 mg / mL, 170 mg / mL, 175 mg / mL, 180 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL of an NMDA receptor modulator. In some embodiments, the first solution or first composition has a concentration of at most about 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL L, containing an NMDA receptor modulator at a concentration of 110 mg / mL, 115 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, 150 mg / mL, 155 mg / mL, 160 mg / mL, 165 mg / mL, 170 mg / mL, 175 mg / mL, 180 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL.

[0055]

[0068] In some embodiments, the first solution or composition contains ketamine (free base or free base equivalent from a salt) at a concentration of about 1 milligram per milliliter (mg / mL) to 200 mg / mL. In some embodiments, the first solution or composition contains at least about 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, 300 mg / mL, 310 mg / mL, 320 mg / mL, 330 mg / mL, 340 mg / mL, 350 mg / mL, 360 mg / mL, 370 mg / mL, 380 mg / mL, 390 mg / mL, 400 mg / mL, 410 mg / mL, 420 mg / mL, 430 mg / mL, 440 mg / mL, 450 mg / mL, 460 mg / mL, 470 mg / mL, 480 mg / mL, 490 mg Contains ketamine (free base or free base equivalent from salts) at concentrations of 0 mg / mL, 115 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, 150 mg / mL, 155 mg / mL, 160 mg / mL, 165 mg / mL, 170 mg / mL, 175 mg / mL, 180 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL. In some embodiments, the first solution or first composition has a concentration of at most about 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, 300 mg / mL, 310 mg / mL, 320 mg / mL, 330 mg / mL, 340 mg / mL, 350 mg / mL, 360 mg / mL, 370 mg / mL, 380 mg / mL, 390 mg / mL, 400 mg / mL, 410 mg / mL, 420 mg / mL, 430 mg / mL, 440 mg / mL, 450 mg / mL, 460 mg / mL, 470 mg / mL, 480 mg / mL, 490 mg / mL, 500 mg / mL, 510 mg / mL, 520 mg / mL, 530 mg / mL, 540 mg / mL, 550 Contains ketamine (free base or free base equivalent from salts) at concentrations of 115mg / mL, 120mg / mL, 125mg / mL, 130mg / mL, 135mg / mL, 140mg / mL, 145mg / mL, 150mg / mL, 155mg / mL, 160mg / mL, 165mg / mL, 170mg / mL, 175mg / mL, 180mg / mL, 185mg / mL, 190mg / mL, 195mg / mL, or 200mg / mL.

[0056]

[0069] In some embodiments, the second solution or composition comprises an mTOR inhibitor at a concentration of about 0.05 mg / mL to 25 mg / mL, or at least about 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 16 mg / mL, 18 mg / mL, 20 mg / mL, or 25 mg / mL. In some embodiments, the second solution or second composition comprises an mTOR inhibitor at a concentration of up to about 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 16 mg / mL, 18 mg / mL, 20 mg / mL, or 25 mg / mL.

[0057]

[0070] In some embodiments, the second solution or composition contains temsirolimus at a concentration of about 0.05 mg / mL to 25 mg / mL, or at a concentration of at least about 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 16 mg / mL, 18 mg / mL, 20 mg / mL, or 25 mg / mL. In some embodiments, the second solution or second composition contains temsirolimus at a concentration of up to about 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 16 mg / mL, 18 mg / mL, 20 mg / mL, or 25 mg / mL.

[0058]

[0071] In some embodiments, a first solution or composition and a second solution or composition can be mixed to form a solution. In some embodiments, the volume ratio of the first solution to the second solution is about 1.2:1 to about 3:1. In some embodiments, the volume ratio of the first solution to the second solution is about 3:2, about 2.2:1.2, about 2.4:1.2, or about 2.5:1.2. In some embodiments, the volume ratio of the first solution to the second solution is about 3:2. In some embodiments, the volume ratio of the first solution to the second solution is about 2.2:1.2. In some embodiments, the volume ratio of the first solution to the second solution is about 2.4:1.2. In some embodiments, the volume ratio of the first solution to the second solution is about 2.5:1.2.

[0059]

[0072] After mixing the first solution or composition with the second solution or composition, the solution comprises the NMDA receptor modulator and the mTOR inhibitor in a weight ratio greater than about 1:1. In some embodiments, the solution comprises the NMDA receptor modulator and the mTOR inhibitor in a weight ratio ranging from about 1000:1 to about 2:1. In some embodiments, the solution comprises the NMDA receptor modulator and the mTOR inhibitor in a weight ratio ranging from about 800:1 to about 5:1. In some embodiments, the solution comprises the NMDA receptor modulator and the mTOR inhibitor in a weight ratio ranging from about 600:1 to about 5:1. In some embodiments, the solution comprises the NMDA receptor modulator and the mTOR inhibitor in a weight ratio ranging from about 500:1 to about 5:1. In some embodiments, the solution comprises the NMDA receptor modulator and the mTOR inhibitor in a weight ratio ranging from about 300:1 to about 5:1. In some embodiments, the solution comprises an NMDA receptor modulator and an mTOR inhibitor in a weight ratio ranging from about 1000:1 to about 10:1. In some embodiments, the solution comprises an NMDA receptor modulator and an mTOR inhibitor in a weight ratio ranging from about 1000:1 to about 30:1. In some embodiments, the solution comprises an NMDA receptor modulator and an mTOR inhibitor in a weight ratio ranging from about 1000:1 to about 50:1. In some embodiments, the solution comprises an NMDA receptor modulator and an mTOR inhibitor in a weight ratio ranging from about 1000:1 to about 100:1. In some embodiments, the solution comprises an NMDA receptor modulator and an mTOR inhibitor in a weight ratio ranging from about 1000:1 to about 200:1. In some embodiments, the solution comprises an NMDA receptor modulator and an mTOR inhibitor in a weight ratio ranging from about 1000:1 to about 2:1. In some embodiments, the solution comprises an NMDA receptor modulator and an mTOR inhibitor in a weight ratio range of about 1000:1, 900:1, 800:1, 700:1, 600:1, 500:1, 400:1, 300:1, 200:1, 100:1, 80:1, 60:1, 40:1, 20:1, 10:1, 5:1, or any and all whole or partial increments therebetween.

[0060]

[0073] After mixing the first solution or composition with the second solution or composition, the solution comprises an NMDA receptor modulator at a concentration of about 0.04 milligrams per milliliter (mg / mL) to 150 mg / mL. In some embodiments, the solution comprises an NMDA receptor modulator at a concentration of at least about 0.04 mg / mL, 0.06 mg / mL, 0.08 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, or 40 mg / mL. , 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 110 mg / mL, 115 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, or 150 mg / mL of an NMDA receptor modulator. In some embodiments, the solution contains at most about 0.04 mg / mL, 0.06 mg / mL, 0.08 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, containing an NMDA receptor modulator at a concentration of 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 110 mg / mL, 115 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, or 150 mg / mL.

[0061]

[0074] After mixing the first solution or composition with the second solution or composition, the solution contains ketamine (free base or free base equivalent from a salt) at a concentration of about 0.04 milligrams per milliliter (mg / mL) to 150 mg / mL. In some embodiments, the solution contains at least about 0.04 mg / mL, 0.06 mg / mL, 0.08 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, or 50 mg / mL. Contains ketamine (free base or free base equivalent from salts) at concentrations of 100mg / mL, 50mg / mL, 55mg / mL, 60mg / mL, 65mg / mL, 70mg / mL, 75mg / mL, 80mg / mL, 85mg / mL, 90mg / mL, 95mg / mL, 100mg / mL, 110mg / mL, 115mg / mL, 120mg / mL, 125mg / mL, 130mg / mL, 135mg / mL, 140mg / mL, 145mg / mL, or 150mg / mL. In some embodiments, the solution contains at most about 0.04 mg / mL, 0.06 mg / mL, 0.08 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL Contains ketamine (free base or free base equivalent from salts) at concentrations of 50mg / mL, 55mg / mL, 60mg / mL, 65mg / mL, 70mg / mL, 75mg / mL, 80mg / mL, 85mg / mL, 90mg / mL, 95mg / mL, 100mg / mL, 110mg / mL, 115mg / mL, 120mg / mL, 125mg / mL, 130mg / mL, 135mg / mL, 140mg / mL, 145mg / mL, or 150mg / mL.

[0062]

[0075] After mixing the first solution or composition with the second solution or composition, the solution contains an mTOR inhibitor at a concentration of about 0.02 mg / mL to 10 mg / mL. In some embodiments, the solution contains an mTOR inhibitor at a concentration of at least about 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL, 0.05 mg / mL, 0.06 mg / mL, 0.07 mg / mL, 0.08 mg / mL, 0.09 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, or 10 mg / mL. In some embodiments, the solution comprises an mTOR inhibitor at a concentration of up to about 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL, 0.05 mg / mL, 0.06 mg / mL, 0.07 mg / mL, 0.08 mg / mL, 0.09 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, or 10 mg / mL.

[0063]

[0076] After mixing the first solution or composition with the second solution or composition, the solution contains temsirolimus at a concentration of about 0.02 mg / mL to 10 mg / mL. In some embodiments, the solution comprises temsirolimus at a concentration of at least about 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL, 0.05 mg / mL, 0.06 mg / mL, 0.07 mg / mL, 0.08 mg / mL, 0.09 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, or 10 mg / mL. In some embodiments, the solution comprises temsirolimus at a concentration of up to about 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL, 0.05 mg / mL, 0.06 mg / mL, 0.07 mg / mL, 0.08 mg / mL, 0.09 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, or 10 mg / mL.

[0064]

[0077] In some embodiments, the solution may be further diluted with a diluent, after which the solution contains the NMDA receptor modulator at a concentration of about 0.01 mg / mL to 1.0 mg / mL. In some embodiments, the solution comprises an NMDA receptor modulator at a concentration of at least about 0.01 mg / mL, 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL, 0.05 mg / mL, 0.06 mg / mL, 0.07 mg / mL, 0.08 mg / mL, 0.09 mg / mL, 0.1 mg / mL, 0.15 mg / mL, 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.4 mg / mL, 0.45 mg / mL, 0.5 mg / mL, 0.55 mg / mL, 0.6 mg / mL, 0.65 mg / mL, 0.7 mg / mL, 0.75 mg / mL, 0.8 mg / mL, 0.85 mg / mL, 0.9 mg / mL, 0.95 mg / mL, or 1.0 mg / mL. In some embodiments, the solution comprises an NMDA receptor modulator at a concentration of up to about 0.01 mg / mL, 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL, 0.05 mg / mL, 0.06 mg / mL, 0.07 mg / mL, 0.08 mg / mL, 0.09 mg / mL, 0.1 mg / mL, 0.15 mg / mL, 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.4 mg / mL, 0.45 mg / mL, 0.5 mg / mL, 0.55 mg / mL, 0.6 mg / mL, 0.65 mg / mL, 0.7 mg / mL, 0.75 mg / mL, 0.8 mg / mL, 0.85 mg / mL, 0.9 mg / mL, 0.95 mg / mL, or 1.0 mg / mL.

[0065]

[0078] In some embodiments, the solution may be further diluted with a diluent, after which the solution contains ketamine (free base or free base equivalent from a salt) at a concentration of about 0.01 mg / mL to 1.0 mg / mL. In some embodiments, the solution comprises ketamine (free base or free base equivalent from a salt) at a concentration of at least about 0.01 mg / mL, 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL, 0.05 mg / mL, 0.06 mg / mL, 0.07 mg / mL, 0.08 mg / mL, 0.09 mg / mL, 0.1 mg / mL, 0.15 mg / mL, 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.4 mg / mL, 0.45 mg / mL, 0.5 mg / mL, 0.55 mg / mL, 0.6 mg / mL, 0.65 mg / mL, 0.7 mg / mL, 0.75 mg / mL, 0.8 mg / mL, 0.85 mg / mL, 0.9 mg / mL, 0.95 mg / mL, or 1.0 mg / mL. In some embodiments, the solution contains ketamine (free base or free base equivalent from a salt) at a concentration of up to about 0.01 mg / mL, 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL, 0.05 mg / mL, 0.06 mg / mL, 0.07 mg / mL, 0.08 mg / mL, 0.09 mg / mL, 0.1 mg / mL, 0.15 mg / mL, 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.4 mg / mL, 0.45 mg / mL, 0.5 mg / mL, 0.55 mg / mL, 0.6 mg / mL, 0.65 mg / mL, 0.7 mg / mL, 0.75 mg / mL, 0.8 mg / mL, 0.85 mg / mL, 0.9 mg / mL, 0.95 mg / mL, or 1.0 mg / mL.

[0066]

[0079] After dilution, the solution contains the mTOR inhibitor at a concentration of about 0.5 micrograms per milliliter (μg / mL) to about 100 μg / mL. In some embodiments, the solution comprises an mTOR inhibitor at a concentration of at least about 0.5 μg / mL, 1 μg / mL, 2 μg / mL, 3 μg / mL, 4 μg / mL, 5 μg / mL, 6 μg / mL, 7 μg / mL, 8 μg / mL, 9 μg / mL, 10 μg / mL, 15 μg / mL, 20 μg / mL, 25 μg / mL, 30 μg / mL, 35 μg / mL, 40 μg / mL, 45 μg / mL, 50 μg / mL, 55 μg / mL, 60 μg / mL, 65 μg / mL, 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL, or 100 μg / mL. In some embodiments, the solution comprises an mTOR inhibitor at a concentration of up to about 0.5 μg / mL, 1 μg / mL, 2 μg / mL, 3 μg / mL, 4 μg / mL, 5 μg / mL, 6 μg / mL, 7 μg / mL, 8 μg / mL, 9 μg / mL, 10 μg / mL, 15 μg / mL, 20 μg / mL, 25 μg / mL, 30 μg / mL, 35 μg / mL, 40 μg / mL, 45 μg / mL, 50 μg / mL, 55 μg / mL, 60 μg / mL, 65 μg / mL, 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL, or 100 μg / mL.

[0067]

[0080] After dilution, the solution contains temsirolimus at a concentration of about 0.5 micrograms per milliliter (μg / mL) to about 100 μg / mL. In some embodiments, the solution comprises temsirolimus at a concentration of at least about 0.5 μg / mL, 1 μg / mL, 2 μg / mL, 3 μg / mL, 4 μg / mL, 5 μg / mL, 6 μg / mL, 7 μg / mL, 8 μg / mL, 9 μg / mL, 10 μg / mL, 15 μg / mL, 20 μg / mL, 25 μg / mL, 30 μg / mL, 35 μg / mL, 40 μg / mL, 45 μg / mL, 50 μg / mL, 55 μg / mL, 60 μg / mL, 65 μg / mL, 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL, or 100 μg / mL. In some embodiments, the solution comprises temsirolimus at a concentration of up to about 0.5 μg / mL, 1 μg / mL, 2 μg / mL, 3 μg / mL, 4 μg / mL, 5 μg / mL, 6 μg / mL, 7 μg / mL, 8 μg / mL, 9 μg / mL, 10 μg / mL, 15 μg / mL, 20 μg / mL, 25 μg / mL, 30 μg / mL, 35 μg / mL, 40 μg / mL, 45 μg / mL, 50 μg / mL, 55 μg / mL, 60 μg / mL, 65 μg / mL, 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL, or 100 μg / mL.

[0068]

[0081] In some embodiments, the solution comprises about 0.9% (w / v) sodium chloride in water or about 5% (w / v) dextrose in water. In some embodiments, the solution comprises at least about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.8%, 1.9%, or 2.0% (w / v) sodium chloride in water. In some embodiments, the solution comprises up to about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.8%, 1.9%, or 2.0% (w / v) sodium chloride in water. In some embodiments, the solution comprises at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (w / v) dextrose in water, hi some embodiments, the solution comprises up to about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (w / v) dextrose in water.

[0069]

[0082] In some embodiments, the solution further comprises an excipient selected from the group consisting of an aqueous vehicle, a water-miscible vehicle, a non-aqueous vehicle, a preservative, a solubility enhancer, a stabilizer, an antioxidant, a buffer, an emulsifier, a suspending agent, a complexing agent, a sequestering or chelating agent, a thickening agent, an osmotic / tonicity agent, an antifoaming / defoaming agent, an osmotic agent, a polymer, a spreading agent, a wetting agent, and a pH adjuster.

[0070]

[0083] In some embodiments, the first solution or first composition further comprises a polysorbate, polyethylene glycol (PEG), ethanol, water, or any combination thereof. In some embodiments, the first solution or first composition comprises a polysorbate. In some embodiments, the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the first solution or first composition comprises PEG. In some embodiments, the PEG has an average molecular weight of about 300 to about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the first solution or first composition comprises ethanol. In some embodiments, the ethanol is absolute ethanol.

[0071]

[0084] In some embodiments, the first solution or composition further comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 10% (w / w) water, or any combination thereof. In some embodiments, the first solution or composition further comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 15% (w / w) water, or any combination thereof. In some embodiments, the first solution or composition further comprises about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 20% (w / w) water, or any combination thereof. In some embodiments, the first solution or composition further comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 25% (w / w) water, or any combination thereof. In some embodiments, the first solution or first composition further comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 30% (w / w) water, or any combination thereof.

[0072]

[0085] In some embodiments, the second solution or composition further comprises ethanol, DL-alpha-tocopherol, propylene glycol, citric acid, or any combination thereof. In some embodiments, the second solution or composition further comprises about 39.5% (w / v) absolute ethanol, about 0.075% (w / v) DL-alpha-tocopherol, about 50.3% (w / v) propylene glycol, about 0.0025% (w / v) anhydrous citric acid, or any combination thereof.

[0073]

[0086] In some embodiments, the second solution or composition further comprises ethanol, propylene glycol, or any combination thereof. In some embodiments, the second solution or composition further comprises about 39.5% (w / v) absolute ethanol, about 50.3% (w / v) propylene glycol, or any combination thereof. In some embodiments, the second solution or composition does not comprise citric acid or DL-alpha-tocopherol.

[0074]

[0087] In some embodiments, the solution further comprises an excipient selected from the group consisting of water, ethanol, propylene glycol, polyethylene glycol (PEG), polysorbate, citric acid, and DL-alpha-tocopherol. In some embodiments, the solution comprises water. In some embodiments, the solution comprises a polysorbate. In some embodiments, the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the solution comprises PEG. In some embodiments, the PEG has an average molecular weight of about 300 to about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the solution comprises ethanol. In some embodiments, the ethanol is absolute ethanol.

[0075]

[0088] After mixing the first solution or composition with the second solution or composition, in some embodiments, the concentration of polysorbate ranges from about 5% w / w to about 80% w / w. In some embodiments, the concentration of polysorbate ranges from about 10% w / w to about 50% w / w. In some embodiments, the concentration of polysorbate is at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of polysorbate is at most about 5, 10, 15, 20, 25, 30, 35, 40, 45, and 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of polysorbate 80 is in the range of about 5-80, 10-75, 15-70, 20-65, 25-60, 30-55, 35-50, or 40-45% w / w. In some embodiments, the concentration of polysorbate 80 is in the range of about 5% w / w to about 80% w / w. In some embodiments, the concentration of polysorbate 80 is in the range of about 10% w / w to about 50% w / w. In some embodiments, the concentration of polysorbate 80 is at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of polysorbate 80 is up to about 5, 10, 15, 20, 25, 30, 35, 40, 45, and 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of polysorbate 80 is in the range of about 5-80, 10-75, 15-70, 20-65, 25-60, 30-55, 35-50, or 40-45% w / w.

[0076]

[0089] After mixing the first solution or composition with the second solution or composition, in some embodiments, the concentration of PEG ranges from about 0.01% w / w to about 50% w / w. In some embodiments, the concentration of PEG ranges from about 0.1% w / w to about 30% w / w. In some embodiments, the concentration of PEG is at least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w. In some embodiments, the concentration of PEG is at most about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w. In some embodiments, the concentration of PEG is in the range of about 0.01-50, 0.05-45, 0.1-40, 0.5-35, 1-30, 5-25, 10-20, or 15-50% w / w. In some embodiments, the concentration of PEG 400 is in the range of about 0.01% w / w to about 50% w / w. In some embodiments, the concentration of PEG 400 is in the range of about 0.1% w / w to about 30% w / w. In some embodiments, the concentration of PEG 400 is at least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w. In some embodiments, the concentration of PEG 400 is up to about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w, or in some embodiments, the concentration of PEG 400 is in the range of about 0.01-50, 0.05-45, 0.1-40, 0.5-35, 1-30, 5-25, 10-20, or 15-50% w / w.

[0077]

[0090] After mixing the first solution or composition with the second solution or composition, in some embodiments, the ethanol concentration ranges from about 1% w / w to about 80% w / w. In some embodiments, the ethanol concentration ranges from about 10% w / w to about 50% w / w. In some embodiments, the ethanol concentration is at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the ethanol concentration is at most about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of ethanol is in the range of about 1-80, 5-75, 10-70, 15-65, 20-60, 25-55, 30-50, 35-45, or 40-80% w / w. In some embodiments, the concentration of absolute ethanol is in the range of about 1% w / w to about 80% w / w. In some embodiments, the concentration of absolute ethanol is in the range of about 10% w / w to about 50% w / w. In some embodiments, the concentration of absolute ethanol is at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of absolute ethanol is up to about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w, hi some embodiments, the concentration of absolute ethanol is in the range of about 1-80, 5-75, 10-70, 15-65, 20-60, 25-55, 30-50, 35-45, or 40-80% w / w.

[0078]

[0091] After mixing the first solution or composition with the second solution or composition, in some embodiments, the concentration of water ranges from about 0.01% w / w to about 50% w / w. In some embodiments, the concentration of water ranges from about 0.1% w / w to about 30% w / w. In some embodiments, the concentration of water is at least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w. In some embodiments, the concentration of water is at most about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w. In some embodiments, the concentration of water ranges from about 0.01-50, 0.05-45, 0.1-40, 0.5-35, 1-30, 5-25, 10-20, or 15-50% w / w.

[0079]

[0092] After mixing the first solution or composition with the second solution or composition, in some embodiments, the concentration of propylene glycol ranges from about 1% w / w to about 60% w / w. In some embodiments, the concentration of propylene glycol ranges from about 5% w / w to about 50% w / w. In some embodiments, the concentration of propylene glycol is at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60% w / w. In some embodiments, the concentration of propylene glycol is at most about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60% w / w. In some embodiments, the concentration of propylene glycol ranges from about 1-60, 5-65, 10-50, 15-45, 20-40, 25-35, 10-60, or 15-50% w / w.

[0080]

[0093] After mixing the first solution or composition with the second solution or composition, the solution contains ethanol in a concentration range of about 10% w / w to about 50% w / w. In some embodiments, the solution contains water in a concentration range of about 0.1% w / w to about 30% w / w. In some embodiments, the solution contains propylene glycol in a concentration range of about 5% w / w to about 50% w / w. In some embodiments, the solution contains polysorbate in a concentration range of about 5% w / w to about 50% w / w. In some embodiments, the solution contains PEG in a concentration range of about 0.1% w / w to about 30% w / w. In some embodiments, the solution comprises about 23.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 6% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution comprises about 20.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 9% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution comprises about 17.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 12% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution comprises about 14.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 15% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution comprises about 11.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 18% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof.

[0081]

[0094] After mixing the first solution or composition with the second solution or composition, in some embodiments, the weight ratio of the N-methyl-D-aspartate receptor modulator is greater than the weight of the mTOR inhibitor. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is greater than about 1:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 1000:1 to about 2:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 800:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 600:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 500:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 300:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 10:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 30:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 50:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 100:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 200:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 2:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is about 1000:1, 900:1, 800:1, 700:1, 600:1, 500:1, 400:1, 300:1, 200:1, 100:1, 80:1, 60:1, 40:1, 20:1, 10:1, 5:1, or any and all whole or partial increments therebetween.

[0082]

[0095] In some embodiments, the solution comprises about 20 mg to about 150 mg, about 30 mg to about 140 mg, about 40 mg to about 120 mg, about 50 mg to about 100 mg, or about 60 mg to about 80 mg of an NMDA receptor modulator. In some embodiments, the solution comprises at least about 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg of an NMDA receptor modulator. In some embodiments, the solution comprises up to about 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg of an NMDA receptor modulator.

[0083]

[0096] In some embodiments, the solution contains about 0.05 mg to about 2.0 mg, about 0.1 mg to about 1.8 mg, about 0.2 mg to about 1.5 mg, about 0.4 mg to about 1.2 mg, or about 0.8 mg to about 1.0 mg of an mTOR inhibitor. In some embodiments, the solution contains at least about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 0.95 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, or 2.0 mg of an mTOR inhibitor. In some embodiments, the solution comprises up to about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 0.95 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, or 2.0 mg of an mTOR inhibitor.

[0084]

[0097] The present disclosure also provides a solution comprising an NMDA receptor modulator, an mTOR inhibitor, and an excipient selected from the group consisting of water, polysorbate 80, PEG 400, propylene glycol, and absolute ethanol. In some embodiments, the NMDA receptor modulator binds to a component of the NMDA receptor and activates or inhibits the NMDA receptor. In some embodiments, the mTOR inhibitor binds to a domain of mTOR and inhibits mTOR activity. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is greater than about 1:1. In some embodiments, the weight of the N-methyl-D-aspartate receptor modulator is greater than the weight of the mTOR inhibitor.

[0085]

[0098] Also provided herein are solutions comprising an NMDA receptor modulator and an excipient. In some embodiments, the NMDA receptor modulator binds to a component of the NMDA receptor and activates or inhibits the NMDA receptor. In some embodiments, the excipient is selected from the group consisting of ethanol, propylene glycol, PEG, and polysorbate. In some embodiments, the solution further comprises an excipient selected from the group consisting of an aqueous vehicle, a water-miscible vehicle, a non-aqueous vehicle, a preservative, a solubility enhancer, a stabilizer, an antioxidant, a buffer, an emulsifier, a suspending agent, a complexing agent, a sequestering or chelating agent, a thickening agent, an osmotic / tonicity agent, an antifoaming / defoaming agent, an osmotic agent, a polymer, a spreading agent, a wetting agent, and a pH adjuster. In some embodiments, the solution further comprises an excipient selected from the group consisting of water, ethanol, propylene glycol, polyethylene glycol (PEG), polysorbate, citric acid, and DL-α-tocopherol. In some embodiments, the solution comprises water. In some embodiments, the solution comprises a polysorbate. In some embodiments, the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the solution comprises PEG. In some embodiments, the PEG has an average molecular weight of about 300 to about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the solution comprises ethanol. In some embodiments, the ethanol is absolute ethanol.

[0086]

[0099] In some embodiments, the concentration of polysorbate ranges from about 5% w / w to about 80% w / w. In some embodiments, the concentration of polysorbate ranges from about 5% w / w to about 50% w / w. In some embodiments, the concentration of polysorbate is at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of polysorbate is up to about 5, 10, 15, 20, 25, 30, 35, 40, 45, and 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of polysorbate 80 is in the range of about 5-80, 10-75, 15-70, 20-65, 25-60, 30-55, 35-50, or 40-45% w / w. In some embodiments, the concentration of polysorbate 80 is in the range of about 5% w / w to about 80% w / w. In some embodiments, the concentration of polysorbate 80 is in the range of about 10% w / w to about 50% w / w. In some embodiments, the concentration of polysorbate 80 is at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of polysorbate 80 is up to about 5, 10, 15, 20, 25, 30, 35, 40, 45, and 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of polysorbate 80 is in the range of about 5-80, 10-75, 15-70, 20-65, 25-60, 30-55, 35-50, or 40-45% w / w.

[0087]

[0100] In some embodiments, the concentration of PEG ranges from about 0.01% w / w to about 50% w / w. In some embodiments, the concentration of PEG ranges from about 0.1% w / w to about 30% w / w. In some embodiments, the concentration of PEG is at least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w. In some embodiments, the concentration of PEG is up to about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w. In some embodiments, the concentration of PEG is in the range of about 0.01-50, 0.05-45, 0.1-40, 0.5-35, 1-30, 5-25, 10-20, or 15-50% w / w. In some embodiments, the concentration of PEG 400 is in the range of about 0.01% w / w to about 50% w / w. In some embodiments, the concentration of PEG 400 is in the range of about 0.1% w / w to about 30% w / w. In some embodiments, the concentration of PEG 400 is at least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w. In some embodiments, the concentration of PEG 400 is up to about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w, or in some embodiments, the concentration of PEG 400 is in the range of about 0.01-50, 0.05-45, 0.1-40, 0.5-35, 1-30, 5-25, 10-20, or 15-50% w / w.

[0088]

[0101] In some embodiments, the concentration of ethanol ranges from about 1% w / w to about 80% w / w. In some embodiments, the concentration of ethanol ranges from about 10% w / w to about 50% w / w. In some embodiments, the concentration of ethanol is at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of ethanol is up to about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of ethanol is in the range of about 1-80, 5-75, 10-70, 15-65, 20-60, 25-55, 30-50, 35-45, or 40-80% w / w. In some embodiments, the concentration of absolute ethanol is in the range of about 1% w / w to about 80% w / w. In some embodiments, the concentration of absolute ethanol is in the range of about 10% w / w to about 50% w / w. In some embodiments, the concentration of absolute ethanol is at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of absolute ethanol is up to about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w, hi some embodiments, the concentration of absolute ethanol is in the range of about 1-80, 5-75, 10-70, 15-65, 20-60, 25-55, 30-50, 35-45, or 40-80% w / w.

[0089]

[0102] In some embodiments, the concentration of water ranges from about 0.01% w / w to about 50% w / w. In some embodiments, the concentration of water ranges from about 0.1% w / w to about 30% w / w. In some embodiments, the concentration of water is at least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w. In some embodiments, the concentration of water is at most about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w. In some embodiments, the concentration of water ranges from about 0.01-50, 0.05-45, 0.1-40, 0.5-35, 1-30, 5-25, 10-20, or 15-50% w / w.

[0090]

[0103] In some embodiments, the concentration of propylene glycol ranges from about 1% w / w to about 60% w / w. In some embodiments, the concentration of propylene glycol ranges from about 5% w / w to about 50% w / w. In some embodiments, the concentration of propylene glycol is at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60% w / w. In some embodiments, the concentration of propylene glycol is at most about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60% w / w. In some embodiments, the concentration of propylene glycol ranges from about 1-60, 5-65, 10-50, 15-45, 20-40, 25-35, 10-60, or 15-50% w / w.

[0091]

[0104] In some embodiments, the solution comprises 23.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 6% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution comprises about 20.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 9% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution comprises about 17.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 12% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution comprises about 14.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 15% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution further comprises about 11.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 18% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof.

[0092]

[0105] In some embodiments, the solution comprises an N-methyl-D-aspartate (NMDA) receptor modulator, an mTOR inhibitor, and an excipient selected from the group consisting of water, ethanol, propylene glycol, polyethylene glycol (PEG), polysorbate, citric acid, and DL-alpha-tocopherol. In some embodiments, the solution comprises an N-methyl-D-aspartate (NMDA) receptor modulator, an mTOR inhibitor, polysorbate 80, PEG 400, absolute ethanol, water, or any combination thereof. In some embodiments, the solution comprises an N-methyl-D-aspartate (NMDA) receptor modulator, a target of rapamycin (mTOR) inhibitor, about 23.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 6% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution comprises an N-methyl-D-aspartate (NMDA) receptor modulator, a target of rapamycin (mTOR) inhibitor, about 20.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 9% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution comprises an N-methyl-D-aspartate (NMDA) receptor modulator, a target of rapamycin (mTOR) inhibitor, about 17.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 12% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof.In some embodiments, the solution comprises an N-methyl-D-aspartate (NMDA) receptor modulator, a target of rapamycin (mTOR) inhibitor, about 14.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 15% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof. In some embodiments, the solution comprises an N-methyl-D-aspartate (NMDA) receptor modulator, a target of rapamycin (mTOR) inhibitor, about 11.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 18% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof.

[0093]

[0106] In some embodiments, the weight ratio of the N-methyl-D-aspartate receptor modulator is greater than the weight of the mTOR inhibitor. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is greater than about 1:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 1000:1 to about 2:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 800:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 600:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 500:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 300:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 1000:1 to about 10:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 30:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 50:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 100:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 200:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 2:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is about 1000:1, 900:1, 800:1, 700:1, 600:1, 500:1, 400:1, 300:1, 200:1, 100:1, 80:1, 60:1, 40:1, 20:1, 10:1, 5:1, or any and all whole or partial increments therebetween.

[0094]

[0107] The present disclosure also provides a solution comprising an NMDA receptor modulator and an excipient. In some embodiments, the NMDA receptor modulator comprises ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any mixture thereof. In some embodiments, the excipient comprises polysorbate or PEG 400. In some embodiments, the excipient comprises polysorbate and PEG 400. In some embodiments, the solution further comprises water, absolute ethanol, or any combination thereof. In some embodiments, the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the solution comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 10% (w / w) water, or any combination thereof. In some embodiments, the solution further comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 15% (w / w) water, or any combination thereof. In some embodiments, the solution further comprises about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 20% (w / w) water, or any combination thereof. In some embodiments, the solution further comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 25% (w / w) water, or any combination thereof. In some embodiments, the solution further comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 30% (w / w) water, or any combination thereof.

[0095]

[0108] In some embodiments, the solution comprises an NMDA receptor modulator at a concentration of about 1 mg / mL to 200 mg / mL. In some embodiments, the solution comprises an NMDA receptor modulator at a concentration of at least about 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 200 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, 300 mg / mL, 310 mg / mL, 320 mg / mL, 330 mg / mL, 340 mg / mL, 350 mg / mL, 360 mg / mL, 370 mg / mL, 380 mg / mL, 390 mg / mL, 400 mg / mL, 410 mg / mL, 420 mg / mL, 430 mg / mL, 440 mg / mL, 450 mg / mL, 460 mg / mL, 470 mg / mL, 480 mg / mL, 490 mg / mL, NMDA receptor modulators at a concentration of 115mg / mL, 120mg / mL, 125mg / mL, 130mg / mL, 135mg / mL, 140mg / mL, 145mg / mL, 150mg / mL, 155mg / mL, 160mg / mL, 165mg / mL, 170mg / mL, 175mg / mL, 180mg / mL, 185mg / mL, 190mg / mL, 195mg / mL, or 200mg / mL. In some embodiments, the solution contains up to about 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 110 mg / mL and 200 mg / mL of an NMDA receptor modulator at a concentration of 115 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, 150 mg / mL, 155 mg / mL, 160 mg / mL, 165 mg / mL, 170 mg / mL, 175 mg / mL, 180 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL.

[0096]

[0109] In some embodiments, the solution contains ketamine (free base or free base equivalent from a salt) at a concentration of about 1 mg / mL to 200 mg / mL. In some embodiments, the solution contains at least about 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 110 mg / mL , ketamine (free base or free base equivalent from salts) at concentrations of 115mg / mL, 120mg / mL, 125mg / mL, 130mg / mL, 135mg / mL, 140mg / mL, 145mg / mL, 150mg / mL, 155mg / mL, 160mg / mL, 165mg / mL, 170mg / mL, 175mg / mL, 180mg / mL, 185mg / mL, 190mg / mL, 195mg / mL, or 200mg / mL. In some embodiments, the solution contains up to about 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 110 mg / mL, Contains ketamine (free base or free base equivalent from salts) at concentrations of 115mg / mL, 120mg / mL, 125mg / mL, 130mg / mL, 135mg / mL, 140mg / mL, 145mg / mL, 150mg / mL, 155mg / mL, 160mg / mL, 165mg / mL, 170mg / mL, 175mg / mL, 180mg / mL, 185mg / mL, 190mg / mL, 195mg / mL, or 200mg / mL.

[0097]

[0110] In some embodiments, the solution comprises about 20 mg to about 150 mg, about 30 mg to about 140 mg, about 40 mg to about 120 mg, about 50 mg to about 100 mg, or about 60 mg to about 80 mg of an NMDA receptor modulator. In some embodiments, the solution comprises at least about 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg of an NMDA receptor modulator. In some embodiments, the solution comprises up to about 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg of an NMDA receptor modulator.

[0098]

[0111] In some embodiments, the solution contains about 20 mg to about 150 mg, about 30 mg to about 140 mg, about 40 mg to about 120 mg, about 50 mg to about 100 mg, or about 60 mg to about 80 mg of ketamine (free base or free base equivalent from a salt). In some embodiments, the solution contains at least about 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg of ketamine (free base or free base equivalent from a salt). In some embodiments, the solution contains up to about 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg of ketamine (free base or free base equivalent from a salt).

[0099]

[0112] In an additional aspect, the present disclosure provides a solution comprising a target of rapamycin (mTOR) inhibitor. In some embodiments, the mTOR inhibitor comprises rapamycin (sirolimus, AY22989, ABI-009, Rapamune, Fyaro) or temsirolimus (Torisel, CCI-779). In some embodiments, the solution comprises the mTOR inhibitor at a concentration of about 0.05 mg / mL to 25 mg / mL. In some embodiments, the solution comprises an mTOR inhibitor at a concentration of at least about 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 16 mg / mL, 18 mg / mL, 20 mg / mL, or 25 mg / mL. In some embodiments, the solution comprises an mTOR inhibitor at a concentration of up to about 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 16 mg / mL, 18 mg / mL, 20 mg / mL, or 25 mg / mL.

[0100]

[0113] In some embodiments, the solution contains temsirolimus at a concentration of about 0.05 mg / mL to 25 mg / mL, hi some embodiments, the solution contains temsirolimus at a concentration of at least about 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 16 mg / mL, 18 mg / mL, 20 mg / mL, or 25 mg / mL. In some embodiments, the solution contains temsirolimus at a concentration of up to about 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 16 mg / mL, 18 mg / mL, 20 mg / mL, or 25 mg / mL.

[0101]

[0114] In some embodiments, the solution contains about 0.05 mg to about 2.0 mg, about 0.1 mg to about 1.8 mg, about 0.2 mg to about 1.5 mg, about 0.4 mg to about 1.2 mg, or about 0.8 mg to about 1.0 mg of an mTOR inhibitor. In some embodiments, the solution contains at least about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 0.95 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, or 2.0 mg of an mTOR inhibitor. In some embodiments, the solution comprises up to about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 0.95 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, or 2.0 mg of an mTOR inhibitor.

[0102]

[0115] In some embodiments, the solution contains about 0.05 mg to about 2.0 mg, about 0.1 mg to about 1.8 mg, about 0.2 mg to about 1.5 mg, about 0.4 mg to about 1.2 mg, or about 0.8 mg to about 1.0 mg of temsirolimus. In some embodiments, the solution contains at least about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 0.95 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, or 2.0 mg of temsirolimus. In some embodiments, the solution contains up to about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 0.95 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, or 2.0 mg of temsirolimus.

[0103]

[0116] In some embodiments, the solution further comprises about 39.5% (w / v) absolute ethanol, about 0.075% (w / v) DL-alpha-tocopherol, about 50.3% (w / v) propylene glycol, about 0.0025% (w / v) anhydrous citric acid, or any combination thereof.

[0104]

[0117] In some embodiments, the first solution or first composition is stable at room temperature for at least about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 6 months, 8 months, 10 months, 12 months, 2 years, or 3 years. In some embodiments, the first solution or first composition is stable at temperatures up to about 60°C for about 1 week to about 2 years, 2 weeks to 12 months, 3 weeks to 10 months, 1 month to 10 months, 2 months to 8 months, or 6 months to 2 years. In some embodiments, the first solution or first composition is stable at temperatures below about 60°C for at least about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 6 months, 8 months, 10 months, 12 months, or 2 years. In some embodiments, the first solution or first composition is stable at temperatures of about 10, 20, 30, 40, 50, or 60°C. In some embodiments, the first solution or first composition is stable at a temperature of about 10°C to 60°C, 20°C to 50°C, or 30°C to 40°C.

[0105]

[0118] In some embodiments, the second solution or second composition is stable at room temperature for at least about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 6 months, 8 months, 10 months, 12 months, 2 years, or 3 years. In some embodiments, the second solution or second composition is stable at temperatures up to about 60°C for about 1 week to about 2 years, 2 weeks to 12 months, 3 weeks to 10 months, 1 month to 10 months, 2 months to 8 months, or 6 months to 2 years. In some embodiments, the second solution or second composition is stable at temperatures below about 60°C for at least about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 6 months, 8 months, 10 months, 12 months, or 2 years. In some embodiments, the second solution or second composition is stable at temperatures of about 10, 20, 30, 40, 50, or 60°C. In some embodiments, the second solution or second composition is stable at a temperature of about 10°C to 60°C, 20°C to 50°C, or 30°C to 40°C.

[0106]

[0119] In some embodiments, the solution is stable for at least about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 6 months, 8 months, 10 months, 12 months, or 2 years at a temperature of up to about 60° C. In some embodiments, the solution is stable for about 1 week to about 2 years, 2 weeks to 12 months, 3 weeks to 10 months, 1 month to 10 months, 2 months to 8 months, or 6 months to 2 years at a temperature of up to about 60° C. In some embodiments, the solution is stable at a temperature of about 10, 20, 30, 40, 50, or 60° C. In some embodiments, the solution is stable at a temperature of about 10° C. to 60° C., 20° C. to 50° C., or 30° C. to 40° C.

[0107]

[0120] In some embodiments, a solution containing 30.67 mg / mL ketamine HCl in 38.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, and 10% (w / w) water is stable for two weeks of storage at 50° C. In some embodiments, a solution containing 61.34 mg / mL ketamine HCl in 23.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, and 25% (w / w) water is stable for two weeks of storage at 50° C.

[0108]

[0121] In an additional aspect, the present disclosure provides a solution comprising water, ethanol, polyethylene glycol (PEG), a polysorbate, or any combination thereof. In some embodiments, the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the PEG has an average molecular weight of about 300 to about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the solution comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 10% (w / w) water, or any combination thereof. In some embodiments, the solution comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 15% (w / w) water, or any combination thereof. In some embodiments, the solution comprises about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 20% (w / w) water, or any combination thereof. In some embodiments, the solution comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 25% (w / w) water, or any combination thereof. In some embodiments, the solution comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 30% (w / w) water, or any combination thereof. Treatment method

[0122] The present disclosure also provides methods for treating or preventing a disease, disorder, or condition in a subject in need thereof. In some embodiments, the method comprises administering a solution or composition disclosed herein to the subject. In some embodiments, the solution is administered to the subject within at least about 1, 2, 3, 4, 5, 6, 7, 10, 12, 16, 28, or 24 hours after the solution is formed by mixing a first solution disclosed herein with a second solution disclosed herein. In some embodiments, the solution is administered to the subject within at most about 1, 2, 3, 4, 5, 6, 7, 10, 12, 16, 28, or 24 hours after the solution is formed by mixing a first solution disclosed herein with a second solution disclosed herein.

[0109]

[0123] In some embodiments, a solution or composition disclosed herein is administered via an intramuscular route. In some embodiments, a solution or composition disclosed herein is administered via an intravenous route. In some embodiments, a solution or composition disclosed herein is administered via a subcutaneous route. In some embodiments, a solution or composition disclosed herein is administered via an oral route. In some embodiments, a solution or composition disclosed herein is administered via an intranasal route. In some embodiments, a solution or composition disclosed herein is administered via an inhalation route.

[0110]

[0124] In some cases, the subject may not respond to the NMDA receptor modulator. In some cases, the subject may partially respond to the NMDA receptor modulator. In some cases, the subject may show an inadequate response to the NMDA receptor modulator. In some embodiments, an inadequate response refers to not achieving a clinical response in the current trial. In some cases, the subject may show treatment resistance to the NMDA receptor modulator. In some embodiments, treatment resistance refers to failing two trials using drugs from different classes. In some cases, the subject may not respond to ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer, and geometric isomer thereof, or any mixture thereof. In some cases, the subject may partially respond to ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer, and geometric isomer thereof, or any mixture thereof. In some cases, a subject may exhibit an inadequate response to ketamine, any salts, solvates, enantiomers, tautomers, stereoisomers, and geometric isomers thereof, or any mixture thereof. In some cases, a subject may exhibit treatment resistance to ketamine, any salts, solvates, enantiomers, tautomers, stereoisomers, and geometric isomers thereof, or any mixture thereof.

[0111]

[0125] In some embodiments, the solution is administered once a day, twice a day, three times a day, four times a day, or five times a day. In some embodiments, the solution is administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or seven times a week. In some embodiments, the solution is administered once a week, once every two weeks, once a month, twice a month, three times a month, four times a month, five times a month, six times a month, seven times a month, eight times a month, nine times a month, or ten times a month. In some embodiments, the solution is administered every two weeks.

[0112]

[0126] In some embodiments, the NMDA receptor modulator is administered at a dose of about 0.1 mg / kg to about 1 mg / kg. In some embodiments, the NMDA receptor modulator is administered at a dose of about 0.3 mg / kg to about 0.7 mg / kg. In some embodiments, the NMDA receptor modulator is administered at a dose of about 0.5 mg / kg. In some embodiments, the NMDA receptor modulator is administered at a dose of about 30 mg to about 90 mg. In some embodiments, the NMDA receptor modulator is administered at a dose of about 30 mg to about 60 mg.

[0113]

[0127] In some embodiments, ketamine (free base or free base equivalent from a ketamine salt) is administered at a dose of about 0.1 mg / kg to about 1 mg / kg. In some embodiments, ketamine (free base or free base equivalent from a ketamine salt) is administered at a dose of about 0.3 mg / kg to about 0.7 mg / kg. In some embodiments, ketamine (free base or free base equivalent from a ketamine salt) is administered at a dose of about 0.5 mg / kg. In some embodiments, ketamine (free base or free base equivalent from a ketamine salt) is administered at a dose of about 30 mg to about 90 mg. In some embodiments, ketamine (free base or free base equivalent from a ketamine salt) is administered at a dose of about 30 mg to about 60 mg.

[0114]

[0128] In some embodiments, the mTOR inhibitor is administered at a dose of about 1 μg / kg to about 100 μg / kg. In some embodiments, the mTOR inhibitor is administered at a dose of about 2.5 μg / kg to about 30 μg / kg. In some embodiments, the mTOR inhibitor is administered at a dose of about 3 μg / kg to about 25 μg / kg. In some embodiments, the mTOR inhibitor is administered at a dose of about 1 μg to about 40 μg. In some embodiments, the mTOR inhibitor is administered at a dose of about 20 μg to about 50 μg. In some embodiments, the mTOR inhibitor is administered at a dose of about 1 μg to about 70 μg. In some embodiments, the mTOR inhibitor is administered at a dose of about 5 μg to about 60 μg. In some embodiments, the mTOR inhibitor is administered at a dose of about 0.1 mg to about 4 mg.

[0115]

[0129] In some embodiments, temsirolimus is administered at a dose of about 1 μg / kg to about 100 μg / kg. In some embodiments, temsirolimus is administered at a dose of about 2.5 μg / kg to about 30 μg / kg. In some embodiments, temsirolimus is administered at a dose of about 3 μg / kg to about 25 μg / kg. In some embodiments, temsirolimus is administered at a dose of about 1 μg to about 40 μg. In some embodiments, temsirolimus is administered at a dose of about 20 μg to about 50 μg. In some embodiments, temsirolimus is administered at a dose of about 1 μg to about 70 μg. In some embodiments, temsirolimus is administered at a dose of about 5 μg to about 60 μg. In some embodiments, temsirolimus is administered at a dose of about 0.1 mg to about 4 mg.

[0116]

[0130] In some embodiments, the disease, disorder, or condition is selected from the group consisting of major depressive disorder (MDD), major depressive episode in bipolar disorder (bipolar depression), persistent depressive disorder (dysthymia), major mood dysregulation disorder, major depressive disorder (including major depressive episode), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, depressive disorder due to other medical illness, other specified depressive disorder, depressive disorder not otherwise specified, anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, addictive disorder, bipolar disorder Type I, bipolar disorder Type II, generalized anxiety disorder, social anxiety disorder (social phobia), specific phobia, panic disorder, agoraphobia, separation anxiety disorder, selective mutism, substance-induced anxiety disorder, medication-induced anxiety disorder, anxiety disorder due to other medical illness, borderline personality disorder, treatment-resistant depression, anxiety disorder not otherwise specified, chronic pain, and any combination thereof. In some embodiments, the disease, disorder, or condition is a mood disorder such as major depressive disorder, persistent depressive disorder (dysthymia), severe mood dysregulation disorder, premenstrual dysphoric disorder, substance / medication-induced depressive disorder, anxiety disorder, or post-traumatic stress disorder. In some embodiments, the disease is a depressive disorder.

[0117]

[0131] The present disclosure also relates to a method for treating or preventing a depressive disorder in a subject. In some embodiments, the method comprises administering a solution comprising an NMDA receptor modulator, an mTOR inhibitor, and an excipient selected from the group consisting of water, polysorbate 80, PEG 400, propylene glycol, and absolute ethanol. In some embodiments, the method comprises administering a solution comprising ketamine HCl, temsirolimus, and an excipient selected from the group consisting of water, polysorbate 80, PEG 400, propylene glycol, and absolute ethanol. In some embodiments, the method comprises administering a solution comprising ketamine HCl, temsirolimus, and an excipient selected from the group consisting of water, polysorbate 80, PEG 400, propylene glycol, DL-alpha-tocopherol, citric acid, and absolute ethanol. In some embodiments, the NMDA receptor modulator binds to a component of the NMDA receptor and activates or inhibits the NMDA receptor. In some embodiments, the mTOR inhibitor binds to a domain of mTOR and inhibits mTOR activity. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is greater than about 1: 1. In some embodiments, the weight of the N-methyl-D-aspartate receptor modulator is greater than the weight of the mTOR inhibitor.

[0118] Preparation method

[0132] In additional embodiments, a method for preparing a solution is provided, comprising the steps of: (1) mixing a solution of an NMDA receptor modulator that binds to a component of the NMDA receptor and activates or inhibits the NMDA receptor; and (2) mixing a solution of an mTOR inhibitor that binds to a domain of mTOR and inhibits mTOR activity. In some embodiments, the NMDA receptor modulator solution further comprises an excipient selected from the group consisting of an aqueous vehicle, a water-miscible vehicle, a non-aqueous vehicle, a preservative, a solubility enhancer, a stabilizer, an antioxidant, a buffer, an emulsifier, a suspending agent, a complexing agent, a sequestering or chelating agent, a thickening agent, an osmotic / tonicity agent, an antifoaming / defoaming agent, an osmotic agent, a polymer, a spreading agent, a wetting agent, and a pH adjuster. In some embodiments, the NMDA receptor modulator solution further comprises an excipient selected from the group consisting of water, ethanol, propylene glycol, polyethylene glycol (PEG), polysorbate, citric acid, and DL-alpha-tocopherol. In some embodiments, the NMDA receptor modulator solution comprises water. In some embodiments, the NMDA receptor modulator solution comprises a polysorbate. In some embodiments, the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the NMDA receptor modulator solution comprises PEG. In some embodiments, the PEG has an average molecular weight of about 300 to about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the NMDA receptor modulator solution comprises ethanol. In some embodiments, the ethanol is absolute ethanol.

[0119]

[0133] The present disclosure provides a method for preparing a solution, the method comprising: (i) mixing a first solution containing an N-methyl-D-aspartate (NMDA) receptor modulator with (ii) a second solution containing a target of rapamycin (mTOR) inhibitor, thereby producing a solution containing both the NMDA receptor modulator and the mTOR inhibitor. In some embodiments, the volume ratio of the first solution to the second solution after mixing is about 3:2. In some embodiments, the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer, and geometric isomer thereof, or any mixture thereof. In some embodiments, the ketamine is ketamine HCl. In some embodiments, the mTOR inhibitor comprises rapamycin (sirolimus, AY22989, ABI-009, Rapamune, Fyaro) or temsirolimus (Torisel, CCI-779). In some embodiments, the mTOR inhibitor is temsirolimus. In some embodiments, the first solution comprises polysorbate, PEG 400, or both. In some embodiments, the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the first solution comprises polysorbate 80 and PEG 400.

[0120]

[0134] In some embodiments, the solution further comprises about 0.9% (w / v) sodium chloride in water or about 5% (w / v) dextrose in water. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is greater than about 1:1. In some embodiments, the weight ratio of the N-methyl-D-aspartate receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 2:1. In some embodiments, the weight ratio of the N-methyl-D-aspartate receptor modulator to the mTOR inhibitor ranges from about 600:1 to about 5:1.

[0121]

[0135] In some embodiments, the second solution further comprises ethanol, DL-alpha-tocopherol, propylene glycol, citric acid, or any combination thereof. In some embodiments, the second solution further comprises ethanol, propylene glycol, or any combination thereof.

[0122]

[0136] In some embodiments, the first solution further comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 10% (w / w) water, or any combination thereof. In some embodiments, the first solution further comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 15% (w / w) water, or any combination thereof. In some embodiments, the first solution further comprises about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 20% (w / w) water, or any combination thereof. In some embodiments, the first solution further comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 25% (w / w) water, or any combination thereof. In some embodiments, the first solution further comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 30% (w / w) water, or any combination thereof. In some embodiments, the second solution further comprises about 39.5% (w / v) absolute ethanol, about 0.075% (w / v) DL-alpha-tocopherol, about 50.3% (w / v) propylene glycol, about 0.0025% (w / v) anhydrous citric acid, or any combination thereof.

[0123]

[0137] In some embodiments, the NMDA receptor modulator is selected from the group consisting of ketamine, R-ketamine, S-ketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, dextromethorphan, a fixed-dose combination of dextromethorphan and quinidine, a fixed-dose combination of dextromethorphan and bupropion, GM-1020, besonprodil, eliprodil, ifenprodil, lislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro8-4304, traxoprodil (CP-101,606), BMT-108908, omfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP37849, 1-aminocyclopropanecarboxylic acid, traxoprodil, Ro25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxyzine, tiletamine, neramexane, etoxadrol, dexoxadrol le, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delsemin, dextralorphan, dextrorphan, diphenidine, eticcyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7-Dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnalone sulfate (3α5βS), UBP608, UBP618, UBP551, UBP512, HA-9 66, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, and NYX-783, and any salts, solvates, enantiomers, tautomers, stereoisomers, and geometric isomers thereof, and any mixtures thereof. In some embodiments, the NMDP receptor modulator is selected from the group consisting of an NMDA receptor channel blocker, such as, but not limited to, ketamine (R / S-ketamine, R-ketamine), memantine, a fixed-dose combination of dextromethorphan and quinidine, a fixed-dose combination of dextromethorphan and bupropion, or GM-1020. In some embodiments, the NMDP receptor modulator is an NR2B NAM / GluN2B NAM, such as, but not limited to, besonprodil, eliprodil, ifenprodil, lislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, traxoprodil (CP-101,606), BMT-108908, omfasprodil, radiprodil, NP10679, or GluN2B NAM. In some embodiments, the NMDA receptor modulator is a fixed-dose combination of dextromethorphan hydrobromide and quinidine sulfate. In some embodiments, the NMDA receptor modulator is a fixed-dose combination of dextromethorphan and quinidine, comprising 20 mg of dextromethorphan hydrobromide and 10 mg of quinidine sulfate. In some embodiments, the NMDA receptor modulator is a fixed-dose combination of dextromethorphan and bupropion. In some embodiments, the fixed-dose combination of dextromethorphan and bupropion comprises 45 mg of dextromethorphan and 105 mg of bupropion.

[0124]

[0138] In some embodiments, the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any mixture thereof. In some embodiments, the ketamine is ketamine HCl.

[0125]

[0139] In some embodiments, the mTOR inhibitor is BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), KU-0063794, PI-103 (mTOR inhibitor V, PI3-K inhibitor V, PI-103-CAS371935-74-9), tolquinib (PP242), tacrolimus (FK-506, fujimycin, Envarsus XR), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), torin-1 (DNA-PK inhibitor VI, PI3-K inhibitor XVIII, mTOR inhibitor XI, torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-0 27 (ASP7486, CERC006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE390), GSK1059615, WYE-354 (mTOR inhibitor II), gedatolisib (PF-05212384, PKI-587), AZD-2014 (bistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839) , AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomide-529 (P529, SG00529), PP121, WYE-687 (WAY-687), CH 5132799(MEN1611, PA799), Way-600, ETP-46464(ATRi), GDC-0349(RG-7603), XL388, PI-103, NU7441(KU-57788), KU -0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound401, GNE-477, vimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC223), clemastine (HS-592) fumarate, nitazoxanide (NSC697855), 4EGI-1, ABTL-0812, astragaloside IV,The mTOR inhibitor may comprise samotricisib (LY3023414), chrysophanic acid, or zotarolimus (ABT-578), or a salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some embodiments, the mTOR inhibitor comprises sirolimus, temsirolimus, or everolimus. In some embodiments, the mTOR inhibitor comprises a natural product derived from food or drink, such as, but not limited to, curcumin, resveratrol, epigallocatechin gallate (EGCG), genistein, 3,3-diindolylmethane (DIM), or caffeine.

[0126]

[0140] In some embodiments, the concentration of polysorbate ranges from about 5% w / w to about 80% w / w. In some embodiments, the concentration of polysorbate ranges from about 10% w / w to about 50% w / w. In some embodiments, the concentration of polysorbate is at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of polysorbate is up to about 5, 10, 15, 20, 25, 30, 35, 40, 45, and 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of polysorbate 80 is in the range of about 5-80, 10-75, 15-70, 20-65, 25-60, 30-55, 35-50, or 40-45% w / w. In some embodiments, the concentration of polysorbate 80 is in the range of about 5% w / w to about 80% w / w. In some embodiments, the concentration of polysorbate 80 is in the range of about 10% w / w to about 50% w / w. In some embodiments, the concentration of polysorbate 80 is at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of polysorbate 80 is up to about 5, 10, 15, 20, 25, 30, 35, 40, 45, and 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of polysorbate 80 is in the range of about 5-80, 10-75, 15-70, 20-65, 25-60, 30-55, 35-50, or 40-45% w / w.

[0127]

[0141] In some embodiments, the concentration of PEG ranges from about 0.01% w / w to about 50% w / w. In some embodiments, the concentration of PEG ranges from about 0.1% w / w to about 30% w / w. In some embodiments, the concentration of PEG is at least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w. In some embodiments, the concentration of PEG is up to about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w. In some embodiments, the concentration of PEG is in the range of about 0.01-50, 0.05-45, 0.1-40, 0.5-35, 1-30, 5-25, 10-20, or 15-50% w / w. In some embodiments, the concentration of PEG 400 is in the range of about 0.01% w / w to about 50% w / w. In some embodiments, the concentration of PEG 400 is in the range of about 0.1% w / w to about 30% w / w. In some embodiments, the concentration of PEG 400 is at least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w. In some embodiments, the concentration of PEG 400 is up to about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w, or in some embodiments, the concentration of PEG 400 is in the range of about 0.01-50, 0.05-45, 0.1-40, 0.5-35, 1-30, 5-25, 10-20, or 15-50% w / w.

[0128]

[0142] In some embodiments, the concentration of ethanol ranges from about 1% w / w to about 80% w / w. In some embodiments, the concentration of ethanol ranges from about 10% w / w to about 50% w / w. In some embodiments, the concentration of ethanol is at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of ethanol is up to about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of ethanol is in the range of about 1-80, 5-75, 10-70, 15-65, 20-60, 25-55, 30-50, 35-45, or 40-80% w / w. In some embodiments, the concentration of absolute ethanol is in the range of about 1% w / w to about 80% w / w. In some embodiments, the concentration of absolute ethanol is in the range of about 10% w / w to about 50% w / w. In some embodiments, the concentration of absolute ethanol is at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of absolute ethanol is up to about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w, hi some embodiments, the concentration of absolute ethanol is in the range of about 1-80, 5-75, 10-70, 15-65, 20-60, 25-55, 30-50, 35-45, or 40-80% w / w.

[0129]

[0143] In some embodiments, the concentration of water ranges from about 0.01% w / w to about 50% w / w. In some embodiments, the concentration of water ranges from about 0.1% w / w to about 30% w / w. In some embodiments, the concentration of water is at least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w. In some embodiments, the concentration of water is at most about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% w / w. In some embodiments, the concentration of water ranges from about 0.01-50, 0.05-45, 0.1-40, 0.5-35, 1-30, 5-25, 10-20, or 15-50% w / w.

[0130]

[0144] In some embodiments, the concentration of propylene glycol ranges from about 1% w / w to about 60% w / w. In some embodiments, the concentration of propylene glycol ranges from about 5% w / w to about 50% w / w. In some embodiments, the concentration of propylene glycol is at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60% w / w. In some embodiments, the concentration of propylene glycol is at most about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60% w / w. In some embodiments, the concentration of propylene glycol ranges from about 1-60, 5-65, 10-50, 15-45, 20-40, 25-35, 10-60, or 15-50% w / w.

[0131]

[0145] In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is greater than about 1:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 1000:1 to about 2:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 800:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 600:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 500:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 300:1 to about 5:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 1000:1 to about 10:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is in the range of about 1000:1 to about 30:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 50:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 100:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 200:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 2:1. In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is about 1000:1, 900:1, 800:1, 700:1, 600:1, 500:1, 400:1, 300:1, 200:1, 100:1, 80:1, 60:1, 40:1, 20:1, 10:1, 5:1, or any and all whole or partial increments therebetween.

[0132]

[0146] In some embodiments, the method further comprises adding a diluent. In some embodiments, the diluent comprises saline containing water and sodium chloride (NaCl). In some embodiments, the concentration of NaCl ranges from about 0.1 milligrams per milliliter (mg / ml) to about 50 mg / ml. In some embodiments, the concentration of NaCl is at least about 0.1, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg / ml. In some embodiments, the concentration of NaCl is at most about 0.1, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg / ml.

[0133]

[0147] In some embodiments, the solution comprises about 0.9% (w / v) sodium chloride in water or about 5% (w / v) dextrose in water. In some embodiments, the solution comprises at least about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.8%, 1.9%, or 2.0% (w / v) sodium chloride in water. In some embodiments, the solution comprises up to about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.8%, 1.9%, or 2.0% (w / v) sodium chloride in water. In some embodiments, the solution comprises at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (w / v) dextrose in water, hi some embodiments, the solution comprises up to about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (w / v) dextrose in water.

[0134]

[0148] In some embodiments, the solution of the mTOR inhibitor comprises an excipient selected from the group consisting of anhydrous alcohol, DL-alpha-tocopherol, propylene glycol, and anhydrous citric acid. In some embodiments, the anhydrous alcohol comprises ethyl alcohol. In some embodiments, the solution of the mTOR inhibitor comprises an excipient comprising anhydrous alcohol or propylene glycol. In some embodiments, the solution of the mTOR inhibitor does not comprise DL-alpha-tocopherol or anhydrous citric acid.

[0135]

[0149] In some embodiments, the concentration of absolute alcohol in the solution of the mTOR inhibitor ranges from about 10% w / w to about 50% w / w. In some embodiments, the concentration of absolute alcohol in the solution of the mTOR inhibitor is at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of absolute alcohol in the solution of the mTOR inhibitor is at most about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of absolute alcohol in the mTOR inhibitor solution is in the range of about 1-80, 5-75, 10-70, 15-65, 20-60, 25-55, 30-50, 35-45, or 40-80% w / w. In some embodiments, the concentration of absolute ethanol in the mTOR inhibitor solution is in the range of about 1% w / w to about 80% w / w. In some embodiments, the concentration of absolute ethanol in the mTOR inhibitor solution is in the range of about 10% w / w to about 50% w / w. In some embodiments, the concentration of absolute ethanol is up to about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% w / w. In some embodiments, the concentration of absolute ethanol in the solution of mTOR inhibitor ranges from about 1-80, 5-75, 10-70, 15-65, 20-60, 25-55, 30-50, 35-45, or 40-80% w / w.

[0136]

[0150] In some embodiments, the concentration of DL-alpha-tocopherol in the solution of the mTOR inhibitor ranges from about 0.01% w / w to about 1.0% w / w, hi some embodiments, the concentration of DL-alpha-tocopherol in the solution of the mTOR inhibitor is at least about 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10% w / w. In some embodiments, the concentration of DL-alpha-tocopherol in a solution of an mTOR inhibitor is at most about 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10% w / w. In some embodiments, the concentration of DL-alpha-tocopherol in a solution of an mTOR inhibitor is in the range of about 0.01-10, 0.05-9, 0.1-8, 0.2-7, 0.3-6, 0.4-5, 0.5-4, 0.6-3, 0.7-2, 0.8-1, or 0.9-10% w / w.

[0137]

[0151] In some embodiments, the concentration of propylene glycol in the solution of the mTOR inhibitor ranges from about 20% w / w to about 70% w / w. In some embodiments, the concentration of propylene glycol in the solution of the mTOR inhibitor is at least about 5, 10, 20, 30, 40, 50, 60, 70, or 80% w / w. In some embodiments, the concentration of propylene glycol in the solution of the mTOR inhibitor is at most about 5, 10, 20, 30, 40, 50, 60, 70, or 80% w / w. In some embodiments, the concentration of propylene glycol in the solution of the mTOR inhibitor ranges from about 5-80, 10-70, 20-60, 30-50, or 40-80% w / w.

[0138]

[0152] In some embodiments, the concentration of anhydrous citric acid in the solution of the mTOR inhibitor ranges from about 0.001% w / w to about 0.01% w / w, hi some embodiments, the concentration of anhydrous citric acid in the solution of the mTOR inhibitor is at least about 0.0005, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1% w / w. In some embodiments, the concentration of anhydrous citric acid in the solution of the mTOR inhibitor is at most about 0.0005, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1% w / w. In some embodiments, the concentration of anhydrous citric acid in the solution of mTOR inhibitor is in the range of about 0.0005-0.1, 0.001-0.09, 0.002-0.08, 0.003-0.07, 0.004-0.06, 0.005-0.05, 0.006-0.04, 0.007-0.03, 0.008-0.02, or 0.009-0.01% w / w.

[0139] Kits, Dual-Chamber Syringes, and Dual-Compartment Devices

[0153] In certain aspects, the present disclosure provides a kit for preparing a solution or composition disclosed herein for administration to a subject in need thereof. In some embodiments, the kit comprises a first container containing a first solution or a first composition comprising an NMDA receptor modulator, and a second container containing a second solution or a second component comprising an mTOR inhibitor. In some embodiments, the NMDA receptor modulator binds to a component of the NMDA receptor and activates or inhibits the NMDA receptor. In some embodiments, the mTOR inhibitor binds to a domain of mTOR and inhibits mTOR activity. In some embodiments, the kit comprises a first container containing a first solution or a first composition comprising ketamine HCl, and a second container containing a second solution or a second component comprising temsirolimus.

[0140]

[0154] In some embodiments, the first solution or composition comprises an NMDA receptor modulator at a concentration of about 1 mg / mL to about 200 mg / mL. In some embodiments, the first solution or composition comprises an NMDA receptor modulator at a concentration of at least about 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, or 120 mg / mL. mL, 110 mg / mL, 115 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, 150 mg / mL, 155 mg / mL, 160 mg / mL, 165 mg / mL, 170 mg / mL, 175 mg / mL, 180 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL of an NMDA receptor modulator. In some embodiments, the first solution or first composition has a concentration of at most about 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL L, containing an NMDA receptor modulator at a concentration of 110 mg / mL, 115 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, 150 mg / mL, 155 mg / mL, 160 mg / mL, 165 mg / mL, 170 mg / mL, 175 mg / mL, 180 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL.

[0141]

[0155] In some embodiments, the first solution or composition contains ketamine (free base or free base equivalent from a salt) at a concentration of about 1 milligram per milliliter (mg / mL) to 200 mg / mL. In some embodiments, the first solution or composition contains ketamine (free base or free base equivalent from a salt) at a concentration of about 50 mg / mL. In some embodiments, the first solution or composition contains ketamine (free base or free base equivalent from a salt) at a concentration of at least about 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 11 Contains ketamine (free base or free base equivalent from salts) at concentrations of 0 mg / mL, 115 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, 150 mg / mL, 155 mg / mL, 160 mg / mL, 165 mg / mL, 170 mg / mL, 175 mg / mL, 180 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL. In some embodiments, the first solution or first composition has a concentration of at most about 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, 300 mg / mL, 310 mg / mL, 320 mg / mL, 330 mg / mL, 340 mg / mL, 350 mg / mL, 360 mg / mL, 370 mg / mL, 380 mg / mL, 390 mg / mL, 400 mg / mL, 410 mg / mL, 420 mg / mL, 430 mg / mL, 440 mg / mL, 450 mg / mL, 460 mg / mL, 470 mg / mL, 480 mg / mL, 490 mg / mL, 500 mg / mL, 510 mg / mL, 520 mg / mL, 530 mg / mL, 540 mg / mL, 550 Contains ketamine (free base or free base equivalent from salts) at concentrations of 115mg / mL, 120mg / mL, 125mg / mL, 130mg / mL, 135mg / mL, 140mg / mL, 145mg / mL, 150mg / mL, 155mg / mL, 160mg / mL, 165mg / mL, 170mg / mL, 175mg / mL, 180mg / mL, 185mg / mL, 190mg / mL, 195mg / mL, or 200mg / mL.

[0142]

[0156] In some embodiments, the second solution or composition comprises an mTOR inhibitor at a concentration of about 0.05 mg / mL to 25 mg / mL, or at least about 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 16 mg / mL, 18 mg / mL, 20 mg / mL, or 25 mg / mL. In some embodiments, the second solution or second composition comprises an mTOR inhibitor at a concentration of up to about 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 16 mg / mL, 18 mg / mL, 20 mg / mL, or 25 mg / mL.

[0143]

[0157] In some embodiments, the second solution or composition comprises temsirolimus at a concentration of about 0.05 mg / mL to about 25 mg / mL, hi some embodiments, the second solution or composition comprises temsirolimus at a concentration of about 0.47 mg / mL to about 9.375 mg / mL. In some embodiments, the second solution or second composition contains temsirolimus at a concentration of at least about 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 16 mg / mL, 18 mg / mL, 20 mg / mL, or 25 mg / mL. In some embodiments, the second solution or second composition contains temsirolimus at a concentration of up to about 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 12 mg / mL, 14 mg / mL, 16 mg / mL, 18 mg / mL, 20 mg / mL, or 25 mg / mL.

[0144]

[0158] In some embodiments, a first solution or composition and a second solution or composition can be mixed to form a solution. In some embodiments, the volume ratio of the first solution to the second solution is about 1.2:1 to about 3:1. In some embodiments, the volume ratio of the first solution to the second solution is about 3:2, about 2.2:1.2, about 2.4:1.2, or about 2.5:1.2. In some embodiments, the volume ratio of the first solution to the second solution is about 3:2. In some embodiments, the volume ratio of the first solution to the second solution is about 2.2:1.2. In some embodiments, the volume ratio of the first solution to the second solution is about 2.4:1.2. In some embodiments, the volume ratio of the first solution to the second solution is about 2.5:1.2.

[0145]

[0159] In some embodiments, the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is greater than about 1:1. In some embodiments, the first container contains a first solution or a first composition further comprising water, ethanol, polyethylene glycol (PEG), a polysorbate, or any combination thereof. In some embodiments, the first container contains a first solution or a first composition further comprising water. In some embodiments, the first container contains a first solution or a first composition further comprising a polysorbate. In some embodiments, the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the first container contains a first solution or a first composition further comprising PEG. In some embodiments, the PEG has an average molecular weight of about 300 to about 600. In some embodiments, the PEG is PEG 400.

[0146]

[0160] In some embodiments, the second container contains a second solution or composition further comprising ethanol, DL-alpha-tocopherol, propylene glycol, citric acid, or any combination thereof. In some embodiments, the second container contains a second solution or composition further comprising ethanol, propylene glycol, or any combination thereof. In some embodiments, the second container contains a second solution or composition that does not contain DL-alpha-tocopherol or citric acid.

[0147]

[0161] In some embodiments, the first composition is a solution. In some embodiments, the solution further comprises water, ethanol, polyethylene glycol (PEG), a polysorbate, or any combination thereof. In some embodiments, the solution comprises water. In some embodiments, the solution comprises a polysorbate. In some embodiments, the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the solution comprises PEG. In some embodiments, the PEG has an average molecular weight of about 300 to about 600. In some embodiments, the PEG is PEG 400.

[0148]

[0162] In some embodiments, the first composition is a solid. In some embodiments, the solid is a powder. In some embodiments, the solid is dissolved in a diluent. In some embodiments, the diluent comprises polyethylene glycol (PEG), a polysorbate, or both. In some embodiments, the diluent comprises a polysorbate. In some embodiments, the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the diluent comprises PEG. In some embodiments, the PEG has an average molecular weight of about 300 to about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the diluent comprises PEG 400 and polysorbate 80.

[0149]

[0163] In some embodiments, the second composition is a solution.In some embodiments, the solution further comprises ethanol, DL-alpha-tocopherol, propylene glycol, citric acid, or any combination thereof.In some embodiments, the solution further comprises ethanol, propylene glycol, or any combination thereof.

[0150]

[0164] In some embodiments, the second composition is a solid. In some embodiments, the solid is a powder. In some embodiments, the solid is dissolved in a diluent. In some embodiments, the diluent further comprises ethanol, DL-alpha-tocopherol, propylene glycol, citric acid, or any combination thereof. In some embodiments, the diluent comprises ethanol, propylene glycol, or any combination thereof.

[0151]

[0165] In some embodiments, the solution or composition disclosed herein from the first container and the second container is mixed before administration.In some embodiments, the first solution or composition in the first container and the second solution or composition in the second container can be mixed to form a solution at least about 1, 2, 3, 4, 5, 6, 7, 10, 12, 16, 28, or 24 hours before administering the solution to a subject.In some embodiments, the first solution or composition in the first container and the second solution or composition in the second container can be mixed to form a solution at most about 1, 2, 3, 4, 5, 6, 7, 10, 12, 16, 28, or 24 hours before administering the solution to a subject. In some embodiments, the ketamine HCl in the first container and the temsirolimus in the second container can be mixed to form a solution at least about 1, 2, 3, 4, 5, 6, 7, 10, 12, 16, 28, or 24 hours before administering the solution to a subject. In some embodiments, the ketamine HCl in the first container and the temsirolimus in the second container can be mixed to form a solution at most about 1, 2, 3, 4, 5, 6, 7, 10, 12, 16, 28, or 24 hours before administering the solution to a subject.

[0152]

[0166] In a further aspect, the present disclosure provides a dual-chamber syringe for preparing a solution or composition disclosed herein for administration to a subject in need thereof. In some embodiments, the dual chamber comprises a first chamber containing a first solution or composition comprising an NMDA receptor modulator, and a second chamber containing a second solution or composition comprising an mTOR inhibitor. In some embodiments, the dual chamber comprises a first chamber containing a first solution or composition comprising ketamine HCl, and a second chamber containing a second solution or composition comprising temsirolimus. In some embodiments, the solutions or compositions disclosed herein from the first and second chambers are mixed prior to administration.

[0153]

[0167] The present disclosure also relates to a dual-compartment device for preparing a solution or composition for administration to a subject in need thereof. In some embodiments, the dual-compartment device comprises a first compartment containing a first solution or composition comprising an NMDA receptor modulator and a second compartment containing a second solution or composition comprising an mTOR inhibitor. In some embodiments, the dual chamber comprises a first compartment containing a first solution or composition comprising ketamine HCl and a second compartment containing a second solution or composition comprising temsirolimus. In some embodiments, the solutions or compositions from the first and second compartments are mixed prior to administration. In some embodiments, the dual-compartment device is a dual-compartment nasal inhaler.

[0154]

[0168] In some embodiments, the kit is in the form of a two-vial kit. In some embodiments, the kit is in the form of a two-compartment container. In some embodiments, the two-compartment container comprises a two-compartment syringe or a dual-compartment inhaler.

[0155] definition

[0169] Unless otherwise defined, all technical terms, notations, and other technical and scientific terms or terminology used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms having a commonly understood meaning are defined herein for clarity and / or ready reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from what is commonly understood in the art.

[0156]

[0170] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. Thus, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0157]

[0171] As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "sample" includes multiple samples, including mixtures thereof.

[0158]

[0172] Whenever the terms "at least," "greater than," or "greater than or equal to" precede the first number in a series of two or more numbers, the terms "at least," "greater than," or "greater than or equal to" apply to each and every number in the series. For example, 1, 2, or 3 or more is equivalent to 1 or more, 2 or more, or 3 or more.

[0159]

[0173] Whenever the term "slightly," "less than," or "equal to or less than" precedes the first number in a series of two or more numbers, the term "slightly," "less than," or "equal to or less than" applies to each of the numbers in the series. For example, 3, 2, or 1 or less is equivalent to 3 or less, 2 or less, or 1 or less.

[0160]

[0174] The phrases "at least one of A and B" and "at least one of A or B" may be interpreted to mean at least A, at least B, or at least A and B (i.e., a set that includes A and B, and that may include one or more additional elements). The term "A and / or B" may be interpreted to mean A only, B only, or both A and B.

[0161]

[0175] The phrases "at least about A, B, and C" and "at least about A, B, or C" can be interpreted to mean at least about A, at least about B, or at least about C. The phrases "up to about A, B, and C" and "up to about A, B, or C" can be interpreted to mean up to about A, up to about B, or up to about C.

[0162]

[0176] The phrase "about A to B, C to D, and E to F" can be interpreted to mean about A to about B, about C to about D, and about E to about F. The phrase "about A to B, C to D, or E to F" can be interpreted to mean about A to about B, about C to about D, or about E to about F.

[0163]

[0177] The phrase "about A to B and C to D" can be interpreted as meaning about A to about B and about C to about D. The phrase "about A to B or C to D" can be interpreted as meaning about A to about B or about C to about D.

[0164]

[0178] The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any embodiment described herein as "exemplary" is not to be construed as preferred or advantageous over other embodiments.

[0165]

[0179] As used herein, the term "API" refers to an active pharmaceutical ingredient, including an N-methyl-D-aspartate (NMDA) receptor modulator or an inhibitor of the target of rapamycin (mTOR inhibitor).

[0166]

[0180] The terms "determining," "measuring," "evaluating," "assessing," "assaying," and "analyzing" are often used interchangeably herein to refer to forms of measurement. These terms include determining whether an element is present or not (e.g., detecting). These terms can include quantitative, qualitative, or quantitative and qualitative determinations. Evaluation may be relative or absolute. "Detecting the presence" can include determining the amount of something present, as well as determining whether something is present or absent, depending on the context.

[0167]

[0181] The terms "subject," "individual," or "patient" are often used interchangeably herein. A "subject" may be a biological entity containing expressed genetic material. The biological entity may be a plant, an animal, or a microorganism, including, for example, bacteria, viruses, fungi, and protozoa. A subject may be tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro. A subject may be a mammal. A mammal may be a human. A subject may have been diagnosed with or be suspected of being at high risk for a disease. In some cases, a subject is not necessarily diagnosed with or suspected of being at high risk for a disease.

[0168]

[0182] A "disease" is a state of health in an animal in which the animal is unable to maintain homeostasis and the animal's health continues to deteriorate if the disease is not ameliorated.

[0183] In contrast, a "disorder" in an animal is a health condition in which the animal is able to maintain homeostasis, but in which the animal's health is less favorable than it would be in the absence of the disorder. If left untreated, the disorder does not necessarily cause a further deterioration in the animal's health.

[0169]

[0184] "MDD" refers to major depressive disorder. "OCD" refers to obsessive-compulsive disorder. "PTSD" refers to post-traumatic stress disorder.

[0185] As used herein, the term "NMDA" refers to N-methyl-D-aspartic acid.

[0170]

[0186] As used herein, the term "NMDAR" or "NMDA-R" refers to NMDA receptor. The terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to any animal or its cells, either in vitro or in situ, suitable for the methods described herein. In certain non-limiting embodiments, the patient, subject, or individual is a human.

[0171]

[0187] As used herein, "RAAD" refers to rapid acting antidepressants.

[0188] As used herein, "mTOR" refers to the mammalian target of rapamycin protein or the gene encoding this protein product. An "mTOR inhibitor" refers to any of a class of drugs that inhibit the biochemical action of mTOR, a typical example being rapamycin (also known as sirolimus), with a non-limiting list of other examples provided below.

[0172]

[0189] An "effective amount" or "therapeutically effective amount" of a compound or composition is the amount of the compound or composition sufficient to provide a beneficial effect to the subject to which it is administered. An "effective amount" of a delivery vehicle is an amount sufficient to effectively bind or deliver the compound or composition.

[0173]

[0190] As used herein, the term "inhibit" refers to a measurable reduction in the expression, stability, function, or activity of a molecule, reaction, interaction, gene, mRNA, and / or protein. Inhibitors are compounds, e.g., antagonists, that bind to, partially or completely block stimulation, reduce, prevent, delay, inactivate, desensitize, or downregulate the stability, expression, function, and activity of proteins, genes, and mRNAs.

[0174]

[0191] "Naturally occurring" as applied to an object refers to the fact that the object can be found in nature. For example, a polypeptide or polynucleotide sequence present in an organism (including a virus) that can be isolated from a natural source and has not been intentionally modified by humans is a naturally occurring sequence.

[0175]

[0192] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting a compound or composition useful within the invention within or to a patient so that it may perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound or composition useful within the invention, and not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic, compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carriers" also include any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds or compositions useful within the present invention and are physiologically acceptable to the patient. Supplementary active compounds can also be incorporated into the compositions. "Pharmaceutically acceptable carriers" can further include pharmaceutically acceptable salts of compounds useful within the present invention.Other additional ingredients that may be included in pharmaceutical compositions used to practice the present invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0176]

[0193] As used herein, the language "pharmaceutically acceptable salts" or "therapeutically acceptable salts" refers to salts of the compound being administered prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof.

[0177]

[0194] As used herein, the terms "pharmaceutically effective amount" and "effective amount" or "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent to provide a desired biological result. That result may be reduction and / or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system. The amount of a compound of the invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient being treated, and the like. An appropriate effective amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0178]

[0195] A "therapeutic" treatment is a treatment administered to a subject who exhibits symptoms of a pathology with the intent of reducing or eliminating those symptoms.

[0196] As used herein, "treating a disease or disorder" means reducing the frequency and / or intensity with which a patient experiences symptoms of a disease or disorder. Disease and disorder are used interchangeably herein. Treatment encompasses prophylaxis and / or therapy. Thus, the compositions and methods of the present invention are not limited to therapeutic applications and can be used for prophylactic applications. Thus, "treating" a condition, disorder, or condition or "treatment" thereof includes (i) preventing or delaying the onset of clinical symptoms of the condition, disorder, or condition that develops in a subject who may be suffering from or susceptible to the condition, disorder, or condition but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, or condition; (ii) inhibiting the condition, disorder, or condition, i.e., halting or reducing the onset of the disease or at least one clinical or subclinical symptom thereof; or (iii) alleviating the disease, i.e., causing regression of the condition, disorder, or condition or at least one clinical or subclinical symptom thereof.

[0179]

[0197] As used herein, the term "about" a number refers to that number plus or minus 10%. The term "about" a range refers to a range from the lowest value minus 10% to the highest value of the range plus 10%.

[0180]

[0198] As used herein, the term "treatment" or "treating" refers to a pharmaceutical or other interventional regimen for obtaining beneficial or desired results in a recipient. Beneficial or desired results include, but are not limited to, a therapeutic effect and / or a prophylactic effect. A therapeutic effect can refer to the eradication or amelioration of the symptoms or underlying disease being treated. A therapeutic effect can also be achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disease, such that an improvement is observed in the subject, even though the subject may still be suffering from the underlying disease. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For a prophylactic effect, a subject at risk of developing a particular disease or reporting one or more physiological symptoms of a disease can receive treatment even if the disease has not been diagnosed.

[0181]

[0199] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Illustrative Embodiments

[0200] Embodiment 1. a. an N-methyl-D-aspartate (NMDA) receptor modulator at a concentration of about 0.04 milligrams per milliliter (mg / mL) to about 150 mg / mL; and b. a target of rapamycin (mTOR) inhibitor at a concentration of about 0.02 mg / mL to about 10 mg / mL; A solution containing

[0182]

[0201] Embodiment 2. a N-methyl-D-aspartate (NMDA) receptor modulator; b. a target of rapamycin (mTOR) inhibitor; the NMDA receptor modulator and the mTOR inhibitor have a weight ratio of greater than about 1:1; solution.

[0183]

[0202] Embodiment 3. a. an N-methyl-D-aspartate (NMDA) receptor modulator at a concentration of about 0.01 mg / mL to about 1.0 mg / mL; and b. a target of rapamycin (mTOR) inhibitor at a concentration of about 0.5 micrograms per milliliter (μg / mL) to about 100 μg / mL; A solution containing

[0184]

[0203] Embodiment 4. The solution of embodiment 2 or 3, wherein the solution comprises about 0.9% (w / v) sodium chloride in water or about 5% (w / v) dextrose in water.

[0204] Embodiment 5. The solution of embodiment 1, 3, or 4, wherein the NMDA receptor modulator and the mTOR inhibitor have a weight ratio of greater than about 1:1.

[0185]

[0205] Embodiment 6. The solution of embodiment 2 or 5, wherein the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 2:1.

[0206] Embodiment 7. The solution of embodiment 2 or 5, wherein the weight ratio of NMDA receptor modulator to mTOR inhibitor ranges from about 600:1 to about 5:1.

[0186]

[0207] Embodiment 8 The solution of any one of embodiments 1 to 7, wherein the solution further comprises polyethylene glycol (PEG), polysorbate, or both.

[0208] Embodiment 9 The solution of embodiment 8, wherein the solution comprises a polysorbate.

[0187]

[0209] Embodiment 10. The solution of embodiment 9, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[0188]

[0210] Embodiment 11 The solution of embodiment 9, wherein the polysorbate is polysorbate 80.

[0211] Embodiment 12 The solution of embodiment 8, wherein the solution comprises PEG.

[0189]

[0212] Embodiment 13. The solution of embodiment 12, wherein the PEG has an average molecular weight of about 300 to about 600.

[0213] Embodiment 14 The solution of embodiment 13, wherein the PEG is PEG400.

[0190]

[0214] Embodiment 15. The solution of any one of embodiments 8 to 14, wherein the solution comprises polysorbate 80 and PEG 400.

[0215] Embodiment 16. a N-methyl-D-aspartate (NMDA) receptor modulator and b. a target of rapamycin (mTOR) inhibitor; c. Polysorbate or PEG400 A solution containing

[0191]

[0216] Embodiment 17. The solution of embodiment 16, wherein the solution comprises about 0.9% (w / v) sodium chloride in water or about 5% (w / v) dextrose in water.

[0217] Embodiment 18 The solution of embodiment 16 or 17, wherein the NMDA receptor modulator and the mTOR inhibitor have a weight ratio of greater than about 1:1.

[0192]

[0218] Embodiment 19. The solution of embodiment 18, wherein the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 2:1.

[0219] Embodiment 20. The solution of embodiment 18, wherein the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 600:1 to about 5:1.

[0193]

[0220] Embodiment 21. The solution of any one of embodiments 16 to 20, wherein the solution comprises a polysorbate, and the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[0194]

[0221] Embodiment 22 The solution of embodiment 21, wherein the polysorbate is polysorbate 80.

[0222] Embodiment 23. The NMDA receptor modulator is selected from the group consisting of ketamine, R-ketamine, S-ketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, dextromethorphan, a fixed-dose combination of dextromethorphan and quinidine, a fixed-dose combination of dextromethorphan and bupropion, GM-1020, besonprodil, eliprodil, ifenprodil, lisrenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro8-4304, traxoprodil (CP-101,606), BMT-108908, omfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP37849, 1-aminocyclopropanecarboxylic acid, traxoprodil, Ro25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxyzine, tiletamine, neramexane, etoxadrol, dexoxadrol le, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delsemin, dextralorphan, dextrorphan, diphenidine, eticcyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7-Dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnalone sulfate (3α5βS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate , PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salts, solvates, enantiomers, tautomers, stereoisomers and geometric isomers thereof, and any mixtures thereof.

[0195]

[0223] Embodiment 24 The solution of embodiment 23, wherein the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any mixture thereof.

[0196]

[0224] Embodiment 25 The solution of embodiment 24, wherein the ketamine is ketamine HCl.

[0225] Embodiment 26. The mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), KU-0063794, PI-103 (mTOR inhibitor V, PI3-K inhibitor V, PI-103-CAS371935-74-9), tolquinib (PP242), tacrolimus (FK-506, Fujimycin), ridaforolimus (AP23573, MK-8669, deforolimus), INK-1 28 (MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), torin-1 (DNA-PK inhibitor VI, PI3-K inhibitor XVIII, mTOR inhibitor XI, torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE390), GSK1059615, W YE-354 (mTOR inhibitor II), gedatolisib (PF-05212384, PKI-587), AZD-2014 (bistusertib), Torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC-0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound401, GNE-477, vimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC223), clemastine (HS-592) fumarate, nitazoxanide (NSC697855), 4EGI-1, ABTL-0812, astragaloside IV,The solution of any one of embodiments 1 to 25, wherein the compound is selected from the group consisting of samotricisib (LY3023414), chrysophanic acid, and zotarolimus (ABT-578), and any salts, solvates, enantiomers, tautomers, diastereomers, stereoisomers, and geometric isomers thereof, and any mixtures thereof.

[0197]

[0226] Embodiment 27. The solution of embodiment 26, wherein the mTOR inhibitor comprises rapamycin (sirolimus, AY22989, ABI-009) or temsirolimus (CCI-779).

[0198]

[0227] Embodiment 28. The solution of any one of embodiments 1 to 27, wherein the solution further comprises an excipient selected from the group consisting of water, ethanol, propylene glycol, citric acid, and DL-alpha-tocopherol.

[0199]

[0228] Embodiment 29 The solution of embodiment 28, wherein the solution comprises water.

[0229] Embodiment 30 The solution of embodiment 28 or 29, wherein the solution comprises ethanol.

[0200]

[0230] Embodiment 31 The solution of embodiment 30, wherein the ethanol is absolute ethanol.

[0231] Embodiment 32. The solution of any one of embodiments 28 to 31, wherein the concentration of ethanol ranges from about 10% w / w to about 50% w / w.

[0201]

[0232] Embodiment 33. The solution of any one of embodiments 28 to 32, wherein the concentration of water ranges from about 0.1% w / w to about 30% w / w.

[0233] Embodiment 34. The solution of any one of embodiments 28 to 33, wherein the concentration of propylene glycol ranges from about 5% w / w to about 50% w / w.

[0202]

[0234] Embodiment 35. The solution of any one of embodiments 8 to 34, wherein the concentration of polysorbate ranges from about 5% w / w to about 50% w / w.

[0235] Embodiment 36. The solution of any one of embodiments 8 to 35, wherein the concentration of PEG ranges from about 0.1% w / w to about 30% w / w.

[0203]

[0236] Embodiment 37. The solution of embodiment 28, comprising about 23.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 6% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof.

[0204]

[0237] Embodiment 38. The solution of embodiment 28, comprising about 20.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 9% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof.

[0205]

[0238] Embodiment 39. The solution of embodiment 28, comprising about 17.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 12% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof.

[0206]

[0239] Embodiment 40. The solution of embodiment 28, comprising about 14.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 15% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof.

[0207]

[0240] Embodiment 41. The solution of embodiment 28, comprising about 11.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 18% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof.

[0208]

[0241] Embodiment 42 The solution of any one of embodiments 1 to 27, wherein the solution does not contain citric acid or DL-alpha-tocopherol.

[0242] Embodiment 43. The solution of any one of embodiments 1 to 42, wherein the solution comprises from about 20 mg to about 150 mg, from about 30 mg to about 140 mg, from about 40 mg to about 120 mg, from about 50 mg to about 100 mg, or from about 60 mg to about 80 mg of the NMDA receptor modulator.

[0209]

[0243] Embodiment 44. The solution of any one of embodiments 1 to 43, wherein the solution comprises from about 0.05 mg to about 2.0 mg, from about 0.1 mg to about 1.8 mg, from about 0.2 mg to about 1.5 mg, from about 0.4 mg to about 1.2 mg, or from about 0.8 mg to about 1.0 mg of the mTOR inhibitor.

[0210]

[0244] Embodiment 45. (i) a first container containing a first solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator at a concentration of about 5 mg / mL to about 200 mg / mL; (ii) a second container containing a second solution comprising a target of rapamycin (mTOR) inhibitor at a concentration of about 0.1 mg / mL to about 25 mg / mL; Kit including:

[0211]

[0245] Embodiment 46. (i) a first container containing a first solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator; (ii) a second container containing a second solution comprising a target of rapamycin (mTOR) inhibitor; A kit, wherein the volume ratio of the first solution to the second solution is about 1.2:1 to about 3:1.

[0212]

[0246] Embodiment 47. The kit of embodiment 46, wherein the volume ratio of the first solution to the second solution is about 3:2, about 2.2:1.2, about 2.4:1.2, or about 2.5:1.2.

[0213]

[0247] Embodiment 48 The kit of any one of embodiments 45 to 47, wherein the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is greater than about 1:1.

[0248] Embodiment 49 The kit of any one of embodiments 45 to 48, wherein the first container further comprises water, ethanol, polyethylene glycol (PEG), polysorbate, or any combination thereof.

[0214]

[0249] Embodiment 50 The kit of embodiment 49, wherein the first container contains water.

[0250] Embodiment 51 The kit of embodiment 49, wherein the first container comprises a polysorbate.

[0215]

[0251] Embodiment 52 The kit of embodiment 51, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[0216]

[0252] Embodiment 53 The kit of embodiment 52, wherein the polysorbate is polysorbate 80.

[0253] Embodiment 54 The kit of embodiment 49, wherein the first container contains a PEG.

[0217]

[0254] Embodiment 55. The kit of embodiment 54, wherein the PEG has an average molecular weight of about 300 to about 600.

[0255] Embodiment 56 The kit of embodiment 55, wherein the PEG is PEG400.

[0218]

[0256] Embodiment 57 The kit of any one of embodiments 45 to 56, wherein the second container further comprises ethanol, DL-alpha-tocopherol, propylene glycol, citric acid, or any combination thereof.

[0219]

[0257] Embodiment 58 The kit of any one of embodiments 45 to 56, wherein the second container further comprises ethanol, propylene glycol, or any combination thereof.

[0220]

[0258] Embodiment 59. (i) a first container containing a first composition comprising an N-methyl-D-aspartate (NMDA) receptor modulator; (ii) a second container containing a second composition comprising an mTOR inhibitor; The kit, wherein the NMDA receptor modulator and the mTOR inhibitor have a weight ratio of greater than about 1:1.

[0221]

[0259] Embodiment 60 The kit of embodiment 59, wherein the first composition is a solution.

[0260] Embodiment 61 The kit of embodiment 59 or 60, wherein the solution further comprises water, ethanol, polyethylene glycol (PEG), polysorbate, or any combination thereof.

[0222]

[0261] Embodiment 62 The kit of embodiment 61, wherein the solution comprises water.

[0262] Embodiment 63 The kit of embodiment 61, wherein the solution comprises polysorbate.

[0263] Embodiment 64 The kit of embodiment 63, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[0223]

[0264] Embodiment 65 The kit of embodiment 64, wherein the polysorbate is polysorbate 80.

[0265] Embodiment 66 The kit of embodiment 61, wherein the solution comprises PEG.

[0224]

[0266] Embodiment 67. The kit of embodiment 66, wherein the PEG has an average molecular weight of about 300 to about 600.

[0267] Embodiment 68 The kit of embodiment 67, wherein the PEG is PEG400.

[0225]

[0268] Embodiment 69 The kit of embodiment 59, wherein the first composition is a solid.

[0269] Embodiment 70 The kit of embodiment 69, wherein the solid is a powder.

[0270] Embodiment 71 The kit of embodiment 69 or 70, wherein the solid is dissolved in a diluent.

[0226]

[0271] Embodiment 72 The kit of embodiment 71, wherein the diluent comprises polyethylene glycol (PEG), polysorbate, or both.

[0272] Embodiment 73 The kit of embodiment 72, wherein the diluent comprises polysorbate.

[0227]

[0273] Embodiment 74 The kit of embodiment 73, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[0228]

[0274] Embodiment 75 The kit of embodiment 74, wherein the polysorbate is polysorbate 80.

[0275] Embodiment 76 The kit of embodiment 73, wherein the diluent comprises PEG.

[0229]

[0276] Embodiment 77. The kit of embodiment 76, wherein the PEG has an average molecular weight of about 300 to about 600.

[0277] Embodiment 78 The kit of embodiment 77, wherein the PEG is PEG400.

[0230]

[0278] Embodiment 79 The kit of any one of embodiments 59 to 78, wherein the second composition is a solution.

[0279] Embodiment 80 The kit of embodiment 79, wherein the solution further comprises ethanol, DL-alpha-tocopherol, propylene glycol, citric acid, or any combination thereof.

[0231]

[0280] Embodiment 81 The kit of any one of embodiments 59 to 78, wherein the second composition is a solid.

[0281] Embodiment 82 The kit of embodiment 81, wherein the solid is a powder.

[0232]

[0282] Embodiment 83 The kit of embodiment 81 or 82, wherein the solid is dissolved in a diluent.

[0283] Embodiment 84 The kit of embodiment 83, wherein the diluent comprises ethanol, DL-alpha-tocopherol, propylene glycol, citric acid, or any combination thereof.

[0233]

[0284] Embodiment 85 The kit of embodiment 83, wherein the diluent comprises ethanol, propylene glycol, or any combination thereof.

[0285] Embodiment 86. (i) a first container containing a first composition comprising an N-methyl-D-aspartate (NMDA) receptor modulator; (ii) a second container containing a second composition comprising a target of rapamycin (mTOR) inhibitor; (iii) a diluent containing polysorbate, PEG400, or both; Kit including:

[0234]

[0286] Embodiment 87 The kit of embodiment 86, wherein the NMDA receptor modulator and the mTOR inhibitor have a weight ratio of greater than about 1:1.

[0287] Embodiment 88 The kit of embodiment 86 or 87, wherein the diluent comprises polysorbate.

[0235]

[0288] Embodiment 89. The kit of embodiment 88, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[0236]

[0289] Embodiment 90 The kit of embodiment 89, wherein the polysorbate is polysorbate 80.

[0290] Embodiment 91 The kit of embodiment 86 or 87, wherein the diluent comprises PEG400.

[0237]

[0291] Embodiment 92 The kit of any one of embodiments 86 to 91, wherein the second container further comprises ethanol, DL-alpha-tocopherol, propylene glycol, citric acid, or a combination thereof.

[0238]

[0292] Embodiment 93 The kit of any one of embodiments 86 to 91, wherein the second container further comprises ethanol, propylene glycol, or a combination thereof.

[0293] Embodiment 94. The NMDA receptor modulator is selected from the group consisting of ketamine, R-ketamine, S-ketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, dextromethorphan, a fixed-dose combination of dextromethorphan and quinidine, a fixed-dose combination of dextromethorphan and bupropion, GM-1020, besonprodil, eliprodil, ifenprodil, lisrenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro8-4304, traxoprodil (CP-101,606), BMT-108908, omfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP37849, 1-aminocyclopropanecarboxylic acid, traxoprodil, Ro25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxyzine, tiletamine, neramexane, etoxadrol, dexoxadrol le, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delsemin, dextralorphan, dextrorphan, diphenidine, eticcyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7-Dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnalone sulfate (3α5βS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PE The kit of any one of embodiments 45 to 93, wherein the compound is selected from the group consisting of AQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, and NYX-783, and any salts, solvates, enantiomers, tautomers, stereoisomers, and geometric isomers thereof, and any mixtures thereof.

[0239]

[0294] Embodiment 95 The kit of embodiment 94, wherein the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any mixture thereof.

[0240]

[0295] Embodiment 96 The kit of embodiment 95, wherein the ketamine is ketamine HCl.

[0296] Embodiment 97. The mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), KU-0063794, PI-103 (mTOR inhibitor V, PI3-K inhibitor V, PI-103-CAS371935-74-9), tolquinib (PP242), tacrolimus (FK-506, fujimycin, EnvarsusXR), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), torin-1 (DNA-PK inhibitor VI, PI3-K inhibitor XVIII, mTOR inhibitor XI, torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC006, AEVI-006), PF -04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE390), GSK1059615, WYE-354 (mTOR inhibitor II), gedatolisib (PF-05212384, PKI-587), AZD-2014 (bistusertib), torin-2 (MLS006011167, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), and palomido-529 (P529 , SG00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC-0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound401, GNE-477, bimiralisib (PQR309), SF2523, CZ415, paxalisib 97. The kit of any one of embodiments 45 to 96, comprising methadone (GDC-0084), CC-115, onatasertib (CC223), clemastine (HS-592) fumarate, nitazoxanide (NSC697855), 4EGI-1, ABTL-0812, astragaloside IV, samotricisib (LY3023414), chrysophanic acid, or zotarolimus (ABT-578), or a salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, or geometric isomer thereof.

[0241]

[0297] Embodiment 98 The kit of embodiment 97, wherein the mTOR inhibitor comprises rapamycin (sirolimus, AY22989, ABI-009) or temsirolimus (CCI-779).

[0242]

[0298] Embodiment 99. The kit of any one of embodiments 45 to 98, wherein the first solution or first composition further comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 10% (w / w) water, or any combination thereof.

[0243]

[0299] Embodiment 100. The kit of any one of embodiments 45 to 98, wherein the first solution or first composition further comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 15% (w / w) water, or any combination thereof.

[0244]

[0300] Embodiment 101. The kit of any one of embodiments 45 to 98, wherein the first solution or first composition further comprises about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 20% (w / w) water, or any combination thereof.

[0245]

[0301] Embodiment 102. The kit of any one of embodiments 45 to 98, wherein the first solution or first composition further comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 25% (w / w) water, or any combination thereof.

[0246]

[0302] Embodiment 103 The kit of any one of embodiments 45 to 98, wherein the first solution or first composition further comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 30% (w / w) water, or any combination thereof.

[0247]

[0303] Embodiment 104. The kit of any one of embodiments 45 to 103, wherein the second solution or second composition further comprises about 39.5% (w / v) absolute ethanol, about 0.075% (w / v) DL-alpha-tocopherol, about 50.3% (w / v) propylene glycol, about 0.0025% (w / v) anhydrous citric acid, or any combination thereof.

[0248]

[0304] Embodiment 105 The kit of any one of embodiments 45 to 103, wherein the second solution or second composition further comprises about 39.5% (w / v) absolute ethanol, about 50.3% (w / v) propylene glycol, or any combination thereof.

[0249]

[0305] Embodiment 106 The kit of any one of embodiments 45 to 105, wherein the first solution or first composition is stable at room temperature for at least about 1 week, 1 month, 3 months, 6 months, or 1 year.

[0250]

[0306] Embodiment 107 The kit of any one of embodiments 45 to 105, wherein the first solution or first composition is stable at a temperature of less than about 60°C for at least about 1 week.

[0307] Embodiment 108 The kit of any one of embodiments 45 to 105, wherein the second solution or second composition is stable at room temperature for at least about 1 week, 1 month, 3 months, 6 months, or 1 year.

[0251]

[0308] Embodiment 109 The kit of any one of embodiments 45 to 105, wherein the second solution or second composition is stable at a temperature of less than about 60°C for at least about 1 week.

[0309] Embodiment 110 The kit of any one of embodiments 45 to 109, wherein the second solution or second composition does not comprise citric acid or DL-alpha-tocopherol.

[0252]

[0310] Embodiment 111 The kit of any one of embodiments 45 to 110, wherein the kit is in the form of a two-vial kit.

[0311] Embodiment 112 The kit of any one of embodiments 45 to 110, wherein the kit is in the form of a two-compartment container.

[0253]

[0312] Embodiment 113. The kit of embodiment 112, wherein the two-compartment container comprises a two-compartment syringe or a dual-compartment inhaler.

[0313] Embodiment 114. A method for preparing a solution, comprising: (i) mixing a first solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator and (ii) a second solution comprising an mTOR inhibitor, thereby producing a solution comprising both the NMDA receptor modulator and the mTOR inhibitor; The method wherein the volume ratio of the first solution to the second solution is about 3:2.

[0254]

[0314] Embodiment 115. The method of embodiment 114, wherein the first solution further comprises polysorbate or PEG400.

[0315] Embodiment 116. A method for preparing a solution, comprising: A method comprising the step of mixing (i) a first solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator and polysorbate or PEG400 with (ii) a second solution comprising a target of rapamycin (mTOR) inhibitor, thereby producing a solution comprising both the NMDA receptor modulator and the mTOR inhibitor.

[0255]

[0316] Embodiment 117. The method of any one of embodiments 114 to 116, wherein the solution further comprises about 0.9% (w / v) sodium chloride in water or about 5% (w / v) dextrose in water.

[0256]

[0317] Embodiment 118 The method of any one of embodiments 114 to 117, wherein the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is greater than about 1:1.

[0318] Embodiment 119. The method of embodiment 118, wherein the weight ratio of the N-methyl-D-aspartate receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 2:1.

[0257]

[0319] Embodiment 120 The method of embodiment 119, wherein the weight ratio of the N-methyl-D-aspartate receptor modulator to the mTOR inhibitor ranges from about 600:1 to about 5:1.

[0258]

[0320] Embodiment 121. The method of any one of embodiments 114 to 120, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[0259]

[0321] Embodiment 122. The method of embodiment 121, wherein the polysorbate is polysorbate 80.

[0322] Embodiment 123 The method of any one of embodiments 114 to 122, wherein the second solution further comprises ethanol, DL-alpha-tocopherol, propylene glycol, citric acid, or any combination thereof.

[0260]

[0323] Embodiment 124 The method of any one of embodiments 114 to 122, wherein the second solution further comprises ethanol, propylene glycol, or any combination thereof.

[0261]

[0324] Embodiment 125. The method of any one of embodiments 114 to 124, wherein the first solution further comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 10% (w / w) water, or any combination thereof.

[0262]

[0325] Embodiment 126. The method of any one of embodiments 114 to 124, wherein the first solution further comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 15% (w / w) water, or any combination thereof.

[0263]

[0326] Embodiment 127. The method of any one of embodiments 114 to 124, wherein the first solution further comprises about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 20% (w / w) water, or any combination thereof.

[0264]

[0327] Embodiment 128. The method of any one of embodiments 114 to 124, wherein the first solution further comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 25% (w / w) water, or any combination thereof.

[0265]

[0328] Embodiment 129. The method of any one of embodiments 114 to 124, wherein the first solution further comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 30% (w / w) water, or any combination thereof.

[0266]

[0329] Embodiment 130. The method of any one of embodiments 114 to 129, wherein the second solution further comprises about 39.5% (w / v) absolute ethanol, about 0.075% (w / v) DL-alpha-tocopherol, about 50.3% (w / v) propylene glycol, about 0.0025% (w / v) anhydrous citric acid, or any combination thereof.

[0267]

[0330] Embodiment 131. The NMDA receptor modulator is selected from the group consisting of ketamine, R-ketamine, S-ketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, dextromethorphan, a fixed-dose combination of dextromethorphan and quinidine, a fixed-dose combination of dextromethorphan and bupropion, GM-1020, besonprodil, eliprodil, ifenprodil, lisrenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro8-4304, traxoprodil (CP-101,606), BMT-108908, omfasprodil, radiprodil, NP10679, and GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP37849, 1-aminocyclopropanecarboxylic acid, traxoprodil, Ro25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxyzine, tiletamine, neramexane, etoxadrol, dexoxadrol le, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delsemin, dextralorphan, dextrorphan, diphenidine, eticcyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7-Dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnalone sulfate (3α5βS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PE The method of any one of embodiments 114 to 130, wherein the compound is selected from the group consisting of AQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, and NYX-783, and any salts, solvates, enantiomers, tautomers, stereoisomers, and geometric isomers thereof, and any mixtures thereof.

[0268]

[0331] Embodiment 132 The method of embodiment 131, wherein the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any mixture thereof.

[0269]

[0332] Embodiment 133 The method of embodiment 132, wherein the ketamine is ketamine HCl.

[0333] Embodiment 134. The mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), KU-0063794, PI-103 (mTOR inhibitor V, PI3-K inhibitor V, PI-103-CAS371935-74-9), tolquinib (PP242), tacrolimus (FK-506, Fujimycin), ridaforolimus (AP23573, MK-8669, deforolimus), INK-1 28 (MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), torin-1 (DNA-PK inhibitor VI, PI3-K inhibitor XVIII, mTOR inhibitor XI, torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE390), GSK1059615, W YE-354 (mTOR inhibitor II), gedatolisib (PF-05212384, PKI-587), AZD-2014 (bistusertib), Torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC-0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound401, GNE-477, vimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC223), clemastine (HS-592) fumarate, nitazoxanide (NSC697855), 4EGI-1, ABTL-0812, astragaloside IV,The method of any one of embodiments 114 to 133, comprising samotricisib (LY3023414), chrysophanic acid, or zotarolimus (ABT-578), or a salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, or geometric isomer thereof.

[0270]

[0334] Embodiment 135 The method of embodiment 134, wherein the mTOR inhibitor comprises rapamycin (sirolimus, AY22989, ABI-009) or temsirolimus (CCI-779).

[0271]

[0335] Embodiment 136. A method of treating or preventing a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a solution described in any one of embodiments 1 to 44.

[0272]

[0336] Embodiment 137. A method of treating or preventing a disease, disorder, or condition in a subject in need thereof, comprising: 1. A method comprising: mixing a first solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator and a second solution comprising a target of rapamycin (mTOR) inhibitor, thereby producing a solution comprising both the NMDA receptor modulator and the mTOR inhibitor; and administering the solution to a subject within about 4, 6, or 24 hours after the solution is produced.

[0273]

[0337] Embodiment 138 The method of embodiment 137, wherein the solution comprises a polysorbate.

[0338] Embodiment 139. The method of embodiment 138, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[0274]

[0339] Embodiment 140. The method of embodiment 139, wherein the polysorbate is polysorbate 80.

[0340] Embodiment 141 The method of any one of embodiments 137 to 140, wherein the solution comprises PEG.

[0275]

[0341] Embodiment 142. The method of embodiment 141, wherein the PEG has an average molecular weight of about 300 to about 600.

[0342] Embodiment 143. The method of embodiment 142, wherein the PEG is PEG400.

[0276]

[0343] Embodiment 144. The method of any one of embodiments 137 to 143, wherein the first solution further comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 10% (w / w) water, or any combination thereof.

[0277]

[0344] Embodiment 145. The method of any one of embodiments 137 to 143, wherein the first solution further comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 15% (w / w) water, or any combination thereof.

[0278]

[0345] Embodiment 146. The method of any one of embodiments 137 to 143, wherein the first solution further comprises about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 20% (w / w) water, or any combination thereof.

[0279]

[0346] Embodiment 147. The method of any one of embodiments 137 to 143, wherein the first solution further comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 25% (w / w) water, or any combination thereof.

[0280]

[0347] Embodiment 148. The method of any one of embodiments 137 to 143, wherein the first solution further comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 30% (w / w) water, or any combination thereof.

[0281]

[0348] Embodiment 149. The method of any one of embodiments 137 to 148, wherein the second solution further comprises about 39.5% (w / v) absolute ethanol, about 0.075% (w / v) DL-alpha-tocopherol, about 50.3% (w / v) propylene glycol, about 0.0025% (w / v) anhydrous citric acid, or any combination thereof.

[0282]

[0349] Embodiment 150 The method of any one of embodiments 137 to 148, wherein the second solution further comprises about 39.5% (w / v) absolute ethanol, about 50.3% (w / v) propylene glycol, or any combination thereof.

[0283]

[0350] Embodiment 151 The method of any one of embodiments 137 to 150, wherein the weight ratio of the N-methyl-D-aspartate receptor modulator to the mTOR inhibitor is greater than about 1:1.

[0284]

[0351] Embodiment 152 The method of embodiment 151, wherein the weight ratio of the N-methyl-D-aspartate receptor modulator to the mTOR inhibitor ranges from about 1000:1 to about 2:1.

[0285]

[0352] Embodiment 153 The method of embodiment 152, wherein the weight ratio of the N-methyl-D-aspartate receptor modulator to the mTOR inhibitor ranges from about 600:1 to about 5:1.

[0286]

[0353] Embodiment 154. The NMDA receptor modulator is selected from the group consisting of ketamine, R-ketamine, S-ketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, dextromethorphan, a fixed-dose combination of dextromethorphan and quinidine, a fixed-dose combination of dextromethorphan and bupropion, GM-1020, besonprodil, eliprodil, ifenprodil, lisrenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro8-4304, traxoprodil (CP-101,606), BMT-108908, omfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP37849, 1-aminocyclopropanecarboxylic acid, traxoprodil, Ro25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxyzine, tiletamine, neramexane, etoxadrol, dexoxadrol le, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delsemin, dextralorphan, dextrorphan, diphenidine, eticcyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7-Dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnalone sulfate (3α5βS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PE The method of any one of embodiments 137 to 153, wherein the compound is selected from the group consisting of AQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, and NYX-783, and any salts, solvates, enantiomers, tautomers, stereoisomers, and geometric isomers thereof, and any mixtures thereof.

[0287]

[0354] Embodiment 155 The method of embodiment 154, wherein the NMDA receptor modulator comprises ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any mixture thereof.

[0288]

[0355] Embodiment 156. The method of embodiment 155, wherein the ketamine is ketamine HCl.

[0356] Embodiment 157. The mTOR inhibitor is BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (toricel, CCI-779), KU-0063794, PI-103 (mTOR inhibitor V, PI3-K inhibitor V, PI-103-CAS371935-74-9), tolquinib (PP242), tacrolimus (FK-506, Fujimycin), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), Torin-1 (DNA-PK inhibitor VI, PI3-K inhibitor XVIII, mTOR inhibitor XI, Torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE390), GSK105961 5, WYE-354 (mTOR inhibitor II), gedatolisib (PF-05212384, PKI-587), AZD-2014 (bistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi ), GDC-0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound401, GNE-477, vimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC223), clemastine (HS-592) fumarate, nitazoxanide (NSC697855), 4EGI-1, ABTL-0812, astragaloside IV,The method of any one of embodiments 137 to 156, comprising samotricisib (LY3023414), chrysophanic acid, or zotarolimus (ABT-578), or salts, solvates, enantiomers, tautomers, diastereomers, stereoisomers, and geometric isomers thereof.

[0289]

[0357] Embodiment 158. The method of embodiment 157, wherein the mTOR inhibitor comprises rapamycin (sirolimus, AY22989, ABI-009, Rapamune, Fyaro) or temsirolimus (Torisel, CCI-779).

[0290]

[0358] Embodiment 159. The method of any one of embodiments 137 to 158, wherein the solution is administered via intramuscular, intravenous, subcutaneous, oral, inhaled, or intranasal route.

[0291]

[0359] Embodiment 160 The method of any one of embodiments 137 to 158, wherein the solution is administered once a day, twice a day, three times a day, four times a day, or five times a day.

[0360] Embodiment 161. The method of any one of embodiments 137 to 158, wherein the solution is administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or seven times a week.

[0292]

[0361] Embodiment 162. The method of any one of embodiments 137 to 158, wherein the solution is administered once a week, once every two weeks, once a month, twice a month, three times a month, four times a month, five times a month, six times a month, seven times a month, eight times a month, nine times a month, or ten times a month.

[0293]

[0362] Embodiment 163 The method of any one of embodiments 137 to 158, wherein the NMDA receptor modulator is administered at a dose of about 0.1 mg / kg to about 1 mg / kg.

[0294]

[0363] Embodiment 164 The method of embodiment 163, wherein the NMDA receptor modulator is administered at a dose of about 0.3 mg / kg to about 0.7 mg / kg.

[0364] Embodiment 165 The method of embodiment 164, wherein the NMDA receptor modulator is administered at a dose of about 0.5 mg / kg.

[0295]

[0365] Embodiment 166 The method of any one of embodiments 137 to 158, wherein the NMDA receptor modulator is administered at a dose of about 30 mg to about 90 mg.

[0366] Embodiment 167 The method of embodiment 166, wherein the NMDA receptor modulator is administered at a dose of about 30 mg to about 60 mg.

[0296]

[0367] Embodiment 168 The method of any one of embodiments 137 to 158, wherein the mTOR inhibitor is administered at a dose of about 1 μg / kg to about 70 μg / kg.

[0368] Embodiment 169 The method of embodiment 168, wherein the mTOR inhibitor is administered at a dose of about 2.5 μg / kg to about 30 μg / kg.

[0297]

[0369] Embodiment 170 The method of embodiment 169, wherein the mTOR inhibitor is administered at a dose of about 3 μg / kg to about 25 μg / kg.

[0370] Embodiment 171 The method of any one of embodiments 137 to 158, wherein the mTOR inhibitor is administered at a dose of about 0.1 mg to about 4 mg.

[0298]

[0371] Embodiment 172. The method of any one of embodiments 137 to 171, wherein the disease, disorder, or condition is selected from the group consisting of major depressive disorder (MDD), major depressive episode in bipolar disorder (bipolar depression), persistent depressive disorder (dysthymia), major mood dysregulation disorder, major depressive disorder (including major depressive episode), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, depressive disorder due to other medical illness, other specified depressive disorder, depressive disorder not otherwise specified, anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, addictive disorder, bipolar disorder I, bipolar disorder II, generalized anxiety disorder, social anxiety disorder (social phobia), specific phobia, panic disorder, agoraphobia, separation anxiety disorder, selective mutism, substance-induced anxiety disorder, medication-induced anxiety disorder, anxiety disorder due to other medical illness, borderline personality disorder, treatment-resistant depression, anxiety disorder not otherwise specified, chronic pain, and any combination thereof.

[0299]

[0372] Embodiment 173 The method of any one of embodiments 137 to 171, wherein the disease, disorder, or condition is a mood disorder, optionally a depressive disorder.

[0373] Embodiment 174. An N-methyl-D-aspartate (NMDA) receptor modulator and b. Polysorbate or PEG400 A solution containing

[0300]

[0374] Embodiment 175. The solution of embodiment 174, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[0301]

[0375] Embodiment 176. The solution of embodiment 175, wherein the polysorbate is polysorbate 80.

[0376] Embodiment 177. The solution of any one of embodiments 174 to 176, wherein the solution further comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 10% (w / w) water, or any combination thereof.

[0302]

[0377] Embodiment 178. The solution of any one of embodiments 174 to 176, wherein the solution further comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 15% (w / w) water, or any combination thereof.

[0303]

[0378] Embodiment 179. The solution of any one of embodiments 174 to 176, wherein the solution further comprises about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 20% (w / w) water, or any combination thereof.

[0304]

[0379] Embodiment 180. The solution of any one of embodiments 174 to 176, wherein the solution further comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 25% (w / w) water, or any combination thereof.

[0305]

[0380] Embodiment 181. The solution of any one of embodiments 174 to 176, wherein the solution further comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 30% (w / w) water, or any combination thereof.

[0306]

[0381] Embodiment 182. The NMDA receptor modulator is selected from the group consisting of ketamine, R-ketamine, S-ketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, dextromethorphan, a fixed-dose combination of dextromethorphan and quinidine, a fixed-dose combination of dextromethorphan and bupropion, GM-1020, besonprodil, eliprodil, ifenprodil, lisrenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro8-4304, traxoprodil (CP-101,606), BMT-108908, omfasprodil, radiprodil, NP10679, and GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP37849, 1-aminocyclopropanecarboxylic acid, traxoprodil, Ro25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxyzine, tiletamine, neramexane, etoxadrol, dexoxadrol le, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delsemin, dextralorphan, dextrorphan, diphenidine, eticcyclidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7-Dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnalone sulfate (3α5βS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PE The solution of any one of embodiments 174 to 181, wherein the compound is selected from the group consisting of AQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, and NYX-783, and any salts, solvates, enantiomers, tautomers, stereoisomers, and geometric isomers thereof, and any mixtures thereof.

[0307]

[0382] Embodiment 183. The solution of embodiment 182, wherein the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any mixture thereof.

[0308]

[0383] Embodiment 184. The solution of embodiment 183, wherein the ketamine is ketamine HCl.

[0384] Embodiment 185. A compound comprising an mTOR inhibitor, A solution having an mTOR inhibitor concentration of about 0.05 mg / mL to about 10 mg / mL, about 0.2 mg / mL to about 8 mg / mL, about 0.5 mg / mL to about 6 mg / mL, about 1 mg / mL to about 4 mg / mL, or about 2 mg / mL to about 3 mg / mL.

[0309]

[0385] Embodiment 186. The solution of embodiment 185, further comprising about 39.5% (w / v) absolute ethanol, about 0.075% (w / v) DL-alpha-tocopherol, about 50.3% (w / v) propylene glycol, about 0.0025% (w / v) anhydrous citric acid, or any combination thereof.

[0310]

[0386] Embodiment 187. The mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), KU-0063794, PI-103 (mTOR inhibitor V, PI3-K inhibitor V, PI-103-CAS371935-74-9), tolquinib (PP242), tacrolimus (FK-506, Fujimycin), ridaforolimus (AP23573, MK-8669, deforolimus), INK-1 28 (MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), torin-1 (DNA-PK inhibitor VI, PI3-K inhibitor XVIII, mTOR inhibitor XI, torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE390), GSK1059615, W YE-354 (mTOR inhibitor II), gedatolisib (PF-05212384, PKI-587), AZD-2014 (bistusertib), Torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC-0349 (RG-7603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound401, GNE-477, vimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC223), clemastine (HS-592) fumarate, nitazoxanide (NSC697855), 4EGI-1, ABTL-0812, astragaloside IV,The solution of embodiment 185 or 186, comprising samotricisib (LY3023414), chrysophanic acid, or zotarolimus (ABT-578), or salts, solvates, enantiomers, tautomers, diastereomers, stereoisomers, and geometric isomers thereof.

[0311]

[0387] Embodiment 188. The solution of embodiment 187, wherein the mTOR inhibitor comprises rapamycin (sirolimus, AY22989, ABI-009) or temsirolimus (CCI-779).

[0312]

[0388] Embodiment 189. A method for preparing a solution according to any one of embodiments 174 to 184, comprising: A method comprising the step of contacting an N-methyl-D-aspartate (NMDA) receptor modulator with a diluent comprising PEG400 or polysorbate.

[0313]

[0389] Embodiment 190 The method of embodiment 189, wherein the concentration of the NMDA receptor modulator is from about 5 mg / mL to about 200 mg / mL.

[0390] Embodiment 191. The solution of embodiment 189 or 190, wherein the solution comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 10% (w / w) water, or any combination thereof.

[0314]

[0391] Embodiment 192. The solution of embodiment 189 or 190, wherein the solution further comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 15% (w / w) water, or any combination thereof.

[0315]

[0392] Embodiment 193. The solution of embodiment 189 or 190, wherein the solution comprises about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 20% (w / w) water, or any combination thereof.

[0316]

[0393] Embodiment 194. The solution of embodiment 189 or 190, wherein the solution further comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 25% (w / w) water, or any combination thereof.

[0317]

[0394] Embodiment 195. The solution of embodiment 189 or 190, wherein the solution comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 30% (w / w) water, or any combination thereof.

[0318]

[0395] Embodiment 196. A solution comprising water, ethanol, polyethylene glycol (PEG), polysorbate, or any combination thereof.

[0396] Embodiment 197. The solution of embodiment 196, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[0319]

[0397] Embodiment 198. The solution of embodiment 197, wherein the polysorbate is polysorbate 80.

[0398] Embodiment 199. The solution of embodiment 198, wherein the PEG has an average molecular weight of about 300 to about 600.

[0320]

[0399] Embodiment 200. The solution of embodiment 199, wherein the PEG is PEG400.

[0400] Embodiment 201. The solution of any one of embodiments 196 to 200, wherein the solution comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 10% (w / w) water, or any combination thereof.

[0321]

[0401] Embodiment 202. The solution of any one of embodiments 196 to 200, wherein the solution comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 15% (w / w) water, or any combination thereof.

[0322]

[0402] Embodiment 203. The solution of any one of embodiments 196 to 200, wherein the solution comprises about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 20% (w / w) water, or any combination thereof.

[0323]

[0403] Embodiment 204. The solution of any one of embodiments 196 to 200, wherein the solution comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 25% (w / w) water, or any combination thereof.

[0324]

[0404] Embodiment 205. The solution of any one of embodiments 196 to 200, wherein the solution comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 30% (w / w) water, or any combination thereof. [Example]

[0325]

[0405] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention. Example 1: Stability of Ketamine HCl and Temsirolimus

[0406] The short-term stability of temsirolimus and ketamine HCl was evaluated for two weeks at 50°C for the following samples:

[0326] [Table 1]

[0327]

[0407] Temsirolimus is a prodrug of sirolimus, and a 25 mg dose of temsirolimus is approved. In this example, the temsirolimus vehicle includes absolute alcohol (39.5% w / v), DL-alpha-tocopherol (0.075% w / v), propylene glycol (50.3% w / v), and anhydrous citric acid (0.0025% w / v). In this example, the diluent (also known as Diluent A) includes polysorbate 80 (40.0% w / v), polyethylene glycol 400 (42.8% w / v), and absolute alcohol (19.9% ​​w / v).

[0328]

[0408] Appearance (Figure 1) suggested that both temsirolimus and ketamine remained soluble in the vehicle for temsirolimus, both individually and after they were combined (vials 1a-d). The diluent (vial 2a) and 3 mg / mL temsirolimus in diluent (vial 2c) were clear and slightly yellowish. Vial 2b, containing ketamine in diluent, was clear yellow.

[0329]

[0409] HPLC assays indicated that the recovery of ketamine HCl was approximately 100% under all conditions. After 2 weeks at 50°C, the recoveries of temsirolimus were approximately 90% (in vehicle, vial 1c), 3.6% (in the presence of ketamine HCl in vehicle, vial 1d), and 0% (in diluent, vial 2c). Significant amounts of impurities were detected in vials 1d and 2c.

[0330]

[0410] Stability appearance of samples at 50℃, t=2 weeks

[0411] Prior to storage, vials 1a-d were clear, colorless, and viscous at room temperature. Vials 2a and 2c were clear, slightly yellow, and viscous at room temperature. Vial 2b was cloudy and slightly yellowish. The chemicals did not completely dissolve. Samples were filtered through 0.2 μm nylon syringe filters before undergoing stability testing.

[0331]

[0412] After 2 weeks at 50°C, vials 1a-d were clear, colorless, and viscous; vials 2a and 2c were clear, slightly yellow, and viscous; and vial 2b was clear with a dark yellow tint.

[0332] [Table 2]

[0333] Example 2: Dilution test in saline

[0413] In this example, two sets of vials were prepared: (1) vial 1d contained 3 mg / mL temsirolimus and 23 mg / mL ketamine HCl in 2.4 mL of vehicle, and (2) vial 2a contained 4.8 mL of diluent. 3.6 mL of vial 2a was transferred to vial 1d, and the mixture was mixed by gentle inversion. 5 mL of the mixture was transferred to 250 mL and 125 mL of saline solution. The solution was mixed by inversion and allowed to stand at room temperature for 1 hour to allow air bubbles to settle (Figure 2). 500 μL of vial 3 and each saline dilution were aliquoted for HPLC injection. Prior to the HPLC procedure, the samples were spun at 10,000 rpm for 5 minutes using a 0.2 μm nylon spin filter. The sample from vial 3 was diluted 50-fold for the temsirolimus method and 100-fold for the ketamine method with the corresponding diluent (Figure 3). Samples from the two saline dilutions were injected without further dilution.

[0334]

[0414] Dilution in Saline (Torisel Formulation Vials 1 and 2; Temsirolimus and Ketamine HCl in Vial 1): Ketamine HCl and temsirolimus were completely soluble in Vial 1, resulting in a solution containing 27.5 mg / mL ketamine HCl and 3.4 mg / mL temsirolimus in the vehicle. The solution was clear and colorless. Mixing Vial 1 with 3.6 mL of diluent in Vial 2 resulted in a completely soluble solution containing 11.3 mg / mL ketamine HCl and 1.4 mg / mL temsirolimus. The mixture was clear and slightly yellow. After dilution with saline, the solution was clear and colorless. Target concentrations were reached after dilution of the mixture in 250 mL and 125 mL of saline solution, with dilution in 250 mL of saline yielding 0.186 mg / mL ketamine HCl and 0.022 mg / mL temsirolimus, and dilution in 125 mL of saline yielding 0.359 mg / mL ketamine HCl and 0.044 mg / mL temsirolimus.

[0335] [Table 3]

[0336] Example 3: Solubility of Ketamine HCl in Modified Diluents

[0415] Diluent B and Diluent C were made based on the original diluent (Diluent A). The compositions of the diluents are summarized in the table below.

[0337] [Table 4]

[0338]

[0416] To prepare saturated solutions, approximately 80 mg of ketamine HCl was added to 2.5 mL of each diluent in a 20 mL scintillation vial. The samples were stirred at room temperature for approximately 2 hours. The appearance was recorded (Figure 4). The samples were filtered through a 0.2 μm nylon syringe filter. 500 μL of diluent and sample were aliquoted for HPLC analysis. The solution was spun at 10,000 rpm for 5 minutes using a 0.2 μm nylon spin filter. The solution was diluted 50-fold before HPLC injection. The results are summarized in the table below.

[0339] [Table 5]

[0340]

[0417] Ketamine HCl has the highest solubility in Diluent B, which contains the highest % w / w of absolute alcohol. Example 4: Solubility of Ketamine HCl in Vial 2 with Modified Diluent

[0418] Diluent D and Diluent E were made based on the original diluent (Diluent A) and Diluent B, respectively. Based on the composition of Diluent E, Diluent E and Diluent F were made. The compositions of the diluents are summarized in the table below.

[0341] [Table 6]

[0342]

[0419] To create a saturated solution, approximately 80 mg of ketamine HCl was added to 2.5 mL of Diluent D, approximately 100 mg of ketamine HCl was added to 2.5 mL of Diluent E, and approximately 150 mg of ketamine HCl was added to 2.5 mL of Diluent F and Diluent G. The samples were stirred at room temperature for approximately 2 hours. The appearance was recorded (Figures 5 and 6). The samples were filtered through 0.2 μm nylon syringe filters. 500 μL of diluent and sample were aliquoted for HPLC analysis. The solution was spun at 10,000 rpm for 5 minutes using a 0.2 μm nylon spin filter. The solution was diluted 50-fold before HPLC injection. The results are summarized in the table below.

[0343] [Table 7]

[0344]

[0420] The target concentration was reached in diluents E, F, and G, with the greatest solubility (53.0 mg / mL) in diluent G. The solubility of ketamine HCl in various diluents, including A, B, C, D, E, F, and G, was related to the water composition. The results are summarized in Figure 7.

[0345] Example 5: Solubility Assay of Sirolimus and Ketamine HCl (I)

[0421] Sirolimus was tested at a concentration of 20 mg / mL in 10 excipients, with the highest concentrations found in the modified temsirolimus vehicle (18.8 mg / mL), absolute ethanol (17.2 mg / mL), and N-methyl-2-pyrrolidone (21.5 mg / mL). The modified temsirolimus vehicles were absolute alcohol (39.5% w / w) and propylene glycol (50.3% w / w). Concentrations above the target concentration of 6 mg / mL were also observed in propylene glycol (12.1 mg / mL), PEG300 (12.0 mg / mL), and PEG400 (9.8 mg / mL). The appearance is shown in Figure 8.

[0346] [Table 8]

[0347]

[0422] Ketamine HCl was tested at a concentration of 50 mg / mL in 10 excipients, with the highest concentrations found in glycerin (53.5 mg / mL), temsirolimus vehicle (52.8 mg / mL), and water (54.9 mg / mL). The temsirolimus vehicles were absolute alcohol (39.5% w / w) and propylene glycol (50.3% w / w). High concentrations were also observed in PG (40.2 mg / mL) and absolute ethanol (40.2 mg / mL). The appearance is shown in Figure 9.

[0348] [Table 9]

[0349] [Table 10]

[0350]

[0423] Excipients with promising recoveries for both ketamine HCl and sirolimus were modified temsirolimus vehicle, polyethylene glycol, and absolute EtOH.

[0351] Example 6: Solubility Assay of Sirolimus and Ketamine HCl (II)

[0424] The solubility and saturation limit of sirolimus were determined in five vehicles composed of various ratios of propylene glycol, absolute ethanol, and water. Sirolimus showed the highest solubility of 13.5 mg / mL in vehicle 5, which contained 80% (w / w) propylene glycol, 10% (w / w) absolute ethanol, and 10% (w / w) water.

[0352]

[0425] Formulations containing both ketamine HCl and sirolimus were made in five vehicles, with sirolimus exhibiting a solubility of 11.0 mg / mL in vehicle 5.

[0426] The solubility and saturation limit of ketamine HCl were determined in five vehicles composed of various ratios of propylene glycol, absolute ethanol, and water. Ketamine HCl exhibited extremely high solubility (>100%) in vehicles 1–3, which contained 40–60% (w / w) propylene glycol, 10% (w / w) absolute ethanol, and 30–50% (w / w) water. A decrease in ketamine HCl solubility was observed between vehicles 3 and 4, or between 60–70% (w / w) propylene glycol, 10% (w / w) absolute ethanol, and 20–30% (w / w) water.

[0353]

[0427] Formulations containing both ketamine HCl and sirolimus were made in five vehicles, with ketamine HCl showing high percent solubility recovery in all vehicles except vehicle 05.

[0354] [Table 11]

[0355]

[0428] Ketamine HCl solubility assay

[0429] Ketamine was added to all vehicles until excess ketamine was observed at the bottom. The samples were tumbled in a rotary mixer for 24 hours. After the mixing period, no excess ketamine HCl was observed in the vials, and saturation was not achieved. 0.5 mL of each sample was centrifuged at 14,000 RPM for 10 minutes through a 0.2 μm nylon membrane. Samples were diluted to 0.1 mg / mL in diluent for HPLC analysis. The appearance is shown in Figure 10.

[0356] [Table 12]

[0357]

[0430] Sirolimus solubility assay

[0431] Sirolimus was added in excess to all vehicles to approximately 50 mg / mL. Samples were tumbled in a rotary mixer for 24 hours. All samples were turbid after the mixing period. 0.5 mL of sample was centrifuged at 14,000 RPM for 10 minutes through a 0.2 μm nylon membrane. For HPLC analysis, samples were diluted to 0.1 mg / mL in diluent. The appearance is shown in Figure 11.

[0358] [Table 13]

[0359]

[0432] Combined solubility assay of sirolimus and ketamine HCl

[0433] Sirolimus was added in excess to all vehicles to give approximately 35 mg / mL. Ketamine was added to all vehicles to give approximately 75 mg / mL. Samples were tumbled in a rotary mixer for 24 hours. All samples were turbid after the mixing period. 0.5 mL samples were centrifuged at 14,000 RPM for 10 minutes through a 0.2 μm nylon membrane. Samples were diluted to 0.1 mg / mL in diluent for HPLC analysis for both sirolimus and ketamine HCl. The appearance is shown in Figure 12.

[0360] [Table 14]

[0361] Example 7: Solution Composition of Sirolimus and Ketamine HCl

[0434] Case I

[0435] Vial 1 contains 12 mg / mL sirolimus in 90% propylene glycol, 10% ethanol, and 0% water, and vial 2 contains 100 mg / mL ketamine HCl in 60% propylene glycol, 10% ethanol, and 30% water. For administration, 1 mL of vial 1 and 1 mL of vial 2 are mixed to obtain 2 mL of a composition containing 6 mg / mL sirolimus and 50 mg / mL ketamine HCl in 75% propylene glycol, 10% ethanol, and 15% water. One mL of the composition can be administered to an 80 kg person, and 2 mL can be administered to a 160 kg person.

[0362]

[0436] Case II

[0437] Vial 1 contains 6 mg / mL sirolimus in 90% propylene glycol, 10% ethanol, and 0% water, and vial 2 contains 50 mg / mL ketamine HCl in 60% propylene glycol, 10% ethanol, and 30% water. For administration, 1 mL of vial 1 and 1 mL of vial 2 are mixed to obtain a 2 mL composition containing 3 mg / mL sirolimus and 25 mg / mL ketamine HCl in 75% PG, 10% ethanol, and 15% water. One 2 mL dose can be administered to an 80 kg individual, and two 2 mL doses (two injection sites) can be administered to a 160 kg individual.

[0363] Example 8: Development of Temsirolimus-Ketamine HCl Co-Formulation - Optimization of Ketamine HCl Concentration

[0438] Solubility of Ketamine HCl in Variations of Diluent G

[0439] The ketamine HCl concentration level in the Diluent G formulation was set at 30.67 mg / mL, which was determined based on dosing requirements at approximately 75% saturation level in the vehicle (Diluent G, 38.95% (w / w) Polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, 10% (w / w) water). To accommodate the need to prepare a 61.34 mg / mL ketamine HCl formulation, double the current level of ketamine HCl, the solubility of ketamine HCl in a variant of Diluent G with increased water content and decreased polysorbate 80 content was measured.

[0364]

[0440] The following four variations of Diluent G and Diluent G itself were prepared on a 20 g scale:

[0441] Diluent G: 38.95% (w / w) Polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, 10% (w / w) water

[0442] Diluent G15: 33.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, 15% (w / w) water.

[0365]

[0443] Diluent G20: 28.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, 20% (w / w) water.

[0366]

[0444] Diluent G25: 23.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, 25% (w / w) water.

[0367]

[0445] Diluent G30: 18.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, 30% (w / w) water.

[0368]

[0446] To set up the test, 1.0 mL of each diluent was mixed with 100–200 mg of ketamine HCl in a microcentrifuge tube. Triplicate replicates were prepared for each diluent. The resulting mixtures were tumbled at ambient conditions (t0). The appearance of the mixtures was monitored over time to ensure saturation of the diluents. 24h The mixtures were centrifuged at 14,000 rpm for 5 minutes, after which an aliquot of each supernatant was taken and diluted for HPLC analysis of ketamine HCl. 500 μL of each supernatant was then taken and filtered through a 0.2 μm nylon membrane by centrifugation at 14,000 rpm for 5 minutes, after which an aliquot of each filtrate was taken and diluted for HPLC analysis.

[0369]

[0447] Solubility results of ketamine HCl in variations of diluent G (t 24h , room temperature) are summarized in Table 15 below.

[0370] [Table 15]

[0371]

[0448] Based on the results, a suitable modification of Diluent G for solubilizing 61.34 mg / mL of ketamine HCl at a 75% saturation level is believed to be Diluent G25, which has a solubilizing capacity of 110 mg / mL. Therefore, Diluent G25, which has a content of 23.95% (w / w) polysorbate and 25% (w / w) water, was selected as the vehicle for the ketamine HCl formulation at a c(ketamine HCl) level of 61.34 mg / mL.

[0372]

[0449] Stability of ketamine HCl in diluents G and G25

[0450] The stability of the following two ketamine HCl formulations was evaluated:

[0451] 30.67 mg / mL ketamine HCl in Diluent G. Diluent G contains 38.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, 10% (w / w) water.

[0373]

[0452] 61.34 mg / mL ketamine HCl in Diluent G25, which contains 23.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) absolute ethanol, and 25% (w / w) water.

[0374]

[0453] To set up the study, each formulation was prepared in a volumetric flask at a 5 mL scale and dispensed into three 2 mL amber serum vials at 1.0 mL / vial for triplicate replicates of the formulation. The remaining 2 mL was used for the t0 analysis. The headspace of the serum vials was gently sparged with nitrogen gas for 30 seconds, after which the vials were stoppered, sealed, and placed in an oven set at 50°C in the dark.

[0375]

[0454] The stability of two vehicles, Diluents G and G25, was also evaluated. Each vehicle was dispensed into one 2 mL amber serum vial at 1.0 mL / vial. The headspace of the serum vial was gently flushed with nitrogen gas for 30 seconds, after which the vial was stoppered, sealed, and placed in an oven set at 50°C in the dark.

[0376]

[0455] t0 and t 2wk After adjusting the formulation and vehicle stability samples to ambient temperature, their appearance was visually observed. After brief vortexing, an aliquot was taken from each sample, diluted, and analyzed for concentration and purity.

[0377]

[0456] The results of the stability testing of the ketamine HCl formulations and vehicle are summarized below in Table 16. No significant changes in appearance were observed in either the formulation or vehicle. After heating at 50° C. for 2 weeks, c (ketamine HCl) decreased by approximately 8% in both formulations without producing any obvious degradant peaks in the chromatograms.

[0378] [Table 16]

[0379] Example 9: Evaluation of Ketamine and Temsirolimus In-Use Stability and IV Bags

[0457] Temsirolimus and ketamine HCl were evaluated for in-use stability in 0.9% NaCl IV bags and lines using a laboratory-made formulation (FREE001, a co-formulation of temsirolimus and ketamine HCl) and commercially available Torisel (temsirolimus injection) and Ketalar (ketamine HCl injection).

[0380]

[0458] Initial formulation work was conducted to evaluate the solubility and in-use stability of a laboratory-mixed co-formulation of temsirolimus and ketamine HCl in 0.9% saline at ambient laboratory temperature. Formulations were tested neat and after in-line filtration through a 0.2 μm PES membrane. In-use stability studies were conducted in two stages, the first utilizing the ketamine HCl and temsirolimus co-formulation (FREE001), followed by the commercially available Ketalar and Torisel, which were evaluated separately.

[0381]

[0459] Studies using co-formulations of temsirolimus and ketamine HCl are summarized below. The diluent compositions are listed in Table 17 below.

[0460] Vehicles and diluents (Table 17) were prepared by weighing the ingredients into an appropriately sized beaker equipped with a stir bar and mixing at medium speed until homogenous. The mixture was transferred to a foil-covered glass bottle or 50 mL scintillation vial and stored at 2-8 °C.

[0382] [Table 17]

[0383]

[0461] Stock solutions for each test were prepared using volumetric flasks. The API was weighed into a volumetric flask equipped with a stir bar and filled with the respective diluent. The solution was mixed at a moderate speed until homogeneous, the stir bar was removed, and the flask's volume was adjusted to the diluent level and gently inverted to mix. The contents of both flasks were clear and particle-free prior to filtration. The solution was then syringe filtered through a 0.2 μm nylon syringe filter into a clean flask.

[0384]

[0462] The components of the IV pump, IV set, and saline bag are listed in Table 18 below.

[0385] [Table 18]

[0386]

[0463] Study 1: 5 mg / ml temsirolimus, 30.67 mg / ml ketamine HCl (Formulation G)

[0464] Using volumetric flasks, two stock solutions were prepared: 30.67 mL ketamine HCl in Diluent G, and 5 mg / mL temsirolimus in temsirolimus vehicle. A 3.6 mL aliquot of temsirolimus stock and a 5.4 mL aliquot of ketamine HCl stock were combined in a 10 mL vial using a positive displacement micropipettor and mixed by gentle inversion to create a solution that was 2.0 mg / mL temsirolimus and 18.4 mg / mL ketamine HCl (16.0 mg / mL ketamine free base).

[0387]

[0465] A 2.7 mL aliquot of the mixed solution was added to three 250 mL saline bags (270 mL nominal fill volume according to the manufacturer). The bags were inverted to disperse the mixture. The bags were clear and colorless after the addition of the mixed solution. A 2.7 mL aliquot was extracted from each bag to assess the pre-filtration concentration. An IV set with an in-line PES filter was connected to the saline bag and loaded into an IV pump. 20 mL of saline solution was infused, and the final 5 mL was collected for analysis. After the infusion, the IV set was locked, removed from the pump, and left at ambient laboratory conditions for 2 hours. Two hours after the infusion, the IV set was loaded into the pump, and 50 mL of solution was allowed to flow through the IV set into a waste beaker, and the final 5 mL was collected for analysis. After the 2 hours of aliquot collection, the IV set was locked and removed from the pump. The bags and IV setup were left at ambient laboratory conditions for an additional 2 hours. After an additional 2 hours at ambient laboratory temperature, the IV set was loaded onto the pump and the remaining solution was transferred from the bag to a bottle and stored for analysis.

[0388]

[0466] Although there was a slight decrease in recovery for temsirolimus, all recoveries were greater than 100%. Recovery decreases that were potentially within the variability of the analytical method were observed over the course of the study and are shown in Table 19. As seen in Table 20, no decrease in recovery of ketamine HCl was observed.

[0389] [Table 19]

[0390] [Table 20]

[0391]

[0467] Study 2: 9.375 mg / ml temsirolimus, 57.67 mg / ml ketamine HCl (formulation G25)

[0468] Using volumetric flasks, two stock solutions were prepared: 57.67 mg / mL ketamine HCl in Diluent G25, and 9.375 mg / mL temsirolimus in temsirolimus vehicle. A 2.4 mL aliquot of temsirolimus stock and a 3.6 mL aliquot of ketamine HCl stock were combined in a 10 mL vial using a positive displacement micropipettor and mixed by gentle inversion to create a solution that was 3.75 mg / mL temsirolimus and 36.40 mg / mL ketamine HCl (30.0 mg / mL ketamine free base).

[0392]

[0469] A 1.5 mL aliquot of the mixed solution was added to three 250 mL saline bags (270 mL nominal fill volume according to the manufacturer). The bags were inverted to disperse the mixture. The bags were clear and colorless after the addition of the mixed solution. A 1.5 mL aliquot was extracted from each bag to assess the pre-filtration concentration. An IV set with an in-line PES filter was connected to the saline bag and loaded into an IV pump. 20 mL of saline solution was infused, and the final 5 mL was collected for analysis. After the infusion, the IV set was locked, removed from the pump, and left at ambient laboratory conditions for 2 hours. Two hours after the infusion, the IV set was loaded into the pump, and 50 mL of solution was allowed to flow through the IV set into a waste beaker, and the final 5 mL was collected for analysis. After the 2-hour aliquot collection, the IV set was locked and removed from the pump. The bags and IV setup were left at ambient laboratory conditions for an additional 2 hours. After an additional 2 hours at ambient laboratory temperature, the IV set was loaded onto the pump and the remaining solution was transferred from the bag to a bottle and stored for analysis.

[0393]

[0470] A decrease in recovery (0.9-4.5%) was observed in the temsirolimus injection volume samples, with this decrease largely reversing at the 2-hour time point. As observed in Table 21, a 0.8%-2% decrease in recovery was observed in temsirolimus over the course of the study. As shown in Table 22, no decrease in recovery was observed in ketamine HCl over the study period.

[0394] [Table 21]

[0395] [Table 22]

[0396]

[0471] Study 3: 0.25 mg / ml temsirolimus, 30.67 mg / ml ketamine HCl (Formulation G)

[0472] Using volumetric flasks, two stock solutions were prepared: 30.67 mg / mL ketamine HCl in Diluent G and 0.25 mg / mL temsirolimus in temsirolimus vehicle. A 3.6 mL aliquot of temsirolimus stock and a 5.4 mL aliquot of ketamine HCl stock were combined in a 10 mL vial using a positive displacement micropipettor and mixed by gentle inversion to create a solution that was 0.1 mg / mL temsirolimus and 18.4 mg / mL ketamine HCl (16.0 mg / mL ketamine free base).

[0397]

[0473] A 2.7 mL aliquot of the mixed solution was added to three 250 mL saline bags (270 mL nominal fill volume according to the manufacturer). The bags were inverted to disperse the mixture. The bags were clear and colorless after the addition of the mixed solution. A 2.7 mL aliquot was extracted from each bag to assess the pre-filtration concentration. An IV set with an in-line PES filter was connected to the saline bag and loaded into an IV pump. 20 mL of saline solution was infused, and the final 5 mL was collected for analysis. After the infusion, the IV set was locked, removed from the pump, and left at ambient laboratory conditions for 2 hours. Two hours after the infusion, the IV set was loaded into the pump, and 50 mL of solution was allowed to flow through the IV set into a waste beaker, and the final 5 mL was collected for analysis. After the 2 hours of aliquot collection, the IV set was locked and removed from the pump. The bags and IV setup were left at ambient laboratory conditions for an additional 2 hours. After an additional 2 hours at ambient laboratory temperature, the IV set was loaded onto the pump and the remaining solution was transferred from the bag to a bottle and stored for analysis.

[0398]

[0474] A decrease in temsirolimus recovery (1.4-4.7%) was observed in the initial dose samples of temsirolimus, which recovered by the 2-hour time point. As observed in Table 23, an overall recovery decrease of 1.2-1.4% was observed in temsirolimus over the course of the study. As shown in Table 24, no recovery decrease was observed in ketamine HCl over the study period.

[0399] [Table 23]

[0400] [Table 24]

[0401]

[0475] Study 4: 0.47 mg / ml temsirolimus, 57.57 mg / ml ketamine HCl (formulation G25)

[0476] Two stock solutions were prepared using volumetric flasks: 57.6 mg / mL ketamine HCl in Diluent G25 and 0.47 mg / mL temsirolimus in temsirolimus vehicle. A 2.4 mL aliquot of temsirolimus stock and a 3.6 mL aliquot of ketamine HCl stock were combined in a 10 mL vial using a positive displacement micropipettor and mixed by gentle inversion to create a solution that was 0.188 mg / mL temsirolimus and 36.40 mg / mL ketamine HCl (30.0 mg / mL ketamine free base).

[0402]

[0477] A 1.5 mL aliquot of the mixed solution was added to three 250 mL saline bags (270 mL nominal fill volume according to the manufacturer). The bags were inverted to disperse the mixture. The bags were clear and colorless after the addition of the mixed solution. A 1.5 mL aliquot was extracted from each bag to assess the pre-filtration concentration. An IV set with a PES filter was connected to the saline bag and loaded into an IV pump. 20 mL of saline solution was infused, and the final 5 mL was collected for analysis. After the infusion, the IV set was locked, removed from the pump, and left at ambient laboratory conditions for 2 hours. Two hours after the infusion, the IV set was loaded into the pump, and 50 mL of solution was allowed to flow through the IV set into a waste beaker, and the final 5 mL was collected for analysis. After the 2-hour aliquot collection, the IV set was locked and removed from the pump. The bags and IV setup were left at ambient laboratory conditions for an additional 2 hours. After an additional 2 hours at ambient laboratory temperature, the IV set was loaded onto the pump and the remaining solution was transferred from the bag to a bottle and stored for analysis.

[0403]

[0478] A decrease in recovery (5.5-7.1%) was observed in the temsirolimus injection volume samples, with this decrease largely reversing at the 2-hour time point. As observed in Table 25, a 0.1-1.7% decrease in recovery was observed in temsirolimus over the course of the study. As shown in Table 26, no decrease in recovery was observed in ketamine HCl over the study period.

[0404] [Table 25]

[0405] [Table 26]

[0406]

[0479] Torisel

[0480] Three vials of commercially available Torisel were prepared by adding 1.8 mL of Torisel diluent to the corresponding Torisel vial to create a 3 mL mixed solution containing 10 mg / mL temsirolimus. The compositions of the Torisel vehicle and Torisel diluent are shown in Table 27. Dilution of the Torisel mixed solution to a target concentration of 0.003 mg / mL temsirolimus in 0.9% NaCl (saline) was accomplished using two-step dilutions.

[0407] [Table 27]

[0408]

[0481] In the first dilution step, a 2.7 mL aliquot of each mixed solution was added to a 250 mL saline bag (nominal fill volume of 270 mL according to the manufacturer). The bag was gently inverted to disperse the mixture. The bag was colorless and free of particles after the addition of the mixed solution. The bag concentration after the first dilution was 0.099 mg / mL temsirolimus, assuming a total volume of 272.7 mL. A 1 mL aliquot was extracted from each bag to assess the concentration.

[0409]

[0482] For the second dilution, 8.2 mL of saline was removed from three new IV bags to achieve a nominal volume of 261.8 mL (270 mL - 8.2 mL). An 8.2 mL aliquot from the first dilution bag was added to the 261.8 mL bag. The bag concentration after the second dilution was 0.003 mg / mL temsirolimus, assuming a final bag volume of 270 mL. A 1 mL aliquot was extracted from each bag to assess concentration. The bags in the second dilution were also colorless and free of particles.

[0410]

[0483] An IV set with an in-line PES filter was connected to the saline bag and loaded onto an IV pump. 20 mL of saline solution was infused, with the final 5 mL withdrawn for analysis. After the infusion, the IV set was locked, removed from the pump, and left at ambient laboratory conditions for 2 hours. Two hours after the infusion, the IV set was loaded onto the pump, 50 mL of solution was flushed through the IV set into a waste beaker, and the final 5 mL withdrawn for analysis. After two hours of collecting aliquots, the IV set was locked and removed from the pump. The bag and IV setup were left at ambient laboratory conditions for an additional two hours. After another two hours at ambient laboratory temperature, the IV set was loaded onto the pump, and the remaining solution was transferred from the bag into a bottle and stored for analysis.

[0411]

[0484] The mixture was filtered through a 0.2 μm nylon membrane by centrifugation at 14,000 RPM for 5 minutes and diluted to the target temsirolimus diluent. The saline solution was injected undiluted into the HPLC.

[0412]

[0485] The results are shown in Table 28. No loss in recovery was observed in the mixed solution or Dilution 1 samples, but a significant loss in recovery was observed in the Dilution 2 samples. A loss in recovery of 8.5 to 15.1% was observed between Dilution 1 and Dilution 2 in each sample series. Temsirolimus was not detected in the initial volume samples in any of the Dilution 2 bags, but at 2 hours, recovery had almost returned to pre-filtration levels. A slight loss in recovery (0.5 to 1.6%) was observed in the Dilution 2 bags over the course of the study.

[0413] [Table 28]

[0414]

[0486] Ketalar

[0487] Ketalar injection (100 mg / mL ketamine free base, 115.33 mg / mL ketamine HCl) was diluted to a final concentration of 0.166 mg ketamine free base (0.1918 mg / mL ketamine HCl) by injecting 0.45 mL aliquots of Ketalar into three saline bags. The bags were gently inverted to disperse the mixture. After addition, the bags were colorless and free of particles. A 1 mL aliquot was extracted from each bag to assess the concentration before filtration.

[0415]

[0488] As in previous studies, an IV set with an in-line PES filter was connected to the saline bag and loaded onto an IV pump. 20 mL of saline solution was infused, with the final 5 mL withdrawn for analysis. After the infusion, the IV set was locked, removed from the pump, and left at ambient laboratory conditions for 2 hours. Two hours after the infusion, the IV set was loaded onto the pump, 50 mL of solution was drained through the IV set into a waste beaker, and the final 5 mL withdrawn for analysis. After two hours of aliquot collection, the IV set was locked and removed from the pump. The bag and IV setup were left at ambient laboratory conditions for an additional 2 hours. After another two hours at ambient laboratory temperature, the IV set was loaded onto the pump, and the remaining solution was transferred from the bag to a bottle and stored for analysis.

[0416]

[0489] The mixture was filtered through a 0.2 μm nylon membrane by centrifugation at 14,000 RPM for 5 minutes and diluted to the target temsirolimus diluent. The saline solution was injected undiluted into the HPLC.

[0417]

[0490] The results are shown in Table 29. No loss of recovery was observed.

[0418] [Table 29]

[0419] [Table 30]

[0420]

[0491] Sample preparation for each test is described below. Dilutions of stock solutions and mixed stock solutions were performed with a positive displacement micropipettor. Aliquots of saline were injected directly without dilution.

[0421]

[0492] Test 1 and Test 3:

[0493] Ketamine stock: A 0.5 mL aliquot was pipetted onto a 0.2 μm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted with Ketamine HCl diluent to a target concentration of 0.3067 mg / mL.

[0422]

[0494] Ketamine Stock Mixture: A 0.5 mL aliquot was pipetted onto a 0.2 μm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted with Ketamine HCl Diluent to a target concentration of 0.1840 mg / mL.

[0423]

[0495] Test 2 and Test 4:

[0496] Ketamine stock: A 0.5 mL aliquot was pipetted onto a 0.2 μm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted with Ketamine HCl diluent to a target concentration of 0.6134 mg / mL.

[0424]

[0497] Ketamine Stock Mixture: A 0.5 mL aliquot was pipetted onto a 0.2 μm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted with Ketamine HCl Diluent to a target concentration of 0.3640 mg / mL.

[0425]

[0498] Ketalar:

[0499] Ketalar stock: A 0.5 mL aliquot was pipetted onto a 0.2 μm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted with Ketamine HCl diluent to a target concentration of 0.5757 mg / mL.

[0426] [Table 31]

[0427]

[0500] Sample preparation for each test is described below: An aliquot of saline was injected directly.

[0501] Test 1:

[0502] Temsirolimus stock: A 0.5 mL aliquot was pipetted onto a 0.2 μm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted with temsirolimus diluent to a target concentration of 0.50 mg / mL.

[0428]

[0503] Temsirolimus Stock Mixture: A 0.5 mL aliquot was pipetted onto a 0.2 μm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted with Temsirolimus Diluent to a target concentration of 0.20 mg / mL.

[0429]

[0504] Test 2:

[0505] Temsirolimus stock: A 0.5 mL aliquot was pipetted onto a 0.2 μm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted with temsirolimus diluent to a target concentration of 0.10 mg / mL.

[0430]

[0506] Temsirolimus Stock Mixture: A 0.5 mL aliquot was pipetted onto a 0.2 μm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted with Temsirolimus Diluent to a target concentration of 0.375 mg / mL.

[0431]

[0507] Test 3:

[0508] Temsirolimus stock: 0.5 mL aliquots were pipetted onto 0.2 μm nylon spin filters and centrifuged at 14,000 RPM for 5 minutes. The filtrate was directly injected at a target concentration of 0.25 mg / mL.

[0432]

[0509] Temsirolimus Stock Mixture: 0.5 mL aliquots were pipetted onto 0.2 μm nylon spin filters and centrifuged at 14,000 RPM for 5 minutes. The filtrate was injected directly at a target concentration of 0.1 mg / mL.

[0433]

[0510] Test 4:

[0511] Temsirolimus stock: 0.5 mL aliquots were pipetted onto 0.2 μm nylon spin filters and centrifuged at 14,000 RPM for 5 minutes. The filtrate was directly injected at a target concentration of 0.47 mg / mL.

[0434]

[0512] Temsirolimus Stock Mixture: 0.5 mL aliquots were pipetted onto 0.2 μm nylon spin filters and centrifuged at 14,000 RPM for 5 minutes. The filtrate was injected directly at a target concentration of 0.188 mg / mL.

[0435]

[0513] Toricell:

[0514] Torycel Mix Vial: A 0.1 mL aliquot was pipetted onto a 0.2 μm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted 20-fold with Torycel Diluent to a target concentration of 0.5 mg / mL.

[0436] Example 10: Stability of Co-formulations of Ketamine HCl and Temsirolimus

[0515] Temsirolimus and ketamine HCl co-formulations were evaluated to enhance stability.

[0516] Four formulations and one co-formulation were prepared according to Table 32.

[0437] [Table 32]

[0438]

[0517] The diluent and temsirolimus vehicle were prepared by weighing the ingredients into an appropriately sized beaker equipped with a stir bar and mixing until the solution was homogeneous. The mixture was transferred to a foil-covered glass bottle or a 50 mL scintillation vial.

[0439]

[0518] Ketamine HCl and temsirolimus were weighed into 20 mL scintillation vials equipped with a stir bar. The vehicle or diluent was added, and the vials were then mixed at moderate speed until each solution was homogenous. The solutions were filtered through 0.2 μm nylon syringe filters and aliquoted into prepared vials to a fill volume of 1 mL, which were then blanketed with N2 gas before being sealed and crimped.

[0440]

[0519] All formulations were clear and particle-free after 3 months at 25° C. "TEM High" showed a slight discoloration (from colorless to very pale yellow) after 3 months at 25° C., but the color of the other formulations did not change from t-0.

[0441]

[0520] No decline in ketamine purity or recovery was observed at the end of the study period under any of the stability conditions.

[0521] The co-formulation "TEM High" showed a 4% loss in recovery at t-3 months for stability at 25°C, while the co-formulation "TEM Combi" showed a 19% loss in recovery under the same conditions. At the end of the study period, a significant increase in impurity levels was observed in "TEM Combi."

[0442]

[0522] After 6 months at 25°C, the formulations remained clear and particle-free at the end of the study period. "TEM High" remained a very pale yellow color at 6 months at 25°C, while the color of the other formulations did not change from t-0. No decline in ketamine purity or recovery was observed at the end of the study period. Formulation "TEM High" showed no decline in recovery at 6 months at 25°C, while formulation "TEM Low" showed a 4% decline in recovery. TEM Combi showed a 40% recovery over the study period at 25°C.

[0443]

[0523] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be used in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. a. an N-methyl-D-aspartate (NMDA) receptor modulator at a concentration of about 0.04 milligrams / milliliter (mg / mL) to about 150 mg / mL; b. a target of rapamycin (mTOR) inhibitor at a concentration of about 0.02 mg / mL to about 10 mg / mL; A solution containing

2. a. an N-methyl-D-aspartate (NMDA) receptor modulator; and b. a target of rapamycin (mTOR) inhibitor; The solution, wherein the NMDA receptor modulator and the mTOR inhibitor have a weight ratio of greater than about 1:

1.

3. a. an N-methyl-D-aspartate (NMDA) receptor modulator at a concentration of about 0.01 mg / mL to about 1.0 mg / mL; b. a target of rapamycin (mTOR) inhibitor at a concentration of about 0.5 micrograms / milliliter (μg / mL) to about 100 μg / mL; A solution containing

4. 4. The solution of claim 2 or 3, comprising about 0.9% (w / v) sodium chloride in water or about 5% (w / v) dextrose in water.

5. 4. The solution of claim 1 or 3, wherein the NMDA receptor modulator and the mTOR inhibitor have a weight ratio of greater than about 1:

1.

6. 6. The solution of claim 2 or 5, wherein the weight ratio of the NMDA receptor modulator to the mTOR inhibitor ranges from about 600:1 to about 5:

1.

7. 4. The solution of claim 1, further comprising polyethylene glycol (PEG), polysorbate, or both.

8. 8. The solution of claim 7, comprising a polysorbate, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

9. 8. The solution of claim 7, comprising PEG, said PEG having an average molecular weight of about 300 to about 600, and optionally PEG 400.

10. 4. The solution of claim 1, comprising polysorbate 80 and PEG 400.

11. a. an N-methyl-D-aspartate (NMDA) receptor modulator; and b. a target of rapamycin (mTOR) inhibitor; c. Polysorbate or PEG 400 A solution containing

12. The NMDA receptor modulator is selected from the group consisting of ketamine, R-ketamine, S-ketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, a fixed-dose combination of dextromethorphan and quinidine, dextromethorphan, a fixed-dose combination of dextromethorphan and bupropion, GM-1020, besonprodil, eliprodil, ifenprodil, lisrenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro8-4304, traxoprodil (CP-101,606), BMT-108908, omfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP37849, 1-aminocyclopropanecarboxylic acid, traxoprodil, Ro25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxyzine, tiletamine, neramexane, etoxadrol, dexoxadrol ru, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delsemin, dextralorphan, dextrorphan, diphenidine, eticlidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7-Dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnalone sulfate (3α5βS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, P The solution according to any one of claims 1 to 3 or 11, wherein the compound is selected from the group consisting of EAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salts, solvates, enantiomers, tautomers, stereoisomers and geometric isomers thereof, and any mixtures thereof.

13. 13. The solution of claim 12, wherein the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixture thereof.

14. 14. The solution of claim 13, wherein the ketamine is ketamine HCl.

15. The mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), KU-0063794, PI-103 (mTOR inhibitor V, PI3-K inhibitor V, PI-103-CAS371935-74-9), tolquinib (PP242), tacrolimus (FK-506, Fujimycin), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 ( MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), torin-1 (DNA-PK inhibitor VI, PI3-K inhibitor XVIII, mTOR inhibitor XI, torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE390), GSK1059615, WYE-354 (m TOR inhibitor II), gedatolicib (PF-05212384, PKI-587), AZD-2014 (bistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC-0349 (RG-7 603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound 401, GNE-477, bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC223), clemastine (HS-592) fumarate, nitazoxanide (NSC697855), 4EGI-1, ABTL-0812, astragaloside IV, samotricisib (LY3023414),The solution of any one of claims 1 to 3 or 11, wherein the compound is selected from the group consisting of chrysophanic acid, and zotarolimus (ABT-578), and any salts, solvates, enantiomers, tautomers, diastereomers, stereoisomers and geometric isomers thereof, and any mixtures thereof.

16. 16. The solution of claim 15, wherein the mTOR inhibitor comprises rapamycin (sirolimus, AY22989, ABI-009) or temsirolimus (CCI-779).

17. 17. The solution of any one of claims 1 to 16, further comprising an excipient selected from the group consisting of water, ethanol, propylene glycol, citric acid, and DL-alpha-tocopherol.

18. 18. The solution of claim 17, wherein the concentration of the ethanol ranges from about 10% w / w to about 50% w / w, from about 0.1% w / w to about 30% w / w, or from about 5% w / w to about 50% w / w.

19. 17. The solution of any one of claims 8 to 16, wherein the concentration of the polysorbate ranges from about 5% w / w to about 50% w / w.

20. 17. The solution of any one of claims 8 to 16, wherein the concentration of the PEG ranges from about 0.1% w / w to about 30% w / w.

21. 21. The solution of claim 20, comprising about 23.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 6% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof.

22. 21. The solution of claim 20, comprising about 20.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 9% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof.

23. 21. The solution of claim 20, comprising about 17.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 12% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof.

24. 21. The solution of claim 20, comprising about 14.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 15% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof.

25. 21. The solution of claim 20, comprising about 11.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) absolute ethanol, about 18% (w / w) water, about 20.12% (w / v) propylene glycol, or any combination thereof.

26. 26. The solution of any one of claims 1 to 25, which does not contain citric acid or DL-alpha-tocopherol.

27. 27. The solution of any one of claims 1 to 26, comprising about 20 mg to about 150 mg, about 30 mg to about 140 mg, about 40 mg to about 120 mg, about 50 mg to about 100 mg, or about 60 mg to about 80 mg of the NMDA receptor modulator.

28. 27. The solution of any one of claims 1 to 26, comprising about 0.05 mg to about 2.0 mg, about 0.1 mg to about 1.8 mg, about 0.2 mg to about 1.5 mg, about 0.4 mg to about 1.2 mg, or about 0.8 mg to about 1.0 mg of said mTOR inhibitor.

29. (i) a first container containing a first solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator at a concentration of about 5 mg / mL to about 200 mg / mL; (ii) a second container containing a second solution comprising a target of rapamycin (mTOR) inhibitor at a concentration of about 0.1 mg / mL to about 25 mg / mL; Kit including:

30. (i) a first container containing a first solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator; (ii) a second container containing a second solution comprising a target of rapamycin (mTOR) inhibitor; The volume ratio of the first solution to the second solution is from about 1.2:1 to about 3:

1.

31. 31. The kit of claim 30, wherein the volume ratio of the first solution to the second solution is about 3:2, about 2.2:1.2, about 2.4:1.2, or about 2.5:1.

2.

32. 31. The kit of claim 29 or 30, wherein the weight ratio of the NMDA receptor modulator to the mTOR inhibitor is greater than about 1:

1.

33. 31. The kit of claim 29 or 30, wherein the first container further comprises water, ethanol, polyethylene glycol (PEG), polysorbate, or any combination thereof.

34. 34. The kit of claim 33, wherein the first container comprises a polysorbate, the polysorbate being selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, and optionally polysorbate 80.

35. 34. The kit of claim 33, wherein the first container comprises PEG, the PEG having an average molecular weight of about 300 to about 600, and optionally PEG 400.

36. 36. The kit of any one of claims 29 to 35, wherein the second container further comprises ethanol, DL-alpha-tocopherol, propylene glycol, citric acid, or any combination thereof.

37. 36. The kit of any one of claims 29-35, wherein the second container further comprises ethanol, propylene glycol, or any combination thereof.

38. (i) a first container containing a first composition comprising an N-methyl-D-aspartate (NMDA) receptor modulator; (ii) a second container containing a second composition comprising a target of rapamycin (mTOR) inhibitor; The kit, wherein the NMDA receptor modulator and the mTOR inhibitor have a weight ratio of greater than about 1:

1.

39. 39. The kit of claim 38, wherein the first composition is a solution.

40. 39. The kit of claim 38, wherein the solution further comprises water, ethanol, polyethylene glycol (PEG), polysorbate, or any combination thereof.

41. 39. The kit of claim 38, wherein the first composition is a solid.

42. 42. The kit of claim 41, wherein the solid is a powder.

43. 42. The kit of claim 41, wherein the solid is dissolved in a diluent.

44. (i) a first container containing a first composition comprising an N-methyl-D-aspartate (NMDA) receptor modulator; (ii) a second container containing a second composition comprising a target of rapamycin (mTOR) inhibitor; (iii) a diluent comprising polysorbate, PEG 400, or both; Kit including:

45. 45. The kit of claim 44, wherein the NMDA receptor modulator and the mTOR inhibitor have a weight ratio of greater than about 1:

1.

46. The NMDA receptor modulator is selected from the group consisting of ketamine, R-ketamine, S-ketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, dextromethorphan, a fixed-dose combination of dextromethorphan and quinidine, a fixed-dose combination of dextromethorphan and bupropion, GM-1020, besonprodil, eliprodil, ifenprodil, lisrenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro8-4304, traxoprodil (CP-101,606), BMT-108908, omfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP37849, 1-aminocyclopropanecarboxylic acid, traxoprodil, Ro25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxyzine, tiletamine, neramexane, etoxadrol, dexoxadrol ru, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delsemin, dextralorphan, dextrorphan, diphenidine, eticlidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7-Dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnalone sulfate (3α5βS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, P The kit according to any one of claims 29 to 45, wherein the compound is selected from the group consisting of EAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, and NYX-783, and any salts, solvates, enantiomers, tautomers, stereoisomers, and geometric isomers thereof, and any mixtures thereof.

47. 47. The kit of claim 46, wherein the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixture thereof.

48. 48. The kit of claim 47, wherein the ketamine is ketamine HCl.

49. The mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), KU-0063794, PI-103 (mTOR inhibitor V, PI3-K inhibitor V, PI-103-CAS371935-74-9), tolquinib (PP242), tacrolimus (FK-506, Fujimycin), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 ( MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), torin-1 (DNA-PK inhibitor VI, PI3-K inhibitor XVIII, mTOR inhibitor XI, torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE390), GSK1059615, WYE-354 (m TOR inhibitor II), gedatolicib (PF-05212384, PKI-587), AZD-2014 (bistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC-0349 (RG-7 603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound 401, GNE-477, bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC223), clemastine (HS-592) fumarate, nitazoxanide (NSC697855), 4EGI-1, ABTL-0812, astragaloside IV, samotricisib (LY3023414),The kit of any one of claims 29 to 48, comprising chrysophanic acid, or zotarolimus (ABT-578), or a salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, or geometric isomer thereof.

50. 50. The kit of claim 49, wherein the mTOR inhibitor comprises rapamycin (sirolimus, AY22989, ABI-009) or temsirolimus (CCI-779).

51. 51. The kit of any one of claims 29 to 50, wherein the first solution or first composition further comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 10% (w / w) water, or any combination thereof.

52. 51. The kit of any one of claims 29 to 50, wherein the first solution or first composition further comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 15% (w / w) water, or any combination thereof.

53. 51. The kit of any one of claims 29 to 50, wherein the first solution or first composition further comprises about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 20% (w / w) water, or any combination thereof.

54. 51. The kit of any one of claims 29 to 50, wherein the first solution or first composition further comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 25% (w / w) water, or any combination thereof.

55. 51. The kit of any one of claims 29 to 50, wherein the first solution or first composition further comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 30% (w / w) water, or any combination thereof.

56. 56. The kit of any one of claims 29 to 55, wherein the second solution or second composition further comprises about 39.5% (w / v) absolute ethanol, about 0.075% (w / v) DL-alpha-tocopherol, about 50.3% (w / v) propylene glycol, about 0.0025% (w / v) anhydrous citric acid, or any combination thereof.

57. 56. The kit of any one of claims 29 to 55, wherein the second solution or second composition further comprises about 39.5% (w / v) absolute ethanol, about 50.3% (w / v) propylene glycol, or any combination thereof.

58. 56. The kit of any one of claims 29-55, wherein the first solution or first composition is stable at room temperature for at least about 1 week, 1 month, 3 months, 6 months, or 1 year.

59. 59. The kit of any one of claims 29 to 58, wherein the first solution or first composition is stable at a temperature of less than about 60°C for at least about 1 week.

60. 60. The kit of any one of claims 29-59, wherein the second solution or second composition is stable at room temperature for at least about 1 week, 1 month, 3 months, 6 months, or 1 year.

61. 61. The kit of any one of claims 29 to 60, wherein the second solution or second composition is stable at a temperature of less than about 60°C for at least about 1 week.

62. 62. The kit of any one of claims 29 to 61, wherein the second solution or second composition does not contain citric acid or DL-alpha-tocopherol.

63. 1. A method for preparing a solution comprising: (i) mixing a first solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator and (ii) a second solution comprising a target of rapamycin (mTOR) inhibitor, thereby producing a solution comprising both the NMDA receptor modulator and the mTOR inhibitor; The method, wherein the volume ratio of the first solution to the second solution is about 3:

2.

64. 1. A method of treating or preventing a disease, disorder, or condition in a subject in need thereof, comprising:

29. A method comprising administering to the subject a solution according to any one of claims 1 to 28.

65. 1. A method of treating or preventing a disease, disorder, or condition in a subject in need thereof, comprising: mixing a first solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator and a second solution comprising an mTOR inhibitor, thereby producing a solution comprising both the NMDA receptor modulator and the mTOR inhibitor; and administering the solution to the subject within about 4, 6, or 24 hours after the solution is produced.

66. The NMDA receptor modulator is selected from the group consisting of ketamine, R-ketamine, S-ketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, dextromethorphan, a fixed-dose combination of dextromethorphan and quinidine, a fixed-dose combination of dextromethorphan and bupropion, GM-1020, besonprodil, eliprodil, ifenprodil, lisrenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro8-4304, traxoprodil (CP-101,606), BMT-108908, omfasprodil, radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP37849, 1-aminocyclopropanecarboxylic acid, traxoprodil, Ro25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxyzine, tiletamine, neramexane, etoxadrol, dexoxadrol ru, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delsemin, dextralorphan, dextrorphan, diphenidine, eticlidine, gacyclidine, aptiganel, HU-211, huperzine A, dipeptide D-Phe-L-Tyr, ibogaine, rhynchophylline, rapastinel, NRX-1074, 7-chlorokynurenic acid, 4-chlorokynurenine, 5,7-Dichlorokynurenic acid, kynurenic acid, TK-40, L-phenylalanine, xenon, methadone, EU1180-438, radiprodil, ifenprodil, TCN-201, MPX-004, MPX-007, NAB-14, EVT-101, QNZ-46, DQP-1105, pregnalone sulfate (3α5βS), UBP608, UBP618, UBP551, UBP512, HA-966, ferricyanide 66. The method of claim 65, wherein the compound is selected from the group consisting of bamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, and NYX-783, and any salts, solvates, enantiomers, tautomers, stereoisomers, and geometric isomers thereof, and any mixtures thereof.

67. 66. The method of claim 65, wherein the NMDA receptor modulator comprises ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any mixture thereof.

68. 68. The method of claim 67, wherein the ketamine is ketamine HCl.

69. The mTOR inhibitor is selected from the group consisting of BEZ235 (dactolisib, RTB101), rapamycin (sirolimus, AY22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), temsirolimus (CCI-779), KU-0063794, PI-103 (mTOR inhibitor V, PI3-K inhibitor V, PI-103-CAS371935-74-9), tolquinib (PP242), tacrolimus (FK-506, Fujimycin), ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 ( MLN0128, sapanisertib), voxtalisib (XL-765, SAR245409), torin-1 (DNA-PK inhibitor VI, PI3-K inhibitor XVIII, mTOR inhibitor XI, torin-1), omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC006, AEVI-006), PF-04691502 (PF4691502), apitolisib (GDC0980, RG7422, GNE390), GSK1059615, WYE-354 (m TOR inhibitor II), gedatolicib (PF-05212384, PKI-587), AZD-2014 (bistusertib), torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG00529), PP121, WYE-687 (WAY-687), CH5132799 (MEN1611, PA799), Way-600, ETP-46464 (ATRi), GDC-0349 (RG-7 603), XL388, PI-103, NU7441 (KU-57788), KU-0063794, sapanisertib (MLN0128), MTI-31, PQR620, Compound 401, GNE-477, bimiralisib (PQR309), SF2523, CZ415, paxalisib (GDC-0084), CC-115, onatasertib (CC223), clemastine (HS-592) fumarate, nitazoxanide (NSC697855), 4EGI-1, ABTL-0812, astragaloside IV, samotricisib (LY3023414),66. The method of claim 65, comprising chrysophanic acid, or zotarolimus (ABT-578), or salts, solvates, enantiomers, tautomers, diastereomers, stereoisomers, and geometric isomers thereof.

70. 66. The method of claim 65, wherein the mTOR inhibitor comprises rapamycin (sirolimus, AY22989, ABI-009) or temsirolimus (CCI-779).

71. 71. The method of any one of claims 64 to 70, wherein the solution is administered via intramuscular, intravenous, subcutaneous, oral, inhalation or intranasal route.

72. 71. The method of any one of claims 64-70, wherein the solution is administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or seven times a week.

73. 73. The method of any one of claims 64 to 72, wherein the NMDA receptor modulator is administered at a dose of about 0.1 mg / kg to about 1 mg / kg.

74. 74. The method of claim 73, wherein the NMDA receptor modulator is administered at a dose of about 0.3 mg / kg to about 0.7 mg / kg.

75. 75. The method of any one of claims 64 to 74, wherein the NMDA receptor modulator is administered at a dose of from about 30 mg to about 90 mg.

76. 76. The method of claim 75, wherein the NMDA receptor modulator is administered at a dose of about 30 mg to about 60 mg.

77. 77. The method of any one of claims 64 to 76, wherein the mTOR inhibitor is administered at a dose of about 1 μg / kg to about 100 μg / kg.

78. 78. The method of claim 77, wherein the mTOR inhibitor is administered at a dose of about 2.5 μg / kg to about 30 μg / kg.

79. 78. The method of claim 77, wherein the mTOR inhibitor is administered at a dose of about 3 μg / kg to about 25 μg / kg.

80. 80. The method of any one of claims 64 to 79, wherein the mTOR inhibitor is administered at a dose of about 0.1 mg to about 4 mg.

81. 81. The method of any one of claims 64 to 80, wherein the disease, disorder, or condition is selected from the group consisting of major depressive disorder (MDD), major depressive episode in bipolar disorder (bipolar depression), persistent depressive disorder (dysthymia), major mood dysregulation disorder, major depressive disorder (including major depressive episode), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, depressive disorder due to other medical illness, other specified depressive disorder, unspecified depressive disorder, anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, addictive disorder, bipolar disorder Type I, bipolar disorder Type II, generalized anxiety disorder, social anxiety disorder (social phobia), specific phobia, panic disorder, agoraphobia, separation anxiety disorder, selective mutism, substance-induced anxiety disorder, medication-induced anxiety disorder, anxiety disorder due to other medical illness, borderline personality disorder, treatment-resistant depression, unspecified anxiety disorder, chronic pain, and any combination thereof.

82. 81. The method of any one of claims 64 to 80, wherein the disease, disorder, or condition is a mood disorder, optionally a depressive disorder.

83. a. an N-methyl-D-aspartate (NMDA) receptor modulator; and b. Polysorbate or PEG 400 A solution containing

84. comprising a target of rapamycin (mTOR) inhibitor, A solution having an mTOR inhibitor concentration of about 0.05 mg / mL to about 10 mg / mL, about 0.2 mg / mL to about 8 mg / mL, about 0.5 mg / mL to about 6 mg / mL, about 1 mg / mL to about 4 mg / mL, or about 2 mg / mL to about 3 mg / mL.

85. 85. A method for preparing the solution of claim 84, comprising: A method comprising the step of contacting an N-methyl-D-aspartate (NMDA) receptor modulator with a diluent comprising PEG 400 or polysorbate.

86. A solution comprising water, ethanol, polyethylene glycol (PEG), polysorbate, or any combination thereof.

87. 87. The solution of claim 86, comprising about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 10% (w / w) water, or any combination thereof.

88. 87. The solution of claim 86, comprising about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 15% (w / w) water, or any combination thereof.

89. 87. The solution of claim 86, comprising about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 20% (w / w) water, or any combination thereof.

90. 87. The solution of claim 86, comprising about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 25% (w / w) water, or any combination thereof.

91. 87. The solution of claim 86, comprising about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) absolute ethanol, about 30% (w / w) water, or any combination thereof.

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