Treatment or prevention of depressive disorders through combination therapy

Abstract

Provided here are compositions and methods for treating diseases or disorders using a therapeutically effective amount of a N-methyl-D-aspartate (NMDA) receptor modulator and a therapeutically effective amount of a mechanistic target of rapamycin (mTOR) inhibitor.

Description

TREATMENT OR PREVENTION OF DEPRESSIVE DISORDERS THROUGH COMBINATION THERAPYCROSS REFERENCE

[0001] This application claims benefit of U.S. Provisional Patent Application No. 63 / 386,340 filed on December 07, 2022, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] N-methyl-D-aspartate (NMD A) receptors have been implicated in various nervous system disorders including neurodegenerative, mood, and neurodevelopmental disorders. NMDA receptor modulators have been categorized as rapidly acting antidepressant drugs (RAADs) due to their rapid antidepressant effects, compared to slowly acting antidepressant drugs (SAADs). They have made a paradigm shift in thinking about the pharmacological treatment of depression and other mood disorders. In some cases, co-administering a NMDA receptor modulator and a mechanistic target of rapamycin (mTOR) inhibitor can extend the effect of the NMDA receptor modulator by mTOR inhibition. In certain cases, mTOR inhibitor may prolong the clinical effect(s) of NMDA receptor modulator. In other cases, mTOR inhibitor may reduce the abuse liability of NMDA receptor modulator. Currently, coadministration of NMDA receptor modulator and mTOR inhibitor is performed by a consecutive administration of NMDA receptor modulator and mTOR inhibitor in any order and any interval between their separate administrations. Thus, there are unmet needs for the development of a pharmaceutical composition comprising both NMDA receptor modulator and mTOR inhibitor to be effectively and conveniently co-administered, to improve compliance, and to potentially reduce the abuse liability associated with the NMDA receptor modulator.SUMMARY

[0003] Provided herein, in some aspects, is a solution comprising: a N-methyl-D-aspartate (NMDA) receptor modulator and a mechanistic target of rapamycin (mTOR) inhibitor. In some embodiments, the mTOR inhibitor binds to a domain of a mTOR and inhibits the mTOR’s activity. In some embodiments, the NMDA receptor modulator binds to a component of a NMDA receptor and activates or inhibits the NMDA receptor. In a certain aspect, this disclosure provides a solution comprising: an N-methyl-D-aspartate (NMDA)receptor modulator at a concentration of about 0.04 milligram per milliliter (mg / mL) to about 150 mg / mL, and a mechanistic target of rapamycin (mTOR) inhibitor at a concentration of about 0.02 mg / mL to about 10 mg / mL. In a certain aspect, this disclosure provides a solution comprising: an N-methyl-D-aspartate (NMD A) receptor modulator, and a mechanistic target of rapamycin (mTOR) inhibitor, wherein the NMDA receptor modulator and the mTOR inhibitor have a weight ratio greater than about 1 : 1. In some aspects, this 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 a mechanistic target of rapamycin (mTOR) inhibitor at a concentration of about 0.5 microgram per milliliter (pg / mL) to about 100 g / 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 and 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 polysorbate, and 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, and wherein the PEG has an average molecular weight from about 300 to about 600, optionally is PEG 400. In some embodiments, the solution comprises polysorbate 80 and PEG 400. In some aspects, this disclosure also provides a solution comprising: an N-methyl-D-aspartate (NMDA) receptor modulator, a mechanistic target of rapamycin (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 buffering agent, an emulsifying agent, a suspending agent, a complexing agent, a sequestering or chelating agent, a thickening agent, an osmolality / tonicity agent, an antifoam er / defoam er, a penetrating agent, a polymer, a spreading agent, a wetting agent, and a pH adjusting agent. 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 polysorbate. In some embodiments, the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, andpolysorbate 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 between about 300 and about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the solution comprises ethanol. In some embodiments, the ethanol is dehydrated ethanol.

[0005] In some embodiments, a concentration of the polysorbate ranges from about 10 %w / w to about 50 %w / w. In some embodiments, a concentration of the PEG ranges from about 0.1 %w / w to about 30 %w / w. In some embodiments, a concentration of the ethanol ranges from about 10 %w / w to about 50 %w / w. In some embodiments, a concentration of the 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) dehydrated ethanol, 10% (w / w) water, or any combinations thereof. In some embodiments, the solution further comprises 33.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) dehydrated 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) dehydrated 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) dehydrated 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) dehydrated ethanol, or 30% (w / w) water.

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

[0008] This disclosure provides a solution comprising: an NMDA receptor modulator, wherein the NMDA receptor modulator binds to a component of a NMDA receptor and activates or inhibits the NMDA receptor, a mechanistic target of rapamycin (mTOR) inhibitor. In some embodiments, the mTOR inhibitor binds to a domain of a mTOR and inhibits the mTOR’s activity, and an excipient selected from the group consisting of water, polysorbate 80, PEG 400, propylene glycol, and dehydrated ethanol.

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

[0010] In a certain aspect, this 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 a 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 buffering agent, an emulsifying agent, a suspending agent, a complexing agent, a sequestering or chelating agent, a thickening agent, an osmolality / tonicity agent, an antifoamer / defoamer, a penetrating agent, a polymer, a spreading agent, a wetting agent, and a pH adjusting agent. 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 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 between about 300 and about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the solution comprises ethanol. In some embodiments, the ethanol is dehydrated ethanol.

[0011] In some embodiments, a concentration of the polysorbate ranges from about 10 %w / w to about 50 %w / w. In some embodiments, a concentration of the PEG ranges from about 0.1 %w / w to about 30 %w / w. In some embodiments, a concentration of the ethanol ranges from about 10 %w / w to about 50 %w / w. In some embodiments, a concentration of the 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) dehydrated ethanol, 10% (w / w) water, or any combinations thereof. In some embodiments, the solution comprises 33.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) dehydrated 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) dehydrated 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) dehydrated 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) dehydrated ethanol, or 30% (w / w) water.

[0013] This disclosure also provides a composition comprising: a N-methyl-D-aspartate (NMD A) receptor modulator and a mechanistic target of rapamycin (mTOR) inhibitor. In some embodiments, the NMDA receptor modulator binds to a component of a NMDA receptor and activates or inhibits the NMDA receptor. In some embodiments, the mTOR inhibitor binds to a domain of a mTOR and inhibits the mTOR’s activity.

[0014] In some embodiments, a weight of the N-methyl-D-aspartate receptor modulator is greater than the mTOR inhibitor. In some embodiments, a weight ratio of the NMDA receptor modulator and the mTOR inhibitor is greater than about 1 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 2: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 800: 1 to about 5 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 600: 1 to about 5 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 500: 1 to about 5 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 300: 1 to about 5 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 10: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 30: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 50: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 100: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and 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 an aqueous vehicle, a water-miscible vehicle, a non-aqueous vehicle, a preservative, a solubility enhancer, a stabilizer, an antioxidant, a buffering agent, an emulsifying agent, a suspending agent, a complexing agent, a sequestering or chelating agent, a thickening agent, an osmolality / tonicity agent, an antifoamer / defoamer, a penetrating agent, a polymer, a spreading agent, a wetting agent and a pH adjusting agent. 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.

[0016] 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 dextromethophane and bupropion, GM-1020, Besonprodil, Eliprodil, Ifenprodil, Rislenemdaz (CERC-301 / MK- 0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, Traxoprodil (CP-101,606), BMT- 108908, Onfasprodil, Radiprodil, NP 10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1-aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A- PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, 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, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP- AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783 and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, or any mixtures thereof. In some embodiments, the NMDA receptor modulator comprises ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, or any mixtures thereof. In some embodiments, the ketamine is ketamine HC1.

[0017] In some embodiments, the mTOR inhibitor is selected from the group consisting of BEZ235 (Dactolisib, RTB101), rapamycin (Sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), Temsirolimus (CCI-779), KU-0063794, PI- 103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74-9 -), Torkinib (PP242), Tacrolimus (FK-506, fujimycin,), Ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, Sapanisertib), Voxtalisib (XL-765, SAR245409), Torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), Omipalisib (GSK2126458, UNII- 1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF- 04691502 (PF4691502), Apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE- 354 (mTOR Inhibitor II), Gedatolisib (PF-05212384, PKI-587), AZD- 2014 (Vistusertib), T orin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG 00529), 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, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib (CC 223), Clemastine (HS-592) fumarate, Nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, Astragaloside IV, Samotolisib (LY3023414), Chrysophanic Acid, and Zotarolimus (ABT-578), any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof. In some embodiments, the mTOR inhibitor comprises rapamycin (Sirolimus, AY 22989, 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, a 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. In some embodiments, a concentration of the polysorbate ranges from about 5 %w / w to about 50 %w / w. In some embodiments, a concentration of the 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) dehydrated ethanol, about 6% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations 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) dehydrated ethanol, about 9% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations 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) dehydrated ethanol, about 12% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations 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) dehydrated ethanol, about 15% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations 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) dehydrated ethanol, about 18% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof. In some embodiments, the solution does not comprise citric acid or DL-alpha- tocopherol.

[0019] In some embodiments, the solution comprises the NMDA receptor modulator of 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. In some embodiments, the solution comprises the mTOR inhibitor of 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.

[0020] In some embodiments, the solution is stable for at least about one week at a temperature of at most about 60°C.

[0021] In additional embodiments, this disclosure provides a method for treating or preventing a disease in a subject in need thereof, comprising administering the solution or composition disclosed herein to the subject. In some embodiments, the administration is through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route or an intranasal route. In some embodiments, the solution or composition is administered once per day, twice per day, three times per day, four times per day, or five times per day. In some embodiments, the solution or composition 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 solution or composition is administered once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten time per month.

[0022] In some embodiments, the disease is selected from the group consisting of a major depressive disorder (MDD), a major depressive episode in bipolar disorder (bipolar depression), a persistent depressive disorder (dysthymia), a disruptive mood dysregulation disorder, a major depressive disorder (including major depressive episode), a premenstrual dysphoric disorder, a substance / medication-induced depressive disorder, a depressivedisorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, a posttraumatic stress disorder, an addictive disorder, bipolar I disorder, bipolar II disorder, 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 another medical condition, borderline personality disorder, treatment-resistant depression, unspecified anxiety disorder, chronic pain, and any combinations thereof. In some embodiments, the disease, disorder, or condition is a mood disorder, optionally a depressive disorder. In some embodiments, the treating or preventing is by an adjunctive therapy.

[0023] Provided herein is a method for treating or preventing a depressive disorder of a subject, comprising administering a solution comprising: an NMD A receptor modulator, wherein the NMDA receptor modulator binds to a component of a NMDA receptor and activates or inhibits the NMDA receptor, a mechanistic target of rapamycin (mTOR) inhibitor, wherein the mTOR inhibitor binds to a domain of a mTOR and inhibits the mTOR’s activity, wherein a weight ratio of the NMDA receptor modulator and the mTOR inhibitor is greater than about 1 : 1, and an excipient selected from the group consisting of water, polysorbate 80, PEG 400, propylene glycol, and dehydrated ethanol. In some aspects, this disclosure provides a method of treating or preventing a disease, disorder, or condition in a subject in need thereof comprising: mixing a first solution comprising a N-methyl-D- aspartate (NMDA) receptor modulator and a second solution comprising a mechanistic target of rapamycin (mTOR) inhibitor, thereby generating 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 generated.

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

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

[0026] In some embodiments, the solution of the NMDA receptor modulator 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 buffering agent, an emulsifying agent, a suspending agent, a complexing agent, a sequestering or chelating agent, a thickening agent, an osmolality / tonicity agent, an antifoam er / defoam er, a penetrating agent, a polymer, a spreading agent, a wetting agent and a pH adjusting agent. In some embodiments, the solution of the NMDA receptor modulator 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 of the NMDA receptor modulator comprises water. In some embodiments, the solution of the NMDA receptor modulator comprises 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 of the NMDA receptor modulator comprises PEG. In some embodiments, the PEG has an average molecular weight between about 300 and about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the solution of the NMDA receptor modulator comprises ethanol. In some embodiments, the ethanol is dehydrated ethanol.

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

[0028] In some embodiments, the solution comprises 38.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) dehydrated ethanol, 10% (w / w) water, or any combinations thereof. In some embodiments, the solution comprises 33.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) dehydrated 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) dehydrated 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) dehydrated 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) dehydrated ethanol, or 30% (w / w) water.

[0029] In some embodiments, a weight of the N-methyl-D-aspartate receptor modulator is greater than the mTOR inhibitor. In some embodiments, a weight ratio of the N-methyl-D- aspartate receptor modulator and 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 a saline solution comprising water and sodium chloride (NaCl). In some embodiments, a concentration of the NaCl ranges from about 0.5 milligram 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 dehydrated alcohol, DL-alpha-tocopherol, propylene glycol, and anhydrous citric acid. In some embodiments, the dehydrated alcohol comprises ethyl alcohol.

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

[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 dextromethophane and bupropion, GM-1020, Besonprodil, Eliprodil, Ifenprodil, Rislenemdaz (CERC-301 / MK- 0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, Traxoprodil (CP-101,606), BMT- 108908, Onfasprodil, Radiprodil, NP 10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1-aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A- PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, 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, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP- AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783 and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, or any mixtures thereof. In some embodiments, the NMDA modulator comprises ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, or any mixtures thereof. In some embodiments, the ketamine is ketamine HC1.

[0032] In some embodiments, the mTOR inhibitor is selected from the group consisting of BEZ235 (Dactolisib, RTB101), rapamycin (Sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), Temsirolimus (CCI-779), KU-0063794, PI- 103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74-9 -), Torkinib (PP242), Tacrolimus (FK-506, fujimycin,), Ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, Sapanisertib), Voxtalisib (XL-765, SAR245409), Torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), Omipalisib (GSK2126458, UNII- 1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF- 04691502 (PF4691502), Apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE- 354 (mTOR Inhibitor II), Gedatolisib (PF-05212384, PKI-587), AZD- 2014 (Vistusertib), T orin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG 00529), 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, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib (CC 223), Clemastine (HS-592) fumarate, Nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, Astragaloside IV, Samotolisib (LY3023414), Chrysophanic Acid, and Zotarolimus (ABT-578), any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof. In some embodiments, the mTOR inhibitor comprises rapamycin (Sirolimus, AY 22989, ABI-009) or Temsirolimus (CCI-779).

[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 adose 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 dose of about 30 mg to about 90 mg. In some embodiments, the NMDA receptor modulator is administered at dose of about 30 mg to about 60 mg. In some embodiments, the mTOR inhibitor is administered at a dose of about 1 pg / kg to about 100 pg / kg. In some embodiments, the mTOR inhibitor is administered at a dose of about 2.5 pg / kg to about 30 pg / kg. In some embodiments, the mTOR inhibitor is administered at a dose of about 3 pg / kg to about 25 pg / kg. In some embodiments, the mTOR inhibitor is administered at dose of about 1 pg to about 40 pg. In some embodiments, the mTOR inhibitor is administered at dose of about 20 pg to about 50 pg. In some embodiments, the mTOR inhibitor is administered at dose of about 1 pg to about 70 pg. In some embodiments, the mTOR inhibitor is administered at dose of about 5 pg to about 60 pg. In some embodiments, the mTOR inhibitor is administered at dose of about 0.1 mg to about 4 mg.

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

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

[0036] In some embodiments, the volume ratio of the first solution and 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, a weight ratio of the NMDA receptor modulator and 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 combinations thereof. In some embodiments, the first container comprises polysorbate, and wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, optionally is polysorbate 80. In some embodiments, the first container comprises PEG, and wherein the PEG has an average molecular weight between about 300 and about 600, optionally is PEG 400. In some embodiments, the second container further comprises ethanol, DL-alpha-tocopherol, propylene glycol, citric acid, or any combinations thereof. In some embodiments, the second container further comprises ethanol, propylene glycol, or any combinations thereof.

[0037] In a certain aspect, this disclosure provides a kit comprising: (i) a first container housing a first composition comprising an N-methyl-D-aspartate (NMD A) receptor modulator; and (ii) a second container housing a second composition comprising a mechanistic target of rapamycin (mTOR) inhibitor, wherein the NMDA receptor modulator and the mTOR inhibitor have a weight ratio 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 combinations thereof. In some embodiments, the first composition is a solid. In some embodiments, the solid is powder. In some embodiments, the solid is dissolved in a diluent.

[0038] In some aspects, this disclosure also provides a kit 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 a mechanistic target of rapamycin (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 greater than about 1 : 1.

[0039] In some embodiments, the first solution or the first composition further comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 10% (w / w) water, or any combinations thereof. In some embodiments, the first solution or the first composition further comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 15% (w / w) water, or any combinations thereof. In some embodiments, the first solution or the first composition further comprises about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 20% (w / w) water, or any combinations thereof. In some embodiments, the first solution or the first composition further comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 25% (w / w) water, or any combinations thereof. Insome embodiments, the first solution or the first composition further comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 30% (w / w) water, or any combinations thereof. In some embodiments, the second solution or the second composition further comprises about 39.5% (w / v) dehydrated 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 combinations thereof. In some embodiments, the second solution or the second composition further comprises about 39.5% (w / v) dehydrated ethanol, about 50.3% (w / v) propylene glycol, or any combinations thereof.

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

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

[0042] In some aspects, this disclosure provides a solution comprising: an N-methyl-D- aspartate (NMDA) receptor modulator, polysorbate or PEG 400. In some aspects, this disclosure provides a solution comprising: a mechanistic target of rapamycin (mTOR) inhibitor, wherein a concentration of mTOR inhibitor is about 0.05 mg / mL to about 10mg / 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.

[0043] In additional aspects, this disclosure provides a solution comprising water, ethanol, polyethylene glycol (PEG), polysorbate, or any combinations 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) dehydrated ethanol, about 10% (w / w) water, or any combinations 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) dehydrated ethanol, about 15% (w / w) water, or any combinations 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) dehydrated ethanol, about 20% (w / w) water, or any combinations 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) dehydrated ethanol, about 25% (w / w) water, or any combinations 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) dehydrated ethanol, about 30% (w / w) water, or any combinations thereof.

[0044] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this 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 disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.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.BRIEF DESCRIPTION OF THE DRAWINGS

[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 beobtained 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 of which:

[0047] FIG. 1 shows visual appearances of stability samples at 50°C and t is 2 weeks, according to some embodiments of the present disclosure.

[0048] FIG. 2 shows visual appearances of two-vial kit before and after mixing, according to some embodiments of the present disclosure.

[0049] FIG. 3 shows visual appearances of saline solutions before and after adding formulated APIs, according to some embodiments of the present disclosure.

[0050] FIG. 4 shows visual appearances of diluents and solubility samples in Diluent A, B, and C, according to some embodiments of the present disclosure.

[0051] FIG. 5 shows visual appearances of diluents and solubility samples in Diluent D and E, according to some embodiments of the present disclosure.

[0052] FIG. 6 shows visual appearances of diluents and solubility samples in Diluent F and G, according to some embodiments of the present disclosure.

[0053] FIG. 7 displays solubility of ketamine HC1 as a function of water composition, according to some embodiments of the present disclosure.

[0054] FIG. 8 shows visual appearances of sirolimus solubility assay, according to some embodiments of the present disclosure.

[0055] FIG. 9 shows visual appearances of ketamine HC1 solubility assay, according to some embodiments of the present disclosure.

[0056] FIG. 10 shows visual appearances of ketamine HC1 solubility assay, according to some embodiments of the present disclosure.

[0057] FIG. 11 shows visual appearances of sirolimus solubility assay, according to some embodiments of the present disclosure.

[0058] FIG. 12 shows visual appearances of combination solubility assay, according to some embodiments of the present disclosure.DETAILED DESCRIPTIONCOADMINISTRATION THERAPHY

[0059] N-methyl-D-aspartate (NMD A) receptors are ionotropic glutamate receptors functioning in synaptic transmission, plasticity and cognition. NMDA receptors have been implicated in various nervous system disorders including neurodegenerative, mood, andneurodevelopmental disorders. NMDA receptor modulators have been categorized as rapidly acting antidepressant drugs (RAADs) due to their rapid antidepressant effects, compared to slowly acting antidepressant drugs (SAADs). Among various NMDA receptor modulators, the s-isomer of ketamine, esketamine (Spravato), has been approved by the U.S. FDA for prescription to patients with treatment-resistant depression and depressed patients at risk for suicide. However, the effects of ketamine and other NMDA receptor modulators are transient, for example, persisting for approximately 7 days in the case of ketamine. Further, prototypical NMDA receptor modulators can induce transient psychotomimetic and dissociative effects, can produce hemodynamic instability, may cause nausea and vomiting, and are associated with significant abuse liability. Mechanistic target of rapamycin (mTOR) is a threonine and serine protein kinase and is implicated in governing cell growth and proliferation. mTOR has been known as a target of immunosuppressive drug rapamycin. Rapamycin is the prototype of the first generation of mTOR inhibitors.

[0060] According to some embodiments of the present disclosure, subject in need of treatment for a mood disorder (e.g., depression) can be co-administered a NMDA receptor modulator and an mTOR inhibitor for the extension of the effect of the NMDA receptor modulator by mTOR inhibition. In certain cases, mTOR inhibitor prolongs the clinical effect(s) of NMDA receptor modulator. In other embodiments, mTOR inhibitor reduces the abuse liability of NMDA receptor modulator. In some cases, administering a single dose of mTOR inhibitor, two hours prior to a single ketamine infusion, increases the duration of benefits produced by ketamine from a few days to at least two weeks. In some cases, a single dose of mTOR inhibitor at a dose that blocks mTOR blocks the antidepressant effects of NMDA receptor modulator.SOLUTION BASED COFORMULATION

[0061] Provided herein in one aspect is a solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator and a mechanistic target of rapamycin (mTOR) inhibitor. In some embodiments, the NMDA receptor modulator binds to a component of a NMDA receptor and activates or inhibits the NMDA receptor. In some embodiments, the mTOR inhibitor binds to a domain of a mTOR and inhibits the mTOR’s activity.

[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 dextromethophane andbupropion, GM-1020, Besonprodil, Eliprodil, Ifenprodil, Rislenemdaz (CERC-301 / MK- 0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, Traxoprodil (CP-101,606), BMT- 108908, Onfasprodil, Radiprodil, NP 10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1-aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A- PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, 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, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP- AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, and NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof. In some embodiments, the NMDP receptor modulator is a 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 dextromethophane and bupropion, or GM-1020. In some embodiments, the NMDP receptor modulator is NR2B NAMs / GluN2B NAMs, such as, but not limited to, Besonprodil, Eliprodil, Ifenprodil, Rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, Traxoprodil (CP-101,606), BMT-108908, Onfasprodil, 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, which comprises 20 mg of dextromethorphan hydrobromide and 10 mg of quinidine sulfate. In some embodiments, the NMDA receptor modulator is a fixed dose combination of dextromethophane and bupropion. In some embodiments, a fixed dose combination of dextromethophane and bupropion comprises 45 mg of dextromethorphan and 105 mg of bupropion.

[0063] In some embodiments, the NMDA receptor modulator comprises ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixtures thereof. In some embodiments, the ketamine is ketamine HC1.

[0064] In some embodiments, the mTOR inhibitor comprises BEZ235 (Dactolisib, RTB101), rapamycin (Sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), Temsirolimus (CCI-779), KU-0063794, PI- 103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI- 103 - CAS 371935-74-9), Torkinib (PP242), Tacrolimus (FK-506, fujimycin,), Ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, Sapanisertib), Voxtalisib (XL-765, SAR245409), Torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), Omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), Apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), Gedatolisib (PF- 05212384, PKI-587), AZD- 2014 (Vistusertib), Torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG 00529), 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, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib (CC 223), Clemastine (HS-592) fumarate, Nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, Astragaloside IV, Samotolisib (LY3023414), Chrysophanic Acid, or Zotarolimus (ABT- 578), or a salt, solvate, enantiomer, tautomer, diastereomer, steroisomer, 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 diet-derived natural products, such as, but not limited to, curcumin, resveratrol, epigallocatechin gallate (EGCG), genistein, 3, 3-diindolylmethane (DIM) or caffeine.

[0065] In some embodiments, the mTOR inhibitor comprises rapamycin (Sirolimus, AY 22989, ABI-009) or Temsirolimus (CCI-779).

[0066] In some embodiments, the solution is produced by mixing a first solution or a first composition comprising an NMDA receptor modulator and a second solution or a second composition comprising an mTOR inhibitor. In some embodiments, the solution is produced by mixing a first solution or a first composition comprising ketamine HC1 and a second solution or a second composition comprising temsirolimus.

[0067] In some embodiments, the first solution or the first composition comprises NMDA receptor modulator at a concentration of about 1 milligram per milliliter (mg / mL) to 200mg / mL. In some embodiments, the first solution or the first composition comprises 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, 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, 1 80 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL. In some embodiments, the first solution or the first composition comprises NMDA receptor modulator at 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, 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, 1 80 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL.

[0068] In some embodiments, the first solution or the first composition comprises 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 the first composition comprises 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, 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, 1 80 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL. In some embodiments, the first solution or the first composition comprises ketamine (free base or free base equivalent from a salt) at 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, 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, 1 80 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL.

[0069] In some embodiments, the second solution or the second composition comprises mTOR inhibitor at a concentration of about 0.05 mg / mL to 25 mg / mL. In some embodiments, the second solution or the second composition comprises mTOR inhibitor at aconcentration 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 the second composition comprises mTOR inhibitor at a concentration of at most 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.

[0070] In some embodiments, the second solution or the second composition comprises temsirolimus at a concentration of about 0.05 mg / mL to 25 mg / mL. In some embodiments, the second solution or the second composition comprises 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 the second composition comprises temsirolimus at a concentration of at most 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.

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

[0072] After mixing of the first solution or the first composition, and the second solution or the second composition, the solution comprises NMDA receptor modulator and mTOR inhibitor at a weight ratio greater than about 1 : 1. In some embodiments, the solutioncomprises NMDA receptor modulator and mTOR inhibitor at a weight ratio ranges from about 1000: 1 to about 2: 1. In some embodiments, the solution comprises NMDA receptor modulator and mTOR inhibitor at a weight ratio ranges from about 800: 1 to about 5 : 1. In some embodiments, the solution comprises NMDA receptor modulator and mTOR inhibitor at a weight ratio ranges from about 600: 1 to about 5: 1. In some embodiments, the solution comprises NMDA receptor modulator and mTOR inhibitor at a weight ratio ranges from about 500: 1 to about 5: 1. In some embodiments, the solution comprises NMDA receptor modulator and mTOR inhibitor at a weight ratio from about 300: 1 to about 5 : 1. In some embodiments, the solution comprises NMDA receptor modulator and mTOR inhibitor at a weight ratio ranges from about 1000: 1 to about 10: 1. In some embodiments, the solution comprises NMDA receptor modulator and mTOR inhibitor at a weight ratio ranges from about 1000: 1 to about 30: 1. In some embodiments, the solution comprises NMDA receptor modulator and mTOR inhibitor at a weight ratio ranges from about 1000: 1 to about 50: 1. In some embodiments, the solution comprises NMDA receptor modulator and mTOR inhibitor at a weight ratio ranges from about 1000: 1 to about 100: 1. In some embodiments, the solution comprises NMDA receptor modulator and mTOR inhibitor at a weight ratio ranges from about 1000: 1 to about 200: 1. In some embodiments, the solution comprises NMDA receptor modulator and mTOR inhibitor at a weight ratio ranges from about 1000: 1 to about 2: 1. In some embodiments, the solution comprises NMDA receptor modulator and mTOR inhibitor at a weight ratio ranges 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.

[0073] After mixing of the first solution or the first composition, and the second solution or the second composition, the solution comprises NMDA receptor modulator at a concentration of about 0.04 milligram per milliliter (mg / mL) to 150 mg / mL. In some embodiments, the solution comprises 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, 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. In some embodiments, the solution comprises NMDA receptor modulator at a concentration of 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, 0.6mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL,l 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, 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.

[0074] After mixing of the first solution or the first composition, and the second solution or the second composition, the solution comprises ketamine (free base or free base equivalent from a salt ) at a concentration of about 0.04 milligram per milliliter (mg / mL) to 150 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 0.04 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, 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. In some embodiments, the solution comprises ketamine (free base or free base equivalent from a salt) at a concentration of 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, 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.

[0075] After mixing of the first solution or the first composition, and the second solution or the second composition, the solution comprises mTOR inhibitor at a concentration of about 0.02 mg / mL to 10 mg / mL. In some embodiments, the solution comprises 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 mTOR inhibitor at a concentration of at most 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, 0.6mg / 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.

[0076] After mixing of the first solution or the first composition, and the second solution or the second composition, the solution comprises 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 at most 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.

[0077] In some embodiments, the solution may be further diluted by a diluent. After the dilution, the solution comprises NMDA receptor modulator at a concentration of about 0.01 mg / mL to 1.0 mg / mL. In some embodiments, the solution comprises 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 NMDA receptor modulator at a concentration of at most 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.

[0078] In some embodiments, the solution may be further diluted by a diluent. After the dilution, the solution comprises 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 comprises ketamine (free base or free base equivalent from a salt) at a concentration of at most 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.

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

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

[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 at most 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. In some embodiments, the solution comprises at most about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (w / v) dextrose in water.

[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 buffering agent, an emulsifying agent, a suspending agent, a complexing agent, a sequestering or chelating agent, a thickening agent, an osmolality / tonicity agent, an antifoam er / defoam er, a penetrating agent, a polymer, a spreading agent, a wetting agent, and a pH adjusting agent.

[0083] In some embodiments, the first solution or the first composition further comprises polysorbate, polyethylene glycol (PEG), ethanol, water, or any combinations thereof. In some embodiments, the first solution or the first composition comprises 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 the first composition comprises PEG. In some embodiments, the PEG has an average molecular weight between about 300 and about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the first solution or the first composition comprises ethanol. In some embodiments, the ethanol is dehydrated ethanol.

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

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

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

[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 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 between about 300 and about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the solution comprises ethanol. In some embodiments, the ethanol is dehydrated ethanol.

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

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

[0090] After mixing of the first solution or the first composition, and the second solution or the second composition, in some embodiments, a concentration of the ethanol ranges from about 1 %w / w to about 80 %w / w. In some embodiments, a concentration of the ethanol ranges from about 10 %w / w to about 50 %w / w. In some embodiments, a concentration of the 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, a concentration of the ethanol 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, a concentration of the ethanol ranges from about 1 to 80, 5 to 75, 10 to 70, 15 to 65, 20 to 60, 25 to 55, 30 to 50, 35 to 45, or 40 to 80 %w / w. In some embodiments, a concentration of the dehydrated ethanol ranges from about 1 %w / w to about 80 %w / w. In some embodiments, a concentration of the dehydrated ethanol ranges from about 10 %w / w to about 50 %w / w. In someembodiments, a concentration of the dehydrated 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, a concentration of the dehydrated ethanol 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, a concentration of the dehydrated ethanol ranges from about 1 to 80, 5 to 75, 10 to 70, 15 to 65, 20 to 60, 25 to 55, 30 to 50, 35 to 45, or 40 to 80 %w / w.

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

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

[0093] After mixing of the first solution or the first composition, and the second solution or the second composition, the solution comprises the ethanol of a concentration ranges from about 10 %w / w to about 50 %w / w. In some embodiments, the solution comprises the water of a concentration ranges from about 0.1 %w / w to about 30 %w / w. In some embodiments, the solution comprises the propylene glycol of a concentration ranges from about 5 %w / w to about 50 %w / w. In some embodiments, the solution comprises the polysorbate of a concentration ranges from about 5 %w / w to about 50 %w / w. In some embodiments, the solution comprises the PEG of a concentration 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) dehydrated ethanol, about 6% (w / w)water, about 20.12% (w / v) propylene glycol, or any combinations 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) dehydrated ethanol, about 9% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations 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) dehydrated ethanol, about 12% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations 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) dehydrated ethanol, about 15% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations 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) dehydrated ethanol, about 18% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof.

[0094] After mixing of the first solution or the first composition, and the second solution or the second composition, in some embodiments, a weight of the N-methyl-D-aspartate receptor modulator is greater than the mTOR inhibitor. In some embodiments, a weight ratio of the NMDA receptor modulator and the mTOR inhibitor is greater than about 1 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 2: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 800: 1 to about 5 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 600: 1 to about 5 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 500: 1 to about 5 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 300: 1 to about 5 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 10: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 30: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 50: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 100: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 200: 1.In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 2: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and 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.

[0095] In some embodiments, the solution comprises the NMDA receptor modulator of 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. In some embodiments, the solution comprises the NMDA receptor modulator of 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. In some embodiments, the solution comprises the NMDA receptor modulator of at most 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.

[0096] In some embodiments, the solution comprises the mTOR inhibitor of 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. In some embodiments, the solution comprises the mTOR inhibitor of 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. In some embodiments, the solution comprises the mTOR inhibitor of at most 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.

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

[0098] Also provided herein is a solution comprising an NMDA receptor modulator and an excipient. In some embodiments, the NMDA receptor modulator binds to a component of a 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 buffering agent, an emulsifying agent, a suspending agent, a complexing agent, a sequestering or chelating agent, a thickening agent, an osmolality / tonicity agent, an antifoam er / defoam er, a penetrating agent, a polymer, a spreading agent, a wetting agent, and a pH adjusting agent. 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 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 between about 300 and about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the solution comprises ethanol. In some embodiments, the ethanol is dehydrated ethanol.

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

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

[0101] In some embodiments, a concentration of the ethanol ranges from about 1 %w / w to about 80 %w / w. In some embodiments, a concentration of the ethanol ranges from about 10 %w / w to about 50 %w / w. In some embodiments, a concentration of the 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, a concentration of the ethanol 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, a concentration of the ethanol ranges from about 1 to 80, 5 to 75, 10 to 70, 15 to 65, 20 to 60, 25 to 55, 30 to 50, 35 to 45, or 40 to 80 %w / w. In some embodiments, a concentration of the dehydrated ethanol ranges from about 1 %w / w to about 80 %w / w. In some embodiments, a concentration of the dehydrated ethanol ranges from about 10 %w / w to about 50 %w / w. In some embodiments, a concentration of the dehydrated 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, a concentration of the dehydrated ethanol 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, a concentration of the dehydrated ethanol ranges from about 1 to 80, 5 to 75, 10 to 70, 15 to 65, 20 to 60, 25 to 55, 30 to 50, 35 to 45, or 40 to 80 %w / w.

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

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

[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) dehydrated ethanol, about 6% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations 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) dehydrated ethanol, about 9% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations 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) dehydrated ethanol, about 12% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations 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) dehydrated ethanol, about 15% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations 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) dehydrated ethanol, about 18% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof.

[0105] In some embodiments, the solution comprises a N-methyl-D-aspartate (NMD A) receptor modulator, a mechanistic target of rapamycin (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 a N-methyl-D-aspartate (NMD A) receptor modulator, a mechanistic target of rapamycin (mTOR) inhibitor, polysorbate 80, PEG 400, dehydrated ethanol, water, or any combinations thereof. In some embodiments, the solution comprises a N-methyl-D-aspartate (NMD A) receptor modulator, a mechanistic target of rapamycin (mTOR) inhibitor, about 23.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) dehydrated ethanol, about 6% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof. In some embodiments, the solution comprises a N-methyl-D-aspartate (NMD A) receptor modulator, a mechanistic target of rapamycin (mTOR) inhibitor, about 20.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) dehydrated ethanol, about 9% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof. In some embodiments, the solution comprises a N-methyl-D-aspartate (NMD A) receptormodulator, a mechanistic target of rapamycin (mTOR) inhibitor, about 17.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) dehydrated ethanol, about 12% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof. In some embodiments, the solution comprises a N-methyl-D-aspartate (NMD A) receptor modulator, a mechanistic target of rapamycin (mTOR) inhibitor, about 14.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) dehydrated ethanol, about 15% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof. In some embodiments, the solution comprises a N-methyl-D-aspartate (NMD A) receptor modulator, a mechanistic target of rapamycin (mTOR) inhibitor, about 11.37% (w / w) polysorbate 80, about 7.38% (w / w) PEG 400, about 39.05% (w / w) dehydrated ethanol, about 18% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof.

[0106] In some embodiments, a weight of the N-methyl-D-aspartate receptor modulator is greater than the mTOR inhibitor. In some embodiments, a weight ratio of the NMDA receptor modulator and the mTOR inhibitor is greater than about 1 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 2: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 800: 1 to about 5 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 600: 1 to about 5 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 500: 1 to about 5 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 300: 1 to about 5 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 10: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 30: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 50: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 100: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 200: 1.In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 2: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and 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.

[0107] This disclosure also provides a solution comprising 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, dehydrated ethanol, or any combinations 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) dehydrated ethanol, about 10% (w / w) water, or any combinations 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) dehydrated ethanol, about 15% (w / w) water, or any combinations 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) dehydrated ethanol, about 20% (w / w) water, or any combinations 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) dehydrated ethanol, about 25% (w / w) water, or any combinations 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) dehydrated ethanol, about 30% (w / w) water, or any combinations thereof.

[0108] In some embodiments, the solution comprises NMDA receptor modulator at a concentration of about 1 mg / mL to 200 mg / mL. In some embodiments, the solution comprises 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, 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, 1 80 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL. In some embodiments, the solution comprises NMDA receptor modulator at 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, 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,l 80 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL.

[0109] In some embodiments, the solution comprises 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 comprises 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, 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, 1 80 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL. In some embodiments, the solution comprises ketamine (free base or free base equivalent from a salt) at 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, 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, 1 80 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL.

[0110] In some embodiments, the solution comprises the NMDA receptor modulator of 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. In some embodiments, the solution comprises the NMDA receptor modulator of 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. In some embodiments, the solution comprises the NMDA receptor modulator of at most 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.[OHl] In some embodiments, the solution comprises ketamine (free base or free base equivalent from a salt) of 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. In some embodiments, the solution comprises ketamine (free base or free base equivalent from a salt) of 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. In some embodiments, the solution comprises ketamine (free base or free base equivalent from a salt) of at most about 20 mg, 30 mg, 40mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg.

[0112] In additional aspects, this disclosure provides a solution comprising a mechanistic target of rapamycin (mTOR) inhibitor. In some embodiments, the mTOR inhibitor comprises rapamycin (Sirolimus, AY 22989, ABI-009, Rapamune, Fyarro) or temsirolimus (Torisel, CCI-779). In some embodiments, the solution comprises mTOR inhibitor at a concentration of about 0.05 mg / mL to 25 mg / mL. In some embodiments, the solution comprises 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 mTOR inhibitor at a concentration of at most 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.

[0113] In some embodiments, the solution comprises temsirolimus at a concentration of about 0.05 mg / mL to 25 mg / mL. In some embodiments, the solution comprises 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 comprises temsirolimus at a concentration of at most 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.

[0114] In some embodiments, the solution comprises the mTOR inhibitor of 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. In some embodiments, the solution comprises the mTOR inhibitor of 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. In some embodiments, the solution comprises the mTOR inhibitor of at most 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.

[0115] In some embodiments, the solution comprises temsirolimus of 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. In some embodiments, the solution comprises temsirolimus of 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. In some embodiments, the solution comprises temsirolimus of at most 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.

[0116] In some embodiments, the solution further comprises about 39.5% (w / v) dehydrated 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 combinations thereof.

[0117] In some embodiments, the first solution or the first composition is stable for at least about one week, two weeks, three weeks, a month, two months, six months, eight months, ten months, twelve months, two years, or three years at room temperature. In some embodiments, the first solution or the first composition is stable for from about one week to about two years, two weeks to twelve months, three weeks to ten months, a month to ten months, two months to eight months, or six months to two years at a temperature of at most about 60°C. In some embodiments, the first solution or the first composition is stable for at least about a week, two weeks, three weeks, a month, two months, six months, eight months, ten months, twelve months, two years at a temperature lower than about 60°C. In some embodiments, the first solution or the first composition is stable at a temperature of about 10, 20, 30, 40, 50, or 60°C. In some embodiments, the first solution or the first composition is stable at a temperature of from about 10°C to 60°C, 20°C to 50°C, or 30°C to 40°C.

[0118] In some embodiments, the second solution or the second composition is stable for at least about one week, two weeks, three weeks, a month, two months, six months, eight months, ten months, twelve months, two years, or three years at room temperature. In some embodiments, the second solution or the second composition is stable for from about one week to about two years, two weeks to twelve months, three weeks to ten months, a month to ten months, two months to eight months, or six months to two years at a temperature of at most about 60°C. In some embodiments, the second solution or the second composition is stable for at least about a week, two weeks, three weeks, a month, two months, six months,eight months, ten months, twelve months, two years at a temperature lower than about 60°C. In some embodiments, the second solution or the second composition is stable at a temperature of about 10, 20, 30, 40, 50, or 60°C. In some embodiments, the second solution or the second composition is stable at a temperature of from about 10°C to 60°C, 20°C to 50°C, or 30°C to 40°C.

[0119] In some embodiments, the solution is stable for at least about one week, two weeks, three weeks, a month, two months, six months, eight months, ten months, twelve months, or two years at a temperature of at most about 60°C. In some embodiments, the solution is stable for from about one week to about two years, two weeks to twelve months, three weeks to ten months, a month to ten months, two months to eight months, or six months to two years at a temperature of at most 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 from about 10°C to 60°C, 20°C to 50°C, or 30°C to 40°C.

[0120] In some embodiments, the solution comprising 30.67 mg / mL Ketamine HC1 in 38.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) dehydrated ethanol, and 10% (w / w) water is stable for 2-week storage at 50°C. In some embodiments, the solution comprising 61.34 mg / mL Ketamine HC1 in 23.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) dehydrated ethanol, and 25% (w / w) water is stable for 2- week storage at 50 °C.

[0121] In additional aspects, this disclosure provides a solution comprising water, ethanol, polyethylene glycol (PEG), polysorbate, or any combinations 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 between about 300 and 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) dehydrated ethanol, about 10% (w / w) water, or any combinations 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) dehydrated ethanol, about 15% (w / w) water, or any combinations 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) dehydrated ethanol, about 20% (w / w) water, or any combinations 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) dehydrated ethanol, about 25% (w / w) water, or any combinations thereof. In someembodiments, the solution comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 30% (w / w) water, or any combinations thereof.METHODS OF TREATMENT

[0122] This disclosure also provides a method for treating or preventing a disease, disorder, or condition in a subject in need thereof. In some embodiments, the method comprises administering the 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 generated by mixing the first solution disclosed herein and the 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 generated by mixing the first solution disclosed herein and the second solution disclosed herein.

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

[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 not achieving 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 two failed trials with agents 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 mixtures thereof. In some cases, the subject may partially respond to ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, or any mixtures thereof. In some cases, the subject may show an inadequate response to ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, or any mixtures thereof. Insome cases, the subject may show treatment resistance to ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, or any mixtures thereof.

[0125] In some embodiments, the solution is administered once per day, twice per day, three times per day, four times per day, or five times per day. 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 solution is administered once per week, once every two weeks, once per month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per months, or ten time per month. In some embodiments, the solution is administered every 2 weeks.

[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 dose of about 30 mg to about 90 mg. In some embodiments, the NMDA receptor modulator is administered at dose of about 30 mg to about 60 mg.

[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 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 dose of about 30 mg to about 60 mg.

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

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

[0130] In some embodiments, the disease, disorder, or condition is selected from the group consisting of a major depressive disorder (MDD), a major depressive episode in bipolar disorder (bipolar depression), a persistent depressive disorder (dysthymia), a disruptive mood dysregulation disorder, a major depressive disorder (including major depressive episode), a premenstrual dysphoric disorder, a substance / medi cation-induced depressive disorder, a depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, a posttraumatic stress disorder, an addictive disorder, bipolar I disorder, bipolar II disorder, 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 another medical condition, borderline personality disorder, treatment-resistant depression, unspecified anxiety disorder, chronic pain, and any combinations thereof. In some embodiments, the disease, disorder, or condition is a mood disorder, such as major depressive disorder, persistent depressive disorder (dysthymia), disruptive 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.

[0131] This disclosure also relates to a method for treating or preventing a depressive disorder of a subject. In some embodiments, the method comprises administering a solution comprising: an NMDA receptor modulator, an mTOR inhibitor, and an excipient selectedfrom the group consisting of water, polysorbate 80, PEG 400, propylene glycol, and dehydrated ethanol. In some embodiments, the method comprises administering a solution comprising: ketamine HC1, temsirolimus, and an excipient selected from the group consisting of water, polysorbate 80, PEG 400, propylene glycol, and dehydrated ethanol. In some embodiments, the method comprises administering a solution comprising: ketamine HC1, temsirolimus, and an excipient selected from the group consisting of water, polysorbate 80, PEG 400, propylene glycol, DL-alpha-tocopherol, citric acid, and dehydrated ethanol. In some embodiments, the NMDA receptor modulator binds to a component of a NMDA receptor and activates or inhibits the NMDA receptor. In some embodiments, the mTOR inhibitor binds to a domain of a mTOR and inhibits the mTOR’s activity. In some embodiments, a weight ratio of the NMDA receptor modulator and the mTOR inhibitor is greater than about 1 : 1. In some embodiments, a weight of the N-methyl-D-aspartate receptor modulator is greater than the mTOR inhibitor.METHODS OF PREPARATION

[0132] In additional embodiments are described methods for preparing a solution comprising mixing 1) a solution of an NMDA receptor modulator, wherein the NMDA receptor modulator binds to a component of a NMDA receptor and activates or inhibits the NMDA receptor and 2) a solution of an mTOR inhibitor, wherein the mTOR inhibitor binds to a domain of a mTOR and inhibits the mTOR’s activity. In some embodiments, the solution of the NMDA receptor modulator 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 buffering agent, an emulsifying agent, a suspending agent, a complexing agent, a sequestering or chelating agent, a thickening agent, an osmolality / tonicity agent, an antifoam er / defoam er, a penetrating agent, a polymer, a spreading agent, a wetting agent, and a pH adjusting agent. In some embodiments, the solution of the NMDA receptor modulator 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 of the NMDA receptor modulator comprises water. In some embodiments, the solution of the NMDA receptor modulator comprises 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 of the NMDA receptor modulator comprises PEG. In someembodiments, the PEG has an average molecular weight between about 300 and about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the solution of the NMDA receptor modulator comprises ethanol. In some embodiments, the ethanol is dehydrated ethanol.

[0133] This disclosure provides a method of preparing a solution comprising: mixing (i) a first solution comprising a N-methyl-D-aspartate (NMDA) receptor modulator, and (ii) a second solution comprising a mechanistic target of rapamycin (mTOR) inhibitor, thereby generating the solution comprising both the NMDA receptor modulator and the mTOR inhibitor. In some embodiments, a volume ratio of the first solution and the second solution is about 3:2 after mixing. In some embodiments, the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, or any mixtures thereof. In some embodiments, the ketamine is ketamine HC1. In some embodiments, the mTOR inhibitor comprises rapamycin (Sirolimus, AY 22989, AB 1-009, Rapamune, Fyarro) 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.

[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, a weight ratio of the NMDA receptor modulator and the mTOR inhibitor is greater than about 1 : 1. In some embodiments, a weight ratio of the N-methyl-D-aspartate receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 2: 1. In some embodiments, a weight ratio of the N-methyl-D-aspartate receptor modulator and the mTOR inhibitor ranges from about 600: 1 to about 5: 1.

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

[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) dehydrated ethanol, about 10% (w / w) water, or any combinations 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) dehydrated ethanol, about 15% (w / w) water, or any combinations thereof. Insome 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) dehydrated ethanol, about 20% (w / w) water, or any combinations 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) dehydrated ethanol, about 25% (w / w) water, or any combinations 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) dehydrated ethanol, about 30% (w / w) water, or any combinations thereof. In some embodiments, the second solution further comprises about 39.5% (w / v) dehydrated 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 combinations thereof.

[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 dextromethophane and bupropion, GM-1020, Besonprodil, Eliprodil, Ifenprodil, Rislenemdaz (CERC-301 / MK- 0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, Traxoprodil (CP-101,606), BMT- 108908, Onfasprodil, Radiprodil, NP 10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1-aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A- PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, 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, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP- AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, and NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof. In some embodiments, the NMDP receptor modulator comprises an NMDA receptor channel blocker such as, but not limited to, ketamine (R / S-ketamine, R-ketamine), Memantine, a fixed dose combination ofdextromethorphan and quinidine, a fixed dose combination of dextromethophane and bupropion, or GM- 1020. In some embodiments, the NMDP receptor modulator comprises NR2B NAMs / GluN2B NAMs such as, but not limited to Besonprodil, Eliprodil, Ifenprodil, Rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, Traxoprodil (CP-101,606), BMT-108908, Onfasprodil, 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, which comprises 20 mg of dextromethorphan hydrobromide and 10 mg of quinidine sulfate. In some embodiments, the NMDA receptor modulator is a fixed dose combination of dextromethophane and bupropion. In some embodiments, a fixed dose combination of dextromethophane and bupropion comprises 45 mg of dextromethorphan and 105 mg of bupropion.

[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 HC1.

[0139] In some embodiments, the mTOR inhibitor comprises BEZ235 (Dactolisib, RTB101), rapamycin (Sirolimus, AY 22989, ABI-009,), everolimus (RAD001), AZD8055 (CCG-168), Temsirolimus (CCI-779), KU-0063794, PI- 103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI- 103 - CAS 371935-74-9), Torkinib (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, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), Omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), Apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), Gedatolisib (PF-05212384, PKI-587), AZD- 2014 (Vistusertib), Torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG 00529), 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, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib (CC 223), Clemastine (HS-592) fumarate, Nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, Astragaloside IV, Samotolisib (LY3023414), Chrysophanic Acid, or Zotarolimus (ABT-578), or a salt, solvate, enantiomer, tautomer, diastereomer, steroisomer,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 diet-derived natural products such as, but not limited to curcumin, resveratrol, epigallocatechin gallate (EGCG), genistein, 3, 3-diindolylmethane (DIM) or caffeine.

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

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

[0142] In some embodiments, a concentration of the ethanol ranges from about 1 %w / w to about 80 %w / w. In some embodiments, a concentration of the ethanol ranges from about 10 %w / w to about 50 %w / w. In some embodiments, a concentration of the 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, a concentration of the ethanol 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, a concentration of the ethanol ranges from about 1 to 80, 5 to 75, 10 to 70, 15 to 65, 20 to 60, 25 to 55, 30 to 50, 35 to 45, or 40 to 80 %w / w. In some embodiments, a concentration of the dehydrated ethanol ranges from about 1 %w / w to about 80 %w / w. In some embodiments, a concentration of the dehydrated ethanol ranges from about 10 %w / w to about 50 %w / w. In some embodiments, a concentration of the dehydrated 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, a concentration of the dehydrated ethanol 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, a concentration of the dehydrated ethanol ranges from about 1 to 80, 5 to 75, 10 to 70, 15 to 65, 20 to 60, 25 to 55, 30 to 50, 35 to 45, or 40 to 80 %w / w.

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

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

[0145] In some embodiments, a weight ratio of the NMDA receptor modulator and the mTOR inhibitor is greater than about 1 : 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 2: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTORinhibitor ranges from about 800: 1 to about 5: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 600: 1 to about 5: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 500: 1 to about 5: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 300: 1 to about 5: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 10: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 30: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 50: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 100: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 200: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and the mTOR inhibitor ranges from about 1000: 1 to about 2: 1. In some embodiments, the weight ratio of the NMDA receptor modulator and 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.

[0146] In some embodiments, the method further comprises adding a diluent. In some embodiments, the diluent comprises a saline solution comprising water and sodium chloride (NaCl). In some embodiments, a concentration of the NaCl ranges from about 0.1 milligram per milliliter (mg / ml) to about 50 mg / ml. In some embodiments, the concentration of the 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 the 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.

[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 at most 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. In some embodiments, the solution comprises at most about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (w / v) dextrose in water.

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

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

[0150] In some embodiments, a concentration of the 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, a concentration of the 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, a concentration of the DL-alpha- tocopherolin the solution of the 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, a concentration of the DL-alpha-tocopherolin the solution of the mTOR inhibitor ranges from about 0.01 to 10, 0.05 to 9.0, 0.1 to 8.0, 0.2 to 7.0, 0.3 to 6.0, 0.4 to 5.0, 0.5 to 4.0, 0.6 to 3.0, 0.7 to 2.0, 0.8 to 1.0, or 0.9 to 10 %w / w.

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

[0152] In some embodiments, a concentration of the anhydrous citric acid in the solution of the mTOR inhibitor ranges from about 0.001 %w / w to about 0.01 %w / w. In some embodiments, a concentration of the 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, 0.1 %w / w. In some embodiments, a concentration of the 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, a concentration of the anhydrous citric acid in the solution of the mTOR inhibitor ranges from about 0.0005 to 0.1, 0.001 to 0.09, 0.002 to 0.08, 0.003 to 0.07, 0.004 to 0.06, 0.005 to 0.05, 0.006 to 0.04, 0.007 to 0.03, 0.008 to 0.02, 0.009 to 0.01 %w / w.KITS, DUAL CHAMBER SYRINGES, AND DUAL COMPARTMENT DEVICES

[0153] In certain aspects, the present disclosure provides a kit for preparing the solution or the composition disclosed herein for administration to a subject in need thereof. In some embodiments, the kit comprises a first container housing a first solution or a first composition comprising the NMDA receptor modulator and a second container housing a second solution or a second component comprising the mTOR inhibitor. In some embodiments, the NMDA receptor modulator binds to a component of a NMDA receptor and activates or inhibits the NMDA receptor. In some embodiments, the mTOR inhibitor binds to a domain of a mTOR and inhibits the mTOR’s activity. In some embodiments, the kit comprises a first container housing a first solution or a first composition comprising ketamine HC1 and a second container housing a second solution or a second component comprising temsirolimus.

[0154] In some embodiments, the first solution or the first 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 the first composition comprises NMDA receptor modulatorat 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, 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, 1 80 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL. In some embodiments, the first solution or the first composition comprises NMDA receptor modulator at 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, 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, 1 80 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL.

[0155] In some embodiments, the first solution or the first composition comprises 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 the first composition comprises 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 the first composition comprises 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, 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, 1 80 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL. In some embodiments, the first solution or the first composition comprises ketamine (free base or free base equivalent from a salt) at 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, 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, 1 80 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, or 200 mg / mL.

[0156] In some embodiments, the second solution or the second composition comprises mTOR inhibitor at a concentration of about 0.05 mg / mL to 25 mg / mL. In someembodiments, the second solution or the second composition comprises 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 second solution or the second composition comprises mTOR inhibitor at a concentration of at most 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.

[0157] In some embodiments, the second solution or the second composition comprises temsirolimus at a concentration of about 0.05 mg / mL to 25 mg / mL. In some embodiments, the second solution or the second composition comprises temsirolimus at a concentration of from about 0.47 mg / mL to about 9.375 mg / mL. In some embodiments, the second solution or the second composition comprises 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 the second composition comprises temsirolimus at a concentration of at most 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.

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

[0159] In some embodiments, a weight ratio of the NMDA receptor modulator and the mTOR inhibitor is greater than about 1 : 1. In some embodiments, the first container houses the first solution or the first composition further comprising water, ethanol, polyethylene glycol (PEG), polysorbate, or any combinations thereof. In some embodiments, the first container houses the first solution or the first composition further comprising water. In some embodiments, the first container houses the first solution or the first composition further comprising 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 houses the first solution or the first composition further comprising PEG. In some embodiments, the PEG has an average molecular weight between about 300 and about 600. In some embodiments, the PEG is PEG 400.

[0160] In some embodiments, the second container houses the second solution or the second composition further comprising ethanol, DL-alpha-tocopherol, propylene glycol, citric acid, or any combinations thereof. In some embodiments, the second container houses the second solution or the second composition further comprising ethanol, propylene glycol, or any combinations thereof. In some embodiments, the second container houses the second solution or the second composition not comprising DL-alpha-tocopherol or citric acid.

[0161] In some embodiments, the first composition is a solution. In some embodiments, the solution further comprises water, ethanol, polyethylene glycol (PEG), polysorbate, or any combinations thereof. In some embodiments, the solution comprises water. In some embodiments, the solution comprises 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 between about 300 and about 600. In some embodiments, the PEG is PEG 400.

[0162] In some embodiments, the first composition is a solid. In some embodiments, the solid is powder. In some embodiments, the solid is dissolved in a diluent. In some embodiments, the diluent comprises polyethylene glycol (PEG), polysorbate, or both. In some embodiments, the diluent comprises 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 anaverage molecular weight between about 300 and about 600. In some embodiments, the PEG is PEG 400. In some embodiments, the diluent comprises PEG400 and polysorbate 80.

[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 combinations thereof. In some embodiments, the solution further comprises ethanol, propylene glycol, or any combinations thereof.

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

[0165] In some embodiments, the solution or the composition disclosed herein from the first container and the second container are mixed prior to the administration. In some embodiments, the first solution or first composition in the first container and the second solution or the second composition in the second container may be mixed to generate the solution at least about 1, 2, 3, 4, 5, 6, 7, 10, 12, 16, 28, or 24 hours prior to the administration of the solution to the subject. In some embodiments, the first solution or first composition in the first container and the second solution or the second composition in the second container may be mixed to generate the solution at most about 1, 2, 3, 4, 5, 6, 7, 10, 12, 16, 28, or 24 hours prior to the administration of the solution to the subject. In some embodiments, ketamine HC1 in the first container and temsirolimus in the second container may be mixed to generate the solution at least about 1, 2, 3, 4, 5, 6, 7, 10, 12, 16, 28, or 24 hours prior to the administration of the solution to the subject. In some embodiments, ketamine HC1 in the first container and temsirolimus in the second container may be mixed to generate the solution at most about 1, 2, 3, 4, 5, 6, 7, 10, 12, 16, 28, or 24 hours prior to the administration of the solution to the subject.

[0166] In additional aspects, the present disclosure provides a dual chamber syringe for preparing the solution or the composition disclosed herein for administration to a subject in need thereof. In some embodiments, the dual chamber comprises a first chamber housing a first solution or a first composition comprising the NMDA receptor modulator and a second chamber housing a second solution or a second composition comprising the mTOR inhibitor. In some embodiments, the dual chamber comprises a first chamber housing a first solution or a first composition comprising ketamine HC1 and a second chamber housing a second solution or a second composition comprising temsirolimus. In some embodiments, thesolution or the composition disclosed herein from the first chamber and the second chamber are mixed prior to the administration.

[0167] The present disclosure also relates to a dual compartment device for preparing the solution or the composition for administration to a subject in need thereof. In some embodiments, the dual compartment device comprises a first compartment housing a first solution or a first composition comprising the NMDA receptor modulator and a second chamber housing a second solution or a second compartment comprising the mTOR inhibitor. In some embodiments, the dual chamber comprises a first compartment housing a first solution or a first composition comprising ketamine HC1 and a second compartment housing a second solution or a second composition comprising temsirolimus. In some embodiments, the solution or the composition from the first compartment and the second compartment are mixed prior to the administration. In some embodiments, the dual compartment device is a dual compartment nasal inhaler.

[0168] In some embodiments, the kit is in a form of a 2-vial kit. In some embodiments, the kit is in a form of a 2-compartment container. In some embodiments, the 2-compartment container comprises a 2-compartment syringe or a dual compartment inhaler.DEFINITIONS

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

[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 disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0171] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0172] Whenever the term “at least,” “greater than,” or “greater than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “at least,” “greater than” or “greater than or equal to” applies to each of the numerical values in that series of numerical values. For example, greater than or equal to 1, 2, or 3 is equivalent to greater than or equal to 1, greater than or equal to 2, or greater than or equal to 3.

[0173] Whenever the term “no more than,” “less than,” or “less than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “no more than,” “less than,” or “less than or equal to” applies to each of the numerical values in that series of numerical values. For example, less than or equal to 3, 2, or 1 is equivalent to less than or equal to 3, less than or equal to 2, or less than or equal to 1.

[0174] The expressions “at least one of A and B” and “at least one of A or B” may be construed to mean at least A, at least B, or at least A and B (i.e., a set comprising A and B, which set may include one or more additional elements). The term "A and / or B" may be construed to mean only A, only B, or both A and B.

[0175] The expressions “at least about A, B, and C” and “at least about A, B, or C” may be construed to mean at least about A, at least about B, or at least about C. The expressions “at most about A, B, and C” and “at most about A, B, or C” may be construed to mean at most about A, at most about B, or at most about C.

[0176] The expression “between about A and B, C and D, and E and F” may be construed to mean between about A and about B, between about C and about D, and between about E and about F. The expression “between about A and B, C and D, or E and F” may be construed to mean between about A and about B, between about C and about D, or between about E and about F.

[0177] The expression “about A to B and C to D” may be construed to mean between about A and about B and between about C and about D. The expression “about A to B or C to D” may be construed to mean between about A and about B or between about C and about D.

[0178] The term “exemplary” as used herein means “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.

[0179] The term “API” as used herein refers to the active pharmaceutical ingredient comprising a N-methyl-D-aspartate (NMD A) receptor modulator or an inhibitor of a mechanistic target of rapamycin (mTOR inhibitor).

[0180] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of’ can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

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

[0182] A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

[0183] In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

[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 “NMD A” refers to N-methyl-D-aspartate.

[0186] As used herein, the term “NMD AR” or “NMDA-R” refers to an NMD A receptor. The terms “patient,” “subject,” “individual,” and the like are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In certain non-limiting embodiments, the patient, subject, or individual is a human.

[0187] As used herein, “RAAD” refers to a rapidly acting antidepressant.

[0188] As used herein, “mTOR” refers to the protein mammalian target of rapamycin, or to the gene encoding this protein product. “mTOR inhibitor” refers to any of a range of drugs that inhibit the biochemical action of mTOR; a paradigmatic example is rapamycin (also called sirolimus), and a non-limiting list of other examples is given below.

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

[0190] The phrase “inhibit,” as used herein, means to reduce a molecule, a reaction, an interaction, a gene, an mRNA, and / or a protein’s expression, stability, function, or activity by a measurable amount. Inhibitors are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate a protein, a gene, and an mRNA stability, expression, function and activity, e.g., antagonists.

[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 that is present in an organism (including viruses) that can be isolated from a source in nature and which has not been intentionally modified by man is a naturally-occurring sequence.

[0192] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound or composition useful within the invention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. 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 injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose 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, com 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;buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound or composition useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example, in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0193] As used herein, the language “pharmaceutically acceptable salt” or “therapeutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof.

[0194] As used herein, the terms “pharmaceutically effective amount” and “effective amount” or “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result can 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” varies depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. An appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0195] A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.

[0196] As used herein, “treating a disease or disorder” means reducing the frequency and / or intensity with which a symptom of the disease or disorder is experienced by a patient. Disease and disorder are used interchangeably herein. Treatment encompasses prophylaxis and / or therapy. Accordingly, the compositions and methods of the present invention are not limited to therapeutic applications and can be used in prophylaxis ones. Thus “treating” or “treatment” of a state, disorder or condition includes: (i) preventing or delaying theappearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (ii) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (iii) relieving the disease, i.e. causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0197] As used herein, the term “about” a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.

[0198] As used herein, the terms “treatment” or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. 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 prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.

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

[0200] Embodiment 1. A solution comprising: a. an N-methyl-D-aspartate (NMD A) receptor modulator at a concentration of about 0.04 milligram per milliliter (mg / mL) to about 150 mg / mL, and b. a mechanistic target of rapamycin (mTOR) inhibitor at a concentration of about 0.02 mg / mL to about 10 mg / mL.

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

[0202] Embodiment s. A solution comprising: 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 mechanistic target of rapamycin (mTOR) inhibitor at a concentration of about 0.5 microgram per milliliter (pg / mL) to about 100 pg / mL.

[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 greater than about 1 : 1.

[0205] Embodiment 6. The solution of Embodiment 2 or 5, wherein the weight ratio of the NMDA receptor modulator and 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 the NMDA receptor modulator and the mTOR inhibitor ranges from about 600: 1 to about 5: 1.

[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 polysorbate.

[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.

[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 comprisesPEG.

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

[0213] Embodiment 14. The solution of Embodiment 13, wherein the PEG is PEG 400.

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

[0215] Embodiment 16. A solution comprising: a. an N-methyl-D-aspartate (NMD A) receptor modulator, b. a mechanistic target of rapamycin (mTOR) inhibitor, and c. polysorbate or PEG 400.

[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 greater than about 1 : 1.

[0218] Embodiment 19. The solution of Embodiment 18, wherein the weight ratio of the NMDA receptor modulator and 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 and the mTOR inhibitor ranges from about 600: 1 to about 5: 1.

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

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

[0222] Embodiment 23. The solution of any one of Embodiments 1 to 22, wherein 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 dextromethophane and bupropion, GM- 1020, Besonprodil, Eliprodil, Ifenprodil, Rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, Traxoprodil (CP-101,606), BMT-108908, Onfasprodil, Radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1- aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, 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, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PDO 196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof.

[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.

[0224] Embodiment 25. The solution of Embodiment 24, wherein the ketamine is ketamine HC1.

[0225] Embodiment 26. The solution of any one of Embodiments 1 to 25, wherein the mTOR inhibitor is selected from the group consisting of BEZ235 (Dactolisib, RTB101), rapamycin (Sirolimus, AY 22989, ABI-009,), everolimus (RAD001), AZD8055 (CCG-168), Temsirolimus (CCI-779), KU-0063794, PI- 103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI- 103 - CAS 371935-74-9), Torkinib (PP242), Tacrolimus (FK-506, fujimycin), Ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, Sapanisertib), Voxtalisib (XL-765, SAR245409), Torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), Omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), Apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), Gedatolisib (PF- 05212384, PKI-587), AZD- 2014 (Vistusertib), Torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG 00529), 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, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib (CC 223), Clemastine (HS-592) fumarate, Nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, Astragaloside IV, Samotolisib (LY3023414), Chrysophanic Acid, and Zotarolimus (ABT- 578), and any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof.

[0226] Embodiment 27. The solution of Embodiment 26, wherein the mTOR inhibitor comprises rapamycin (Sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).

[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.

[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.

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

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

[0232] Embodiment 33. The solution of any one of Embodiments 28 to 32, wherein a concentration of the 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 a concentration of the propylene glycol ranges from about 5 %w / w to about 50 %w / w.

[0234] Embodiment 35. The solution of any one of Embodiments 8 to 34, wherein a concentration of the 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 a concentration of the PEG ranges from about 0.1 %w / w to about 30 %w / w.

[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) dehydrated ethanol, about 6% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof.

[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) dehydrated ethanol, about 9% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof.

[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) dehydrated ethanol, about 12% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof.

[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) dehydrated ethanol, about 15% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof.

[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) dehydrated ethanol, about 18% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof.

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

[0242] Embodiment 43. The solution of any one of Embodiments 1 to 42, wherein the solution comprises the NMDA receptor modulator of 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.

[0243] Embodiment 44. The solution of any one of Embodiments 1 to 43, wherein the solution comprises the mTOR inhibitor of 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.

[0244] Embodiment 45. A kit comprising:(i) a first container housing 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 housing a second solution comprising a mechanistic target of rapamycin (mTOR) inhibitor at a concentration of about 0.1 mg / mL to about 25 mg / mL.

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

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

[0247] Embodiment 48. The kit of any one of Embodiments 45 to 47, wherein a weight ratio of the NMDA receptor modulator and 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 combinations thereof.

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

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

[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.

[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 comprises PEG.

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

[0255] Embodiment 56. The kit of Embodiment 55, wherein the PEG is PEG 400.

[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 combinations thereof.

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

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

[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 combinations thereof.

[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 polysorbate80.

[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.

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

[0267] Embodiment 68. The kit of Embodiment 67, wherein the PEG is PEG 400.

[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 powder.

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

[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.

[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 polysorbate80.

[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.

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

[0277] Embodiment 78. The kit of Embodiment 77, wherein the PEG is PEG 400.

[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 combinations thereof.

[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 powder.

[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 combinations thereof.

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

[0285] Embodiment 86. A kit comprising:(i) a first container housing a first composition comprising an N-methyl-D-aspartate (NMD A) receptor modulator;(ii) a second container housing a second composition comprising a mechanistic target of rapamycin (mTOR) inhibitor; and(iii) a diluent comprising polysorbate, PEG 400, or both.

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

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

[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.

[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.

[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.

[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 kit of any one of Embodiments 45 to 93, wherein the NMD A 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 dextromethophane and bupropion, GM- 1020, Besonprodil, Eliprodil, Ifenprodil, Rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro8-4304, Traxoprodil (CP-101,606), BMT-108908, Onfasprodil, Radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1- aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, 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, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PDO 196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, and NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof.

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

[0295] Embodiment 96. The kit of Embodiment 95, wherein the ketamine is ketamine HC1.

[0296] Embodiment 97. The kit of any one of Embodiments 45 to 96, wherein the mTOR inhibitor comprises BEZ235 (Dactolisib, RTB101), rapamycin (Sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), Temsirolimus (CCI-779), KU- 0063794, PI-103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74-9), Torkinib (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, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), Omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), Apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), Gedatolisib (PF- 05212384, PKI-587), AZD- 2014 (Vistusertib), Torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG 00529), 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, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib (CC 223), Clemastine (HS-592) fumarate, Nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, Astragaloside IV, Samotolisib (LY3023414), Chrysophanic Acid, or Zotarolimus (ABT- 578), or a salt, solvate, enantiomer, tautomer, diastereomer stereoisomer, or geometric isomer thereof.

[0297] Embodiment 98. The kit of Embodiment 97, wherein the mTOR inhibitor comprises rapamycin (Sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).

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

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

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

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

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

[0303] Embodiment 104. The kit of any one of Embodiments 45 to 103, wherein the second solution or the second composition further comprises about 39.5% (w / v) dehydrated 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 combinations thereof.

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

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

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

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

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

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

[0310] Embodiment 111. The kit of any one of Embodiments 45 to 110, wherein the kit is in a form of a 2-vial kit.

[0311] Embodiment 112. The kit of any one of Embodiments 45 to 110, wherein the kit is in a form of a 2-compartment container.

[0312] Embodiment 113. The kit of Embodiment 112, wherein the 2-compartment container comprises a 2-compartment syringe or a dual compartment inhaler.

[0313] Embodiment 114. A method of preparing a solution comprising: mixing (i) a first solution comprising a N-methyl-D-aspartate (NMD A) receptor modulator, and (ii) a second solution comprising a mechanistic target of rapamycin (mTOR) inhibitor, thereby generating the solution comprising both the NMDA receptor modulator and the mTOR inhibitor, wherein a volume ratio of the first solution and the second solution is about 3:2.

[0314] Embodiment 115. The method of Embodiment 114, wherein the first solution further comprises polysorbate or PEG 400.

[0315] Embodiment 116. A method of preparing a solution comprising:mixing (i) a first solution comprising a N-methyl-D-aspartate (NMD A) receptor modulator, and polysorbate or PEG 400, and (ii) a second solution comprising a mechanistic target of rapamycin (mTOR) inhibitor, thereby generating the solution comprising both the NMDA receptor modulator and the mTOR inhibitor.

[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.

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

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

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

[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.

[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 combinations thereof.

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

[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) dehydrated ethanol, about 10% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 15% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 20% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 25% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 30% (w / w) water, or any combinations thereof.

[0329] Embodiment 130. The method of any one of Embodiments 114 to 129, wherein the second solution further comprises about 39.5% (w / v) dehydrated 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 combinations thereof.

[0330] Embodiment 131. The method of any one of Embodiments 114 to 130, wherein 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 dextromethophane and bupropion, GM- 1020, Besonprodil, Eliprodil, Ifenprodil, Rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, Traxoprodil (CP-101,606), BMT-108908, Onfasprodil, Radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1- aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, 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, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512,HA-966, felbamate, PEAQX (NVP-AAM077), PDO 196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, and NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof.

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

[0332] Embodiment 133. The method of Embodiment 132, wherein the ketamine is ketamine HC1.

[0333] Embodiment 134. The method of any one of Embodiments 114 to 133, wherein the mTOR inhibitor comprises BEZ235 (Dactolisib, RTB101), rapamycin (Sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), Temsirolimus (CCI-779), KU-0063794, PI-103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74-9), Torkinib (PP242), Tacrolimus (FK-506, fujimycin), Ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, Sapanisertib), Voxtalisib (XL-765, SAR245409), Torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), Omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), Apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), Gedatolisib (PF-05212384, PKI-587), AZD- 2014 (Vistusertib), Torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE- 125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG 00529), 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, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib (CC 223), Clemastine (HS-592) fumarate, Nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, Astragaloside IV, Samotolisib (LY3023414), Chrysophanic Acid, or Zotarolimus (ABT-578), or a salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, or geometric isomer thereof.

[0334] Embodiment 135. The method of Embodiment 134, wherein the mTOR inhibitor comprises rapamycin (Sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).

[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 the solution of any one of Embodiments 1-44.

[0336] Embodiment 137. A method of treating or preventing a disease, disorder, or condition in a subject in need thereof comprising:-n-mixing a first solution comprising a N-methyl-D-aspartate (NMDA) receptor modulator and a second solution comprising a mechanistic target of rapamycin (mTOR) inhibitor, thereby generating 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 generated.

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

[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.

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

[0342] Embodiment 143. The method of Embodiment 142, wherein the PEG is PEG 400.

[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) dehydrated ethanol, about 10% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 15% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 20% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 25% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 30% (w / w) water, or any combinations thereof.

[0348] Embodiment 149. The method of any one of Embodiments 137 to 148, wherein the second solution further comprises about 39.5% (w / v) dehydrated 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 combinations thereof.

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

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

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

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

[0353] Embodiment 154. The method of any one of Embodiments 137 to 153, wherein 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 dextromethophane and bupropion, GM- 1020, Besonprodil, Eliprodil, Ifenprodil, Rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, Traxoprodil (CP-101,606), BMT-108908, Onfasprodil, Radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1- aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, 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, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PDO 196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, and NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof.

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

[0355] Embodiment 156. The method of Embodiment 155, wherein the ketamine is ketamine HC1.

[0356] Embodiment 157. The method of any one of Embodiments 137 to 156, wherein the mTOR inhibitor comprises BEZ235 (Dactolisib, RTB101), rapamycin (Sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168), Temsirolimus (Torisel, CCI-779), KU-0063794, PI- 103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI- 103 - CAS 371935-74-9), Torkinib (PP242), Tacrolimus (FK-506, fujimycin), Ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, Sapanisertib), Voxtalisib (XL-765, SAR245409), Torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), Omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), Apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), Gedatolisib (PF- 05212384, PKI-587), AZD- 2014 (Vistusertib), Torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG 00529), 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, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib (CC 223), Clemastine (HS-592) fumarate, Nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, Astragaloside IV, Samotolisib (LY3023414), Chrysophanic Acid, or Zotarolimus (ABT- 578), or a salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer and geometric isomer thereof.

[0357] Embodiment 158. The method of Embodiment 157, wherein the mTOR inhibitor comprises rapamycin (Sirolimus, AY 22989, ABI-009, Rapamune, Fyarro) or Temsirolimus (Torisel, CCI-779).

[0358] Embodiment 159. The method of any one of Embodiments 137 to 158, wherein the solution is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route.

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

[0360] Embodiment 161. The method of any one of Embodiments 137 to 158, wherein 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.

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

[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.

[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.

[0365] Embodiment 166. The method of any one of Embodiments 137 to 158, wherein the NMDA receptor modulator is administered at 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 dose of about 30 mg to about 60 mg.

[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 pg / kg to about 70 pg / kg.

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

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

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

[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 a major depressive disorder (MDD), a major depressive episode in bipolar disorder (bipolar depression), a persistent depressive disorder (dysthymia), a disruptive mood dysregulation disorder, a major depressive disorder (including major depressive episode), a premenstrual dysphoric disorder, a substance / medication-induced depressive disorder, a depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, a posttraumatic stress disorder, an addictive disorder, bipolar I disorder, bipolar II disorder, 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 another medical condition, borderline personality disorder, treatment-resistant depression, unspecified anxiety disorder, chronic pain, and any combinations thereof.

[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. A solution comprising: a. an N-methyl-D-aspartate (NMD A) receptor modulator, b. polysorbate or PEG 400.

[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.

[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) dehydrated ethanol, about 10% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 15% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 20% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 25% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 30% (w / w) water, or any combinations thereof.

[0381] Embodiment 182. The solution of any one of Embodiments 174 to 181, wherein 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 dextromethophane and bupropion, GM- 1020, Besonprodil, Eliprodil, Ifenprodil, Rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, Traxoprodil (CP-101,606), BMT-108908, Onfasprodil, Radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1- aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methox / mLydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, 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, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512,HA-966, felbamate, PEAQX (NVP-AAM077), PDO 196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, and NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof.

[0382] Embodiment 183. The solution Embodiment 182, wherein the NMD A receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixtures thereof.

[0383] Embodiment 184. The solution of Embodiment 183, wherein the ketamine is ketamine HC1.

[0384] Embodiment 185. A solution comprising: a mechanistic target of rapamycin (mTOR) inhibitor, wherein a concentration of 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.

[0385] Embodiment 186. The solution of Embodiment 185, further comprising about 39.5% (w / v) dehydrated 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 combinations thereof.

[0386] Embodiment 187. The solution of Embodiment 185 or 186, wherein the mTOR inhibitor comprises BEZ235 (Dactolisib, RTB101), rapamycin (Sirolimus, AY 22989, ABI- 009), everolimus (RAD001), AZD8055 (CCG-168), Temsirolimus (CCI-779), KU-0063794, PI-103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74-9), Torkinib (PP242), Tacrolimus (FK-506, fujimycin), Ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, Sapanisertib), Voxtalisib (XL-765, SAR245409), Torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), Omipalisib (GSK2126458, UNIL1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), Apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), Gedatolisib (PF-05212384, PKI-587), AZD- 2014 (Vistusertib), Torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE- 125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG 00529), 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, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib (CC 223), Clemastine (HS-592) fumarate, Nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, Astragaloside IV, Samotolisib(LY3023414), Chrysophanic Acid, or Zotarolimus (ABT-578), or a salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer and geometric isomer thereof.

[0387] Embodiment 188. The solution of Embodiment 187, wherein the mTOR inhibitor comprises rapamycin (Sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779).

[0388] Embodiment 189. A method of preparing a solution Embodiments 174 to 184 comprising: contacting an N-methyl-D-aspartate (NMD A) receptor modulator with a diluent comprising PEG400 or polysorbate.

[0389] Embodiment 190. The method of Embodiment 189, wherein a concentration of the NMDA receptor modulator is 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) dehydrated ethanol, about 10% (w / w) water, or any combinations thereof.

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

[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) dehydrated ethanol, about 20% (w / w) water, or any combinations thereof.

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

[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) dehydrated ethanol, about 30% (w / w) water, or any combinations thereof.

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

[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 between about 300 and about 600.

[0399] Embodiment 200. The solution of Embodiment 199, wherein the PEG is PEG 400.

[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) dehydrated ethanol, about 10% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 15% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 20% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 25% (w / w) water, or any combinations thereof.

[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) dehydrated ethanol, about 30% (w / w) water, or any combinations thereof.EXAMPLES

[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 HC1 and temsirolimus

[0406] Short-term stability of temsirolimus and ketamine HC1 was assessed at 50 °C for two weeks for the following samples:Table 1. Samples

[0407] Temsirolimus is a pro-drug of sirolimus and 25 mg dose of temsirolimus has been approved. In this example, Vehicle for temsirolimus comprises dehydrated 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, Diluent (also known as Diluent A) comprises polysorbate 80 (40.0% w / v), polyethylene glycol 400 (42.8% w / v), and dehydrated alcohol (19.9% w / v).

[0408] Visual appearances (FIG. 1) suggested that both temsirolimus and ketamine were still soluble in the Vehicle for temsirolimus individually and after they were combined (Vials lad Diluent (Vial 2a) and 3 mg / mL temsirolimus in Diluent (Vial 2c) appeared clear and slightly yellow. Vial 2b containing ketamine in Diluent was clear yellow.

[0409] HPLC assays suggested that the percent recovery of ketamine HC1 was about 100% in under all conditions. After 2 weeks at 50°C, the percent recovery of temsirolimus was about 90% (in Vehicle, Vial 1c), 3.6% (in the presence of ketamine HC1 in Vehicle, Vial Id), and 0% (in Diluent, Vial 2c). Significant amounts of impurities were detected in Vial Id and Vial 2c.

[0410] Visual appearances of stability samples at 50°C, t=2 weeks

[0411] Before the storage, Vials la-d appeared clear, colorless and viscous at room temperature. Vials 2a and 2c appeared clear, slightly yellow and viscous at room temperature. Vial 2b appeared cloudy and slightly yellow. The chemicals did not fully dissolve. Sample was filtered with 0.2 pm nylon syringe filter before being placed on stability.

[0412] After two weeks at 50°C, Vials la-d appeared clear, colorless and viscous. Vials 2a and 2c appeared clear, slightly yellow and viscous. Vial 2b appeared clear and dark yellow.Table 2. Stability summary of ketamine HC1 and temsirolimus at 50°CExample 2: Study of dilution in saline

[0413] For this example, two sets of the following vials were prepared: (1) Vial Id contained 3 mg / mL temsirolimus and 23 mg / mL ketamine HC1 in 2.4 mL Vehicle; (2) Vial 2a contained 4.8 mL Diluent. 3.6 mL of Vial 2a was transferred to Vial Id and the mixture was mixed by gentle inversion. 5 mL of the mixture was transferred into 250 mL and 125 mL saline solution. The solutions were mixed by inversion and sat at room temperature for 1 hour to let bubbles subside (FIG. 2). 500 pL of Vial 3 and of each saline dilution were aliquoted for HPLC injection. Prior to the HPLC procedure, samples were spun for 5 min at 10,000 rpm with 0.2 pm nylon spin filters. Sample from Vial 3 were diluted 50x for temsirolimusmethod, and lOOx for ketamine method with diluent corresponding to each method (FIG. 3). Samples from two saline dilutions were injected without further dilution.

[0414] Dilution in saline (Torisel formulation Vial 1 and 2; temsirolimus and ketamine HC1 in Vial 1): Ketamine HC1 and temsirolimus were fully soluble in Vial 1, resulting in a solution containing 27.5 mg / mL ketamine HC1 and 3.4 mg / mL temsirolimus in Vehicle. The solution was clear and colorless. Mixing Vial 1 with 3.6 mL of Diluent in Vial 2 resulted in a fully soluble solution containing 11.3 mg / mL ketamine HC1 and 1.4 mg / mL temsirolimus. The mixture was clear and slightly yellow. After diluting in saline, the solution appeared clear and colorless. The target concentrations were reached after the mixture was diluted in 250 mL and 125 mL saline solution: dilution in 250 mL saline resulted in 0.186 mg / mL ketamine HC1 and 0.022 mg / mL temsirolimus and dilution in 125 mL saline resulted in 0.359 mg / mL ketamine HC1 and 0.044 mg / mL temsirolimus.Table 3. Concentrations of temsirolimus and ketamine HC1 analyzed by HPLCExample 3: Ketamine HC1 solubility in modified diluents

[0415] Diluent B and Diluent C were created based on the original Diluent (Diluent A). The compositions of the Diluents are summarized in the following table:Table 4. Composition of various Diluents, A, B, and C

[0416] To prepare saturated solution, about 80 mg ketamine HC1 were added to 2.5 mL of each diluent in a 20 mL scintillation vial. The samples were stirred at room temperature for about 2 hours. Visual appearances were recorded (FIG. 4). The samples were filtered with 0.2 pm nylon syringe filter. 500 pL of Diluents and the samples were aliquoted for HPLC analysis. The solutions were spun for 5 mins, 10,000 rpm using 0.2 pm nylon spin filters. The solutions were diluted 50 times prior to HPLC injection. The results are summarized in the following table:Table 5. Ketamine HC1 solubility in various Diluents A, B, and C

[0417] Ketamine HC1 has the highest solubility in Diluent B, which contains the highest % w / w of dehydrated alcohol.Example 4: Ketamine HC1 solubility in Vial 2 with modified diluent

[0418] Diluent D and Diluent E were created based on the original Diluent (Diluent A) and Diluent B, respectively. Diluent E and Diluent F were created based on the composition of Diluent E. The compositions of the Diluents are summarized in the following table:Table 6. Composition of various Diluents, D, E, F, and G

[0419] To create saturated solutions, about 80 mg ketamine HC1 were added to 2.5 mL ofDiluent D, about 100 mg ketamine HC1 were added to 2.5 mL of Diluent E, and about 150 mg ketamine HC1 were added to 2.5 mL of Diluent F and Diluent G. Samples were stirred at room temperature for about 2h. Visual appearances were recorded (FIG. 5 and FIG. 6). The samples were filtered with 0.2 pm nylon syringe filter. 500 pL of Diluents and the samples were aliquoted for HPLC analysis. The solutions were spun for 5 mins, 10,000 rpm using 0.2 pm nylon spin filters. The solutions were diluted 50 times prior to HPLC injection. The results are summarized in the following table:Table 7. Ketamine HC1 solubility in various Diluents D, E, F, and G

[0420] The target concentration was reached in Diluent E, F, and G, with the highest solubility in Diluent G (53.0 mg / mL). Solubility of ketamine HC1 in various Diluents including A, B, C, D, E, F, and G was related to water composition. The results were summarized in FIG. 7.Example 5: Solubility assay of sirolimus and ketamine HC1 (I)

[0421] Sirolimus was tested in 10 excipients at a concentration of 20 mg / mL; highest concentrations were found in modified temsirolimus vehicle (18.8 mg / mL), dehydrated ethanol (17.2 mg / mL), and N-Methyl-2-pyrrolidone (21.5 mg / mL). Modified temsirolimus vehicle was dehydrated alcohol (39.5% w / w) and propylene glycol (50.3% w / w). Concentrations above the target of 6 mg / mL were also observed in propylene glycol (12.1 mg / mL), PEG 300 (12.0 mg / mL), and PEG 400 (9.8 mg / mL). Visual appearances are shown in FIG. 8.Table 8. Results of Sirolimus Solubility Assay* Average of two injections

[0422] Ketamine HC1 was tested in 10 excipients at a concentration of 50 mg / mL; highest concentrations were found in glycerin (53.5 mg / mL), temsirolimus vehicle (52.8 mg / mL), and water (54.9 mg / mL). Temsirolimus vehicle was dehydrated alcohol (39.5% w / w) and propylene glycol (50.3% w / w). High concentrations were also observed in PG (40.2 mg / mL) and dehydrated ethanol (40.2 mg / mL). Visual appearances are shown in FIG. 9.Table 9. Results of Ketamine HC1 Solubility Assay* Average of two injectionsTable 10. Comparative Sirolimus and Ketamine HC1 Samples

[0423] The excipients with promising recoveries for both ketamine HC1 and sirolimus were the modified temsirolimus vehicle, polyethylene glycol, and dehydrated EtOH.Example 6: Solubility assay of sirolimus and ketamine HC1 (II)

[0424] The solubility and saturation limit of sirolimus was determined in 5 vehicles made up of varying ratios of propylene glycol, dehydrated ethanol, and water. Sirolimus exhibited the highest solubility, 13.5 mg / mL, in Vehicle 5, which contained 80 % (w / w) propylene glycol, 10% (w / w) dehydrated ethanol, and 10% (w / w) water.

[0425] Formulations with both ketamine HC1 and sirolimus were made up in the 5 vehicles; sirolimus exhibited a solubility of 11.0 mg / mL in Vehicle 5.

[0426] The solubility and saturation limit of ketamine HC1 was determined in 5 vehicles made up of varying ratios of propylene glycol, dehydrated ethanol, and water. Ketamine HC1 exhibited extremely high solubility (over 100%) in Vehicles 1-3, which contained 40-60% (w / w) propylene glycol, 10% (w / w) dehydrated ethanol, and 30-50% (w / w) water. A falloff in ketamine HC1 solubility was observed between Vehicles 3 and 4, or between 60-70% (w / w) propylene glycol, 10% (w / w) dehydrated ethanol, and 20-30% (w / w) water.

[0427] Formulations with both ketamine HC1 and sirolimus were made up in the 5 vehicles; ketamine HC1 exhibited high solubility percent recoveries in all vehicles except Vehicle 05.Table 11. Composition of Vehicles

[0428] Ketamine HC1 Solubility Assay

[0429] Ketamine was added to all vehicles until excess was seen at the bottom. Samples were tumbled in a rotisserie mixer for 24 hours. No excess ketamine HC1 was observed in vials after mixing period; saturation was not achieved. 0.5 mL of each sample was centrifuged for 10 minutes at 14,000 RPM through a 0.2 pm nylon membrane. Samples were diluted to 0.1 mg / mL in diluent for HPLC analysis. Visual appearances are shown in FIG. 10.Table 12. Results of Ketamine HC1 Solubility Assay*Average of two replicates

[0430] Sirolimus Solubility Assay

[0431] Sirolimus was added in excess of all vehicles, to ~ 50 mg / mL. Samples were tumbled in a rotisserie mixer for 24 hours. All samples were cloudy after mixing period. 0.5 mL of sample was centrifuged for 10 minutes at 14,000 RPM through a 0.2 pm nylon membrane. Samples were diluted to 0.1 mg / mL in diluent for HPLC analysis. Visual appearances are shown in FIG. 11.Table 13. Results of Sirolimus Solubility Assay*Average of two replicates

[0432] Combination Solubility Assay for Sirolimus and Ketamine HC1

[0433] Sirolimus was added in excess of all vehicles, to about 35 mg / mL. Ketamine was added to all vehicles to about 75 mg / mL. Samples were tumbled in a rotisserie mixer for 24 hours. All samples were cloudy after mixing period. 0.5 mL of sample was centrifuged for 10 minutes at 14,000 RPM through a 0.2 pm nylon membrane. Samples were diluted to 0.1 mg / mL in diluent for HPLC analysis for both sirolimus and ketamine HC1. Visual appearances are shown in FIG. 12.Table 14. Results of Combination Solubility Assay for Sirolimus and Ketamine HC1*Average of two replicatesExample 7: Solution compositions of sirolimus and ketamine HC1

[0434] Case I

[0435] Vial 1 comprises sirolimus at 12 mg / mL in 90% propylene glycol -10% ethanol - 0% water and Vial 2 comprises ketamine HC1 at 100 mg / mL in 60% propylene glycol-10%ethanol - 30% water. For the administration, 1 mL of Vial 1 and 1 mL of Vial 2 can be mixed to get 2 mL with the composition of: 6 mg / mL sirolimus, 50 mg / mL ketamine HCL in 75% propylene glycol - 10% ethanol- 15% water. 1 mL of the composition can be administered to an 80 kg person and a 160 kg person can be administered with 2 mL of the composition.

[0436] Case II

[0437] Vial 1 comprises sirolimus at 6 mg / mL in 90% propylene glycol -10% Ethanol - 0% water and Vial 2 comprises ketamine HC1 at 50 mg / mL in 60% propylene glycol -10% Ethanol - 30% water. For the administration, 1 mL of Vial 1 and 1 mL of Vial 2 can be mixed to get 2 mL with the composition of: 3 mg / mL sirolimus, 25 mg / mL ketamine HCL in 75% PG - 10% ethanol- 15% water. 2 mL of the composition can be administered to an 80 kg person and a 160 kg person can be administered with 2 x 2 mL (2 injection sites) of the composition.Example 8: Temsirolimus-Ketamine-HCl co-formulation development - optimization of Ketamine HC1 concentration

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

[0439] The Ketamine HCl concentration level in Diluent G formulation was set to 30.67 mg / mL, which was determined based on the dosing requirement and at around 75% saturation level of the vehicle (Diluent G, 38.95% (w / w) polysorbate 80, 12.30% (w / w) PEG 400, 38.75% (w / w) dehydrated ethanol, 10% (w / w) water). To accommodate the need of preparing a Ketamine HCl formulation with a c(Ketamine HCl) twice as high as the current level at 61.34 mg / mL, the solubility of Ketamine HCl in variations of Diluent G with increasing water and decreasing polysorbate 80 contents was measured.

[0440] The following four variations of Diluent G and Diluent G itself were prepared at 20-g scale.

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

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

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

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

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

[0446] To set up the study, 1.0 mL of each diluent was mixed with 100 - 200 mg Ketamine HC1 in a microcentrifuge tube. Three replicates were prepared for each diluent. The resulting mixtures were tumbled at ambient conditions (to). The appearance of the mixtures was monitored over time to ensure the saturation of the diluents. At t24h, the mixtures were centrifuged at 14000 rpm for 5 min before an aliquot of each supernatant was drawn and diluted for the Ketamine HC1 HPLC method. Then, 500 pL of each supernatant was drawn and filtered through 0.2 pm, Nylon membrane by centrifugation at 14000 rpm for 5 min before an aliquot of each filtrate was drawn and diluted for the HPLC method.

[0447] The results of the solubility of Ketamine HC1 in variations of Diluent G (t24h, rt) are summarized below in Table 15.Table 15. Solubility of Ketamine HC1 in variations of Diluent G (t24h, rt)

[0448] Based on the results, the suitable variation of Diluent G to solubilize 61.34 mg / mL Ketamine HC1 at 75% saturation level would be Diluent G25 with a solubilizing ability at 110 mg / mL. Therefore, Diluent G25 with 23.95% (w / w) polysorbate and 25% (w / w) water contents was selected as the vehicle for the Ketamine HC1 formulation at 61.34 mg / mL c(Ketamine HC1) level.

[0449] Stability of Ketamine HCl in Diluent G and G25

[0450] The stability of the following two Ketamine HCl formulations was assessed.

[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) dehydrated ethanol, 10% (w / w) water.

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

[0453] To set up the study, each formulation was prepared in a volumetric flask at 5-mL scale and distributed into three 2-mL amber serum vials at 1.0 mL / vial as the three replicatesof the formulation. The remaining 2 mL was used for to analysis. A gentle current of nitrogen gas was blown to the headspace of the serum vials for 30 s before they were stoppered, sealed, and placed in an oven set to 50 °C in dark.

[0454] The stability of the two vehicles, Diluent G and G25, was also assessed. Each vehicle was distributed into one 2-mL amber serum vial at 1.0 mL / vial. A gentle current of nitrogen gas was blown to the headspace of the serum vials for 30 s before they were stoppered, sealed, and placed in an oven set to 50 °C in dark.

[0455] At to and t2wk, the formulation and vehicle stability samples were allowed to adjust to ambient temperature before their appearance was observed visually. After brief vortexing, an aliquot was drawn from each sample, diluted, and analyzed for concentration and purity.

[0456] The results from the stability study of the Ketamine HC1 formulations and vehicles are summarized below in Table 16. No significant change in appearance was observed in either the formulations or the vehicles. After being heated at 50 °C for 2 weeks, the c(Ketamine HC1) decreased by approximately 8% in both formulations without generating obvious degradant peaks in the chromatograms.Table 16. Result summary of Ketamine HC1 formulation and vehicle stabilityExample 9: In-use stability and IV bag evaluation of Ketamine and Temsirolimus

[0457] Temsirolimus and ketamine HC1 were evaluated for in-use stability in 0.9% NaCl IV bags and lines using lab-made formulations (FREE001; co-formulations of temsirolimus and ketamine HC1) as well as commercially available TORISEL (temsirolimus injection) and Ketalar (ketamine HC1 injection).

[0458] Initial formulation work was performed to evaluate solubility and in-use stability of lab-mixed co-formulations of temsirolimus and ketamine HC1 in 0.9% saline at lab ambient temperature. Formulations were tested as-is and after in-line filtration through 0.2 pm PES membranes. In-use stability studies were conducted in two stages, the first utilizing coformulations (FREE001) of ketamine HC1 and temsirolimus, then using commercially available Ketalar and TORISEL, which were evaluated separately.

[0459] The studies with the co-formulations of temsirolimus and ketamine HC1 are summarized as follows. Diluent compositions are listed in Table 17 below.

[0460] Vehicles and diluents (Table 17) were prepared by weighing components into appropriately sized beakers with stir bars and mixed at moderate speed until homogeneous. The mixtures were transferred into a glass bottle or 50 mL scintillation vials covered in foil and stored at 2-8°C.Table 17. Vehicle and diluent compositions for ketamine HC1 and temsirolimus studies

[0461] Stock solutions for each study were prepared using volumetric flasks. APIs were weighed into volumetric flasks with stir bars and filled with their respective diluents. The solutions were mixed at moderate speed until homogeneous, the stir bars removed, and the flasks brought to volume with diluent and inverted gently to mix. The contents of both flasks were clear and particulate free prior to filtration. Solutions were then syringe filtered into clean flasks through 0.2 pm nylon syringe filters.

[0462] The IV Pump, IV set, and saline bag components are listed below in Table 18.Table 18. IV administration components

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

[0464] Two stock solutions were prepared using volumetric flasks: ketamine HCl at 30.67 in diluent G, and temsirolimus at 5 mg / mL in the 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 via gentle inversion, creating a solution that was 2.0 mg / mL temsirolimus and 18.4 mg / mL ketamine HCl (16.0 mg / mL ketamine freebase).

[0465] A 2.7 mL aliquot of the mixture solution were added to 3 x 250 mL saline bags (nominal fill 270 mL per manufacturer). The bags were inverted to distribute the mixture. Bags were clear and colorless after addition of the mixture solution. A 2.7 mL aliquot was extracted from each bag to assess pre-filtration concentration. The saline bags were spiked with an IV set with an in-line PES filter, loaded into the IV pump, and primed with 20 mL saline solution, the final 5 mL collected for analysis. After priming, the IV set was locked, removed from the pump, and allowed to sit at lab ambient conditions for two hours. At two hours from priming, the IV set was loaded into the pump and 50 mL of solution was allowed to flow through the IV set and into a waste beaker, the final 5 mL being collected for analysis. After the collection of the two-hour aliquot, the IV set was locked and removed from the pump. The bag and IV setup was allowed to sit for a further two hours at lab ambient. After a further two hours at lab ambient, the IV set was loaded into the pump and the remaining solution was allowed to clear the bag into a bottle that was reserved for analysis.

[0466] A slight loss recovery of temsirolimus; although all recovery values were greater than 100%. The loss in recovery which was potentially within analytical method variability, was observed over the course of test period, noted in Table 19. No reduction in percent recovery of ketamine HCl was observed, as seen in Table 20.Table 19. Temsirolimus results, Study 1*Average of three injectionsTable 20. Ketamine HCl results, Study 1

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

[0468] Two stock solutions were prepared using volumetric flasks: ketamine HC1 at 57.67 in diluent G25, and temsirolimus at 9.375 mg / mL in the temsirolimus vehicle. A 2.4 mL aliquot of temsirolimus stock and a 3.6 mL aliquot of ketamine HC1 stock were combined in a 10 mL vial using a positive displacement micropipettor and mixed via gentle inversion, creating a solution that was 3.75 mg / mL temsirolimus and 36.40 mg / mL ketamine HC1 (30.0 mg / mL ketamine freebase).

[0469] A 1.5 mL aliquot of the mixture solution were added to 3 x 250 mL saline bags (nominal fill 270 mL per manufacturer). The bags were inverted to distribute the mixture. Bags were clear and colorless after addition of the mixture solution. A 1.5 mL aliquot was extracted from each bag to assess pre-filtration concentration. The saline bags were spiked with an IV set with an in-line PES filter, loaded into the IV pump, and primed with 20 mL saline solution, the final 5 mL collected for analysis. After priming, the IV set was locked, removed from the pump, and allowed to sit at lab ambient conditions for two hours. At two hours from priming, the IV set was loaded into the pump and 50 mL of solution was allowed to flow through the IV set and into a waste beaker, the final 5 mL being collected for analysis. After the collection of the two-hour aliquot, the IV set was locked and removed from the pump. The bag and IV setup was allowed to sit for a further two hours at lab ambient. After a further two hours at lab ambient, the IV set was loaded into the pump and the remaining solution was allowed to clear the bag into a bottle that was reserved for analysis.

[0470] A loss in percent recovery (0.9-4.5%) was observed in the priming volume sample of temsirolimus that was largely regained at the 2-hour timepoint. A loss in recovery of 0.8%- 2% was observed in temsirolimus over the course of the study, as seen in Table 21. No reduction in recovery was observed in ketamine HC1 throughout the test period as noted in Table 22.Table 21. Temsirolimus results, Study 2*Average of three injectionsTable 22. Ketamine HC1 results, Study 2

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

[0472] Two stock solutions were prepared using volumetric flasks: ketamine HCl at 30.67 in diluent G, and temsirolimus at 0.25 mg / mL 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 via gentle inversion, creating a solution that was 0.1 mg / mL temsirolimus and 18.4 mg / mL ketamine HCl (16.0 mg / mL ketamine freebase).

[0473] A 2.7 mL aliquot of the mixture solution were added to 3 x 250 mL saline bags (nominal fill 270 mL per manufacturer). The bags were inverted to distribute the mixture. Bags were clear and colorless after addition of the mixture solution. A 2.7 mL aliquot was extracted from each bag to assess pre-filtration concentration. The saline bags were spiked with an IV set with an in-line PES filter, loaded into the IV pump, and primed with 20 mL saline solution, the final 5 mL collected for analysis. After priming, the IV set was locked, removed from the pump, and allowed to sit at lab ambient conditions for two hours. At two hours from priming, the IV set was loaded into the pump and 50 mL of solution was allowed to flow through the IV set and into a waste beaker, the final 5 mL being collected foranalysis. After the collection of the two-hour aliquot, the IV set was locked and removed from the pump. The bag and IV setup was allowed to sit for a further two hours at lab ambient. After a further two hours at lab ambient, the IV set was loaded into the pump and the remaining solution was allowed to clear the bag into a bottle that was reserved for analysis.

[0474] A loss in percent recovery in temsirolimus (1.4-4.7%) was observed in the temsirolimus prime volume sample that was regained by the 2-hour timepoint. A loss in recovery of 1.2- 1.4% overall was observed in temsirolimus over the course of the study, as seen in Table 23. No reduction in ketamine HC1 percent recovery was observed throughout the test period as noted in Table 24.Table 23. Temsirolimus results, Study 3*Average of three injectionsTable 24. Ketamine HC1 results, Study 3*Average of three injections

[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: ketamine HCl at 57.6 mg / mL in diluent G25, and temsirolimus at 0.47 mg / mL in the 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 via gentle inversion, creating a solution that was 0.188 mg / mL temsirolimus and 36.40 mg / mL ketamine HCl (30.0 mg / mL ketamine freebase).

[0477] A 1.5 mL aliquot of the mixture solution were added to 3 x 250 mL saline bags (nominal fill 270 mL per manufacturer). The bags were inverted to distribute the mixture. Bags were clear and colorless after addition of the mixture solution. A 1.5 mL aliquot was extracted from each bag to assess pre-filtration concentration. The saline bags were spiked with an IV set with a PES filter, loaded into the IV pump, and primed with 20 mL saline solution, the final 5 mL collected for analysis. After priming, the IV set was locked, removed from the pump, and allowed to sit at lab ambient conditions for two hours. At two hours from priming, the IV set was loaded into the pump and 50 mL of solution was allowed to flow through the IV set and into a waste beaker, the final 5 mL being collected for analysis. After the collection of the two-hour aliquot, the IV set was locked and removed from the pump. The bag and IV setup was allowed to sit for a further two hours at lab ambient. After a further two hours at lab ambient, the IV set was loaded into the pump and the remaining solution was allowed to clear the bag into a bottle that was reserved for analysis.

[0478] A loss in percent recovery (5.5-7.1%) was observed in the priming volume sample of temsirolimus that was largely regained at the 2-hour timepoint. A loss of 0.1-1.7% percent recovery was observed in temsirolimus over the course of the study as observed in Table 25. No reduction in recovery was observed in ketamine HCl throughout the test period as noted in Table 26.Table 25. Temsirolimus results, Study 4*Average of three injectionsTable 26. Ketamine HC1 results, Study 4

[0479] TORISEL

[0480] Three vials of the commercial product TORISEL were prepared by adding 1.8 mL of Diluent for TORISEL into a corresponding TORISEL vial, creating 3 mL of mixture solutions that were 10 mg / mL temsirolimus. The composition of the TORISEL Vehicle and TORISEL Diluent are shown in Table 27. Dilution of the TORISEL mixture solution to the target concentration of 0.003 mg / mL temsirolimus in 0.9% NaCl (saline) was achieved in two stages of dilution.Table 27. TORISEL diluent and vehicle components

[0481] In the first stage of dilution, a 2.7 mL aliquot of each mixture solution was added to a 250 mL saline bag (270 mL nominal fill per manufacturer). The bags were inverted gently to distribute the mixture. The bags were colorless and particulate free after the addition of mixture 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 concentration.

[0482] In the second round of dilution, 8.2 mL of saline was removed from three fresh IV bags for a nominal volume of 261.8 mL (270 mL-8.2 mL). An 8.2 mL aliquot of a first round dilution bag was added to a 261.8 mL bag. The bag concentration after the second round of 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 round of dilution were also colorless and particulate-free.

[0483] The saline bags were spiked with an IV set with an in-line PES filter, loaded into the IV pump, and primed with 20 mL saline solution, the final 5 mL collected for analysis. After priming, the IV set was locked, removed from the pump, and allowed to sit at lab ambient conditions for two hours. At two hours from priming, the IV set was loaded into the pump and 50 mL of solution was allowed to flow through the IV set and into a waste beaker, the final 5 mL being collected for analysis. After the collection of the two-hour aliquot, the IV set was locked and removed from the pump. The bag and IV setup was allowed to sit for a further two hours at lab ambient. After a further two hours at lab ambient, the IV set wasloaded into the pump and the remaining solution was allowed to clear the bag into a bottle that was reserved for analysis.

[0484] The mixture solution were filtered through 0.2 pm nylon membranes by centrifugation for 5 minutes at 14,000 RPM and diluted to target temsirolimus diluent. The saline solutions were injected into the HPLC with no dilution.

[0485] The results are shown in Table 28. While no loss in recovery was observed in the mixture solution or dilution one samples, a significant loss in recovery was observed in the dilution two samples. A recovery loss of 8.5-15.1% was observed between dilution one and dilution two in each sample series. No temsirolimus was detected in the prime volume sample in any dilution two bags, but percent recovery was mostly recovered to the pre-filtration level at the 2-hour time point. A slight loss of percent recovery was observed (0.5-1.6%) in the dilution 2 bags over the course of the study.Table 28. Torisel Results*Average of three injection

[0486] Ke talar

[0487] Ketalar injection (100 mg / mL ketamine freebase, 115.33 mg / mL ketamine HC1) was diluted to a final concentration of 0.166 mg ketamine freebase (0.1918 mg / mL ketamine HC1) by injecting a 0.45 mL aliquot of Ketalar into three saline bags. The bags were inverted gently to distribute the mixture. Bags were colorless and particulate free post addition. A 1 mL aliquot was extracted from each bag to assess pre-filtration concentration.

[0488] As with prior studies, the saline bags were spiked with an IV set with an in-line PES filter, loaded into the IV pump, and primed with 20 mL saline solution, the final 5 mL collected for analysis. After priming, the IV set was locked, removed from the pump, and allowed to sit at lab ambient conditions for two hours. At two hours from priming, the IV set was loaded into the pump and 50 mL of solution was allowed to flow through the IV set and into a waste beaker, the final 5 mL being collected for analysis. After the collection of the two-hour aliquot, the IV set was locked and removed from the pump. The bag and IV setup was allowed to sit for a further two hours at lab ambient. After a further two hours at lab ambient, the IV set was loaded into the pump and the remaining solution was allowed to clear the bag into a bottle that was reserved for analysis.

[0489] The mixture solution were filtered through 0.2 pm nylon membranes by centrifugation for 5 minutes at 14,000 RPM and diluted to target temsirolimus diluent. The saline solutions were injected into the HPLC with no dilution.

[0490] The results are shown in Table 29. No loss in percent recovery was observed.Table 29. Ketalar ResultsTable 30. HPLC method parameters for ketamine HC1 and Ketalar

[0491] Sample preparation for each study is described below. Dilution of stock and mixture stock solutions was performed with a positive displacement micropipettor. Saline aliquots were injected directly with no dilution.

[0492] Study 1 and Study 3 :

[0493] Ketamine stock: A 0.5 mL aliquot was pipetted into a 0.2 pm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted in ketamine HC1 diluent to a target concentration of 0.3067 mg / mL

[0494] Ketamine mixture stock: 0.5 mL aliquot was pipetted into a 0.2 pm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted in ketamine HC1 diluent to a target concentration of 0.1840 mg / mL

[0495] Study 2 and Study 4:

[0496] Ketamine stock: A 0.5 mL aliquot was pipetted into a 0.2 pm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted in ketamine HC1 diluent to a target concentration of 0.6134 mg / mL

[0497] Ketamine mixture stock: A 0.5 mL aliquot was pipetted into a 0.2 pm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted in ketamine HC1 diluent to a target concentration of 0.3640 mg / mL

[0498] Ke talar.

[0499] Ketalar stock: A 0.5 mL aliquot was pipetted into a 0.2 pm nylon spin filter and centrifuges at 14,000 RPM for 5 minutes. The filtrate was diluted in ketamine HC1 diluent to a target concentration of 0.5757 mg / mL.Table 31. HPLC method parameters for temsirolimus and TORISEL

[0500] Sample preparation for each study is described below. Saline aliquots were injected directly.

[0501] Study 1 :

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

[0503] Temsirolimus mixture stock: 0.5 mL aliquot was pipetted into a 0.2 pm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted in temsirolimus diluent to a target concentration of 0.20 mg / mL.

[0504] Study 2:

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

[0506] Temsirolimus mixture stock: 0.5 mL aliquot was pipetted into a 0.2 pm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted in temsirolimus diluent to a target concentration of 0.375 mg / mL.

[0507] Study 3:

[0508] Temsirolimus stock: A 0.5 mL aliquot was pipetted into a 0.2 pm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was injected directly with a target concentration of 0.25 mg / mL.

[0509] Temsirolimus mixture stock: 0.5 mL aliquot was pipetted into a 0.2 pm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was injected directly with a target concentration of 0.1 mg / mL.

[0510] Study 4:

[0511] Temsirolimus stock: A 0.5 mL aliquot was pipetted into a 0.2 pm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was injected directly with a target concentration of 0.47 mg / mL.

[0512] Temsirolimus mixture stock: 0.5 mL aliquot was pipetted into a 0.2 pm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was injected directly with a target concentration of 0.188 mg / mL.

[0513] TORISEL.

[0514] TORISEL Mix vial: A 0.1 mL aliquot was pipetted into a 0.2 pm nylon spin filter and centrifuged at 14,000 RPM for 5 minutes. The filtrate was diluted 20x in TORISEL diluent to a target concentration of 0.5 mg / mL.Example 10: Stability of co-formulation of Ketamine HC1 and Temsirolimus

[0515] Temsirolimus and ketamine HC1 co-formulations were assessed, accelerated stability.

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

[0517] The diluents and the temsirolimus vehicle were prepared by weighing components into appropriately sized beakers with stir bars and mixing until the solution was homogeneous. The mixtures were transferred into a glass bottle or 50 mL scintillation vial covered in foil.

[0518] Ketamine HC1 and temsirolimus were weighed into 20 mL scintillation vials fitted with stir bars. Vehicle or diluent was added, then the vials were mixed at moderate speed until their respective solutions were homogeneous. The solutions were filtered with 0.2 pm nylon syringe filters and aliquoted into prepared vials to a fill volume of 1 mL, then blanketed with N2 gas before sealing and crimping.

[0519] After 3 months at 25°C, all formulations were clear and particulate free. ‘TEM High’ exhibited faint discoloration (changing from colorless to a very pale yellow) after three months at 25°C while the color for the other formulations was unchanged from t-0.

[0520] No loss in ketamine purity or percent recovery was observed at the end of test period at either stability condition.

[0521] Co-formulation ‘TEM High’ exhibited a 4% loss in recovery at t-3 months on stability at 25°C; co-formulation ‘TEM Combi’ exhibited a 19% loss in recovery at the same conditions. Significant impurity level growth was observed in ‘TEM Combi’ at the end of test period.

[0522] Ager 6 months at 25 °C, formulations continued to be clear and particulate free at the end of test period. ‘TEM High’ remained very pale yellow at six months at 25°C, while the color for the other formulations remained unchanged from t-0. No loss in ketamine purity or percent recovery was observed at the end of test period. Formulation ‘TEM High’ exhibited no loss in recovery at six months at 25°C, while formulation ‘TEM Low’ formulation exhibited a 4% loss in recovery. TEM Combi exhibited a 40% in recovery over the test period at 25 °C.

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

Claims

CLAIMSWhat is claimed is:

1. A solution comprising: a. an N-methyl-D-aspartate (NMD A) receptor modulator at a concentration of about 0.04 milligram per milliliter (mg / mL) to about 150 mg / mL, and b. a mechanistic target of rapamycin (mTOR) inhibitor at a concentration of about 0.02 mg / mL to about 10 mg / mL.

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

3. A solution comprising: 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 mechanistic target of rapamycin (mTOR) inhibitor at a concentration of about 0.5 microgram per milliliter (pg / mL) to about 100 pg / mL.

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

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

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

7. The solution of any one of claims 1 to 3, wherein the solution further comprises polyethylene glycol (PEG), polysorbate, or both.

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

9. The solution of claim 7, wherein the solution comprises PEG, and wherein the PEG has an average molecular weight from about 300 to about 600, optionally is PEG 400.

10. The solution of any one of claims 1-3, wherein the solution comprises polysorbate 80 and PEG 400.A solution comprising: a. an N-methyl-D-aspartate (NMD A) receptor modulator, b. a mechanistic target of rapamycin (mTOR) inhibitor, and c. polysorbate or PEG 400. The solution of any one of claims 1 to 3 or 11, wherein 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 dextromethophane and bupropion, GM- 1020, Besonprodil, Eliprodil, Ifenprodil, Rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, Traxoprodil (CP-101,606), BMT-108908, Onfasprodil, Radiprodil, NP 10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1-aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS- 2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, 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, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof. The solution claim 12, wherein the NMDA receptor modulator is ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixture thereof. The solution of claim 13, wherein the ketamine is ketamine HC1. The solution of any one of claims 1 to 3 or 11, wherein the mTOR inhibitor is selected from the group consisting of BEZ235 (Dactolisib, RTB101), rapamycin (Sirolimus, AY 22989, ABI-009), everolimus (RAD001), AZD8055 (CCG-168),Temsirolimus (CCI-779), KU-0063794, PI- 103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74-9), Torkinib (PP242), Tacrolimus (FK-506, fujimycin,), Ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, Sapanisertib), Voxtalisib (XL-765, SAR245409), Torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), Omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI- 006), PF-04691502 (PF4691502), Apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), Gedatolisib (PF-05212384, PKI- 587), AZD- 2014 (Vistusertib), Torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG 00529), 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, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib (CC 223), Clemastine (HS-592) fumarate, Nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, Astragaloside IV, Samotolisib (LY3023414), Chrysophanic Acid, and Zotarolimus (ABT-578), and any salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer, and geometric isomer thereof, and any mixtures thereof. The solution of claim 15, wherein the mTOR inhibitor comprises rapamycin (Sirolimus, AY 22989, AB 1-009) or temsirolimus (CCI-779). The solution of any one of claims 1 to 16, wherein the solution further comprises an excipient selected from the group consisting of water, ethanol, propylene glycol, citric acid, and DL-alpha-tocopherol. The solution of claim 17, wherein a 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. The solution of any one of claims 8 to 16, wherein a concentration of the polysorbate ranges from about 5 %w / w to about 50 %w / w. The solution of any one of claims 8 to 16, wherein a concentration of the PEG ranges from about 0.1 %w / w to about 30 %w / w. 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) dehydrated ethanol, about 6% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof.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) dehydrated ethanol, about 9% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof. 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) dehydrated ethanol, about 12% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof. 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) dehydrated ethanol, about 15% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof. 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) dehydrated ethanol, about 18% (w / w) water, about 20.12% (w / v) propylene glycol, or any combinations thereof. The solution of any one of claims 1 to 25, wherein the solution does not comprise citric acid or DL-alpha-tocopherol. The solution of any one of claims 1 to 26, wherein the solution comprises the NMDA receptor modulator of 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. The solution of any one of claims 1 to 26, wherein the solution comprises the mTOR inhibitor of 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. A kit comprising:(i) a first container housing 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 housing a second solution comprising a mechanistic target of rapamycin (mTOR) inhibitor at a concentration of about 0.1 mg / mL to about 25 mg / mL. A kit comprising:(i) a first container housing a first solution comprising an N-methyl-D-aspartate (NMDA) receptor modulator; and(ii) a second container housing a second solution comprising a mechanistic target of rapamycin (mTOR) inhibitor,wherein a volume ratio of the first solution and the second solution is from about 1.2:1 to about 3:

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

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

1. The kit of claim 29 or 30, wherein the first container further comprises water, ethanol, polyethylene glycol (PEG), polysorbate, or any combinations thereof. The kit of claim 33, wherein the first container comprises polysorbate, and wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, optionally is polysorbate 80. The kit of claim 33, wherein the first container comprises PEG, and wherein the PEG has an average molecular weight between about 300 and about 600, optionally is PEG 400. 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 combinations thereof. The kit of any one of claims 29 to 35, wherein the second container further comprises ethanol, propylene glycol, or any combinations thereof. 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 a mechanistic target of rapamycin (mTOR) inhibitor, wherein the NMDA receptor modulator and the mTOR inhibitor have a weight ratio greater than about 1 :

1. The kit of claim 38, wherein the first composition is a solution. The kit of claim 38, wherein the solution further comprises water, ethanol, polyethylene glycol (PEG), polysorbate, or any combinations thereof. The kit of claim 38, wherein the first composition is a solid. The kit of claim 41, wherein the solid is powder. The kit of claim 41, wherein the solid is dissolved in a diluent. A kit comprising:(i) a first container housing a first composition comprising an N-methyl-D-aspartate (NMD A) receptor modulator;(ii) a second container housing a second composition comprising a mechanistic target of rapamycin (mTOR) inhibitor; and(iii) a diluent comprising polysorbate, PEG 400, or both. The kit of claim 44, wherein the NMD A receptor modulator and the mTOR inhibitor have a weight ratio greater than about 1 :

1. The kit of any one of claims 29 to 45, wherein 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 dextromethophane and bupropion, GM- 1020, Besonprodil, Eliprodil, Ifenprodil, Rislenemdaz (CERC-301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, Traxoprodil (CP- 101,606), BMT- 108908, Onfasprodil, Radiprodil, NP 10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1-aminocylopropanecarboxylic acid, traxoprodil, Ro 25- 6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD-137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, 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, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP-AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164, LY246492, LY202157, and NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof. 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.The kit of claim 47, wherein the ketamine is ketamine HC1. The kit of any one of claims 29 to 48, wherein the mTOR inhibitor comprises BEZ235 (Dactolisib, RTB101), rapamycin (Sirolimus, AY 22989, ABI-009,), everolimus (RAD001), AZD8055 (CCG-168), Temsirolimus (CCI-779), KU- 0063794, PI-103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74- 9), Torkinib (PP242), Tacrolimus (FK-506, fujimycin), Ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, Sapanisertib), Voxtalisib (XL-765, SAR245409), Torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), Omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), Apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), Gedatolisib (PF-05212384, PKI-587), AZD- 2014 (Vistusertib), Torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE- 125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG 00529), 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, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib (CC 223), Clemastine (HS-592) fumarate, Nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, Astragaloside IV, Samotolisib (LY3023414), Chrysophanic Acid, or Zotarolimus (ABT-578), or a salt, solvate, enantiomer, tautomer, diastereomer stereoisomer, or geometric isomer thereof. The kit of claim 49, wherein the mTOR inhibitor comprises rapamycin (Sirolimus, AY 22989, ABI-009) or temsirolimus (CCI-779). The kit of any one of claims 29 to 50, wherein the first solution or the first composition further comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 10% (w / w) water, or any combinations thereof. The kit of any one of claims 29 to 50, wherein the first solution or the first composition further comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 15% (w / w) water, or any combinations thereof. The kit of any one of claims 29 to 50, wherein the first solution or the first composition further comprises about 28.95% (w / w) polysorbate 80, about 12.30%(w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 20% (w / w) water, or any combinations thereof. The kit of any one of claims 29 to 50, wherein the first solution or the first composition further comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 25% (w / w) water, or any combinations thereof. The kit of any one of claims 29 to 50, wherein the first solution or the first composition further comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 30% (w / w) water, or any combinations thereof. The kit of any one of claims 29 to 55, wherein the second solution or the second composition further comprises about 39.5% (w / v) dehydrated 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 combinations thereof. The kit of any one of claims 29 to 55, wherein the second solution or the second composition further comprises about 39.5% (w / v) dehydrated ethanol, about 50.3% (w / v) propylene glycol, or any combinations thereof. The kit of any one of claims 29 to 55, wherein the first solution or the first composition is stable for at least about a week, a month, three months, six months, or a year at room temperature. The kit of any one of claims 29 to 58, wherein the first solution or the first composition is stable for at least about a week at a temperature lower than about 60°C. The kit of any one of claims 29 to 59, wherein the second solution or the second composition is stable for at least about a week, a month, three months, six months, or a year at room temperature. The kit of any one of claims 29 to 60, wherein the second solution or the second composition is stable for at least about a week at a temperature lower than about 60°C. The kit of any one of claims 29 to 61, wherein the second solution or the second composition does not comprise citric acid or DL-alpha-tocopherol. A method of preparing a solution comprising: mixing (i) a first solution comprising a N-methyl-D-aspartate (NMD A) receptor modulator, and (ii) a second solution comprising a mechanistic target of rapamycin(mTOR) inhibitor, thereby generating the solution comprising both the NMDA receptor modulator and the mTOR inhibitor, wherein a volume ratio of the first solution and the second solution is about 3:

2. A method of treating or preventing a disease, disorder, or condition in a subject in need thereof comprising: administering to the subject the solution of any one of claims 1-28. A method of treating or preventing a disease, disorder, or condition in a subject in need thereof comprising: mixing a first solution comprising a N-methyl-D-aspartate (NMDA) receptor modulator and a second solution comprising a mechanistic target of rapamycin (mTOR) inhibitor, thereby generating 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 generated. The method of claim 65, wherein 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 dextromethophane and bupropion, GM- 1020, Besonprodil, Eliprodil, Ifenprodil, Rislenemdaz (CERC- 301 / MK-0657), EVT-101, EVT-103, Ro-25-6981, MI-4, Ro 8-4304, Traxoprodil (CP-101,606), BMT-108908, Onfasprodil, Radiprodil, NP10679, GluN2B NAM, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1- aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, methoxetamine, CPPene, AP5, AP7, Selfotel (CGS-19755), minocycline, nitromemantine, PD- 137889, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, etoxadrol, dexoxadrol, WMS-2539, NEFA, remacemide, 3-MeO-PCP, 8A-PDHQ, atomoxetine, AZD6765, agmatine, chloroform, delucemine, dextrallorphan, dextrorphan, diphenidine, eticyclidine, 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, pregnanolone sulfate (3a5pS), UBP608, UBP618, UBP551, UBP512, HA-966, felbamate, PEAQX (NVP- AAM077), PD0196860, RGH896, MK0657, L701324, LY293558, LY300164,LY246492, LY202157, and NYX-783, and any salt, solvate, enantiomer, tautomer, stereoisomer and geometric isomer thereof, and any mixtures thereof. The method of claim 65, wherein the NMDA receptor modulator comprises ketamine, any salt, solvate, enantiomer, tautomer, stereoisomer or geometric isomer thereof, or any mixtures thereof. The method of claim 67, wherein the ketamine is ketamine HC1. The method of claim 65, wherein the mTOR inhibitor comprises BEZ235 (Dactolisib, RTB101), rapamycin (Sirolimus, AY 22989, AB 1-009), everolimus (RAD001), AZD8055 (CCG-168), Temsirolimus (CCI-779), KU-0063794, PI- 103 (mTOR Inhibitor V, PI 3-K Inhibitor V, PI-103 - CAS 371935-74-9), Torkinib (PP242), Tacrolimus (FK-506, fujimycin), Ridaforolimus (AP23573, MK-8669, deforolimus), INK-128 (MLN0128, Sapanisertib), Voxtalisib (XL-765, SAR245409), Torin-1 (DNA-PK Inhibitor VI, PI 3-K Inhibitor XVIII, mTOR Inhibitor XI, Torin-1), Omipalisib (GSK2126458, UNII-1X8F5A3NA0, GSK458, GSK-212), OSI-027 (ASP7486, CERC 006, AEVI-006), PF-04691502 (PF4691502), Apitolisib (GDC0980, RG7422, GNE 390), GSK1059615, WYE-354 (mTOR Inhibitor II), Gedatolisib (PF-05212384, PKI-587), AZD- 2014 (Vistusertib), Torin-2 (MLS006011167, GTPL8839, GTPL8839, AOB3537), WYE-125132 (WYE-132), BGT226 (NVP-BGT226), Palomid-529 (P529, SG 00529), 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, Compound 401, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib (CC 223), Clemastine (HS-592) fumarate, Nitazoxanide (NSC 697855), 4EGI-1, ABTL-0812, Astragaloside IV, Samotolisib (LY3023414), Chrysophanic Acid, or Zotarolimus (ABT-578), or a salt, solvate, enantiomer, tautomer, diastereomer, stereoisomer and geometric isomer thereof. The method of claim 65, wherein the mTOR inhibitor comprises rapamycin (Sirolimus, AY 22989, ABI-009) or Temsirolimus (CCI-779). The method of any one of claims 64 to 70, wherein the solution is administered through an intramuscular route, an intravenous route, a subcutaneous route, an oral route, an inhalation route, or an intranasal route.The method of any one of claims 64 to 70, wherein 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. 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. 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. The method of any one of claims 64 to 74, wherein the NMDA receptor modulator is administered at dose of about 30 mg to about 90 mg. The method of claim 75, wherein the NMDA receptor modulator is administered at dose of about 30 mg to about 60 mg. The method of any one of claims 64 to 76, wherein the mTOR inhibitor is administered at a dose of about 1 pg / kg to about 100 pg / kg. The method of claim 77, wherein the mTOR inhibitor is administered at a dose of about 2.5 pg / kg to about 30 pg / kg. The method of claim 77, wherein the mTOR inhibitor is administered at a dose of about 3 pg / kg to about 25 pg / kg. The method of any one of claims 64 to 79, wherein the mTOR inhibitor is administered at dose of about 0.1 mg to about 4 mg. The method of any one of claims 64 to 80, wherein the disease, disorder, or condition is selected from the group consisting of a major depressive disorder (MDD), a major depressive episode in bipolar disorder (bipolar depression), a persistent depressive disorder (dysthymia), a disruptive mood dysregulation disorder, a major depressive disorder (including major depressive episode), a premenstrual dysphoric disorder, a substance / medication-induced depressive disorder, a depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, a posttraumatic stress disorder, an addictive disorder, bipolar I disorder, bipolar II disorder, 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 another medical condition, borderline personality disorder, treatment-resistant depression, unspecified anxiety disorder, chronic pain, and any combinations thereof.

82. 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 solution comprising: a. an N-methyl-D-aspartate (NMD A) receptor modulator, b. polysorbate or PEG 400.

84. A solution comprising: a mechanistic target of rapamycin (mTOR) inhibitor, wherein a concentration of 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.

85. A method of preparing the solution of claim 84 comprising: contacting an N-methyl-D-aspartate (NMD A) receptor modulator with a diluent comprising PEG400 or polysorbate.

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

87. The solution of claim 86, wherein the solution comprises about 38.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 10% (w / w) water, or any combinations thereof.

88. The solution of claim 86, wherein the solution comprises about 33.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 15% (w / w) water, or any combinations thereof.

89. The solution of claim 86, wherein the solution comprises about 28.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 20% (w / w) water, or any combinations thereof.

90. The solution of claim 86, wherein the solution comprises about 23.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 25% (w / w) water, or any combinations thereof.

91. The solution of claim 86, wherein the solution comprises about 18.95% (w / w) polysorbate 80, about 12.30% (w / w) PEG 400, about 38.75% (w / w) dehydrated ethanol, about 30% (w / w) water, or any combinations thereof.

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