Ketamine formulation for subcutaneous injection

Abstract

SOLUTION: To provide subcutaneous formulations of ketamine that are useful for treating a variety of disease and disorders, wherein the subcutaneous ketamine formulations provided herein reduce injection site irritation and pain.SELECTED DRAWING: None

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 848,420, filed May 15, 2019, the entirety of which is incorporated herein by reference. [Background technology]

[0002] Ketamine is an NMDA receptor antagonist that has been used and discovered to treat pain, depression, and numerous other mental and physical disorders. However, several of ketamine's side effects, poor bioavailability, formulation, and pharmacokinetics limit delivery options. These factors, associated with off-label ketamine use, present challenges to effective treatment. Summary of the Invention

[0003] Formulations for subcutaneous delivery of ketamine are provided herein. The formulations provided herein offer numerous advantages over existing formulations of ketamine. Currently available ketamine HCl formulations cause local tissue site irritation when injected subcutaneously. Symptoms include erythema, pruritus, swelling, and pain, which can result in sterile tumours. This is thought to be due to an acidic pH (<4), high osmolality, the presence of ketamine itself, or a combination of these factors. In contrast, the ketamine formulations provided herein can avoid these undesirable side effects through the use of a more neutral pH, an osmolality closer to physiological levels, a lower ketamine concentration, or any combination thereof. Thus, the ketamine formulations provided herein for subcutaneous injection can reduce injection site side effects, making subcutaneous delivery a clinically safe and tolerable option.

[0004] One embodiment provided herein is a pharmaceutical composition, said pharmaceutical composition comprising: (i) Structural formula (I):

[0005] [ka] or an enantiomer, a mixture of enantiomers or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a form for administration by subcutaneous injection.

[0006] In some embodiments, the pharmaceutically acceptable salt comprises a dibasic or tribasic acid.

[0007] In some embodiments, the pharmaceutically acceptable salt comprises an organic acid.

[0008] In some embodiments, the pharmaceutically acceptable salt comprises an inorganic acid.

[0009] In some embodiments, the acid is a substituted or unsubstituted carboxylic acid, a substituted or unsubstituted phenol, a substituted or unsubstituted sulfonic acid, a substituted or unsubstituted alcohol, a substituted or unsubstituted thiol, a substituted or unsubstituted enol, or a carbonic acid.

[0010] In some embodiments, the acid is fumaric acid, malic acid, citric acid, tartaric acid, glutaric acid, succinic acid, maleic acid, or malonic acid.

[0011] In some embodiments, the acid is sulfuric acid, sulfonic acid, phosphonic acid, or phosphoric acid.

[0012] In some embodiments, the pharmaceutical composition further comprises a complexing agent.

[0013] In some embodiments, the complexing agent is a substituted or unsubstituted cyclodextrin.

[0014] In some embodiments, the cyclodextrin is sulfobutyl-ether-beta-cyclodextrin (SBEBCD) or hydroxypropyl-beta-cyclodextrin (HPBCD).

[0015] In some embodiments, the cyclodextrin is SBEBCD.

[0016] In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is from about 1:4 to about 1:8.

[0017] In some embodiments, the pharmaceutical composition further comprises a base, a buffer, or a combination thereof.

[0018] In some embodiments, the pharmaceutical composition does not further comprise a base, a buffer, or a combination thereof.

[0019] In some embodiments, the pharmaceutical composition further comprises an emulsifier, a surfactant, a solubilizer, a co-solvent, or a combination thereof. In some embodiments, the pharmaceutical composition does not further comprise an emulsifier, a surfactant, a solubilizer, a co-solvent, or a combination thereof.

[0020] In some embodiments, the co-solvent is ethanol, propylene glycol, tween 20, tween 80, or glycerin.

[0021] In some embodiments, the compound of Formula (I) has the structural formula (IA):

[0022] [ka] or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, wherein: X - is a counter ion, and further a compound of formula (IA).

[0023] In some embodiments, a compound of structural formula (IA), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, is partially ionized or fully ionized.

[0024] In some embodiments, the compound of structural formula (IA), or an enantiomer, mixture of enantiomers, or isotopic variant thereof; or a solvate or hydrate thereof, is at least about 75% ionized.

[0025] In some embodiments, X - are fumaric, malic, citric, tartaric, glutaric, succinic, maleic, SBEBCD or malonic acid.

[0026] In some embodiments, the pharmaceutical composition further comprises a complexing agent.

[0027] In some embodiments, the complexing agent is a substituted or unsubstituted cyclodextrin.

[0028] In some embodiments, the cyclodextrin is sulfobutyl-ether-beta-cyclodextrin (SBEBCD) or hydroxypropyl-beta-cyclodextrin (HPBCD).

[0029] In some embodiments, the cyclodextrin is SBEBCD.

[0030] In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is from about 1:4 to about 1:8.

[0031] In some embodiments, SBEBCD is present in an amount of about 50 mg / mL to about 600 mg / mL.

[0032] In some embodiments, the pharmaceutical composition further comprises a base, a buffer, or a combination thereof.

[0033] In some embodiments, the pharmaceutical composition further comprises an emulsifier, a surfactant, a solubilizer, an emulsifier, a co-solvent, or a combination thereof.

[0034] In some embodiments, the pharmaceutical composition is free of the excipients emulsifiers, complexing agents, surfactants, or solubilizers.

[0035] In some embodiments, the pharmaceutical composition has a pH of > about 4.

[0036] In some embodiments, the pharmaceutical composition has a pH of about 4 to about 7.

[0037] In some embodiments, the pharmaceutical composition has a pH of about 4.5 to about 6.5.

[0038] In some embodiments, the pharmaceutical composition has an osmolality of about 300 mOsm / kg to about 850 mOsm / kg.

[0039] In some embodiments, the pharmaceutical composition has an osmolality of about <850 mOsm / kg.

[0040] In some embodiments, the pharmaceutical composition is isotonic.

[0041] In some embodiments, the pharmaceutical composition has an osmolality of about 500 mOsm / kg.

[0042] In some embodiments, the compound of Formula (I) or its enantiomer, mixture of enantiomers, or isotopic variant; or solvate or hydrate thereof, has a concentration of from about 20 mg / mL to about 150 mg / mL.

[0043] In some embodiments, the compound of Formula (I) or its enantiomer, mixture of enantiomers, or isotopic variant; or solvate or hydrate thereof, has a concentration of from about 95 mg / mL to about 105 mg / mL.

[0044] In some embodiments, the compound of Formula (I) or its enantiomer, mixture of enantiomers, or isotopic variant; or a solvate or hydrate thereof, has a concentration of about 95 mg / mL, about 96 mg / mL, about 97 mg / mL, about 98 mg / mL, about 99 mg / mL, about 100 mg / mL, about 101 mg / mL, 102 mg / mL, about 103 mg / mL, about 104 mg / mL, or about 105 mg / mL.

[0045] In some embodiments, the pharmaceutical composition further comprises a preservative.

[0046] In some embodiments, the preservative is benzethonium chloride.

[0047] In some embodiments, benzethonium chloride is present in an amount from about 0.1 mg / mL to about 0.5 mg / mL.

[0048] In some embodiments, provided herein are methods of treating pain, said methods comprising administering a therapeutically effective amount of any of the pharmaceutical compositions. In some embodiments, the pain is acute pain or chronic pain.

[0049] In one aspect, provided herein is a method of treating pain, said method comprising administering to a subject a compound of structural formula (I):

[0050] [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof; The compound of formula (I) is administered by subcutaneous injection.

[0051] In some embodiments, the pain is acute pain or chronic pain.

[0052] In one aspect, provided herein is a method of treating a psychiatric, cognitive, or neurological disorder, said method comprising administering to a subject a compound of structural formula (I):

[0053] [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof; The compound of formula (I) is administered by subcutaneous injection.

[0054] In some embodiments, the psychiatric disorder is major depressive disorder, treatment-resistant major depressive disorder, suicidality, suicidal ideation, dysthymia or persistent depressive disorder, bipolar depressive disorder type I, bipolar depressive disorder type II, chronic pain, eating disorder NOS, pain disorder NOS, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, complex regional pain syndrome, reflex sympathetic dystrophy, or any combination thereof.

[0055] In some embodiments, the cognitive or neurological disorder is Huntington's disease, Parkinson's disease, frontotemporal dementia, dementia, Alzheimer's disease, amyotrophic lateral sclerosis, spinal cord trauma, stroke, diffuse traumatic brain injury, HIV-associated dementia, epilepsy, Rett syndrome, dyskinesia, unspecified dystonia, or emotional dysregulation.

[0056] In some embodiments, the compound of Formula (I), its enantiomer, mixture of enantiomers, or isotopic variant, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by bolus injection or infusion pump. In some embodiments, the compound of Formula (I), its enantiomer, mixture of enantiomers, or isotopic variant; or a solvate or hydrate thereof, is administered as a low volume infusion.

[0057] In one aspect, provided herein is a method for preparing a pharmaceutical composition, said method comprising: A complexing agent comprising at least one acidic functional group in its free acid form and structural formula (I):

[0058] [ka] or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof; wherein the compound of structural formula (I) is in its free base form. In some embodiments, the mixing occurs in an aqueous medium. In some embodiments, the pharmaceutical composition is in a form for dosing or administration by subcutaneous injection.

[0059] In some embodiments, the complexing agent comprising at least one acidic functional group is a cyclodextrin, hi some embodiments, the complexing agent comprising at least one acidic functional group is a cyclodextrin substituted with one or more acidic functional groups selected from carboxylic acid, sulfonic acid, phosphonic acid, and phosphinic acid, or any combination thereof.

[0060] In some embodiments, a compound of formula (II):

[0061] [ka] or a stereoisomer, mixture of stereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein each R 1 are independently H, optionally substituted alkyl; each R 2 is independently H, optionally substituted alkyl; and n is 6, 7, or 8.

[0062] In some embodiments, the complexing agent is sulfobutyl-ether-beta-cyclodextrin (SBEBCD).

[0063] In some embodiments, the molar ratio of acidic functional groups of the complexing agent to the compound of Formula (I) is about 1: 1. In some embodiments, the molar ratio of complexing agent to the compound of Formula (I) is from about 1:4 to about 1:10.

[0064] In some embodiments, the method further comprises adjusting the pH of the pharmaceutical composition. In some embodiments, the pH of the pharmaceutical composition is from about 4 to about 7. In some embodiments, the method further comprises adding a preservative to the composition. In some embodiments, the method further comprises adding a base, a buffer, an emulsifier, a surfactant, a solubilizer, an emulsifier, a co-solvent, or any combination thereof.

[0065] In some embodiments, the pharmaceutical composition has an osmolality of about <500 mOsm / kg. In some embodiments, the pharmaceutical composition has a concentration of the compound of Formula (I) of at least about 20 mg / mL.

[0066] Incorporation by Reference 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. DETAILED DESCRIPTION OF THE INVENTION

[0067] For example, provided herein is a composition comprising ketamine that has reduced irritation to subcutaneous tissue and / or dermal tissue. In certain embodiments, the composition comprising ketamine is formulated for subcutaneous administration. For example, provided herein is a method for treating or preventing pain, psychiatric disorders, cognitive disorders, neurological disorders, and various other disorders.

[0068] I. Definition Abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0069] Where substituents are specified by their conventional chemical formula and written from left to right, they equally encompass the chemically identical substituents that result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0070] As used herein, the term "about," when referring to a numerical value or range of values, allows for a variability of the numerical value or range, for example, within 10%, or within 5% of the stated value or stated range limit.

[0071] All percent compositions are given in weight percent unless otherwise specified.

[0072] Average molecular weights of polymers are weight average molecular weights unless otherwise specified.

[0073] As used herein, "individual" (as in subject of treatment) refers to both mammals and non-mammals. Mammals include, for example, humans; non-human primates, such as apes and monkeys; and non-primates, such as dogs, cats, cows, horses, sheep, and goats. Non-mammals include, for example, fish and birds.

[0074] The terms "disease," "disorder," and "condition" refer to a state or condition of a patient or subject that is treatable by the compounds or methods provided herein. The disease can be a mental or psychiatric disease. The disease can be a mood disorder. The disease can be an inflammatory disease. The disease can be a neurological disease or disorder. In some further examples, "mental or psychiatric disorder" refers to a human mental or psychiatric disorder, including major depressive disorder, treatment-resistant major depressive disorder, suicidality, suicidal ideation, bipolar I disorder, bipolar II disorder, post-traumatic stress disorder (PTSD), substance-related disorders (e.g., cannabis dependence or withdrawal, barbiturate dependence or withdrawal, benzodiazepine dependence or withdrawal, amphetamine dependence or withdrawal, opioid dependence or withdrawal, alcohol dependence or withdrawal, cocaine dependence or withdrawal). In some further examples, "neurological disease or disorder" refers to a human neurological disease or disorder, including chronic fatigue syndrome, chronic fatigue and immune deficiency syndrome, neuropathy, fibromyalgia, fibromyalgia syndrome, myalgic encephalomyelitis, migraine, traumatic brain injury (TBI), stroke, dementia, amyotrophic lateral sclerosis, spinal cord injury, shingles, herpes zoster, radiculopathy, polyneuropathy, dyskinesia, dystonia, tinnitus, post-herpetic neuralgia, complex regional pain syndrome, central pain syndrome, chronic pain, acute pain, phantom limb syndrome with pain, phantom limb syndrome without pain, and myelitis.

[0075] The phrase "effective amount," when used to describe treatment for an individual suffering from a disorder, refers to an amount of a compound described herein that is effective to inhibit or otherwise affect NMDA receptors in the particular NMDA-active tissue of the disorder, such inhibition or other effect occurring to a degree sufficient to provide a beneficial therapeutic effect.

[0076] As used herein, the term "substantially" means completely or nearly completely. For example, a composition that is "substantially free" of a component either does not have the component or contains such a small amount that any relevant functional properties of the composition are not affected by the presence of the small amount. For example, a compound that is "substantially pure" has only a negligible amount of impurities present.

[0077] Unless a particular stereochemical or isomeric form is specifically indicated, all chiral, diastereomeric, and / or racemic forms of a structure are intended. The compounds described herein can include enriched or resolved optical isomers at any or all asymmetric atoms, in any degree of enrichment, as is apparent from the description. Both racemic and diastereomeric mixtures, as well as individual optical isomers, can be isolated or synthesized to be substantially free of their enantiomeric or diastereomeric partners, and all are within the scope of this disclosure.

[0078] The inclusion of isotopic forms of one or more atoms in a molecule that differ from the naturally occurring isotopic distribution of the atom in nature is referred to as an "isotopically labeled form" of the molecule. Unless a specific isotopic form of an atom is indicated, all isotopic forms of the atom are optionally included in the composition of any molecule. For example, any hydrogen atom or set of atoms in a molecule may also be any of the isotopic forms of hydrogen, e.g., protium ( 1 H), deuterium ( 2 H), tritium ( 3 Similarly, any carbon atom or set of carbon atoms in a molecule can be 11 C. 12 C. 13 C, or 14 C, or any nitrogen atom or set in the molecule. 13 N, 14 N, or 15N. A molecule can contain any combination of isotopic forms in the component atoms that make up the molecule, and the isotopic forms of all atoms that make up the molecule are independently selected. In a multi-molecular sample of a compound, not all individual molecules necessarily have the same isotopic composition. For example, a sample of a compound may contain radioactive atoms, such as tritium or uranium, where only a small fraction of the set of molecules that make up the macroscopic sample contain radioactive atoms. 14 This includes molecules containing a variety of different isotopic compositions, such as C radiolabeled samples. Many elements that are artificially isotopically enriched are themselves 14 N and 15 N, 32 S and 34 It is equally understood that the isotopic forms are mixtures of naturally occurring isotopic forms such as S. Molecules listed herein are defined to include all isotopic forms of their constituents at each position in the molecule. As is well known in the art, isotopically labeled compounds can be prepared by conventional methods of chemical synthesis, except for substituting isotopically labeled precursor molecules. Radiolabeled or stable isotopes can be obtained by methods known in the art, such as neutron absorption of precursor nuclides in a nuclear reactor, cyclotron reactions, or generation by mass spectrometry. Isotopic forms can be incorporated into precursors as needed for use in any particular synthetic route. For example, 14 C and 3 H can be prepared using neutrons produced in a nuclear reactor. After transmutation, 14 C and 3 H is incorporated into the precursor molecule, followed by further synthesis as needed.

[0079] A "hydrate" is a compound present in a composition that includes water molecules. The composition may include water in stoichiometric amounts, such as a monohydrate or dihydrate, or may include water in any amount. As used herein, "hydrate" refers to a compound in solid form, e.g., an aqueous solution, but may be hydrated rather than a hydrate as used herein.

[0080] A "solvate" is a similar composition except that a solvent other than water replaces the water. For example, methanol or ethanol can form an "alcoholate," which again can be stoichiometric or non-stoichiometric. As this term is used herein, a "solvate" is a compound in solid form, e.g., solution in solution, but which may be solvated, rather than a solvate as used herein.

[0081] A "prodrug," as is well known in the art, is a substance that can be administered to a patient, which is converted in vivo by the action of biochemicals in the patient's body, such as enzymes, on an active pharmaceutical ingredient. Examples of prodrugs include esters of carboxylic acid groups that can be hydrolyzed by endogenous esterases, such as those found in the bloodstream of humans and other mammals. Further examples of prodrugs include boronic acid esters that are hydrolyzable under physiological conditions to provide the corresponding boronic acids. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.

[0082] In various embodiments, a compound shown in any of the Examples or in the Exemplary Compounds is provided.

[0083] Conditions may be applied to any of the disclosed categories or embodiments, and any one or more of the other above-disclosed embodiments or species may be excluded from such category or embodiment.

[0084] Isomerism in the compounds described herein optical isomerism When the compounds of the present disclosure contain one or more chiral centers, the compounds may exist in or be isolated as pure enantiomeric or diastereomeric forms or racemic mixtures. Accordingly, the present disclosure includes any possible enantiomers, diastereomers, racemates, or mixtures thereof of the compounds described herein.

[0085] Isomers resulting from the presence of chiral centers comprise a pair of nonsuperimposable isomers called "enantiomers." Single enantiomers of a pure compound are optically active; for example, they can rotate the plane of plane-polarized light. Single enantiomers are designated according to the Cahn Ingold Prelog system. Substituent priorities are ranked based on atomic weight, with higher atomic weights determined by a systematic procedure having higher priority. Once the priority order of the four groups is determined, the molecule is oriented so that the lowest-ranked group is shown facing away from the viewer. If the other groups in descending order proceed clockwise, the molecule is designated (R), and if the other groups in descending order proceed counterclockwise, the molecule is designated (S). In the following examples, the Cahn Ingold Prelog order is A>B>C>D. The lowest-ranked atom, D, is oriented away from the viewer.

[0086] [ka]

[0087] The present disclosure is meant to encompass diastereomers as well as their racemic and resolved diastereomers, diastereomerically and enantiomerically pure forms and salts thereof. Diastereomeric pairs may also be resolved by known separation techniques, including normal phase and reverse phase chromatography, and crystallization.

[0088] "Isolated optical isomer" means a compound that has been substantially purified from the corresponding optical isomer of the same formula. Preferably, the isolated isomer is at least about 80% pure, more preferably at least 90%, even more preferably at least 98%, and most preferably at least about 99% pure.

[0089] Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques. According to one such method, a racemic mixture of the compounds described herein, or a chiral intermediate thereof, is separated into 99% pure optical isomers by HPLC using a suitable chiral column, such as a member of the DAICEL® CHIRALPAK® family of columns (Daicel Chemical Industries, Ltd., Tokyo Japan). The column is operated according to the manufacturer's instructions.

[0090] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, and stereoisomeric forms may be defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those known in the art to be too unstable to be synthesized and / or separated. The present disclosure is meant to include compounds in racemic and optically pure form. Optically active (R)- and (S)-, or (D)- and (L)-, isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. Where the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers.

[0091] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and hence the same molecular weight, but that differ with regard to the structural arrangement or configuration of the atoms.

[0092] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0093] It will be apparent to one of ordinary skill in the art that certain compounds of the present disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the present disclosure.

[0094] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure (e.g., R and S configurations of each asymmetric center). Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds of the invention are within the scope of the disclosure.

[0095] "Alkyl" refers solely to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, which may be optionally unsaturated with one or more double or triple bonds, and which preferably has from 1 to 15 carbon atoms (i.e., C1-C 15 alkyl). In certain embodiments, alkyl contains 1 to 6 carbon atoms (i.e., C1-C6 alkyl). In certain embodiments, alkyl groups are selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). An alkyl is attached to the remainder of the molecule by a single bond. Unless otherwise specified, the term "alkyl" and its equivalents encompass straight-chain, branched, and / or cyclic alkyl groups. In some instances, "alkyl" includes both cyclic and acyclic (straight-chain and / or branched) alkyl moieties.

[0096] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbon or heteroatoms of the structure. "Substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the allowed valences of the substituted atom and substituent, and that the substitution results in a stable compound that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is considered to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0097] Examples of the substituent include halogen, hydroxyl group, carbonyl (oxo (=O), carboxyl, alkoxycarbonyl, formyl, acyl, etc.), thiocarbonyl (thioxo (=S), thioester, thioacetate, thioformate, etc.), alkoxyl, phosphoryl, phosphoric acid, phosphonic acid, phosphinic acid, amino, amido, amidine, imine, oximo, hydrazino, cyano, nitro, azide, sulfhydryl, alkyl, alkylthio, sulfuric acid, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, aralkyl, carbocyclic ring, heterocyclic ring, cycloalkyl, heterocycloalkyl, aromatic ring, and any substituent on the aromatic heterocyclic ring moiety.

[0098] As used herein, an "acidic functional group" or similar term (e.g., "acidic functionality") refers to a chemical moiety containing at least one dissociable proton (or an isotopic variant thereof). In certain embodiments, the dissociable proton dissociates from the chemical moiety at a pH prevailing in aqueous systems (e.g., a pH of about 1 to about 14). In certain preferred embodiments, the dissociable proton dissociates from the chemical moiety in aqueous systems at a pH of less than 7 (having a pKa value less than 7, such as a pKa less than 6, less than 5, less than 4, less than 3, less than 2, or less than 1). As understood by those skilled in the art, whether an acidic functional group contains a dissociable proton depends on the conditions of the system in which the chemical moiety exists (e.g., the pH of an aqueous system containing a molecule having an acidic functional group or a base molecule). Thus, the term "acidic functional group" (or refer to a specific acidic functional group such as a carboxylic acid or sulfonic acid), as used herein, is intended to cover protonated versions of the moiety, deprotonated versions of the moiety, and any salts of the moiety, unless otherwise specified.

[0099] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms (e.g., isotopic variants), for example, the replacement of a hydrogen by deuterium or tritium; 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure.

[0100] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0101] The terms "a" or "an," as used herein, means one or more. Additionally, the phrase "substituted with a[n]," as used herein, means that the specified group can be substituted with any one or more or all of the specified substituents. For example, when a group such as an alkyl or heteroaryl group is "unsubstituted C-C 20 When "substituted with alkyl, or unsubstituted 2- to 20-membered heteroalkyl," the group is substituted with one or more unsubstituted C-C 20 alkyl, and / or one or more unsubstituted 2- to 20-membered heteroalkyl.

[0102] "Salts," as is well known in the art, include organic compounds such as carboxylic acids, sulfonic acids, or amines in ionic form in combination with a counterion. For example, such anionic acids can form salts with cations such as metal cations, e.g., sodium, potassium, ammonium salts such as NH4, or cations of various amines, including tetraalkylammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium. The terms "pharmaceutically acceptable salts" and / or "pharmacologically acceptable salts" are intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, sublingual acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, or methanesulfonic acid.Also included are salts of amino acids such as arginine acid, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts.

[0103] Thus, the compounds of the present disclosure may exist as salts with pharmaceutically acceptable acids, etc. The present disclosure includes such salts. Non-limiting examples of such salts include salts with amino acids such as hydrochloride, hydrobromide, phosphoric acid, sulfuric acid, methanesulfonic acid, nitric acid, maleic acid, acetic acid, citric acid, fumaric acid, proprionates, tartaric acid (e.g., (+)-tartaric acid, (-)-tartaric acid, or a mixture thereof, including a racemic mixture), succinic acid, benzoic acid, and glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). Such salts can be prepared by methods known to those skilled in the art.

[0104] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In certain embodiments, the compounds of the present disclosure contain both basic and acidic functional groups, which allow the compounds to be converted into either base or acid addition salts. The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. Although the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, the salts disclosed herein are equivalent to the parent form of the compound for purposes of this disclosure, unless otherwise specified.

[0105] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that are easily chemically changed under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein can be converted in vivo after administration. In addition, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, for example, by contacting with a suitable enzyme or chemical reagent.

[0106] Certain compounds of the present disclosure can exist in solvated forms as well as unsolvated forms, including hydrated forms. Typically, solvated forms are equivalent to unsolvated forms and are included within the scope of the present disclosure. Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms. Typically, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0107] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration and absorption of a compound by a subject and that may be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, complexing agents (e.g., cyclodextrins), binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, saline solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, coloring agents, and the like. Such preparations are sterilized and, if necessary, may be mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not adversely react with the compounds of the present disclosure. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0108] The term "preparation" is intended to include formulations of active compounds with encapsulating materials as carriers to provide capsules, where the active ingredient, with or without other carriers, is surrounded by the carrier and is thus associated with the carrier. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0109] The term "treat" or "treatment" refers to any indication of success in treating or ameliorating an injury, disease, condition, or malady, including any subjective or objective parameter, such as reduction; remission; alleviation of symptoms or making the injury, condition, or state more tolerable to the patient; slowing the rate of degeneration or decline; preventing a degenerative end point; or improving the patient's physical or mental well-being. Treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric testing, and / or psychiatric evaluation. The term "treating" and its conjugations can include prevention of an injury, condition, malady, or malady. In certain embodiments, treating is preventing. In certain embodiments, treating does not include preventing.

[0110] As used herein (and as terms well understood in the art), "treating" or "treatment" broadly includes any approach to achieving a beneficial or desired result in a subject's disease, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or disease, reduction in the extent of disease, stabilization of the disease state (e.g., not worsening), prevention of the spread or progression of disease, delay or slowing of disease progression, improvement or palliation of the disease state, reduction in disease recurrence, and remission, whether partial or total and detectable or undetectable. In other words, "treatment" as used herein includes curing, amelioration, or prevention of any disease. Treatment may prevent the disease from occurring; i.e., inhibit the spread of the disease; alleviate symptoms of the disease (e.g., eye pain from looking at lights, red eyes, halos around very high intraocular pressure), fully or partially eliminate the underlying cause of the disease, shorten the duration of the disease, or any combination thereof.

[0111] As used herein, "treating" and "treatment" include prophylactic treatment. A treatment method includes administering a therapeutically effective amount of a compound described herein to a subject. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on various factors, such as the severity of the disease, the age of the patient, the concentration of the compound, the activity of the composition used in the treatment, or a combination thereof. It will also be understood that the effective amount of an agent used for treatment or prevention may increase or decrease during a particular treatment or prevention regimen. Variations in dosage may occur and be evident by standard diagnostic assays known in the art. In some instances, long-term administration may be required. For example, a composition is administered to a subject in an amount and for a period sufficient to treat the patient.

[0112] The term "preventing" refers to a reduction in the occurrence of symptoms of a disease in a patient. As specified above, prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would occur in the absence of treatment. In certain embodiments, preventing refers to slowing the progression of a disease, disorder, or condition, or inhibiting its progression to an adverse or unwanted state.

[0113] "Patient" or "subject in need" refers to a living organism suffering from or susceptible to a disease or disorder treatable by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is a human.

[0114] An "effective amount" is an amount sufficient for a compound to achieve its stated purpose compared to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, decrease a signaling pathway, or reduce one or more symptoms of a disease or disorder). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom of a disease, which may also be referred to as a "therapeutically effective amount." A "reduction" of a symptom (and grammatical equivalents of this phrase) refers to a decrease in the severity or frequency of the symptom, or the elimination of the symptom. A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, has an intended prophylactic effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, condition, or illness, or reducing the likelihood of the onset (or recurrence) of an injury, disease, condition, or illness, or a symptom thereof. A complete prophylactic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. As used herein, an "activity-reducing amount" refers to the amount of an antagonist required to reduce the activity of an enzyme compared to the absence of the antagonist. A "function-interfering amount" refers to the amount of an antagonist required to interfere with the function of an enzyme or protein compared to the absence of the antagonist. The exact amount depends on the purpose of the treatment and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).A therapeutically effective amount can be ascertained by measuring a relevant physiological effect, and can be adjusted in conjunction with dosing regimens, diagnostic assays for a subject's disease, etc. For example, measuring serum levels of an inhibitor (or, e.g., a metabolite thereof) at a particular time after administration can indicate whether a therapeutically effective amount has been administered.

[0115] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. The target concentration is the concentration of active compound that can achieve the methods described herein, as measured using methods described herein or known in the art.

[0116] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, dosages for humans can be formulated to achieve concentrations found to be effective in animals. Dosages in humans can be adjusted by monitoring the effects of the compound and adjusting the dosage upward or downward, as described above. Based on the above and other methods, it is well within the ability of those skilled in the art to adjust dosages to achieve maximum efficacy in humans. Based on the above and other methods, it is well within the ability of those skilled in the art to adjust dosages to achieve maximum therapeutic window efficacy or toxicity in humans.

[0117] As used herein, the term "therapeutically effective amount" refers to that amount of a therapeutic agent sufficient to ameliorate a disorder as described herein. For example, for a given parameter, a therapeutically effective amount would exhibit at least a 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least a 100% increase or decrease. The effectiveness of a therapeutic agent may also be expressed as a "-fold" increase or decrease. For example, a therapeutically effective amount may have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or greater effect than a control.

[0118] Dosage may vary depending on the requirements of the patient and the compound employed. In the context of the present disclosure, the dosage administered to a patient must be sufficient to achieve a beneficial therapeutic response in the patient over time. The size of the dosage is also determined by the existence, nature, and extent of any side effects. Determining the appropriate dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with a low dosage that is less than the optimal amount of the compound. Thereafter, the dosage is increased by small increments until the optimal effect under the circumstances is reached. The amount and interval of administration can be individually adjusted to provide a level of the administered compound that is effective for the specific clinical indication being treated. This provides a treatment regimen that corresponds to the severity of the individual's condition.

[0119] As used herein, the term "administering" refers to subcutaneous (i.e., "SC," "subQ," or "SQ") administration, oral administration, administration as a suppository, topical contact or administration, intravenous, parenteral, intraperitoneal, intramuscular, intraosseous, intralesional, intrathecal, intracranial, intranasal, epidural, or implantation of a sustained-release device (e.g., a mini-osmotic pump) into a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous injection, transdermal patches, and the like. "Co-administration" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents (e.g., anti-cancer agents, chemotherapeutic agents, or treatments for neurodegenerative diseases). The compounds of the present disclosure can be administered alone or simultaneously to a patient. Co-administration includes simultaneous or sequential administration of the compounds alone or in combination (more than one compound or agent). Thus, the preparations may be combined with other agents, if necessary (e.g., to reduce metabolic degradation). The compositions of the present disclosure can be delivered topically or transdermally and can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, pigments, powders, and aerosols. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by a patient. Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid preparations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. The compositions of the present disclosure may further comprise ingredients for sustained release and / or comfort. Such ingredients include high molecular weight, anionic mucosomimetic polymers, gelling polysaccharides, and fine drug carrier matrices. These ingredients are discussed in greater detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760.The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present disclosure can also be delivered as microspheres for delayed release in the body. For example, microspheres can be delivered slowly subcutaneously by intradermal injection of drug-containing microspheres (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995); as biodegradable, injectable gel formulations (see, e.g., Gao, Pharm. Res. 12:857-863, 1995); or as oral microspheres (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, formulations of the compositions of the present disclosure can be delivered by the use of liposomes that fuse with cell membranes or are endocytosed, for example, by using liposome-bound receptor ligands that bind to cell surface membrane protein receptors that result in endocytosis. Liposomes can be used to deliver the compositions of the present disclosure to targeted cells in vivo, particularly when the surface of the liposome carries receptor ligands specific to the target cells or is otherwise preferentially directed to a particular organ. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989). The compositions of the present disclosure can also be delivered as nanoparticles.

[0120] "Co-administered" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents. The compounds of the present disclosure can be administered alone or simultaneously to a patient. Co-administration means simultaneous or sequential administration of the compounds alone or in combination (more than one compound). The compositions of the present disclosure can be delivered topically, transdermally, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, pigments, powders, and aerosols.

[0121] The technology provided herein can be used to design preventative or therapeutic treatment regimens that are effective in treating documented clinical symptoms in a particular patient without causing substantial toxicity. This design must include careful selection of active compounds, taking into account factors such as the compound's potency, relative bioavailability, the patient's weight, the presence and severity of adverse side effects, the preferred method of administration, and the toxicity profile of the selected agent.

[0122] The compounds described herein can be used in conjunction with each other, with other active agents known to be useful in the treatment of psychiatric, mood disorders, neurological diseases or disorders, metabolic disorders (e.g., type 2 diabetes and / or complications thereof), endometriosis, glaucoma, pain or illness or psychiatric disorders, or inflammatory disorders.

[0123] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4 days, 1 week, or 1 month of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be achieved by co-formulation, e.g., preparing a single pharmaceutical composition containing both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agents and / or adjunct agents can be linked or conjugated to each other. In some embodiments, the compounds described herein can be combined with treatments for infection (e.g., bacterial infection), inflammation, and / or vasodilation.

[0124] The compounds described herein can be administered to treat a metabolic disease or disorder (e.g., type 2 diabetes and / or complications thereof), a mental or psychiatric disorder, a mood disorder, a neurological disease or disorder, endometriosis, glaucoma, pain, or an inflammatory disorder. In this regard, the compounds disclosed herein can be administered alone to treat such a disease or disorder or can be co-administered with another therapeutic agent to treat such a disease or disorder.

[0125] The compounds disclosed herein may be co-administered with other active agents, including, but not limited to, antidepressants, antipsychotics, anti-inflammatory agents, anxiolytics, and / or analgesics.

[0126] The inhibitors disclosed herein (e.g., NMDA inhibitors) may be administered once daily until the study reaches its endpoint. The inhibitors disclosed herein may be administered at least three times, but in some studies, four or more times, depending on the length of the study and / or study design.

[0127] As used herein, the term "bioavailability (F)" refers to the proportion of a dose of a drug (e.g., epinephrine) that is absorbed from its site of administration and reaches the systemic circulation in an unchanged form. The term "absolute bioavailability" is used when the fraction of a drug absorbed relates to its IV bioavailability. It may be calculated using the following formula:

[0128]

number

[0129] Relative bioavailability (F rel ) is used to compare two different extravascular routes of drug administration, and it may be calculated using the formula:

[0130]

number

[0131] The term "elimination (CL)", as used herein, is the rate at which a drug is excreted divided by its plasma concentration and indicates the amount of plasma from which the drug is completely removed per unit time. CL is calculated based on the volume of distribution (V d ) multiplied by the elimination rate constant (λ), d " is the volume of fluid required to contain the amount of drug present in the body at the same concentration as in plasma. The term "explicit elimination (CL / F)" as used herein refers to the elimination without taking into account the bioavailability of the drug. It is the ratio of dose to AUC.

[0132] The term "ketamine," as used herein, refers to a compound of the following structure:

[0133] [ka] Alternatively, it may refer to its stereoisomers, pharmaceutically acceptable salts, hydrates, or solvates. The CAS registry number for ketamine is 6740-88-1. Other names for ketamine include, but are not limited to, 2-(2-chlorophenyl)-2-(methylamino)cyclohexanone.

[0134] As used herein, a "cell" refers to a cell that performs metabolic or other functions sufficient to preserve or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, contact with specific dyes, the ability to produce progeny, or, in the case of gametes, the ability to combine with a second gamete to produce viable offspring. Cells can include prokaryotic and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast, and cells of plant or animal origin, such as mammalian, insect (e.g., Spodoptera), and human cells. Cells can be useful if they are naturally non-adherent or if they are treated to prevent them from binding to surfaces, for example, by trypsinization.

[0135] "Control" or "control experiment" is used according to its plain and ordinary meaning and refers to an experiment in which experimental subjects or reagents are treated in parallel with the experiment except for the omission of an experimental procedure, reagent, or variable. In some instances, a control is used as a standard of comparison in evaluating experimental efficacy. In some embodiments, a control is a measurement of protein activity in the absence of a compound as described herein (including embodiments and examples).

[0136] Typically, the dosage level of ketamine in the composition ranges from about 5 μg / kg to about 10 mg / kg, about 0.5 mg / kg to about 5 mg / kg, about 1 mg / kg to about 3 mg / kg, about 10-100 mg, 20-75 mg, 3-60 mg, 10-250 mg, 10-400 mg, or a fixed dose in an amount of 400 mg or more.

[0137] "Substantially pure" indicates that a component comprises about 50% or more of the total content of the composition, typically about 60% or more of the total content. More typically, "substantially pure" refers to a composition in which the component of interest comprises at least 75%, at least 85%, or at least 90% of the total composition. In some cases, the polypeptide will comprise about 90% or more or about 95% or more of the total content of the composition (percent by weight).

[0138] It should be noted that throughout this application, alternatives are written as Markush groups, e.g., at each amino acid position containing more than one possible amino acid. In particular, it is intended that each member of a Markush group must be considered separately, thereby including alternative embodiments, and that the Markush group is not to be read as a single unit.

[0139] "Contacting" is used according to its simple ordinary meaning and refers to a process that allows at least two distinct species (e.g., chemical compounds, including biomolecules or cells) to be sufficiently proximate to react, interact, or come into physical contact. It should be understood, however, that the resulting reaction product may be produced directly from the reaction between additional reagents or from an intermediate from one or more of the additional reagents that may be produced in the reaction product.

[0140] The term "contacting" includes allowing two species to react, interact, or come into physical contact, where the two species can be a compound as described herein and a protein or enzyme. In some embodiments, contacting includes allowing a compound described herein to interact with a protein or enzyme involved in a signaling pathway (e.g., the MAP kinase pathway).

[0141] As defined herein, the reference terms "activation," "activate," "activating," and the like refer to the conversion of a protein from an initial inactive or inactivated state to a biologically active derivative. These terms refer to activation, or activating, sensitizing, or upregulating signal transduction, enzyme activity, or the amount of protein reduction in disease.

[0142] The terms "agonist," "activator," "upregulator," and the like refer to a substance that can detectably increase the expression or activity of a given gene or protein. An agonist can increase expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control in the absence of the agonist. In some instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or even higher than in the absence of the agonist. In embodiments, an agonist is a molecule that interacts with a target to cause or promote increased activation of the target. In embodiments, an activator is a molecule that increases, activates, promotes, enhances activation, sensitizes, or upregulates, for example, a gene, protein, ligand, receptor, or cell.

[0143] The "activity" of a molecule may describe or refer to: binding of the molecule to a ligand or receptor; catalytic activity; gene expression or cell signaling, differentiation or maturation; antigenic activity; or modulation of the activity of another molecule.

[0144] The term "osmolality" as used herein is defined as the number of osmoles (Osm) of solute per kilogram of solvent (osmol / kg or Osm / kg).

[0145] The term "osmolality" as used herein is defined as the number of osmoles (Osm) of solute per liter (L) of solution (osmol / L or Osm / L).

[0146] Osmolality may be calculated from osmolality as follows: Osmolality = Osmolality x (ρ sol -c a );ρ sol is the density of the solution in g / mL, and c a is the (anhydrous) solute concentration in g / mL. Unless otherwise indicated, osmolality is calculated using osmolality according to the formula above. Alternatively, osmolality may be calculated experimentally.

[0147] II. Composition Provided herein are pharmaceutical formulations of ketamine suitable for dosing or administration by subcutaneous injection. Subcutaneously deliverable ketamine has an advantage over other forms of ketamine (e.g., IV or IM delivery) in that it can be used by subjects outside of a hospital or clinical setting, such as at home. Other formulations of ketamine suitable for home use, such as oral or nasal delivery formulations, tend to require higher doses to achieve comparable clinical efficacy and carry risks including bladder dysfunction due to higher doses and dissociative effects. Furthermore, oral or sublingual administration is often unreliable due to the presence of food or mucus in the abdominal or proximal small intestine and substantial first-pass metabolism. Intranasal administration may cause allergic or irritant rhinitis, epistaxis (nosebleeds), or bacterial or viral sinusitis.

[0148] In some embodiments, the pharmaceutical formulations provided herein are capable of combining high concentrations of ketamine (e.g., 20 mg / mL or greater) with additional properties of a formulation ideally suited for subcutaneous injection. These additional properties may include near-physiological osmolality and near-physiological pH, while maintaining formulation stability and ketamine solubility. In some embodiments, these desirable properties are achieved through the use of complexing agents, particularly cyclodextrins, which act to increase ketamine solubility at elevated pH (e.g., as high as about 5.5). In some embodiments, these attributes are enhanced through the use of modified cyclodextrins, particularly cyclodextrins modified with additional polar groups (e.g., hydroxypropyl-beta-cyclodextrin (HPBCD)) or sulfonate (e.g., sodium salt) functional groups (e.g., sulfobutyl-ether-beta-cyclodextrin (SBEBCD)). In some embodiments, sulfonate functional groups (e.g., hydroxypropyl-beta-cyclodextrin (HPBCD)) are preferred because they can act as counter anions to protonate the non-ionized or free base form of ketamine. The use of cyclodextrins modified to replace sodium in the sulfonate sodium salt functional group to form SBEBCD (SEQ ID NO: 1) is particularly advantageous. In such embodiments, additional salts and counterions can be omitted from the formulation, thereby achieving low osmolality in high-concentration ketamine formulations. Thus, high concentrations of ketamine at pH levels compatible with subcutaneous injection can be achieved with osmolality comparable to physiological levels (~300 mOsm / kg), thus enabling subcutaneous administration of ketamine without side effects such as pain or injection site irritation.

[0149] In one embodiment provided herein, the pharmaceutical composition comprises: (i) Structural formula (I):

[0150] [ka] or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a form for dosage or administration by subcutaneous injection.

[0151] In one embodiment provided herein, the pharmaceutical composition comprises: (i) Structural formula (I):

[0152] [ka] or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition comprises from about 50 mg / mL to about 150 mg / mL of a compound of structural formula (I) or its enantiomer, mixture of enantiomers, or isotopic variant, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0153] In one embodiment provided herein, the pharmaceutical composition comprises: (i) Structural formula (I):

[0154] [ka] or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition has a pH of from about 4 to about 7.

[0155] In some embodiments, a compound of structural formula (I) (e.g., ketamine) or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; is racemic. In some embodiments, a compound of structural formula (I) (e.g., ketamine) or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; is the S enantiomer. In some embodiments, a compound of structural formula (I) (e.g., ketamine) or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; is the R enantiomer.

[0156] In some embodiments, the pharmaceutically acceptable salt comprises a dibasic or tribasic acid.

[0157] In some embodiments, the pharmaceutically acceptable salt comprises an organic acid.

[0158] In some embodiments, the pharmaceutically acceptable salt comprises an inorganic acid.

[0159] In some embodiments, the acid is a substituted or unsubstituted carboxylic acid, a substituted or unsubstituted phenol, a substituted or unsubstituted sulfonic acid, a substituted or unsubstituted alcohol, a substituted or unsubstituted thiol, a substituted or unsubstituted enol, or a carbonic acid.

[0160] In some embodiments, the acid is fumaric acid, malic acid, citric acid, tartaric acid, glutaric acid, succinic acid, maleic acid, or malonic acid.

[0161] In some embodiments, the acid is sulfuric acid, sulfonic acid, phosphonic acid, or phosphoric acid.

[0162] In some embodiments, the pharmaceutically acceptable salt comprises a cyclodextrin substituted with at least one acidic functional group. In some embodiments, the at least one acidic functional group is a carboxylic acid, sulfonic acid, sulfinic acid, phosphonic acid, or phosphinic acid, or any combination thereof. In some embodiments, the cyclodextrin is substituted with at least one, at least two, at least three, at least four, at least five, or at least six acidic functional groups. In some embodiments, the cyclodextrin is substituted with 3 to 8 acidic functional groups, 3 to 7 acidic functional groups, 4 to 8 acidic functional groups, 4 to 7 acidic functional groups, 5 to 8 acidic functional groups, 6 to 8 acidic functional groups, or 7 to 8 acidic functional groups.

[0163] In some embodiments, the pharmaceutical composition further comprises a complexing agent.

[0164] In some embodiments, the complexing agent is a substituted or unsubstituted cyclodextrin. In some cases, the substituted cyclodextrins provided herein are complex mixtures, and individual cyclodextrin molecules may contain a different number of substituents than other individual cyclodextrin molecules. In such cases, the number of substituents (e.g., the number of acidic functional groups) described as being present on a cyclodextrin provided herein may refer to the average degree of substitution of the mixture. For example, if a cyclodextrin is described as being substituted with 3 to 8 acidic functional groups, a complex mixture of cyclodextrins having an average degree of substitution of 3 to 8 acidic functional groups is intended to be encompassed. The average degree of substitution need not be an integer value and is often a decimal value. For example, commercially available SBEBCD has an average degree of substitution of about 6.5.

[0165] In some embodiments, the complexing agent is a substituted cyclodextrin. In some embodiments, the substituted cyclodextrin is substituted with one or more acidic functional groups, or pharmaceutically acceptable salts thereof. In some embodiments, the substituted cyclodextrin is substituted with one or more carboxylic, sulfonic, sulfinic, phosphonic, or phosphinic acids. In some embodiments, the cyclodextrin is substituted with at least one, at least two, at least three, at least four, at least five, or at least six acidic functional groups. In some embodiments, the cyclodextrin is substituted with 3 to 8 acidic functional groups, 3 to 7 acidic functional groups, 4 to 8 acidic functional groups, 4 to 7 acidic functional groups, 5 to 8 acidic functional groups, 6 to 8 acidic functional groups, or 7 to 8 acidic functional groups.

[0166] In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (I) is from about 1:4 to about 1:8. In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (I) is from about 1:4 to about 1:10. In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (I) is from about 1:5 to about 1:7. In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (I) is about 1:4. In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (I) is about 1:5. In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (I) is about 1:6. In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (I) is about 1:7. In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (I) is about 1:8. In some embodiments, the molar ratio of cyclodextrin to compound of Formula (I) is about 1:9. In some embodiments, the molar ratio of cyclodextrin to compound of Formula (I) is about 1:10.

[0167] In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (I) is from about 2:1 to about 1:2. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (I) is from about 1.75:1 to about 1:1.75. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (I) is from about 1.5:1 to about 1:1.5. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (I) is from about 1.4:1 to about 1:1.4. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (I) is from about 1.3:1 to about 1:1.3. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (I) is from about 1.25:1 to about 1:1.25. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (I) is from about 1.2:1 to about 1:1.2. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (I) is from about 1.15:1 to about 1:1.15. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (I) is from about 1.1:1 to about 1:1.1. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (I) is from about 1.05:1 to about 1:1.05. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (I) is about 1:1.

[0168] In some embodiments, the cyclodextrin is present in an amount of about 50 mg / mL to about 600 mg / mL. In some embodiments, the cyclodextrin is present in an amount of about 50 mg / mL to about 600 mg / mL. In some embodiments, the cyclodextrin is present in an amount of about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 300 mg / mL, about 50 mg / mL to about 400 mg / mL, about 50 mg / mL to about 500 mg / mL, about 50 mg / mL to about 600 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 300 mg / mL, about 100 mg / mL to about 400 mg / mL, about 100 mg / mL to about 500 mg / mL, about 100 mg / mL to about 600 mg / mL. In some embodiments, the cyclodextrin is present in an amount of about 50 mg / mL, about 100 mg / mL, about 200 mg / mL, about 300 mg / mL, about 400 mg / mL, about 500 mg / mL, or about 600 mg / mL. In some embodiments, the cyclodextrin is present in an amount of about 50 mg / mL, about 100 mg / mL, about 200 mg / mL, about 300 mg / mL, about 400 mg / mL, about 500 mg / mL, or about 600 mg / mL. In some embodiments, the cyclodextrin is present in an amount of at least about 50 mg / mL, about 100 mg / mL, about 200 mg / mL, about 300 mg / mL, about 400 mg / mL, or about 500 mg / mL, hi some embodiments, the cyclodextrin is present in an amount of at most about 100 mg / mL, about 200 mg / mL, about 300 mg / mL, about 400 mg / mL, about 500 mg / mL, or about 600 mg / mL.

[0169] In some embodiments, the cyclodextrin has the formula (II):

[0170] [ka] or a stereoisomer, mixture of stereoisomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, During the ceremony: Each R 1 are independently H, optionally substituted alkyl; Each R 2 are independently H, optionally substituted alkyl; and n is 6, 7, or 8.

[0171] In some embodiments, each R 1 are independently H or alkyl optionally substituted with a polar functional group. In some embodiments, the polar functional group is an amide functional group, an acid functional group, an ester functional group, a hydroxyl functional group, an alkoxy functional group, or a poly(alkylene oxide) functional group. In some embodiments, each R 1 is independently H or alkyl optionally substituted with an acidic or hydroxyl functional group.

[0172] In some embodiments, each R 1 are independently H or alkyl optionally substituted with an acidic functional group. In some embodiments, each R 1 are independently H or alkyl substituted with an acidic functional group. In some embodiments, each R 1 are independently H or C1-C6 alkyl substituted with an acidic functional group. In some embodiments, each R 1 are independently H or C1-C6 alkyl substituted with an acidic functional group selected from carboxylic acid, sulfonic acid, sulfinic acid, phosphonic acid, or phosphinic acid. In some embodiments, each R 1 is independently H,

[0173] [ka] In some embodiments, each R 1 is independently H,

[0174] [ka] In some embodiments, R 1 contains an acidic functional group, and each R 2 is H or acetyl. In some embodiments, R 1 contains an acidic functional group, and each R 2 is H.

[0175] In some embodiments, each R 1 are independently H or alkyl optionally substituted with a hydroxyl functional group. In some embodiments, each R 1 is independently H or an alkyl substituted with a hydroxyl functional group. In some embodiments, each R 1 are independently H or a C1-C6 alkyl substituted with a hydroxyl functional group. In some embodiments, each R 1 is independently H, or hydroxypropyl, hydroxybutyl, hydroxypentyl, or hydroxyhexyl. In some embodiments, each R 1 and R 2 are independently H or hydroxypropyl, hydroxybutyl, hydroxypentyl, or hydroxyhexyl.

[0176] In some embodiments, each R 2 are independently H or alkyl optionally substituted with a polar functional group. In some embodiments, each R 2 are independently H or alkyl optionally substituted with a hydroxyl functional group. In some embodiments, each R 2 is independently H or an alkyl substituted with a hydroxyl functional group. In some embodiments, each R 2 are independently H or a C1-C6 alkyl substituted with a hydroxyl functional group. In some embodiments, each R 2 is independently H, or hydroxypropyl, hydroxybutyl, hydroxypentyl, or hydroxyhexyl. In some embodiments, each R2 is H. In some embodiments, each R 2 is H or acetyl.

[0177] In some embodiments, n is 6 or 7. In some embodiments, n is 7 or 8. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8.

[0178] In some embodiments, the cyclodextrin is sulfobutyl-ether-beta-cyclodextrin (SBEBCD) or hydroxypropyl-beta-cyclodextrin (HPBCD).

[0179] In some embodiments, the cyclodextrin is SBEBCD. In some embodiments, the SBEBCD is the free acid form of SBEBCD.

[0180] In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is from about 1:4 to about 1:8. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is from about 1:4 to about 1:10. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is from about 1:5 to about 1:7. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is about 1:4. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is about 1:5. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is about 1:6. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is about 1:7. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is about 1:8. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is about 1:9. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is about 1:10. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is from about 1:2 to about 1:10. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is from about 1:2 to about 1:3, from about 1:2 to about 1:4, from about 1:2 to about 1:5, from about 1:2 to about 1:6, from about 1:2 to about 1:7, from about 1:2 to about 1:8, from about 1:2 to about 1:9, from about 1:2 to about 1:10, from about 1:3 to about 1:4, from about 1:3 to about 1:5, from about 1:3 to about 1:6, from about 1:3 to about 1:7, from about 1:3 to about 1:8, from about 1:3 to about 1:9, from about 1:3 to about 1:10, from about 1:4 to about 1:5, from about 1:4 to about 1:6 , about 1:4 to about 1:7, about 1:4 to about 1:8, about 1:4 to about 1:9, about 1:4 to about 1:10, about 1:5 to about 1:6, about 1:5 to about 1:7, about 1:5 to about 1:8, about 1:5 to about 1:9, about 1:5 to about 1:10, about 1:6 to about 1:7, about 1:6 to about 1:8, about 1:6 to about 1:9, about 1:6 to about 1:10, about 1:7 to about 1:8, about 1:7 to about 1:9, about 1:7 to about 1:10, about 1:8 to about 1:9, about 1:8 to about 1:10, or about 1:9 to about 1:10.In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is at least about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, or about 1:9. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (I) is at most about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.

[0181] In some embodiments, the pharmaceutical composition comprises a base, a buffer, or a combination thereof.

[0182] In some embodiments, the pharmaceutical composition does not include a base, a buffer, or a combination thereof.

[0183] In some embodiments, the co-solvent is ethanol, propylene glycol, tween 20, tween 80, glycerin, or a combination thereof.

[0184] In some embodiments, the compound of Formula (I) has the structural formula (IA):

[0185] [ka] or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, During the ceremony: X - is a counter ion, and further a compound of formula (IA).

[0186] In some embodiments, a compound of structural formula (IA), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, is partially ionized or fully ionized.

[0187] In some embodiments, the compound of structural formula (IA), or its enantiomer, enantiomeric mixture, or isotopic variant; or solvate or hydrate thereof, is at least about 75% ionized. In some embodiments, the compound of structural formula (IA), or its enantiomer, enantiomeric mixture, or isotopic variant; or solvate or hydrate thereof, is at least about 80% ionized. In some embodiments, the compound of structural formula (IA), or its enantiomer, enantiomeric mixture, or isotopic variant; or solvate or hydrate thereof, is at least about 85% ionized. In some embodiments, the compound of structural formula (IA), or its enantiomer, enantiomeric mixture, or isotopic variant; or solvate or hydrate thereof, is at least about 90% ionized. In some embodiments, the compound of structural formula (IA), or its enantiomer, enantiomeric mixture, or isotopic variant; or solvate or hydrate thereof, is at least about 91% ionized. In some embodiments, the compound of structural formula (IA), or its enantiomer, enantiomeric mixture, or isotopic variant; or solvate or hydrate thereof, is at least about 92% ionized. In some embodiments, the compound of structural formula (IA), or its enantiomer, enantiomeric mixture, or isotopic variant; or solvate or hydrate thereof, is at least about 93% ionized. In some embodiments, the compound of structural formula (IA), or its enantiomer, enantiomeric mixture, or isotopic variant; or solvate or hydrate thereof, is at least about 94% ionized. In some embodiments, the compound of structural formula (IA), or its enantiomer, enantiomeric mixture, or isotopic variant; or solvate or hydrate thereof, is at least about 95% ionized. In some embodiments, the compound of structural formula (IA), or its enantiomer, enantiomeric mixture, or isotopic variant; or solvate or hydrate thereof, is at least about 96% ionized.In some embodiments, a compound of structural formula (IA), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, is at least about 97% ionized. In some embodiments, a compound of structural formula (IA), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, is at least about 98% ionized. In some embodiments, a compound of structural formula (IA), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, is at least about 99% ionized. In some embodiments, a compound of structural formula (IA), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, is at least about 99.1% ionized. In some embodiments, a compound of structural formula (IA), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, is at least about 99.2% ionized. In some embodiments, a compound of structural formula (IA), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, is at least about 99.3% ionized. In some embodiments, a compound of structural formula (IA), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, is at least about 99.4% ionized. In some embodiments, a compound of structural formula (IA), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, is at least about 99.5% ionized. In some embodiments, a compound of structural formula (IA), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, is at least about 99.6% ionized. In some embodiments, a compound of structural formula (IA), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, is at least about 99.7% ionized.In some embodiments, a compound of structural formula (IA), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, is at least about 99.8% ionized. In some embodiments, a compound of structural formula (IA), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, is at least about 99.9% ionized.

[0188] In some embodiments, X - is fumaric acid, malic acid, citric acid, tartaric acid, glutaric acid, succinic acid, maleic acid, SBEBCD, or malonic acid. - is a substituted cyclodextrin. In some embodiments, X - is a cyclodextrin substituted with a deprotonated acidic residue. In some embodiments, the deprotonated acidic residue is a carboxylic acid, sulfonic acid, sulfinic acid, phosphonic acid, or phosphinic acid. In some embodiments, the deprotonated acidic residue is a sulfonic acid. In some embodiments, X - is a compound of formula (II).

[0189] In some embodiments, the pharmaceutical composition further comprises a complexing agent.

[0190] In some embodiments, the complexing agent is a substituted or unsubstituted cyclodextrin. In some cases, the substituted cyclodextrins provided herein are complex mixtures, and individual cyclodextrin molecules may contain a different number of substituents than other individual cyclodextrin molecules. In such cases, the number of substituents (e.g., the number of acidic functional groups) described as being present on the cyclodextrins provided herein may refer to the average degree of substitution of the mixture. For example, if a cyclodextrin is described as being substituted with 3 to 8 acidic functional groups, it is intended to encompass a complex mixture of cyclodextrins having an average degree of substitution of 3 to 8 acidic functional groups.

[0191] In some embodiments, the complexing agent is a substituted cyclodextrin. In some embodiments, the substituted cyclodextrin is substituted with one or more acidic functional groups, or pharmaceutically acceptable salts thereof. In some embodiments, the substituted cyclodextrin is substituted with one or more carboxylic acids, sulfonic acids, sulfinic acids, phosphonic acids, or phosphonic acids. In some embodiments, the cyclodextrin is substituted with at least one, at least two, at least three, at least four, at least five, or at least six acidic functional groups. In some embodiments, the cyclodextrin is substituted with 3 to 8 acidic functional groups, 3 to 7 acidic functional groups, 4 to 8 acidic functional groups, 4 to 7 acidic functional groups, 5 to 8 acidic functional groups, 6 to 8 acidic functional groups, or 7 to 8 acidic functional groups.

[0192] In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (IA) is from about 1:4 to about 1:8. In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (IA) is from about 1:4 to about 1:10. In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (IA) is from about 1:5 to about 1:7. In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (IA) is about 1:4. In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (IA) is about 1:5. In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (IA) is about 1:6. In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (IA) is about 1:7. In some embodiments, the molar ratio of cyclodextrin to the compound of Formula (IA) is about 1:8. In some embodiments, the molar ratio of cyclodextrin to compound of Formula (IA) is about 1:9. In some embodiments, the molar ratio of cyclodextrin to compound of Formula (IA) is about 1:10.

[0193] In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (IA) is from about 2:1 to about 1:2. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (IA) is from about 1.75:1 to about 1:1.75. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (IA) is from about 1.5:1 to about 1:1.5. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (IA) is from about 1.4:1 to about 1:1.4. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (IA) is from about 1.3:1 to about 1:1.3. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (IA) is from about 1.25:1 to about 1:1.25. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (IA) is from about 1.2:1 to about 1:1.2. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (IA) is from about 1.15:1 to about 1:1.15. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (IA) is from about 1.1:1 to about 1:1.1. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (IA) is from about 1.05:1 to about 1:1.05. In some embodiments, the molar ratio of the acidic functional groups of the complexing agent to the compound of Formula (IA) is about 1:1.

[0194] In some embodiments, the cyclodextrin is present in an amount of about 50 mg / mL to about 600 mg / mL. In some embodiments, the cyclodextrin is present in an amount of about 50 mg / mL to about 600 mg / mL. In some embodiments, the cyclodextrin is present in an amount of about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 300 mg / mL, about 50 mg / mL to about 400 mg / mL, about 50 mg / mL to about 500 mg / mL, about 50 mg / mL to about 600 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 300 mg / mL, about 100 mg / mL to about 400 mg / mL, about 100 mg / mL to about 500 mg / mL, about 100 mg / mL to about 100 mg / mL. In some embodiments, the cyclodextrin is present in an amount of about 50 mg / mL, about 100 mg / mL, about 200 mg / mL, about 300 mg / mL, about 400 mg / mL, about 500 mg / mL, or about 600 mg / mL. In some embodiments, the cyclodextrin is present in an amount of about 50 mg / mL, about 100 mg / mL, about 200 mg / mL, about 300 mg / mL, about 400 mg / mL, about 500 mg / mL, or about 600 mg / mL. In some embodiments, the cyclodextrin is present in an amount of at least about 50 mg / mL, about 100 mg / mL, about 200 mg / mL, about 300 mg / mL, about 400 mg / mL, or about 500 mg / mL, hi some embodiments, the cyclodextrin is present in an amount of at most about 100 mg / mL, about 200 mg / mL, about 300 mg / mL, about 400 mg / mL, about 500 mg / mL, or about 600 mg / mL.

[0195] In some embodiments, the cyclodextrin is a compound of formula (II).

[0196] In some embodiments, the cyclodextrin is sulfobutyl-ether-beta-cyclodextrin (SBEBCD) or hydroxypropyl-beta-cyclodextrin (HPBCD).

[0197] In some embodiments, the cyclodextrin is SBEBCD. In some embodiments, the SBEBCD is the free acid form of SBEBCD.

[0198] In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is from about 1:4 to about 1:8. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is from about 1:4 to about 1:10. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is from about 1:5 to about 1:7. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is about 1:4. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is about 1:5. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is about 1:6. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is about 1:7. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is about 1:8. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is about 1:9. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is about 1:10. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is from about 1:2 to about 1:10. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is from about 1:2 to about 1:3, from about 1:2 to about 1:4, from about 1:2 to about 1:5, from about 1:2 to about 1:6, from about 1:2 to about 1:7, from about 1:2 to about 1:8, from about 1:2 to about 1:9, from about 1:2 to about 1:10, from about 1:3 to about 1:4, from about 1:3 to about 1:5, from about 1:3 to about 1:6, from about 1:3 to about 1:7, from about 1:3 to about 1:8, from about 1:3 to about 1:9, from about 1:3 to about 1:10, from about 1:4 to about 1:5, from about 1:4 to about 1:6 , about 1:4 to about 1:7, about 1:4 to about 1:8, about 1:4 to about 1:9, about 1:4 to about 1:10, about 1:5 to about 1:6, about 1:5 to about 1:7, about 1:5 to about 1:8, about 1:5 to about 1:9, about 1:5 to about 1:10, about 1:6 to about 1:7, about 1:6 to about 1:8, about 1:6 to about 1:9, about 1:6 to about 1:10, about 1:7 to about 1:8, about 1:7 to about 1:9, about 1:7 to about 1:10, about 1:8 to about 1:9, about 1:8 to about 1:10, or about 1:9 to about 1:10.In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is at least about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, or about 1:9. In some embodiments, the molar ratio of SBEBCD to the compound of Formula (IA) is at most about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.

[0199] In some embodiments, SBEBCD (or other cyclodextrin compound) is present in an amount of about 50 mg / mL to about 600 mg / mL. In some embodiments, SBEBCD is present in an amount of about 50 mg / mL to about 600 mg / mL. In some embodiments, SBEBCD is present in an amount of about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 300 mg / mL, about 50 mg / mL to about 400 mg / mL, about 50 mg / mL to about 500 mg / mL, about 50 mg / mL to about 600 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 300 mg / mL, about 100 mg / mL to about 400 mg / mL, about 100 mg / mL to about 500 mg / mL, about 100 mg / mL In some embodiments, SBEBCD is present in an amount of about 50 mg / mL, about 100 mg / mL, about 200 mg / mL, about 300 mg / mL, about 400 mg / mL, about 500 mg / mL, or about 600 mg / mL. In some embodiments, SBEBCD is present in an amount of at least about 50 mg / mL, about 100 mg / mL, about 200 mg / mL, about 300 mg / mL, about 400 mg / mL, or about 500 mg / mL, hi some embodiments, SBEBCD is present in an amount of up to about 100 mg / mL, about 200 mg / mL, about 300 mg / mL, about 400 mg / mL, about 500 mg / mL, or about 600 mg / mL.

[0200] In some embodiments, the pharmaceutical composition further comprises a base, a buffer, or a combination thereof.

[0201] In some embodiments, the pharmaceutical composition further comprises an emulsifier, a surfactant, a solubilizer, an emulsifier, a co-solvent, or a combination thereof.

[0202] In some embodiments, the pharmaceutical composition is free of the excipients emulsifiers, complexing agents, surfactants, or solubilizers.

[0203] In some embodiments, the pharmaceutical composition is a solution. In some embodiments, the pharmaceutical composition is a solid. In some embodiments, the pharmaceutical composition has a pH of > about 4.

[0204] In some embodiments, the pharmaceutical composition has a pH of about 4 to about 7. In some embodiments, the pharmaceutical composition has a pH of about 4 to about 7. In some embodiments, the pharmaceutical composition has a pH of about 4 to about 4.5, about 4 to about 5, about 4 to about 5.5, about 4 to about 6, about 4 to about 6.5, about 4 to about 7, about 4.5 to about 5, about 4.5 to about 5.5, about 4.5 to about 6, about 4.5 to about 6.5, about 4.5 to about 7, about 5 to about 5.5, about 5 to about 6, about 5 to about 6.5, about 5 to about 7, about 5.5 to about 6, about 5.5 to about 6.5, about 5.5 to about 7, about 6 to about 6.5, about 6 to about 7, or about 6.5 to about 7. In some embodiments, the pharmaceutical composition has a pH of about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, or about 7. In some embodiments, the pharmaceutical composition has a pH of at least about 4, about 4.5, about 5, about 5.5, about 6, or about 6.5. In some embodiments, the pharmaceutical composition has a pH of at most about 4.5, about 5, about 5.5, about 6, about 6.5, or about 7.

[0205] In some embodiments, the pharmaceutical composition has a pH of from about 4.5 to about 6.5.

[0206] In some embodiments, the pharmaceutical composition has an osmolality of about 250 mOsm / kg to about 850 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about 275 mOsm / kg to about 850 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about 300 mOsm / kg to about 850 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about 325 mOsm / kg to about 850 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about 350 mOsm / kg to about 850 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about 375 mOsm / kg to about 850 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about 400 mOsm / kg to about 850 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about 300 mOsm / kg to about 450 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about 475 mOsm / kg to about 850 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about 500 mOsm / kg to about 850 mOsm / kg.

[0207] In some embodiments, the pharmaceutical composition has an osmolality of at least about 250 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least about 275 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least about 300 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least about 325 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least about 350 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least about 375 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least about 400 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least about 425 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least about 450 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least about 475 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least about 500 mOsm / kg.

[0208] In some embodiments, the pharmaceutical composition has an osmolality of about <850 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <825 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <800 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <775 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <750 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <725 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <700 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <675 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <650 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <625 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <600 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <575 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <550 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <525 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <500 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <450 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <400 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about <350 mOsm / kg.

[0209] In some embodiments, the pharmaceutical composition has an osmolality of about 300 mOsm / kg to about 850 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about 300 mOsm / kg to about 350 mOsm / kg, about 300 mOsm / kg to about 400 mOsm / kg, about 300 mOsm / kg to about 450 mOsm / kg, about 300 mOsm / kg to about 500 mOsm / kg, about 300 mOsm / kg to about 550 mOsm / kg, about 300 mOsm / kg to about 600 mOsm / kg, about 300 mOsm / kg to about 650 mOsm / kg, about 300 mOsm / kg to about 700 mOsm / kg, about 300 mOsm / kg to about 850 mOsm / kg. g to about 750 mOsm / kg, about 300 mOsm / kg to about 800 mOsm / kg, about 300 mOsm / kg to about 850 mOsm / kg, about 350 mOsm / kg to about 400 mOsm / kg, about 350 mOsm / kg to about 450 mOsm / kg, about 350 mOsm / kg to about 500 mOsm / kg, about 350 mOsm / kg to about 550 mOsm / kg, about 350 mOsm / kg to about 600 mOsm / kg, about 350 mOsm / kg to about 650 mOsm / kg, about 350 mOsm / kg to about 7 00mOsm / kg, about 350mOsm / kg to about 750mOsm / kg, about 350mOsm / kg to about 800mOsm / kg, about 350mOsm / kg to about 850mOsm / kg, about 400mOsm / kg to about 450mOsm / kg, about 400mOsm / kg to about 500mOsm / kg, about 400mOsm / kg to about 550mOsm / kg, about 400mOsm / kg to about 600mOsm / kg, about 400mOsm / kg to about 650mOsm / kg, about 400mOsm / kg to about 700mOsm / kg m / kg, about 400 mOsm / kg to about 750 mOsm / kg, about 400 mOsm / kg to about 800 mOsm / kg, about 400 mOsm / kg to about 850 mOsm / kg, about 450 mOsm / kg to about 500 mOsm / kg, about 450 mOsm / kg to about 550 mOsm / kg, about 450 mOsm / kg to about 600 mOsm / kg, about 450 mOsm / kg to about 650 mOsm / kg, about 450 mOsm / kg to about 700 mOsm / kg, about 450 mOsm / kg to about 750 mOsm / kg,About 450mOsm / kg to about 800mOsm / kg, about 450mOsm / kg to about 850mOsm / kg, about 500mOsm / kg to about 550mOsm / kg, about 500mOsm / kg to about 600mOsm / kg, about 500mOsm / kg to about 650mOsm / kg, about 500mOsm / kg to about 700mOsm / kg, about 500mOsm / kg to about 750mOsm / kg, about 500mOsm / kg to about 800 mOsm / kg, about 500mOsm / kg to about 850mOsm / kg, about 550mOsm / kg to about 600mOsm / kg, about 550mOsm / kg to about 650mOsm / kg, about 550mOsm / kg to about 700mOsm / kg, about 550mOsm / kg to about 750mOsm / kg, about 550mOsm / kg to about 800mOsm / kg, about 550mOsm / kg to about 850mOsm / kg, about 600mOsm / kg to about 650mOsm / kg, about 600mOsm / kg to about 700mOsm / kg, about 600mOsm / kg to about 750mOsm / kg, about 600mOsm / kg to about 800mOsm / kg, about 600mOsm / kg to about 850mOsm / kg, about 650mOsm / kg to about 700mOsm / kg, about 650mOsm / kg to about 750mOsm / kg, about 650mOsm / kg to about 800mOsm / kg, The osmolality is from 650 mOsm / kg to about 850 mOsm / kg, from about 700 mOsm / kg to about 750 mOsm / kg, from about 700 mOsm / kg to about 800 mOsm / kg, from about 700 mOsm / kg to about 850 mOsm / kg, from about 750 mOsm / kg to about 800 mOsm / kg, from about 750 mOsm / kg to about 850 mOsm / kg, or from about 800 mOsm / kg to about 850 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about 300 mOsm / kg, about 350 mOsm / kg, about 400 mOsm / kg, about 450 mOsm / kg, about 500 mOsm / kg, about 550 mOsm / kg, about 600 mOsm / kg, about 650 mOsm / kg, about 700 mOsm / kg, about 750 mOsm / kg, about 800 mOsm / kg, or about 850 mOsm / kg.The pharmaceutical composition has an osmolality of about 400 mOsm / kg, about 450 mOsm / kg, about 500 mOsm / kg, about 550 mOsm / kg, about 600 mOsm / kg, about 650 mOsm / kg, about 700 mOsm / kg, about 750 mOsm / kg, or about 800 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at most about 350 mOsm / kg, about 400 mOsm / kg, about 450 mOsm / kg, about 500 mOsm / kg, about 550 mOsm / kg, about 600 mOsm / kg, about 650 mOsm / kg, about 700 mOsm / kg, about 750 mOsm / kg, about 800 mOsm / kg, or about 850 mOsm / kg. ,

[0210] In some embodiments, the pharmaceutical composition is isotonic.

[0211] In some embodiments, the pharmaceutical composition has an osmolality of about 500 mOsm / kg.

[0212] In some embodiments, the compound of Formula (I), its enantiomer, enantiomeric mixture, or isotopic variant; solvate or hydrate thereof has a concentration of about 20 mg / mL to about 150 mg / mL. In some embodiments, the compound of Formula (I), its enantiomer, enantiomeric mixture, or isotopic variant; solvate or hydrate thereof has a concentration of up to about 150 mg / mL. In some embodiments, the compound of Formula (I), its enantiomer, enantiomeric mixture, or isotopic variant; solvate or hydrate thereof has a concentration of at least about 20 mg / mL.

[0213] In some embodiments, the compound of Formula (I), its enantiomer, mixture of enantiomers, or isotopic variant; solvate or hydrate thereof has a concentration of from about 80 mg / mL to about 120 mg / mL.

[0214] In some embodiments, the compound of Formula (I), its enantiomer, mixture of enantiomers, or isotopic variant; solvate or hydrate thereof has a concentration of from about 95 mg / mL to about 105 mg / mL.

[0215] In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 20 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 25 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 30 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 35 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 40 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 45 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 50 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 55 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or solvate or hydrate thereof, is about 60 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or solvate or hydrate thereof, is about 65 mg / mL.In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 70 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 75 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 80 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 85 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 90 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 95 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 100 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 105 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or solvate or hydrate thereof, is about 110 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or solvate or hydrate thereof, is about 115 mg / mL.In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 120 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 125 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 130 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 135 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate or hydrate, is about 140 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate or hydrate, is about 145 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate or hydrate, is about 150 mg / mL.

[0216] In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 95 mg / mL, about 96 mg / mL, about 97 mg / mL, about 98 mg / mL, about 99 mg / mL, about 100 mg / mL, about 101 mg / mL, 102 mg / mL, about 103 mg / mL, about 104 mg / mL, or about 105 mg / mL.

[0217] In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is from about 20 mg / mL to about 150 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 20 mg / mL to about 40 mg / mL, about 20 mg / mL to about 60 mg / mL, about 20 mg / mL to about 80 mg / mL, about 20 mg / mL to about 100 mg / mL, about 20 mg / mL to about 120 mg / mL, about 20 mg / mL to about 140 mg / mL, about 20 mg / mL to about 150 mg / mL, about 40 mg / mL to about 60 mg / mL, about 40 mg / mL to about 80 mg / mL, about 40 mg / mL to about 100 mg / mL, about 40 mg / mL to about 120 mg / mL, about 40 mg / mL to about 140 mg / mL, about 40 mg / mL to about 150 mg / mL, The concentration is about 60 mg / mL to about 150 mg / mL, about 60 mg / mL to about 80 mg / mL, about 60 mg / mL to about 100 mg / mL, about 60 mg / mL to about 120 mg / mL, about 60 mg / mL to about 140 mg / mL, about 60 mg / mL to about 150 mg / mL, about 80 mg / mL to about 100 mg / mL, about 80 mg / mL to about 120 mg / mL, about 80 mg / mL to about 140 mg / mL, about 80 mg / mL to about 150 mg / mL, about 100 mg / mL to about 120 mg / mL, about 100 mg / mL to about 140 mg / mL, about 100 mg / mL to about 150 mg / mL, about 120 mg / mL to about 140 mg / mL, about 120 mg / mL to about 150 mg / mL, or about 140 mg / mL to about 150 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is about 20 mg / mL, about 40 mg / mL, about 60 mg / mL, about 80 mg / mL, about 100 mg / mL, about 120 mg / mL, about 140 mg / mL, or about 150 mg / mL.In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is at least about 20 mg / mL, about 40 mg / mL, about 60 mg / mL, about 80 mg / mL, about 100 mg / mL, about 120 mg / mL, or about 140 mg / mL. In some embodiments, the concentration of the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate, or hydrate, is at most about 40 mg / mL, about 60 mg / mL, about 80 mg / mL, about 100 mg / mL, about 120 mg / mL, about 140 mg / mL, or about 150 mg / mL.

[0218] In some embodiments, the pharmaceutical composition further comprises a preservative. In some embodiments, the preservative is benzethonium chloride. In some embodiments, the benzethonium chloride is present in an amount of about 0.1 mg / mL to about 0.5 mg / mL. In some embodiments, the preservative is benzethonium chloride, benzalkonium chloride, or chloroxylenol. Other preservatives include benzyl alcohol, methylparaben, ethyl, or n-propyl, and parahydroxybenzoic acid. In some embodiments, the preservative is an antimicrobial agent, including, but not limited to, phenol, meta-cresol, benzyl alcohol, paraben (methyl, propyl, or butyl), benzalkonium chloride, benzethonium chloride, chlorobutanol, myristyl gamma picolinium chloride, 2-phenoxyethanol, phenethyl alcohol, sorbates (sorbic acid, sodium sorbate), ethanol, and / or propylene glycol. In some embodiments, the preservative is present in an amount of about 0.1 mg / mL to about 1 mg / mL.In some embodiments, the preservative is from about 0.1 mg / mL to about 0.2 mg / mL, from about 0.1 mg / mL to about 0.3 mg / mL, from about 0.1 mg / mL to about 0.4 mg / mL, from about 0.1 mg / mL to about 0.5 mg / mL, from about 0.1 mg / mL to about 0.6 mg / mL, from about 0.1 mg / mL to about 0.7 mg / mL, from about 0.1 mg / mL to about 0.8 mg / mL, from about 0.1 mg / mL to about 0.9 mg / mL, from about 0.1 mg / mL to about 1 mg / mL, from about 0.2 mg / mL to about 0.3 mg / mL, from about 0.2 mg / mL to about 0.0 mg / mL, .4mg / mL, about 0.2mg / mL to about 0.5mg / mL, about 0.2mg / mL to about 0.6mg / mL, about 0.2mg / mL to about 0.7mg / mL, about 0.2mg / mL to about 0.8mg / mL, about 0.2mg / mL to about 0.9mg / mL, about 0.2m g / mL~about 1mg / mL, about 0.3mg / mL~about 0.4mg / mL, about 0.3mg / mL~about 0.5mg / mL, about 0.3mg / mL~about 0.6mg / mL, about 0.3mg / mL~about 0.7mg / mL, about 0.3mg / mL~about 0.8mg / mL, about 0.3mg / mL~about 0.9mg / mL, about 0.3mg / mL~about 1mg / mL, about 0.4mg / mL~about 0.5mg / mL, about 0.4mg / mL~about 0.6mg / mL, about 0.4mg / mL~about 0.7mg / mL, about 0.4mg / mL~about 0.8mg / mL, approximately 0.4 mg / mL to approximately 0.9 mg / mL, approximately 0.4 mg / mL to approximately 1 mg / mL, approximately 0.5 mg / mL to approximately 0.6 mg / mL, approximately 0.5 mg / mL to approximately 0.7 mg / mL, approximately 0.5 mg / mL to approximately 0.8 mg / mL, approximately 0.5 mg / mL to approximately 0 The compound is present in an amount of about 0.9 mg / mL, about 0.5 mg / mL to 1 mg / mL, about 0.6 mg / mL to about 0.7 mg / mL, about 0.6 mg / mL to about 0.8 mg / mL, about 0.6 mg / mL to about 0.9 mg / mL, about 0.6 mg / mL to about 1 mg / mL, about 0.7 mg / mL to about 0.8 mg / mL, about 0.7 mg / mL to about 0.9 mg / mL, about 0.7 mg / mL to about 1 mg / mL, about 0.8 mg / mL to about 0.9 mg / mL, about 0.8 mg / mL to about 1 mg / mL, or about 0.9 mg / mL to about 1 mg / mL.In some embodiments, the preservative is present in an amount of about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, or about 1 mg / mL. In some embodiments, the preservative is present in an amount of at least about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, or about 0.9 mg / mL. In some embodiments, the preservative is present in an amount of up to about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, or about 1 mg / mL.

[0219] In some embodiments of the pharmaceutical compositions disclosed herein, the form is a subcutaneous (e.g., injection or bolus) dosage form. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 3.0 to about 7.0. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 4.0 to about 5.0. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 4.5 to about 5.5. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 5.0 to about 6.0. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 5.5 to about 6.5. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 6.0 to about 7.0. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 3.0. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 3.5. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 4.0. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 4.5. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 5.0. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 5.1. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 5.2. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 5.3. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 5.4. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 5.5. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 5.6. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 5.7. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 5.8. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 5.9. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 6.0. In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 6.5.In some embodiments of the pharmaceutical composition, the form is a subcutaneous dosage form and has a pH of about 7.0.

[0220] The compounds of the present disclosure (e.g., NMDA receptor antagonists (e.g., ketamine)) may be in the form of compositions suitable for administration to a subject. Generally, such compositions are "pharmaceutical compositions" that include the compound (e.g., NMDA receptor antagonists (e.g., ketamine)) and one or more pharmaceutically or physiologically acceptable diluents, carriers, or excipients. In some embodiments, the compound (e.g., NMDA receptor antagonists (e.g., ketamine)) is present in a therapeutically acceptable amount. Pharmaceutical compositions may be used in the methods of the present disclosure; thus, for example, pharmaceutical compositions can be administered to a subject ex vivo or in vivo to carry out the therapeutic and prophylactic methods and uses described herein.

[0221] Pharmaceutical compositions of the disclosure can be formulated to be compatible with the intended method or route of administration, exemplary routes of administration being described herein.

[0222] In certain embodiments of the pharmaceutical compositions disclosed herein, the co-solvent comprises PEG200, PEG300, PEG400, PEG600, propylene glycol, ethanol, polysorbate 20, polysorbate 80, cremophor, glycerin, benzyl alcohol, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), tert-butanol, or a combination thereof.

[0223] In certain embodiments, the dosage form or pharmaceutical composition comprises a surfactant.

[0224] In certain embodiments of the pharmaceutical compositions disclosed herein, the surfactant comprises polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monooleate, polyoxyethylene sorbitan monolaurate (Tween 20), lecithin, polyoxyethylene-polyoxypropylene copolymer (Pluronics 1), or a combination thereof.

[0225] In certain embodiments, the dosage form or pharmaceutical composition comprises a non-ionic surfactant.

[0226] In certain embodiments of the pharmaceutical compositions disclosed herein, the nonionic surfactant comprises Cremophor® RH40, Cremophor® RH60, d-α-topopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44 / 14, Softigen 767, or a combination thereof.

[0227] In certain embodiments of the pharmaceutical compositions described herein, the NMDA receptor antagonist or modulator is racemic ketamine, (R)-ketamine, or (S)-ketamine.

[0228] In some embodiments, the pharmaceutical composition comprises one or more co-solvents, solubilization / solubilizing agents, stabilizers, antioxidants, preservatives, cryoprotectants, lyoprotectants, bulking agents, tonicity agents, or antimicrobial agents. In some embodiments, the pharmaceutical composition comprises at least one co-solvent. In some embodiments, the pharmaceutical composition comprises at least one solubilizer. In some embodiments, the pharmaceutical composition comprises at least one stabilizer. In some embodiments, the pharmaceutical composition comprises at least one antioxidant. In some embodiments, the pharmaceutical composition comprises at least one preservative. In some embodiments, the pharmaceutical composition comprises at least one cryoprotectant. In some embodiments, the pharmaceutical composition comprises at least one lyoprotectant. In some embodiments, the pharmaceutical composition comprises at least one bulking agent. In some embodiments, the pharmaceutical composition comprises at least one tonicity agent. In some embodiments, the pharmaceutical composition comprises at least one antimicrobial agent.

[0229] In some embodiments, the formulation or pharmaceutical composition is a pharmaceutical composition. In some embodiments, the formulation is in the form of a sterile injectable aqueous or oily suspension. This suspension is formulated according to the art using suitable dispersing or wetting agents and suspending agents as mentioned herein. The sterile injectable preparation can be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable diluents, solvents, and dispersion media that can be used include water, Ringer's solution, isotonic sodium chloride solution, Cremophor® EL (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In addition, sterile, fixed oils are conventionally used as solvents or suspending media; for this purpose, any bland, fixed oil, including synthetic mono- or diglycerides, can be used. In addition, fatty acids such as oleic acid are also used in the preparation of injectable drugs. Prolonged absorption of certain injectable formulations can be achieved by including an agent that delays absorption (e.g., aluminum monostearate or gelatin). In some embodiments, the formulation contains a cosolvent. In some embodiments, suitable cosolvents are propylene glycol, glycerin, ethanol, polyethylene glycol (300 and 400), sorbitol, dimethylacetamide, Cremophor® EL, or N-methyl-2-pyrrolidone, or dimethyl sulfoxide.

[0230] In some embodiments, the formulation or pharmaceutical composition is an aqueous suspension. Aqueous suspensions contain the active ingredient in admixture with excipients suitable for their manufacture. Such excipients can be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic; dispersing or wetting agents, such as naturally occurring phospholipids (e.g., lecithin), or alkylene oxide condensates with fatty acids (e.g., polyoxyethylene stearate), or ethylene oxide condensates with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), or ethylene oxide condensates with partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or ethylene oxide condensates with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives (e.g., benzethonium chloride).

[0231] In some embodiments, the formulation or pharmaceutical composition comprises a stabilizer. In some embodiments, the formulation comprises a surfactant solubilizer. Surfactant solubilizers include, but are not limited to, polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monooleate, polyoxyethylene sorbitan monolaurate (Tween 20), lecithin, and polyoxyethylene-polyoxypropylene copolymer (Pluronics 1). In some embodiments, the formulation comprises a non-ionic surfactant solubilizer. Nonionic surfactants include, but are not limited to, Cremophor® RH 40, Cremophor® RH 60, d-alpha tocopherol-polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS1, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44 / 14, Softigen 767, and mono- and di-fatty acid esters of PEG 300, 400, and 1750. In some embodiments, the formulation includes a phospholipid solubilizer, such as hydrogenated soy phosphatidylcholine, phosphatidylcholine, distearoylphosphatidylglycerol, L-α-dimyristoylphosphatidylcholine, or L-α-dimyristoylphosphatidylglycerol.

[0232] In some embodiments, the formulation or pharmaceutical composition includes a complexing agent. In some embodiments, the complexing agent is hydroxypropyl-β-cyclodextrin, bulfobutylether-β-cyclodextrin (Captisol 1), or polyvinylpyrrolidone. In some embodiments, the complexing agent is an amino acid such as arginine, lysine, or histidine. In some embodiments, the formulation or pharmaceutical composition includes a cyclodextrin excipient. Cyclodextrin excipients are used to enhance the stability, tolerability, and absorption of compounds in parenteral aqueous solutions. Common cyclodextrin excipients include, but are not limited to, α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), diethyl-ethyl-β-cyclodextrin (DE-β-CD), dimethyl-ethyl-β-cyclodextrin (DM-β-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD), hydroxypropyl-γ-cyclodextrin (HP-γ-CD), methyl-β-cyclodextrin (M-β-CD), sulfobutylether-β-cyclodextrin (SBE-β-CD), optionally methylated-β-CD (RM-β-CD), maltosyl-β-CD (Mal-β-CD), and hydroxypropyl-α-CD.

[0233] The formulation or pharmaceutical composition of the present disclosure can also be in the form of an oil-in-water emulsion.The oil phase can be vegetable oil, such as olive oil or peanut oil, or mineral oil, such as liquid paraffin, or their mixture.Suitable emulsifiers can be naturally occurring gums, such as gum arabic, gum tragacanth; naturally occurring phospholipids, such as soybean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; condensates of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0234] A formulation or pharmaceutical composition typically contains a therapeutically effective amount of an active compound (e.g., an NMDA receptor antagonist such as ketamine), or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically and physiologically acceptable formulations. Suitable pharmaceutically or physiologically acceptable diluents, carriers, or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethyl, or n-propyl, p-hydroxybenzoate), emulsifiers, suspending agents, dispersing agents, solvents, fillers, extenders, surfactants, buffers, vehicles, diluents, and / or adjuvants. For example, a suitable vehicle can be saline or citrate-buffered saline, possibly supplemented with other ingredients commonly used in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art can readily recognize various buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Representative buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. By way of example, buffer components can be water-soluble substances such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffering agents include, for example, triethanolamine (Tris) buffer, histidine, bicarbonate; N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid (HEPES); 2-(N-morpholino)ethanesulfonic acid (MES); 2-(N-morpholino)ethanesulfonic acid sodium salt (MES); 3-(N-morpholino)propanesulfonic acid (MOPS); and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0235] Many active pharmaceutical ingredients (APIs) are weak acids or weak bases. They can exist in their non-ionized form or as ionized complexes prepared by the addition of a base or acid, respectively. The resulting complexes, stabilized by ionic interactions, are known as salts. These complexes exist through ionic bonds between the ionized API and an oppositely charged counterion. Salts offer many advantages over non-ionized salts. The choice of counterion can significantly affect the salt's properties, and the use of a particular salt form of a particular API in a pharmaceutical product is influenced and guided by many factors, including stability (light, hydrolysis, heat), solubility, physicochemical properties, solid-state properties (crystallinity, polymorphism, particle size, crystalline morphology, melting point, compressibility), manufacturing considerations (e.g., ease of handling and processing), dissolution rate, drug release modulation, compatibility with excipients and containers, ease and consistency of production, desired route of administration, and organoleptic factors (e.g., taste). Furthermore, with regard to injections, salts can contribute to pain and irritation at the injection site.

[0236] An API that is a weak acid or a weak base can function as its own buffer at a pH close to the API's pKa. For example, ketamine contains an amino functionality with a pKa of ∼7.5 and can therefore function as a buffer in the region of about ±2 pH units from the pKa (e.g., a pH of about 5.5 to about 9.5). If the target pH of the formulation is within this range, an additional buffer may not be required. In some embodiments, the pharmaceutical compositions provided herein do not contain an additional buffer.

[0237] With regard to cyclodextrin solubilization, certain salts of various APIs have been found to form multicomponent complexes / systems or ternary systems that may have distinct and desirable properties compared to their counterparts, standard binary complexes / systems prepared between cyclodextrins and non-ionized APIs, and compared to other multicomponent ternary complexes / systems involving various salt forms of the API. Thus, these multicomponent complexes / systems can dramatically affect the solubility and dissolution rate of the API in aqueous solution, potentially affecting product stability and the pharmacokinetic properties of the drug product.

[0238] After being formulated, the pharmaceutical compositions can be stored in sterile vials as solutions, suspensions, gels, emulsions, solids, or dehydrated or lyophilized powders. Such formulations can be stored in ready-to-use forms, lyophilized forms that require reconstitution before use, liquid forms that require dilution before use, or other acceptable forms. In some embodiments, the pharmaceutical compositions are provided in single-use containers (e.g., single-use vials, ampoules, syringes, or auto-injectors (e.g., similar to EpiPen®)), while in other embodiments, they are provided in multi-use containers (e.g., multi-use vials).

[0239] Preparation or pharmaceutical composition can contain carriers to protect the composition from rapid degradation or elimination from the body, such as controlled release preparations, including liposomes, hydrogels, prodrugs, and microencapsulated delivery systems.For example, time-delay substances such as glyceryl monostearate or glyceryl stearate can be used alone or in combination with wax.NMDA receptor antagonists can be delivered using any drug delivery device, including implants (for example, implantable pumps) and catheter systems, slow infusion pumps and devices, all of which are well known to those skilled in the art.

[0240] In some embodiments, the formulation or pharmaceutical composition is stored in a reservoir of a drug delivery device. In some embodiments, the formulation is stored in a cartridge that is insertable into and / or attachable to the drug delivery device. In some embodiments, the cartridge and / or drug delivery device includes a product label for intramuscular injection. In some embodiments, the cartridge and / or drug delivery device includes a product label for subcutaneous injection. In some embodiments, the cartridge and / or drug delivery device includes a product label for intravenous injection. In some embodiments, disclosed herein are kits that include a product label for intramuscular injection. In some embodiments, disclosed herein are kits that include a product label for subcutaneous injection. In some embodiments, disclosed herein are kits that include a product label for intravenous injection.

[0241] In some embodiments, the formulation or pharmaceutical composition is a liquid formulation comprising ketamine hydrochloride (HCl). In some embodiments, the formulation comprises a racemic ketamine composition. Alternatively, in some embodiments, the formulation comprises a substantially pure stereoisomer of ketamine (e.g., 90%, 95%, 96%, 97%, 98%, or 99% or more of the ketamine is one stereoisomer). In some embodiments, the formulation comprises substantially pure S-ketamine. In some embodiments, the formulation comprises substantially pure R-ketamine. In some embodiments, the NMDA receptor antagonist is about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% pure. In some embodiments, the NMDA receptor antagonist is at least about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.8%, or about 99.9% pure. In some embodiments, the NMRA receptor antagonist contains less than about 5%, about 4%, about 3%, about 2%, or about 1% impurities.

[0242] In some embodiments, the formulation or pharmaceutical composition is a liquid formulation comprising ketamine free base. In some embodiments, the formulation or pharmaceutical composition is a liquid formulation comprising non-ionized ketamine (i.e., free base). In some embodiments, the formulation or pharmaceutical composition is a liquid formulation comprising a mixture of ionized and non-ionized (free base) forms of ketamine.

[0243] In some embodiments, the formulation comprises a racemic ketamine composition. Alternatively, in some embodiments, the formulation comprises a substantially pure stereoisomer of ketamine (e.g., 90%, 95%, 96%, 97%, 98%, or 99% or more of the ketamine is one stereoisomer). In some embodiments, the formulation comprises substantially pure S-ketamine. In some embodiments, the formulation comprises substantially pure R-ketamine. In some embodiments, the NMDA receptor antagonist is about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% pure. In some embodiments, the NMDA receptor antagonist is at least about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.8%, or about 99.9% pure. In some embodiments, the NMRA receptor antagonist contains less than about 5%, about 4%, about 3%, about 2%, or about 1% impurities.

[0244] It is often beneficial to improve one or more physical properties of the treatment modalities disclosed herein and / or the manner in which they are administered. Improvements in physical properties include, for example, methods to increase water solubility, bioavailability, serum half-life, and / or therapeutic half-life, and / or modulate biological activity. Modifications known in the art include pegylation, Fc fusion, and albumin fusion. While typically associated with large molecule drugs (e.g., polypeptides), such modifications have recently been evaluated with certain small molecules. For example, Chiang, M. et al. (J. Am. Chem. Soc., 2014, 136(9):3370-73) describes a small molecule agonist of the adenosine 2a receptor bound to an immunoglobulin Fc domain. The small molecule-Fc conjugate retains strong Fc receptor and adenosine 2a receptor interaction and exhibits superior properties compared to unconjugated small molecules. Covalent attachment of PEG molecules to small molecule therapeutic agents has also been described (Li, W. et al., Progress in Polymer Science, 2013 38:421-44).

[0245] The NMDA receptor antagonists of the present disclosure may be administered to a subject in an amount that depends, for example, on the purpose of administration (e.g., the desired degree of resolution); the age, weight, sex, and health and physical condition of the subject receiving the formulation; the route of administration; and the nature of the disease, disorder, condition, or symptoms thereof. The administration regimen may also take into account the existence, nature, and extent of any side effects associated with the administered agent. Effective dosages and administration regimens can be readily determined, for example, from safety and dose escalation studies, in vivo studies (e.g., animal models), and other methods known to those skilled in the art.

[0246] Generally, dosing parameters dictate that the amount administered is not less than the amount that would be irreversibly toxic to the subject (the maximum tolerated dose (MTD)) and the amount required to produce a measurable effect in the subject. Such amounts are determined, for example, by pharmacokinetic and pharmacodynamic parameters relevant to ADME, taking into account the route of administration and other factors.

[0247] The effective dose (ED) is the dosage or amount of a drug that produces a therapeutic response or desired effect in some subjects taking it. 50 ED is the dose or amount of a drug that produces a therapeutic response or desired effect in 50% of the population to which it is administered. 50 The ED is commonly used as a measure of the reasonable expectation of a drug's effect, but is not necessarily the dose that a clinician might consider appropriate, taking into account all relevant factors. 50 In some cases, the effective dose is calculated as ED 50 In some cases, the effective dose is less than the calculated ED 50 It may be the same as

[0248] Furthermore, an effective amount of an NMDA receptor antagonist of the present disclosure can be an amount that, when administered in one or more doses to a subject, produces a desirable result comparable to that of a healthy subject. For example, in the case of a subject experiencing a particular disorder, an effective amount can be one that improves a diagnostic parameter, measurement, marker, etc. of that disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, where 100% is defined as the diagnostic parameter, measurement, marker, etc. exhibited by a normal subject.

[0249] In embodiments, the dosage of the NMDA receptor antagonist is contained in a "unit dosage form." The phrase "unit dosage form" refers to a physically discrete unit, each unit containing a predetermined amount of a compound (e.g., ketamine, or a hydrate, solvate, or pharmaceutically acceptable salt thereof) sufficient to produce a desired effect. It will be understood that the parameters of the unit dosage form depend on the particular agent and the effect to be achieved.

[0250] Oily suspensions can be prepared by suspending active ingredients in vegetable oils, such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oils such as liquid paraffin.Oily suspensions can contain thickening agents, such as beeswax, hard paraffin, cetyl alcohol.Sweeteners and flavorings, such as those mentioned above, can be added to provide a palatable oral preparation.

[0251] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, and optionally one or more suspending agents and / or preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0252] Depot injections, typically administered subcutaneously or intramuscularly, can also be utilized to release the compounds disclosed herein (e.g., NMDA receptor antagonists (e.g., ketamine)) over a defined period of time. Depot injections are typically solid-based or oil-based and generally contain at least one of the formulation components described herein. Those skilled in the art are familiar with the possible formulations and uses of depot injections.

[0253] Some formulations contain one or more stabilizers. Potential stabilizers contemplated include the following buffers: acetic acid, citric acid, sodium citrate, tartaric acid, phosphoric acid, histidine, bicarbonate, triethanolamine (TRIS), and salts thereof. In some formulations, potential stabilizers may include antioxidants and preservatives such as ascorbic acid, acetylcysteine (NAC), sulfites (bisulfite, metabisulfite), and monothioglycerol. Butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), 2',4',5'-trihydroxybutyrophenone phenylhydrazone (THBP), ethylenediaminetetraacetic acid (EDTA), sodium formaldehyde sulfoxylate (SFS), tocopherol (vitamin E), ascorbyl palmitate, gallates (e.g., propyl gallate, octyl gallate, lauryl gallate), cysteine ethyl ether, tartaric acid, phosphoric acid, thiourea, sodium thioglycolate, nitrogen, and / or argon.

[0254] In some formulations, potential stabilizers may include bulking agents, cryoprotectants, and lyoprotectants. Considered agents include mannitol, glycine, sucrose, lactose, trehalose, dextran, povidone, sorbitol, and / or polydextrose. In some formulations, potential stabilizers may include tonicity agents. Considered agents include sodium chloride, glycerin, mannitol, dextrose, and / or glycerol. In some formulations, potential stabilizers may include antimicrobial agents, including, but not limited to, phenol, meta-cresol, benzyl alcohol, parabens (methyl, propyl, or butyl), benzalkonium chloride, benzethonium chloride, chlorobutanol, myristyl gamma picolinium chloride, 2-phenoxyethanol, phenethyl alcohol, sorbates (sorbic acid, sodium sorbate), ethanol, and / or propylene glycol.

[0255] In some formulations, the soothing agent may include a topical analgesic such as lidocaine, benzocaine, tetracaine, bupivacaine, ropivacaine, and / or levobupivacaine.

[0256] In some formulations, emulsion stabilizers include hydroxyethyl cellulose, hydroxypropyl cellulose, and / or hydroxypropyl methyl cellulose (hypromellose).

[0257] The compounds contemplated by the present disclosure (e.g., NMDA receptor antagonists (e.g., ketamine)) may be in the form of other suitable pharmaceutical compositions now known or developed in the future.

[0258] III. Method In one aspect, provided herein are methods for treating pain, the methods comprising administering a therapeutically effective amount of a compound having structural formula (I):

[0259] [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the compound of Formula (I) is administered by subcutaneous injection. In some embodiments, the compound of Formula (I) is administered as any of the pharmaceutical compositions provided herein.

[0260] In some embodiments, the pain is acute pain or chronic pain. In some embodiments, the pain is acute pain. In some embodiments, the pain is post-surgical pain. In some embodiments, the pain is traumatic, such as battlefield trauma. In some embodiments, the pain is cancer pain.

[0261] In one aspect, provided herein is a method of treating a psychiatric, cognitive, or neurological disorder, the method comprising administering a therapeutically effective amount of a compound represented by structural formula (I):

[0262] [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the compound of formula (I) is administered by subcutaneous injection. In some embodiments, the compound of formula (I) is administered as any of the pharmaceutical compositions provided herein.

[0263] In some embodiments, the psychiatric disorder is major depressive disorder, treatment-resistant major depressive disorder, suicidality, suicidal ideation, dysthymia or persistent depressive disorder, bipolar depressive disorder type I, bipolar depressive disorder type II, chronic pain, eating disorder NOS, pain disorder NOS, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, complex regional pain syndrome, reflex sympathetic dystrophy, or any combination thereof.

[0264] In some embodiments, the cognitive or neurological disorder is Huntington's disease, Parkinson's disease, frontotemporal dementia, dementia, Alzheimer's disease, amyotrophic lateral sclerosis, spinal cord trauma, stroke, diffuse traumatic brain injury, HIV-associated dementia, epilepsy, Rett syndrome, dyskinesia, dystonia unspecified, or pseudobulbar affect.

[0265] In some embodiments, a compound of formula (I), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, is administered as a low volume infusion.

[0266] In another aspect, provided are methods of treating, preventing, or ameliorating at least one symptom of a disorder, disease, or condition using the pharmaceutical compositions disclosed herein, including embodiments where the disorder, disease, or condition is a psychiatric disease or disorder, a mood disorder, a neurological disease or disorder, type 2 diabetes and / or its complications, endometriosis, glaucoma, pain, or an inflammatory disorder.

[0267] Treatment of physical, mental, or neurological disorders Disclosed herein are systems, devices, kits, preparations and methods for the treatment of one or more medical and / or psychiatric disorders.In some embodiments, the psychiatric disorder is major depressive disorder, treatment-resistant major depressive disorder, suicidal tendencies, suicidal ideation, dysthymia or persistent depressive disorder, bipolar depressive disorder type I, bipolar depressive disorder type II, chronic pain, eating disorder NOS, pain disorder NOS, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, complex regional pain syndrome or reflex sympathetic dystrophy.In some embodiments, the psychiatric disorder being treated is depression, major depressive disorder or treatment-resistant major depressive disorder.

[0268] In some embodiments, the formulations and methods disclosed herein are used to administer at least one dosing regimen of a drug formulation for treating chronic pain. In some embodiments, the dosing regimen is configured for treating acute pain. In some embodiments, the dosing regimen is configured for treating chronic regional pain syndromes. In some embodiments, the dosing regimen is configured for treating pain associated with Ehlers-Sudan-Law syndrome. In some embodiments, the dosing regimen is configured for treating post-laminectomy syndrome. In some embodiments, the dosing regimen is configured for treating pain associated with post-laminectomy syndrome. In some embodiments, the dosing regimen is configured for treating spinal pain syndromes. In some embodiments, the dosing regimen is configured for treating pain associated with spinal pain syndromes. In some embodiments, the dosing regimen is configured for treating post-surgical pain. In some embodiments, the dosing regimen is configured for treating diabetic neuropathy.

[0269] In some embodiments, the formulations and methods disclosed herein are used to treat one or more personality disorders. Examples of personality disorders include avoidant personality disorder, dependent personality disorder, antisocial personality disorder, histrionic personality disorder, borderline personality disorder, obsessive-compulsive personality disorder, cyclothymic personality disorder, obsessive-compulsive disorder, and impulse control disorder (NOS).

[0270] In some embodiments, the formulations and methods disclosed herein are used to treat one or more eating disorders. Examples of eating disorders include anorexia nervosa and bulimia.

[0271] In some embodiments, the formulations and methods disclosed herein are used to treat brain cancer. In some embodiments, the formulations and methods disclosed herein are used to treat glioma. In some embodiments, administration of the drug formulations provided herein slows the growth of glioma. In some embodiments, the glioma is glioblastoma multiforme. In some embodiments, the glioma is astrocytoma.

[0272] In some embodiments, the formulations and methods disclosed herein are used to treat one or more of major depressive disorder, treatment-resistant major depressive disorder, suicidality, suicidal ideation, dysthymia, bipolar disorder (type I-depression), bipolar disorder (type II-depression), post-traumatic stress disorder (PTSD), panic disorder, generalized anxiety disorder, and substance abuse-induced mood disorder.

[0273] In some embodiments, the formulations and methods disclosed herein are used to treat a cognitive or neurological disorder or disease, such as Huntington's disease, Parkinson's disease, frontotemporal dementia, dementia, Alzheimer's disease, amyotrophic lateral sclerosis, spinal cord trauma, stroke, diffuse traumatic brain injury, HIV-associated dementia, epilepsy, suicidal ideation, Rett syndrome, dyskinesia, dystonia (unspecified), or pseudobulbar affect.

[0274] Disclosed herein are systems, devices and methods for treating one or more medical and / or psychiatric disorders.In some embodiments, the psychiatric disorder is major depressive disorder, treatment-resistant major depressive disorder, suicidal tendencies, suicidal ideation, dysthymia or persistent depressive disorder, bipolar depressive disorder type I, bipolar depressive disorder type II, chronic pain, eating disorder NOS, pain disorder NOS, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, complex regional pain syndrome or reflex sympathetic dystrophy.In some embodiments, the psychiatric disorder being treated is depression, major depressive disorder or treatment-resistant major depressive disorder.

[0275] In some embodiments, the medical or psychiatric disorder is major depressive disorder, treatment-resistant major depressive disorder, suicidality, suicidal ideation, dysthymia, bipolar disorder-type I-depression, bipolar disorder-type II-depression, post-traumatic stress disorder, impulse control disorder NOS, personality disorder NOS, avoidant personality disorder, dependent personality disorder, antisocial personality disorder, histrionic personality disorder, borderline personality disorder, obsessive-compulsive personality disorder, cyclothymic personality disorder, obsessive-compulsive disorder, eating disorder NOS, anorexia nervosa, bulimia nervosa, panic disorder, generalized anxiety disorder, substance abuse-induced mood disorder, fibromyalgia, chronic fatigue and immune deficiency syndrome, fibromyalgia, Fibromyalgia syndrome, Myalgia, Myositis, Chronic fatigue unspecified, Post-viral fatigue syndrome, Chronic fatigue syndrome NOS, Benign myalgic encephalomyelitis, Other fatigue, Neoplastic (malignant) related fatigue, Other fatigue and fatigue, Drug addiction - NOS, Opiate addiction, Benzodiazepine addiction, Sedative (hypnotic or anxiolytic) addiction, Alcohol addiction, Stimulant addiction, Cocaine addiction, Cannabis detox, Opiate addiction (with withdrawal), Benzodiazepine addiction (with withdrawal), Sedative (hypnotic or anxiolytic) addiction with withdrawal, Alcohol addiction (with withdrawal), Stimulant addiction (with withdrawal) with withdrawal), cocaine dependence (with withdrawal), cannabis detox (with withdrawal), pain disorder - not specified (NOS), pain (unspecified), acute pain, bodily pain, lower back pain / muscle pain, chronic lower back pain for more than 3 months, chronic lower back pain lasting for more than 3 months, chronic tailbone pain for more than 3 months, chronic lower back pain, chronic lower back pain lasting for more than 3 months, chronic malignant pain, chronic neck pain, chronic non-malignant pain, chronic pain, chronic pain due to malignant tumor, generalized pain and pain, generalized pain, neck pain (chronic), pain, pain crisis, buttock pain, tailbone pain (chronic) for more than 3 months, tumor-related pain (acute) (Chronic), chronic pain after other procedures, chronic pain after bilateral total hip replacement, chronic pain after bilateral total knee replacement, chronic pain after left-sided total hip replacement, chronic pain after left-sided total knee replacement, chronic pain after right-sided total hip replacement, chronic pain after right-sided total knee replacement, chronic pain after bilateral total hip replacement, chronic pain after bilateral total knee replacement, chronic pain after left-sided total hip replacement, chronic pain after left-sided total knee replacement, chronic pain after right-sided total hip replacement, chronic pain after right-sided total knee replacement,Chronic pain from bilateral partial hip arthroplasty, Chronic pain from bilateral partial knee arthroplasty, Chronic pain from left side partial hip arthroplasty, Chronic pain from left side partial knee arthroplasty, Chronic pain from right side partial hip arthroplasty, Chronic pain from right side partial knee arthroplasty, Chronic pain after bilateral partial hip arthroplasty, Chronic pain after bilateral partial knee arthroplasty, Chronic pain after left side partial hip arthroplasty, Chronic pain after right side partial hip arthroplasty, Chronic pain after right side partial knee arthroplasty, Acute malignant pain, Acute neck pain, Acute non-malignant pain, Acute pain, Acute pain due to malignant lesion, Generalized pain and pain, Generalized pain, Neck pain (acute), Pain, Pain crisis, Lower back pain, Coccyx pain for more than 3 months (acute), Tumor-related pain (acute), Pain after other acute procedures, Acute pain from bilateral total hip arthroplasty, Bilateral total knee arthroplasty acute pain after left total hip replacement, acute pain after left total knee replacement, acute pain after right total hip replacement, acute pain after right total knee replacement, acute pain after bilateral total hip replacement, acute pain after bilateral total knee replacement, acute pain after left total hip replacement, acute pain after left total knee replacement, acute pain after right total hip replacement, acute pain after right total knee replacement, bilateral Acute pain from partial hip arthroplasty, acute pain from bilateral partial knee arthroplasty, acute pain from left side partial hip arthroplasty, acute pain from left side partial knee arthroplasty, acute pain from right side partial hip arthroplasty, acute pain from right side partial knee arthroplasty, acute pain after bilateral partial hip arthroplasty, acute pain after bilateral partial knee arthroplasty, acute pain after left side partial hip arthroplasty, acute pain after left side partial knee arthroplasty, acute pain after right side partial hip arthroplasty, acute pain after right side partial knee arthroplasty, pain from bilateral total hip arthroplasty, pain from bilateral total knee arthroplasty, pain from left side total hip arthroplasty, pain from left side total knee arthroplasty, pain from right side total hip arthroplasty, pain from right side total knee arthroplasty, pain after bilateral total hip arthroplasty, pain after bilateral total knee arthroplasty, pain after left side total hip arthroplasty, pain after left side total knee arthroplasty, pain after right side total hip arthroplasty,Pain after right-sided total knee arthroplasty, pain from bilateral partial hip arthroplasty, pain from bilateral partial knee arthroplasty, pain from left-sided partial hip arthroplasty, pain from left-sided partial knee arthroplasty, pain from right-sided partial hip arthroplasty, pain from right-sided partial knee arthroplasty, pain after bilateral partial hip arthroplasty, pain after bilateral partial knee arthroplasty, pain after left-sided partial hip arthroplasty, pain after left-sided partial knee arthroplasty, pain after right-sided partial hip arthroplasty, pain after right-sided partial knee arthroplasty, acute pain after mastectomy, acute pain after surgery, acute pain due to trauma or injury, Acute pain syndromes, acute pain associated with psychosocial dysfunction, psychosocial dysfunction due to acute pain, tumor-related pain (acute), tumor-related pain, pain due to tumor, pain due to neoplastic disease, burning pain (lower limb), burning pain (upper limb), central pain syndrome, acute pain syndrome, complex regional pain syndrome ii (lower limb), complex regional pain syndrome ii (upper limb), phantom limb syndrome with pain, phantom limb syndrome without pain, acute tumor-related pain, chronic pain after mastectomy, chronic pain after surgery, chronic pain due to trauma or injury, chronic pain syndromes, chronic pain associated with psychosocial dysfunction, chronic Psychosocial dysfunction due to pain, tumor-related pain (acute) (chronic), tumor-related pain, pain due to tumor, pain due to neoplastic disease, burning pain (lower limb), burning pain (upper limb), central pain syndrome, chronic pain syndrome, complex regional pain syndrome II (lower limb), complex regional pain syndrome II (upper limb), phantom limb syndrome with pain, phantom limb syndrome without pain, tumor-related chronic pain, reflex sympathetic dystrophy, hereditary and idiopathic neuropathies (unspecified), paraneoplastic neuromyopathy and neuropathy (followed by synonyms), neuropathy (nerve damage) (paraneoplastic), neuropathy Nerve damage (peripheral paraneoplastic), paraneoplastic neuropathy, paraneoplastic peripheral neuropathy, type 2 diabetes with diabetic neuropathy (unspecified), type 2 diabetes with neurogenic erectile dysfunction, type 2 diabetes with peripheral neuropathy, type 2 diabetes with peripheral sensory neuropathy, type 2 diabetes with neuropathy, type 2 diabetes-associated diabetic peripheral neuropathy, type 2 diabetes mellitus with neuropathic ulcers of the foot and heel, neurogenic erectile dysfunction due to type 2 diabetes, neuropathic midfoot and / or heel ulcers due to type 2 diabetes, neuropathy due to type 2 diabetes, peripheral neuropathy due to type 2 diabetes,Peripheral sensory neuropathy due to type 2 diabetes, other specified diabetes with diabetic autonomic (poly)neuropathy, other chronic pain, postherpetic polyneuropathy, acute herpetic zoster neuropathy, herpetic radiculitis, herpes zoster with nervous system complications, herpes zoster with nervous system complications, postherpetic neuralgia, postherpetic radiculopathy, postherpetic myelitis, postherpetic ganglionitis, postherpetic trigeminal neuralgia, diabetic neuropathy, neuropathy NOS, postlaminectomy syndrome, low back pain, postoperative pain , endometriosis, migraine, hemiplegic migraine, migraine with aura (refractory), hemiplegic migraine (refractory), other migraine (refractory), migraine, unspecified (refractory), migraine NOS, migraine without aura (refractory), hemiplegic migraine (not refractory), other migraine (not refractory), migraine, unspecified (not refractory), hemiplegic migraine (refractory, no status migraine), migraine with aura, ophthalmoplegic migraine (not refractory), abdominal migraine (refractory) migraine without aura (not refractory, with migraine state), migraine (unspecified, refractory, with migraine state), migraine without aura, migraine without aura (not refractory), migraine with aura (not refractory), chronic migraine without aura, migraine (unspecified, not refractory, without migraine state), migraine (unspecified, refractory without migraine state), other migraine (refractory, without migraine state), abdominal migraine (refractory; refractory allergic migraine) refractory ocular migraine), other migraine (not refractory, no migraine state), menstrual migraine (refractory, no migraine state), Huntington's disease, Parkinson's disease, frontotemporal dementia, dementia, Alzheimer's disease, amyotrophic lateral sclerosis, spinal cord trauma, stroke, diffuse traumatic brain injury, HIV-associated dementia, epilepsy, suicidal ideation, Rett syndrome, dyskinesia, dystonia (unspecified), pseudobulbar affect, tinnitus (unspecified ear), and glaucoma.

[0276] In some embodiments, the formulations and methods disclosed herein are used to treat one or more fatigue and fatigue-related disorders. Examples of fatigue and fatigue-related disorders include fibromyalgia, fibromyalgia syndrome, chronic fatigue and immune deficiency syndrome, myalgia, myositis, chronic fatigue (unspecified), post-viral fatigue syndrome, chronic fatigue syndrome (NOS), benign myalgic encephalomyelitis, tumor-related (malignant) fatigue, and other fatigue and fatigue.

[0277] In some embodiments, the formulations and methods disclosed herein are used to treat post-laminectomy syndrome (e.g., spinal pain syndrome). In some embodiments, the formulations and methods disclosed herein are used to treat post-surgical pain. In some embodiments, the formulations and methods disclosed herein are used to treat cancer pain. In some embodiments, the formulations and methods disclosed herein are used to treat osteoarthritis. In some embodiments, the formulations and methods disclosed herein are used to treat fibromyalgia.

[0278] In some embodiments, the formulations and methods disclosed herein are used to treat pain or pain disorders. In some embodiments, chronic pain refers to pain that lasts for more than three months. Examples of pain and pain disorders include acute pain, bodily pain, buttock muscle pain, lower back pain, chronic lower back pain, chronic tailbone pain, chronic lower back pain, chronic malignant pain, chronic neck pain, chronic non-malignant pain, chronic pain, and not otherwise specified (NOS) pain, such as generalized pain. In some embodiments, pain can include pain attacks, buttock pain, tailbone pain (chronic or acute), or tumor-related pain (chronic or acute).

[0279] In some embodiments, the pain is post-procedural and / or post-operative chronic pain. Examples of post-procedural pain include chronic pain from bilateral total hip replacement, chronic pain from bilateral total knee replacement, chronic pain from left-sided total hip replacement, chronic pain from left-sided total knee replacement, chronic pain from right-sided total hip replacement, chronic pain from right-sided total knee replacement, chronic pain after bilateral partial hip arthroplasty, chronic pain after bilateral partial knee arthroplasty, chronic pain after left-sided partial hip arthroplasty, chronic pain after left-sided partial knee arthroplasty, chronic pain after right-sided partial hip arthroplasty, chronic pain after right-sided partial knee arthroplasty, bilateral Includes pain from total hip replacement, pain from bilateral total knee replacement, pain from left-sided total hip replacement, pain from left-sided total knee replacement, pain from right-sided total hip replacement, pain from right-sided total knee replacement, pain after bilateral partial hip arthroplasty, pain after bilateral partial knee arthroplasty, pain after left-sided partial hip arthroplasty, pain after left-sided partial knee arthroplasty, pain after right-sided partial hip arthroplasty, pain after right-sided partial knee arthroplasty, chronic pain after mastectomy, chronic pain after mastectomy, and chronic pain after surgery.

[0280] In some embodiments, the pain is chronic pain due to trauma or injury. In some embodiments, the pain is a chronic pain syndrome, also known as chronic pain associated with psychosocial dysfunction or psychosocial dysfunction due to chronic pain. In some embodiments, the pain is tumor-related pain or pain due to neoplastic disease (chronic or acute). In some embodiments, the pain is burning pain (lower and / or upper limbs).

[0281] In some embodiments, the pain is central pain syndrome, complex regional pain syndrome I, complex regional pain syndrome II (lower extremities), or complex regional pain syndrome II (upper extremities).

[0282] In some embodiments, the formulations and methods disclosed herein are used to treat disorders such as fibromyalgia, fibromyalgia syndrome, chronic fatigue and immune deficiency syndrome, myalgia, myositis, chronic fatigue (unspecified), postviral fatigue syndrome, chronic fatigue syndrome (NOS), benign myalgic encephalomyelitis, phantom limb syndrome (with or without pain), reflex sympathetic dystrophy, hereditary and idiopathic neuropathies, and paraneoplastic neuromyopathy and neuropathy (including peripheral neuropathy), type 2 diabetes (with diabetic neuropathy, unspecified), or certain diabetes with diabetic autonomic (poly)neuropathy. Examples of type 2 diabetes with unspecified diabetic neuropathy include neurogenic erectile dysfunction, peripheral neuropathy, peripheral sensory neuropathy, neuropathy, and neuropathic ulcers (e.g., of the feet and heels).

[0283] In some embodiments, the formulations and methods disclosed herein are used to treat disorders such as postherpetic polyneuropathy, acute herpetic zoster neuropathy, herpetic radiculitis, herpes zoster with nervous system complications, herpes zoster with nervous system complications, postherpetic neuralgia, postherpetic radiculoneuropathy, postherpetic myelitis, postherpetic ganglionitis, or postherpetic trigeminal neuralgia.

[0284] In some embodiments, the formulations and methods disclosed herein are used to treat disorders or diseases such as post-laminectomy syndrome and endometriosis (unspecified). In some embodiments, the formulations and methods disclosed herein are used to treat disorders or diseases such as migraine with aura (refractory), migraine with aura (not refractory), hemiplegic migraine (refractory), migraine (unspecified, refractory), migraine (NOS), migraine without aura (refractory), migraine without aura (not refractory), migraine (unspecified, not refractory), hemiplegic migraine (refractory, no migraine state), other migraine (refractory), ocular migraine (not refractory), abdominal migraine (not refractory), refractory allergic migraine, It is used to treat migraine headaches, including refractory ocular migraine, migraine with aura (not refractory, with migraine state), migraine (unspecified, not refractory, with migraine state), migraine (unspecified, refractory, with migraine state), chronic migraine without aura, migraine (unspecified, not refractory, without migraine state), migraine (unspecified, refractory, without migraine state), menstrual migraine (refractory, without migraine state), other migraine (refractory, without migraine state), other migraine (not refractory, without migraine state).

[0285] In some embodiments, the formulations and methods disclosed herein are used to treat disorders or diseases such as tinnitus (in any ear), or glaucoma.

[0286] In some embodiments, the formulations and methods disclosed herein are used to treat any combination of the disorders or diseases described herein.

[0287] Drug Addiction Treatment In some embodiments, the formulations and methods disclosed herein are used to treat drug addiction, including opiate addiction, benzodiazepine addiction, sedative (hypnotic or anxiolytic) addiction, alcohol addiction, stimulant addiction, cocaine addiction, cannabis detox, opiate addiction (with withdrawal), benzodiazepine addiction (with withdrawal), sedative addiction (with withdrawal), alcohol addiction (with withdrawal), stimulant addiction (with withdrawal), cocaine addiction (with withdrawal), and cannabis detox (with withdrawal).

[0288] In some embodiments, the methods disclosed herein include a step of selecting or screening for individuals with drug addiction.

[0289] In some embodiments, the pharmaceutically acceptable salt comprises an acid. The pharmaceutically acceptable salt can comprise any of the acids described in the "Compositions" section.

[0290] In some embodiments, the compound of Formula (I) is administered as a pharmaceutical composition further comprising a complexing agent. The complexing agent may include any of the complexing agents described in the "Compositions" section, such as any of the cyclodextrins provided herein, in the amount specified therein. The pharmaceutical composition may further include any of the additional components provided in the "Compositions" section herein, including, but not limited to, a base, a buffer, a cosolvent, a preservative, a surfactant, a solubilizer, a stabilizer, an antioxidant, a cryoprotectant, a lyoprotectant, a bulking agent, a tonicity agent, an antimicrobial agent, a diluent, a soothing agent, and / or an emulsion stabilizer.

[0291] In some embodiments, the compound of Formula (I) has the structural formula (IA):

[0292] [ka] or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, wherein X- is a counter ion, and further a compound of formula (IA). X - can be any of the counterions provided herein in the "Compositions" section.

[0293] In some embodiments, the pharmaceutical composition is a solution. In some embodiments, the pharmaceutical composition is a solid. In some embodiments, the pharmaceutical composition has a pH greater than about 4, e.g., a pH of about 4 to about 7, or any pH value provided in the "Composition" section. The pharmaceutical composition may further comprise any of the characteristics set forth in the "Composition" section, including, but not limited to, an osmolality value (e.g., about 250 mOsm / kg to about 850 mOsm / kg) and / or a concentration of ketamine (e.g., about 20 mg / mL to about 250 mg / mL).

[0294] The pharmaceutical composition may be administered on a regimen of one (1) to four (4) times per day, including once, twice, three times, and four times per day. In some embodiments, the compound of Formula (I), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered once per day.

[0295] In some embodiments, the compound of Formula (I), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered at a dosage of about 20 mg / mL to about 150 mg / mL. In some embodiments, the compound of Formula (I), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered at a dosage of about 100 mg / mL. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered at a dosage of about 128 mg / mL.

[0296] In some embodiments, the compound of Formula (I), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered daily. In some embodiments, the compound of Formula (I), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered once daily.

[0297] In some embodiments, the compound of Formula (I), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by subcutaneous injection (e.g., bolus or infusion) or by implantable minipump (e.g., bolus or infusion). In some embodiments, the compound of Formula (I), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by implantable minipump. In some embodiments, the implantable minipump is a 6-month pump. In some embodiments, a single implantable minipump is used.

[0298] In some embodiments, the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant; or its pharmaceutically acceptable salt, solvate, or hydrate, is administered by subcutaneous injection. In some embodiments, the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant; or its pharmaceutically acceptable salt, solvate, or hydrate, is injected approximately once per month. In some embodiments, the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant; or its pharmaceutically acceptable salt, solvate, or hydrate, is administered for a period of up to about six months. In some embodiments, the compound of Formula (I), or its enantiomer, mixture of enantiomers, or isotopic variant; or its pharmaceutically acceptable salt, solvate, or hydrate, is injected approximately once per week. In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is infused approximately once weekly for a period of up to about 25 weeks or more.

[0299] IV. Methods of Formulating Ketamine In one aspect provided herein is a method of preparing a pharmaceutical composition, the method comprising combining a free acid form of a complexing agent comprising at least one acidic functional group with a compound represented by structural formula (I):

[0300] [ka] or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a solvate or hydrate thereof, wherein the compound of structural formula (I) is in its free base form.

[0301] In some embodiments, the mixing step is performed in a suitable medium. In some embodiments, the suitable medium is an aqueous medium. In some embodiments, the suitable medium is an organic solvent. In some embodiments, the mixing step is performed in a solution. In some embodiments, the mixing step is performed when the complexing agent and the compound of Structural Formula (I) are in powder form.

[0302] In some embodiments, the mixing step is performed by partial addition of one of the reagents, hi some embodiments, the compound of Structural Formula (I) is added partially to a solution containing the complexing agent.

[0303] In some embodiments, the pharmaceutical composition is in a form for dosage or administration by subcutaneous injection.

[0304] In some embodiments, the complexing agent containing at least one acidic functional group is a cyclodextrin. Any of the cyclodextrins provided in the "Compositions" section can be used. The cyclodextrin or other complexing agent can be added in any amount provided in the "Compositions" section or in any molar ratio provided herein, including the ratio of acidic functional groups to the compound of Formula (I).

[0305] In some embodiments, the method further comprises adjusting the pH of the pharmaceutical composition. In some embodiments, only minimal adjustment of the pH is required. In some embodiments, the pH is adjusted with a strong base. In some embodiments, the pH is adjusted with sodium hydroxide, potassium hydroxide, barium hydroxide, cesium hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, lithium hydroxide, or rubidium hydroxide. In some embodiments, the pH is adjusted with sodium hydroxide. In some embodiments, the pH is adjusted to a desired pH. In some embodiments, the desired pH is any of the pH values provided in the "Compositions" section herein.

[0306] In some embodiments, the pharmaceutical formulation has a pH of > about 4. The pH of the pharmaceutical composition can be any of the pH values provided in the "Compositions" section, such as a pH of about 4 to about 7, or any other pH value or range provided herein.

[0307] In some embodiments, the method further comprises adding a preservative to the composition. The preservative may be added to the composition at any time or in any order. In some embodiments, the preservative is added after the complexing agent and the compound of structural formula (I) have been added. In some embodiments, the preservative is added before the compound of structural formula (I) is added. In some embodiments, the preservative is benzethonium chloride. The preservative may be any of the preservatives further provided in the "Compositions" section and may be added at any concentration provided herein.

[0308] In some embodiments, the method further comprises adding a base, a buffer, an emulsifier, a surfactant, a solubilizer, an emulsifier, a co-solvent, or any combination thereof. The method may further comprise adding any of the additional ingredients provided herein under the "Compositions" section, including, but not limited to, a base, a buffer, a co-solvent, a preservative, a surfactant, a solubilizer, a stabilizer, an antioxidant, a cryoprotectant, a lyoprotectant, a bulking agent, a tonicity agent, an antimicrobial, a diluent, a soothing agent, and / or an emulsion stabilizer.

[0309] In some embodiments, the method further comprises adjusting the osmolality of the pharmaceutical composition. In some embodiments, adjusting the osmolality of the pharmaceutical composition comprises diluting the pharmaceutical composition. Diluting the pharmaceutical composition may comprise diluting with water or another physiologically acceptable buffer, such as phosphate buffered saline, or any of the buffers provided in the "Compositions" section. In some embodiments, adjusting the osmolality of the pharmaceutical composition comprises adding a tonicity-modifying agent. The tonicity-modifying agent may be any pharmaceutically acceptable agent, such as sodium chloride, or any of the agents provided in the "Compositions" section. In some embodiments, it is not necessary to adjust the osmolality of the pharmaceutical composition after combining the compound of structural formula (I) and the complexing agent.

[0310] The final osmolality of the pharmaceutical composition can be any of the osmolalities provided in the "Compositions" section, such as an osmolality of about 250 mOsm / kg to about 850 mOsm / kg, or any other range or value provided therein.

[0311] The final concentration of the compound of structural formula (I) in the pharmaceutical composition may be any of the concentrations provided in the "Compositions" section, including values greater than 20 mg / mL or any other value or range provided therein.

[0312] Further provided herein is a method for producing the free acid form of a complexing agent comprising at least one acidic functional group. In some cases, the complexing agent comprising an acidic functional group is commercially available only as a salt of the complexing agent, such as a sodium salt. For example, SBEBCD is commercially sold as the sodium salt.

[0313] The free acid form of such a complexing agent can be generated by any number of methods. For example, a salt of a complexing agent containing an acidic functional group can be bound to a suitable acidic cation exchange resin (e.g., Amberlite® IR120 Hydrogen Foam resin, available from commercial suppliers such as Sigma-Aldrich) and then eluted to obtain the desired free acid form of the complexing agent. An additional method potentially suitable for this purpose may involve treating the sodium salt of the complexing agent (e.g., SBEBCD) with hydrochloric acid or another suitable acid in a suitable organic solvent. Ideally, the organic solvent is selected so that the resulting sodium chloride precipitates from solution, leaving the free acid of the complexing agent in solution. The sodium chloride salt can then be removed by filtration, and the free acid can be obtained by concentrating the filtrate or removing the solvent. Conversely, the filtrate can be solvent-exchanged with water for injection using standard azeotropic distillation under vacuum. Alternatively, the filtrate can be used directly in the preparation of the formulation and removed in a subsequent step.

[0314] Example

[0315] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous modifications, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments described herein may be utilized in carrying out the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0316] Example 1. Subcutaneous formulation of ketamine.

[0317] Until recently, the current standard of care for treating psychiatric disorders with ketamine HCl typically involved in-office use, with intravenous delivery being the most common delivery method. Intravenous delivery can require significant monitoring, IV placement, and various other mechanical requirements of the IV procedure (normal saline, sedatives such as midazolam or propofol, a hospital bed or IV chair). Some practitioners deliver ketamine in-office via intramuscular delivery, which generally requires reduced medical equipment (e.g., no IV, saline bag, cannula, etc.). Depending on the particular practitioner's procedural protocol and practice patterns, this situation also typically involves reduced monitoring, consisting only of intermittent blood pressure and pulse, and / or pulse oximetry. Alternatively, ketamine may be administered outside of the office or hospital in the form of sublingual, compounded "troches," oral compounded capsules, and intranasal compounded sprays. Recently, an intranasal formulation of the S enantiomer of ketamine was approved as an adjunctive treatment for major depression, used exclusively in hospital settings, due to the substantial acute dissociative side effects associated with this bolus approach to ketamine delivery. Each of these four methods of ketamine delivery has various drawbacks that may limit their use depending on the clinical parameters of a particular medical case. Intravenous delivery of ketamine can easily achieve steady-state blood levels that can be maintained for as long as necessary. This pharmacokinetic capability can be highly advantageous in certain treatments; however, this delivery mode can only be achieved in hospital, clinic, or home hospice-style settings, significantly limiting access to ketamine delivered via non-bolus methods. Because bolus administration of ketamine is associated with substantial movement disorders and dissociative side effects, intravenous (IV) administration offers a significant advantage by providing the ability to control dosing and achieve steady-state blood levels within acceptable side-effect parameters. Additionally, ketamine is 100% bioavailable upon IV administration, minimizing exposure to excess metabolites that provide no clinical benefit but increase the risk to non-target tissues such as the bladder (e.g., ketamine cystitis).However, despite all the advantages of IV delivery for ketamine procedures and treatments, this treatment mode is only available in hospitals and clinics, generates significant medical waste, is costly, requires significant time commitments for patients and healthcare providers, and is limited by sometimes compromised venous access. Intramuscular (IM) delivery offers the same advantages regarding bioavailability and reduced exposure to metabolites and is more convenient than IV, but primarily represents a bolus delivery method, making it difficult to manage side effects while delivering a dose sufficient to achieve the desired benefit. Off-label oral, sublingual, and intranasal delivery mechanisms currently used in clinical practice offer the advantage of being relatively safe for use in the home environment, but are limited by the need for milligram-scale dose increases due to bolus delivery only and low bioavailability; this increases exposure to clinically irrelevant metabolites, which increases risk. Oral administration of ketamine equivalent to short IV or IM treatments increases exposure to undesirable inflammatory metabolites by up to 9-fold; sublingual administration (ROA) results in a 3-fold increase, while intranasal administration results in a 2-4-fold increase. A subcutaneous formulation of ketamine for delivery via a pump device would reduce the associated disadvantages of these other ROA while at the same time possessing advantages that clearly distinguish it from all other forms of ketamine delivery. For example, such a product could achieve a plasma steady state of ketamine capable of treating certain identified symptoms, but that is low enough to mitigate or reduce undesirable side effects. Additionally, a small bolus option could be made available, offering potential clinical benefits with more potent pulse-on / pulse-off bolus administration of ketamine in clinical care. Additionally, bioavailability approaches that of IV and IM routes of administration, reducing subject exposure to undesirable, dangerous, and / or non-clinically relevant metabolites.

[0318] [Table 1]

[0319] The systems and methods disclosed herein offer an innovative solution to the problems associated with the ketamine administration route by providing a novel subcutaneous formulation, resolving issues that have rendered this route of ketamine irrelevant to current clinical care. It is understood that subcutaneous delivery of currently available forms of ketamine, either by bolus injection or infusion pump, is extremely rare due to its well-characterized irritating effects on subcutaneous and / or cutaneous tissue. Subcutaneous ketamine has been reported to cause irritation to subcutaneous tissue and even sterile abscesses, and is generally considered a painful administration route, so it is avoided. This irritating effect may be caused by one or more of three fundamental characteristics of current ketamine formulations: 1) the acidic pH of USP label formulations ranges from 3.5 to 5.5, but in reality, it averages approximately 3.5 to 4.0; 2) hypertonicity and / or hyperosmolality resulting from the ketamine in solution and the sodium chloride salt produced in the standard manufacturing process used to create the ionized form of ketamine for solution; and 3) a direct effect of ketamine itself.

[0320] Formulations that reduce the potential contribution of the first and / or second and / or third factors are expected to reduce tissue irritation and increase tissue and / or sensory tolerance to this route of administration. The formulation innovations described herein are designed to produce stable ketamine formulations with a pH close to that of human subcutaneous tissue and / or reduced tonicity and / or osmolality and / or osmolality achieved through one or many of the manufacturing processes described herein. Generally, many features for reducing injection site irritation / pain with SC and IM injections can include reducing the injection volume, and / or reducing the hypertonicity and / or hyperosmolality and / or hyperosmolality, and / or slowing down the injection rate, and / or adjusting the solution toward physiological pH. Any of these factors can be included in one or all of the formulations described herein. Slowing down the injection rate can potentially reduce pain and irritation.

[0321] Decreasing the injection volume may increase tolerance to subcutaneous injection, and tonicity may also affect tissue tolerance. These factors also combine to affect injection site irritation and pain. Therefore, strategies to reduce injection site pain and irritation from SC or IM injections that combine one or more of these factors may consider the effects of one or all of these factors.

[0322] Thus, one advantage offered by the formulations and methods disclosed herein may include providing home delivery of drug formulations, such as ketamine, optionally via subcutaneous delivery. Subcutaneous drug administration avoids various problems associated with traditional home treatments, such as oral capsules and nasal sprays. Oral or nasal delivery tends to require higher doses than intramuscular or subcutaneous delivery to achieve comparable clinical efficacy, which carries the risk of bladder dysfunction due to the higher doses. Oral or sublingual administration is often unreliable due to the presence of food or chyme in the stomach or proximal small intestine and significant first-pass metabolism. Intranasal administration may result in allergic or irritant rhinitis, epistaxis (nosebleeds), or bacterial or viral sinusitis. Furthermore, some patients are unable to regularly visit a clinic for treatment. The time and direct costs associated with repeated in-office ketamine treatments and post-treatment monitoring present significant obstacles to effective treatment. This is particularly true in large urban centers, where arranging the time required for patients to travel to a treatment center can be particularly challenging. The potential for increased access to effective home treatment with ketamine would significantly reduce this barrier to treatment for patients suffering from depression, pain, or other appropriate conditions that could benefit from ketamine treatment nationwide. With the availability of effective home delivery systems and methods, patients would not need to visit a clinic as frequently as required by the current standard of care. Such convenience could save not only time and money for patients, but also money for reimbursement entities. Thus, the formulations and methods disclosed herein can combine the benefits of subcutaneous delivery with the convenience and cost-effectiveness of home treatment.

[0323] Another advantage offered by the formulations and methods disclosed herein is a treatment regimen that provides effective therapy while reducing the risk of side effects and / or dissociative symptoms associated with standard therapies. Such a treatment regimen can allow for smaller doses and / or more frequent administration of one or more continuous doses, mitigating the effects often associated with large bolus doses. For example, administration at a sustained low dose and / or slow infusion rate can reduce many of the unpleasant psychological or dissociative side effects and shorten or eliminate the recovery time required for patients to resume normal activities compared to intravenous or intramuscular injections administered in a clinic. Furthermore, the home administration regimen disclosed herein can provide effective steady-state plasma concentrations outside of a clinic setting that are not achievable with current home-based standard treatments for certain active ingredients, such as ketamine, due to their short half-life and substantial first-pass metabolism.

[0324] Another advantage provided by the formulations and methods disclosed herein is the administration of one or more doses of a drug, such as ketamine, according to a programmed dosing regimen. Such devices not only allow for drug administration in a traditional hospital / clinic setting, but also offer the option of self-administration at home or outside of a hospital / clinic setting. A physician or healthcare provider can program the delivery device with a dosing regimen, and the patient or subject can use the device to self-administer one or more doses at home. Thus, the subject is given limited control over implementing the pre-programmed dosing regimen. Using a pre-programmed dosing regimen for self-treatment outside of a clinic allows for precise titration of blood concentrations of the active ingredient, such as ketamine, at the minimum effective dose. This reduces the procedural burden and medical equipment required during clinic or hospital treatment, which is currently performed using IV infusion or IM bolus injections. Another advantage is the reduction of same-day and next-day side effects associated with current in-clinic and home treatments, such as dissociation, disorientation, confusion, drowsiness, brain fog, and physical fatigue. Additionally, dosing regimens can be programmed to control the rate of drug delivery to mitigate certain side effects, such as adverse cardiac events, known to be associated with ketamine use. In some cases, dosing regimens are programmed for sustained and / or timed-release administration of drugs such as ketamine.

[0325] Another advantage provided by the formulations and methods disclosed herein may include preventing bolus administration of drugs such as ketamine beyond dosage limits. A sudden, large dose of a drug such as ketamine can cause effects such as dissociation, disorientation, confusion, drowsiness, increased heart rate, high blood pressure, euphoria, and even temporary paralysis. Limiting the maximum dose of a drug prevents a subject from exceeding the limits of a set dosing regimen, abusing the drug, or overdosing.

[0326] Another advantage provided by the formulations and methods disclosed herein is tamper-resistant drug delivery, which prevents unauthorized access to the drug stored within the device and / or drug cartridge. Drugs such as ketamine can be subject to abuse, and delivery mechanisms that cede control to the patient carry the risk of abuse and / or addiction. A tamper-resistant device and / or drug cartridge helps prevent unauthorized access to the drug formulation contained therein, thereby limiting drug use to authorized uses, such as according to a pre-programmed dosing regimen.

[0327] Example 2. Testing of formulations disclosed herein. 1. The formulations provided herein are tested to determine their association with reduced subjective experience of erythema and / or pain and / or itching and / or burning and / or stinging and / or irritation and / or other measured parameters compared to standard ketamine, and demonstrate no adverse effects on the tissue to which they are administered in acute and / or chronic studies in animals and / or humans. Animal data can be obtained by treating two cohorts of animals, one subcutaneously treated with a formulation of ketamine and the other subcutaneously treated with currently available ketamine HCl. Animal technicians observe and record signs of irritation and / or erythema in the skin tissue at the local site. Irritation and erythema at the local site are accurate markers of tissue damage and are also generally associated with increased pain. 2. The formulations provided herein will be tested in vitro and / or in vivo in the indicated human and / or animal tissues to determine their association with reduced histological changes and / or signs of tissue damage, scarring, dryness, and / or inflammation compared to standard ketamine. Histological data will be obtained by observing skin tissue samples collected from two animal cohorts: one treated subcutaneously with a ketamine formulation and the other treated subcutaneously with currently available ketamine HCl. Biopsy specimens from each cohort will be fixed, processed, and stained prior to observation by trained histologists. 3. The formulation will be tested to determine whether it successfully retains in solution and / or complexes and / or solubilizes and / or emulsifies any or all of the non-ionized ketamine present at a higher pH than the indicated standard ketamine formulation. The non-ionized ketamine solubility curve in the presence of a complexing agent, possibly including any of the agents described in this document, and / or potentially sulfobutylether-β-cyclodextrin (e.g., Captisol®) or hydroxypropyl-β-cyclodextrin (e.g., Cavasol®), is predicted to establish the percentage of non-ionized ketamine successfully retained in solution at a given target pH, an achievement that would not be possible without the complexing agent. 4. The formulations of ketamine provided herein are tested to determine the concentration of ketamine that can be maintained in solution. 5. The pump selected for formulation delivery is tested to demonstrate faithful performance across the delivery parameters identified compared to the performance of this same pump delivering the first FDA approved drug (potentially including standard insulin or another drug or compound or "biological" drug or molecule or solution). 6. The formulations provided herein are tested to determine their association with a comparative reduction in subjective and / or objective signs or symptoms of chronic and / or acute pain and / or other identified clinical conditions, such as those associated with major depression, post-traumatic stress disorder, dysthymia, anxiety, withdrawal, and / or other psychiatric illnesses described herein, compared to standard of care. 7. The formulations provided herein are tested to determine their association with increased reduction in subjective and / or objective signs or symptoms of acute and / or chronic pain, and / or other identified clinical symptoms, such as those associated with major depression, post-traumatic stress dysthymia, anxiety, withdrawal, and / or other psychiatric disorders, compared to placebo. For pain management, this data may result from animal-induced pain studies, potentially using models such as, but not limited to, tail flick assessment, Randall Selitto, or abdominal cramps. These studies may compare two cohorts of animals and their response to pain stimuli before and after administration of either a ketamine formulation or a placebo. It is predicted that animals treated with the formulations disclosed herein will exhibit reduced central and / or peripheral effects and / or hyperalgesia and / or other types of pain symptoms, compared to placebo. 8. The formulations provided herein are tested compared to standard ketamine to determine that they more stably and effectively maintain total ketamine in solution at a higher pH than currently available concentrations of ketamine HCl titrated to a comparable pH. 9. The formulations provided herein are tested to demonstrate reduced osmolality and / or osmolality and / or tonicity compared to currently available ketamine HCl formulations of comparable or even lower concentrations (e.g., 50 mg / mL). For some formulations, data is expected to be provided demonstrating that the formulations are successful in reducing osmolality and / or osmolality and / or tonicity based on the formulation techniques described herein that avoid or remove unwanted ions. For some formulations described herein, the formulations are expected to successfully reduce osmolality and / or osmolality and / or tonicity compared to standard formulations of ketamine HCl using excipient solubilizing and / or complexing agents, such as substituted cyclodextrins converted to acids, to achieve three effects: 1) titration to the desired pH, 2) solubilization of the portion of unionized ketamine present at high pH, and 3) removal of unwanted sodium groups that would add unwanted osmolality. In some formulations described herein, compared to standard formulations of ketamine at higher pH using standard unmodified excipient solubilizing and / or complexing agents such as substituted cyclodextrins, the formulations are predicted to be successful in reducing osmolality and / or osmolality and / or tonicity using excipient solubilizing and / or complexing agents such as substituted cyclodextrins that have been converted to an acid to achieve three effects: 1) titration to the desired pH, 2) solubilization of the portion of unionized ketamine present at the higher pH, and 3) removal of unwanted sodium groups that would add unwanted osmolality. 10. Formulations provided herein utilizing novel salts of ketamine (e.g., ketamine-SBE-β-CD, ketamine fumarate, ketamine malate) are tested to demonstrate reduced osmolality and / or osmolality and / or tonicity compared to similar formulations using standard ketamine HCl salt. 11. The formulations provided herein are tested to determine whether they successfully complex and / or solubilize and / or emulsify any non-ionized ketamine present at a pH higher than ketamine's pKa and / or at a pH higher than that of standard USP ketamine formulations. It is important to note that although the USP label for ketamine states that the pH of ketamine should be between 3.5 and 5.5, initial experiments have shown that the actual average pH of ketamine falls within a narrower range and is at the lower end of this pH spectrum (e.g., 3.93 formed from powdered ketamine HCl and 3.74 measured in a USP bottle of ketamine 100 mg / mL). Standard ketamine is formulated to a pH such that ketamine is fully ionized and completely dissolved without excipients, emulsifiers, complexing agents, surfactants, or solubilizers. Therefore, as proposed, it is anticipated that a stable ketamine solution formulation will be developed and data will be provided demonstrating that it achieves an average pH at least 0.5 pH points higher (and likely at least 1 pH point higher) than the average found in current standardized USP formulations of equivalent strength ketamine. 12. Solubilizers will be tested to characterize the ketamine solubility curve within different concentrations of solubilizer, potentially including but not limited to sulfobutyl-ether-β-cyclodextrin (e.g., Captisol®), hydroxypropyl-β-cyclodextrin, or other cyclodextrin entities.

[0328] Example 3. Formulation information and description (ingredients, proportions, pH, salinity, etc.).

[0329] Description of Features of Innovation / Novelty: Ketamine hydrochloride is currently only indicated for IV and IM delivery. Off-label use of the approved formulation is somewhat common, and compounding pharmacies are known to prepare formulations for SL, oral, rectal, transdermal, and intranasal use. The formulations provided herein are delivered subcutaneously using a personal pump device, resulting in the following innovations: 1. Novel subcutaneous route of delivery: Currently, ketamine hydrochloride is administered only IM or IV. Device-drug combos specifically for subcutaneous delivery are under development. 2. pH Adjustment and Buffering: Solution pH will be raised at least 0.5 pH points above the average pH found in currently available USP ketamine products to improve comfort and tissue tolerability. 3. Strength Matching: The target solution concentration of ketamine is approximately 20 mg / mL to approximately 150 mg / mL, or more preferably, approximately 50 mg / mL to approximately 120 mg / mL or higher. However, based on research results, the solution concentration can be adjusted to suit subcutaneous pump dynamics. Currently, ketamine hydrochloride is available in 10, 50, and 100 mg / mL. However, depending on the pump dynamics of the proposed ketamine formulation (e.g., pump / formulation validity testing), clinical response findings, side effect findings, adverse event findings, and / or other data regarding the final formulation strength in animal or human studies, the solution concentration may be approximately 20 mg / mL to approximately 150 mg / mL. 4. Complexation of Ketamine Free Base: Addition of a complexing agent, potentially including sulfobutyl-ether-beta-cyclodextrin (e.g., Captisol®), hydroxypropyl-beta-cyclodextrin, or another cyclodextrin, solubilizes the non-ionized portion of ketamine to maintain a therapeutically appropriate ketamine solution concentration, potentially improving tissue tolerability through subcutaneous delivery. Alternative approaches, including emulsifiers and / or buffers, may also be included to achieve this goal. 5. Potential Use of Divalent or Trivalent Salts to Form Novel Ketamine Solutions with Reduced Osmolality: By using ketamine solutions formed from ketamine salts consisting of ketamine combined with trivalent anions to form ketamine salts, potentially including but not limited to citrate and phosphate, or potentially divalent anions including but not limited to sulfate, carboxylate, tartrate, glutarate, succinate, maleate, and malonate, or potentially other polyvalent anions such as variously substituted anionic cyclodextrins, including carboxymethyl-β-CD, succinyl-β-CD, 2-carboxyethyl-β-CD, β-CD-phosphate, beta-β-sulfate, sulfoethyl-β-CD, and SBE-β-CD, we could further reduce the osmolality of the final product with the goal of increasing subcutaneous tissue tolerability. 6. Use of s-ketamine enantiomers: This is another potential innovation, with the goal of increasing the total active ketamine that can be delivered, given that existing pump mechanisms are limited to small drug volumes.

[0330] Currently proposed tags (to be confirmed after testing and finalization): Ketamine hydrochloride for subcutaneous injection ●CIII Rx only pH 4.5 to 6.5 Strength: Possible range: 20-150mg / mL Ingredients: Ketamine (available range: 20-150mg / ml) Captisol (registered trademark) (cyclodextrin) Available range: 50-600 mg / mL Benzethonium chloride possible range: 0.1-0.5mg / mL Buffer solution (TBD) Store at 20°C-25°C (controlled room temperature) or 2°C-8°C (frozen) depending on further testing.

[0331] Example 4A. Potential Example of Initial Formulation Protocol (To be more precisely determined after further development)

[0332] Dissolve ketamine HCl, benzethonium chloride, HP-beta-CD, and potential buffer (TBD) in sterile water. Dilute with water to 90% of the final target volume. Adjust pH to the target range with aqueous NaOH prepared in sterile water. Adjust to final volume by adding sterile water. 1) Initial testing: a. Solubility: Determine the solubility of unionized ketamine at various SBE-β-CD concentrations: The solubility of SBE-β-CD is reported as 0.6 g / mL. This cyclodextrin should complex the unionized portion of ketamine in solution between 200 and 600 mg / mL, over a potential total ketamine concentration range of 20 to 150 mg / mL and a potential pH range of 4.5 to 6.5. The actual pH of the final solution and the concentrations of SBE-β-CD, ketamine, preservatives, and additive buffers required to achieve formulation goals will be determined. b. Stability Testing: Solutions made in this initial phase should be stored at controlled room temperature for 1 month and 3 months to determine initial stability by appearance, pH, osmolality, and concentration of ketamine and SBE-β-CD (e.g., Captisol®). i. Short term 1. Concentration validation by HPLC or other means 2. pH 3. Osmotic pressure 4. Appearance (ketamine precipitate) 5. Additionally, determine the results of ICH-compatible stress tests (e.g., light, heat, pH). ii. Long-term (>=6 months) 1. Stability in temperature cycles (freeze / thaw cycles) 2. Antibacterial properties / contamination sensitivity 3. Short-term and long-term stability in cyclic olefin polymer capsules, device cartridges, and USP glass 3) Buffer solution a. It is believed that ketamine may act as a buffer at pH levels slightly above its pKa and / or higher than the standard USP formulation. If so, a second buffer may not be necessary for pH stability, although a buffer may be needed to maintain pH stability. b. Only non-irritating buffers containing phosphate and histidine may be considered. 4) Emulsifiers a. SBE-β-CD (e.g., Captisol®)—This is the first choice given that it is the industry standard, substantial safety data already exists, and the parent company provides support. b. Other possibilities: i. Hydroxypropyl-beta-cyclodextrin / HP-beta-CD, or ii. Polysorbate / Tween 20 or Tween 80 iii. Glycerin iv. Propylene glycol v. Complexing Agents / Emulsifiers 5) Treatment Model: Although details may change with new data and Phase I and Phase II studies, the current treatment model for subcutaneous delivery of ketamine via patch pump (with both base rate and bolus administration) is as follows: Treatments are preferably administered over a 24-72 hour period (e.g., up to three consecutive 24-hour patch pumps), with patients resting for at least one day and a maximum of three days between uses. No more than 10 treatments per month are recommended. Instructions: 1. Cleanse the skin with the preparation. 2. Remove the adhesive backing and place the patch on the skin. 3. Remove the safety nib. Insert the catheter by pressing firmly downwards. This action will initiate ketamine delivery at a baseline rate according to the pump specifications. 4. For acute or sudden pain, press the bolus button. This bolus function can be used up to 18 times in a 24-hour period. Each activation of the bolus will deliver 2.5 mg of ketamine. 6) Projected Dosing Range for Clinical Use: Three pump strengths are available. See the table below for current projections for basal, bolus, and total dosing of both ketamine and Captisol® for the three different strength pumps currently planned, although final concentrations will be determined after formulation development. Two separate tables are provided showing the differences in dosing ranges for potential differences in ketamine and / or Captisol® concentrations. Ketamine formulations are presented in Tables 2A-2C. Captisol® is included in some formulations as a complexing agent.

[0333] [Table 2-1]

[0334] [Table 3-1]

[0335] [Table 4]

[0336] [Table 5]

[0337] Example 4B. Benefits Provided by Sulfobutyl-ether-beta-cyclodextrin

[0338] A study was conducted to assess the benefits and drawbacks of Captisol® with respect to the efficacy, patentability, and appropriability of the unique ketamine product described herein. This soluble pharmaceutical excipient / vehicle was developed specifically to reduce the risks presented by earlier cyclodextrins (CDs) (e.g., beta-CD, alpha-CD, and even HP-CD). Toxicity: Sulfobutyl-ether-beta-cyclodextrin (SBE-β-CD) is generally safer than other identified unsubstituted CDs. It is also generally accepted that SBE-β-CD is metabolically less active than another substituted CD, hydroxypropyl-beta-cyclodextrin (HP-β-CD). These factors reduce non-targeted systemic effects, making Captisol® an attractive option. CD toxicity primarily revolves around impaired renal physiology and glomerular filtration, believed to result from the precipitation of cholesterol-CD complexes, which impair glomerular function and glomerular filtration rate (GFR). The rate of CD delivery and total dose are significant considerations in any safety assessment of any CD, and this is particularly true for first-generation CDs. The precipitation of early CDs, resulting in toxic effects on the kidneys, was thought to be substantially due to their relatively low water solubility. CDs with polar substitutions were eventually produced that increased water solubility, thereby reducing nephrotoxicity, while still maintaining the complexing and solubilizing capabilities of the original compound. According to the European Medicines Agency, the total plasma clearance of HP-β-CD and SBE-β-CD in all species tested is similar to the glomerular filtration rate. The t1 / 2 varies from 20 to 100 minutes, suggesting high aqueous solubility and / or rapid clearance from the body. The innovation represented by SBE-β-CD has successfully supported the development of numerous parenteral products for IV and IM ROA (see Table 1).

[0339] While approved products containing Captisol® are not yet designed for chronic or subchronic use—developed primarily for IV or IM administration of poorly soluble drugs in acute, medically monitored settings—long-term daily exposure in animals has identified a "no observed effect level," which is reassuring regarding potential toxicity from repeated low-dose administration in humans. The NOEL in rats was 80 mg / kg, based on daily IV injections of SBE-β-CD for one month.

[0340] Previous human studies are also encouraging. In the development of parenteral forms of carbamazepine, two human studies with varying degrees of renal function demonstrated that aqueous-processed SBE-β-CD could be safely administered intravenously as a vehicle at doses up to 35 g / day (700 mg / kg / day) every 6 hours for up to 7 days. SBE-β-CD infusion rates ranged from 292 to 4375 mg / min (between 30 and 2 minutes, respectively). SBE-β-CD was well tolerated and was not associated with clinically relevant side effects or changes in renal biomarkers. HP-β-CD and SBE-β-CD appear to be safe at relatively high doses and are the most widely used parenteral products. Approximately 250 mg / kg / day for 21 days (HP-β-CD) or 6 months (SBE-β-CD) have been confirmed to be safe in humans over the age of 2 years.

[0341] There is little public data available establishing safety parameters for subcutaneous (SC) ROA. However, there is generally no concern that findings differ substantially between SC and IM or IV administration, particularly with regard to nephrotoxicity. However, it has been reported that a product using Captisol® as an excipient has established safety after one year of delivery in divided doses (BID) three times per week to monkeys.

[0342] Example 5. Increasing the pH of a Ketamine Formulation

[0343] explanation:

[0344] The pH of the ketamine solution can be adjusted by adding an acid, such as HCl, or a base, such as NaOH. Additionally, buffers can be used to achieve a stable target pH. Because ketamine has a pKa of 7.5 and the non-ionized portion is poorly water-soluble, titrating a ketamine HCl solution in water above pH 5.5 will cause the non-ionized ketamine to precipitate from solution. Adding a complexing agent (e.g., SBE-β-CD, HP-β-CD) to complex and keep non-ionized ketamine in solution, or adding a cosolvent (e.g., propylene glycol, tween, or glycerin) to solubilize non-ionized ketamine (forming an emulsion), is necessary to prepare ketamine solutions with target pHs that are at least 0.5 pH points and can be 1 pH point or more higher than the average pH in equivalent strength USP ketamine HCl solutions, which in our studies ranged from 3.93 in solutions formed from powdered ketamine HCl to 3.74 measured in the USP bottle of 100 mg / mL ketamine.

[0345] advantage:

[0346] Acidic solutions are thought to cause irritation associated with SC and IM injections. This may be due to the fact that the resulting protons mimic the environment of injured tissue and induce a pain response. Neutral pH solution formulations have been utilized to reduce irritation and pain at the subcutaneous injection site, but success may depend on other factors, such as chemical irritation and tonicity. Raising the pH of the formulation from below 5 to above 5.0 may help reduce the injection site pain, irritation, and response seen after SC injections of more acidic ketamine solutions (pH below 5). Therefore, reducing acidity may be part of a combined strategy that includes reducing tonicity and slow, continuous small-volume infusions (supported by small-volume bolus SC injections, if necessary), resulting in reduced injection site irritation and a better procedural experience for patients.

[0347] Example 6. Reducing tonicity through formulation technology

[0348] Explanation and rationale:

[0349] Many existing commercially available ketamine formulations (e.g., 50 and 100 mg / mL ketamine HCl) are hypertonic. Osmolality is the total amount of particles dissolved in a solution per given volume (liter). Closely related, osmolality is the total amount of particles dissolved in a solution per given mass (kilogram). Osmolality is more commonly measured experimentally, such as with an osmometer. However, the values of osmolality and osmolality rarely differ in most practical application practices. The calculated osmolality of a 100 mg / mL (free base equivalent) ketamine HCl (concentration 0.4206 mol / L) solution is 841 mOsmol / L, and the calculated osmolality of a 50 mg / mL (free base equivalent) ketamine HCl (concentration 0.210 mol / L) solution is 420 mOsmol / L. At both of these concentrations, the solution is hypertonic relative to human serum (~280-295 mOsm / L). This limitation can be overcome by using lower concentrations of ketamine (e.g., 10 mg / mL), but such low concentrations of ketamine are inappropriate and inconvenient for subcutaneous delivery due to the large injection volumes required, thus requiring large boluses for delivery and large device reservoirs for long-term delivery.

[0350] During the formulation of ketamine solutions, it may be necessary to titrate the solution's pH using an acid or base, such as HCl or NaOH, respectively. During the process of neutralizing ketamine HCl with NaOH to raise the pH, excess NaCl is generated, which may contribute to the measured osmolality of the solution. One way to reduce the osmolality of a ketamine solution is to remove this excess NaCl or to prevent its formation in the first place. However, in practice, only small amounts of NaCl are expected to be generated during the titration of existing ketamine formulations (e.g., Ketalar), because the pH of ketamine HCl solutions depends on the ketamine concentration and is within the specified target range (pH: 3.5-5.5). At 100 mg / mL (ketamine free base equivalent) in water, the pH is approximately 4. Therefore, NaOH must be added to raise the pH of this solution to the target pH of 5.5. In addition to ensuring that the non-ionized ketamine formed during the titration process remains soluble in solution, a complexing or emulsifying agent must be added. One example of a complexing agent is SBE-β-CD. This is in contrast to using a complexing agent such as Captisol, since each Captisol molecule has, on average, 6-7 ionizable sulfonic acid side chains (actual average DS = 6.5). Based on this, each mole of Captisol contributes 8 osmoles to the solution (1 from the Captisol molecule and 1 NaCl interacting with the sulfonic acid side chains). + ions) because, when a Captisol molecule dissolves in water (or an equivalent solution / matrix), it raises the dissolved particles in solution to 8. According to the Captisol manufacturer, Captisol solutions in the range of 9.5-11.4% are isotonic with respect to blood and extracellular fluid. Higher concentrations (up to 30%) that are commonly used are hyperosmolal. A 20% SBE-β-CD solution (with a degree of substitution similar to Captisol, e.g., 6.5) has been reported to have an osmolality of 785 mOsm / kg. High osmolality is due to the presence of 7 Na per Captisol® molecule. +This is largely due to the presence of ions. A 15% solution of Captisol® containing 100 mg / mL ketamine HCl would have a calculated osmolality of 1396 mOsmol / L (555 mOsmol / L from Captisol® + 841 mOsmol / L from ketamine HCl). However, because Captisol® contains ~7 anionic sulfonic acid side chains that can interact with up to 7 ionized ketamine cation molecules, excess NaCl formed in this formulation can be removed, significantly reducing the number of dissolved solids in solution and therefore the osmolality. The calculated osmolality of such a solution consisting of 15% Captisol® containing 100 mg ketamine, without NaCl, is 490.3 mOsmol / L. This value of 490.2 mOsmol / L is therefore significantly reduced compared to the value of 841 mOsmol / L for the current commercially available ketamine solution 100 mg / mL.

[0351] Many possibilities exist for preparing Captisol-ketamine salt complex formulations that will exhibit reduced tonicity relative to comparable solutions (e.g., with comparable ketamine concentrations containing different acid salt complexes) due to the lack of introduction or removal of NaCl formed in the solution. Strategies that can accomplish this include dialysis (to remove excess salt from the prepared ketamine-Captisol solution) or the use of ion exchange resins (or comparable solid phase matrices for ion exchange, such as silica or zeolite) at various stages of the formulation of the ketamine-Captisol® solution.

[0352] Suggested process for preparing a reduced NaCl formulation of reduced osmolarity Captisol®-ketamine:

[0353] Process A: To reduce the osmolality of a solution, it is necessary to reduce the total number of particles dissolved in the solution. In the case of SBE-β-CD, its acid-base properties can be very advantageously utilized to achieve this goal. For example, these Na+ By replacing the cation with the ionized ketamine cation, the osmolality of the solution was increased to the standard SBE-β-CD-Na + - may be significantly reduced for ketamine HCl mixtures, which contain ketamine HCl and Captisol®-Na + Therefore, salt-free Captisol®-ketamine formulations contain excess and unwanted NaCl due to the acid-base reaction between Captisol®-Na + For a formulation obtained from mixing with ketamine HCl, the osmolality would be significantly reduced.

[0354] Because there are ~7 ionizable sulfonic acid side chains (or equivalently substituted SBE-β-CD) per Captisol molecule, the formulation requires less than a molar equivalent of Captisol (e.g., 1 / 7 or 0.14 molar equivalent) to compensate and dissolve 1 mole of ionized ketamine in solution. Or, stated another way, 1 mole of Captisol® can form a salt with up to 7 moles of ketamine. Because some ketamine can also complex with the Captisol core, adding 1 mole of ketamine may enable solubilization, thus resulting in a ratio of 1 mole of Captisol® to 8 moles of ketamine. Furthermore, complexation of ketamine within the Captisol molecule may further reduce the osmolality of the solution, depending on the strength of the complexing interaction. Assuming a Captisol® to ketamine ratio of approximately 1:7, 128.8 mg of ketamine (5.42 x 10 -4A 128.8 mg / mL solution of ketamine and 154.5 mg / mL of Captisol® would require 154.5 mg of captisolic acid (7.69 e-5 mol). The calculated osmolality of this 128.8 mg / mL solution of ketamine and 154.5 mg / mL of Captisol® would be approximately 619 mOsmol / L. The calculated osmolality of a 100 mg / mL (free base equivalent) solution of ketamine HCl (0.4206 mol / L) is 841 mOsmol / L. Thus, the described Captisol®-ketamine solution, with its higher ketamine concentration, is hypotonic relative to a 100 mg / mL ketamine HCl solution. The optimal osmolality limit for drug products intended for subcutaneous and intramuscular injection has been reported to be approximately 600 to approximately 800 mOsm / kg.

[0355] In one example, acidic (sulfonic or carboxylic acid-containing) ion exchange resins are used to remove Na from solution. + While removing ions, the acidic or protonated form of SBE-β-CD can be generated. Some examples of resins include, but are not limited to, strong cation exchangers (containing sulfonic acid), such as Amberlite IR-120 Plus(H), Amberlite 15, Amberlite 1200(H), DOWEX 50WX2-100, DOWEX 50WX2-200, DOWEX 50WX2-400, DOWEX 50WX4-50, DOWEX 50WX4-100, DOWEX 50WX4-200, DOWEX 50WX4-200R, and DOWEX 50WX4-400. Also included are "weak cation exchangers" (containing carboxylic acids) such as Amberlite CG-50, Amberlite IRC-50, Amberlite IRC-50S, and Amberlite IRP-64.

[0356] H+ and Na in SBE-β-CD molecules +Cation replacement is accomplished by preparing a solution of SBE-β-CD (in water, organic solvent, or mixed-phase aqueous-organic or organic-organic solvent) at a given concentration and passing this solution of SBE-β-CD through a column containing a suitable immobilized ion exchange material in its acidic form. + Na will displace the proton on the immobilized resin to generate SBE-β-CD acid. + is trapped on the immobilized ion exchange material and therefore does not elute from the column. The resulting acidic SBE-β-CD can then be stored (in solution or as a solid phase) and mixed with ketamine free base immediately or at a later date to form the SBE-β-CD-ketamine salt complex. The resulting solution can be adjusted for volume, additional additives, and the desired pH using NaOH or other suitable base, since these contribute only a small amount to the total solution osmolality. This approach may also involve the addition of buffers, cosolvents, and other excipients known in the art to achieve pH and / or solubilization stability.

[0357] Process B: Protonated and thus ionized ketamine molecules, originating from any suitable ketamine salt (which may have the advantages of monovalent and novel divalent and / or trivalent salts and / or formulations, and thus may include a variety of anions to be considered as described elsewhere in this document), can be exchanged for anions and thus bound to a basic anion exchange resin. Such resins include, but are not limited to, basic carboxylic acid or sulfonic acid functionalized resins, and many variations of these forms exist, including, but not limited to, Amberlite IR-120 Plus, Amberlite IRP-69, Dowex 88, and MSC-1. In some preparations, the basic form of the resin can also be prepared from commercially available cation exchange resins using standard ion exchange techniques. This allows for the use of various cationic resins (K+, Ca) that may not be readily commercially available. 2+, Mg 2+ , NH4 + This allows for greater control over the use of salts of desired cations (such as KCl, KBr, NHCl, MgCl, etc.), thereby facilitating the exchange process with protonated ketamine. For example, a solution of a desired cation salt (such as KCl, KBr, NHCl, MgCl, etc.) is passed through a column containing an immobilized ion exchange resin, causing the desired cation to be exchanged on the immobilized resin. This resin can then be used to prepare a ketamine-cation resin by passing a solution of ketamine as any suitable ketamine salt (which may include monovalent and novel divalent and / or trivalent salts, and / or various anions that may have formulation advantages and therefore be considered as described elsewhere in this document) through the column to form a ketamine-cation ion exchange resin. Once the ketamine-loaded cation exchange resin is prepared, a solution of SBE-β-CD in water or other suitable solvent (e.g., but not limited to, organic solvents such as methanol, ethanol, propanol, isopropanol, etc.), or a solvent mixture containing two or more components (aqueous-organic, organic-organic, etc.), can then be passed through a column containing the ketamine-bound ion exchange resin. The resin will bind to the Na ion of the sulfonic acid side chain of SBE-β-CD. + is exchanged with the ionized ketamine cation, thus forming a NaCl-reduced ketamine-SBE-β-CD salt solution. + Thus, the ketamine-SBE-β-CD salt is removed from the solution by trapping it on an ion exchange resin. The resulting solution can be adjusted for volume, additional additives, and the desired pH using NaOH or other suitable base, since these contribute only a small amount to the total solution osmolality. The resulting ketamine-SBE-β-CD salt can also be isolated and stored for later use or for immediate formulation. This approach may also involve the addition of buffers, cosolvents, and other excipients known in the art to achieve pH and / or solubilization stability.

[0358] Process C: Mix Captisol® and ketamine HCl in the appropriate solution to produce ketamine-Captisol® salt, ketamine HCl, Captisol-Na + A solution containing an equilibrium mixture of salt and NaCl can be produced. A process for removing NaCl can shift the equilibrium in favor of the Captisol-ketamine salt complex while removing NaCl. NaCl removal can be achieved by using dialysis. For example, the ketamine-Captisol® solution can be placed in a dialysis bag (or other suitable container) with an appropriate molecular weight cutoff (such as 100 or 200 daltons) to selectively remove NaCl from the solution while leaving ketamine and Captisol® behind.

[0359] Process D: Various filtration-based methods are commonly utilized to selectively remove low molecular weight dissolved salts from solution. Examples of interest for removing NaCl from ketamine-Captisol® formulations include crossflow membrane filtration methods, such as ultrafiltration and nanofiltration.

[0360] Filtration methods using membranes with MWCOs of 200 Daltons or less may be used to selectively remove NaCl from the solution. Ketamine-Captisol mixtures (containing excess NaCl in equilibrium with ketamine and Captisol®) can be formed at target concentrations, and the resulting concentrated solution (or solid) with excess NaCl removed by these filtration processes can be stored or immediately diluted to produce a low-NaCl ketamine-Captisol®-salt solution.

[0361] In addition to Process AD described above, other routes and techniques can be utilized to produce ketamine-Captisol® salt (which may be isolated as a solid or formed in solution at a stock or final target concentration). These include, but are not limited to, modified synthetic routes (producing protonated Captisol®), liquid-liquid extraction techniques, solid-phase extraction techniques, immobilized liquid extraction, chromatographic techniques (ion exchange, partitioning, etc.), crystallization techniques, electrophoresis, electrodialysis, and freeze-desalting.

[0362] Ketamine osmolality:

[0363] Commercially available ketamine preparations, 50 mg / mL and 100 mg / mL ketamine HCl, are hypertonic due to their high osmolality. This partially limits the administration of ketamine solutions via the subcutaneous (SC) route and reduces the ketamine dose that can be comfortably administered. Osmolality is defined as the total amount of dissolved particles in a given mass of solution (a given mass is generally measured in kilograms; osmolality is an equivalent measurement but per volume, typically liters in this case, and is therefore used in calculations because it is easier to calculate. These values rarely differ in practice for aqueous solutions). The calculated osmolality (based on mOsmol / liter) of a 100 mg / mL ketamine (free base equivalent) HCl solution is 841 mOsmol / L. This high osmolality is responsible for the hypertonicity of commercially available ketamine preparations at this concentration. Hypertonicity can contribute to local tissue irritation after SC injection. Thus, the documented irritation of ketamine after SC injection may be due in part to the hypertonicity of existing formulations. Therefore, products for IM or SC injection may be formulated to have an osmolality of approximately 800 mOsmol / kg, with an upper limit of approximately 600 mOsmol / kg. To lower the osmolality of the solute, it is necessary to reduce the total number of particles dissolved in the solution. Because one mole of Captisol® can theoretically form ionic interactions with seven molecules of ketamine (and may complex with additional molecules of ketamine), this formulation dramatically reduces the amount of anion that needs to be dissolved in solution, thus reducing the amount of Captisol-Na. + This formulation reduces osmolality compared to formulations prepared by mixing ketamine HCl with ketamine HCl, and may even reduce osmolality relative to existing ketamine HCl formulations of comparable concentration. The reduced osmolality may translate into better injection site tolerability.

[0364] Assuming a Captisol® to ketamine ratio of approximately 1:7, 128.8 mg of ketamine free base (5.42 x 10 -4mol) is used to neutralize 154.5 mg of captisolic acid (7.69 x 10 -5 mol). The resulting 128.8 mg / mL ketamine, 154.5 mg / mL Captisol® solution has a calculated osmolality of approximately 619 mOsmol / L, which is close to the upper osmolality limit reported in the literature. By comparison, the calculated osmolality of a 100 mg / mL (free base equivalent) ketamine HCl (0.4206 mol / L) solution is 841 mOsmol / L. The proposed formulation strategy increases the amount of deliverable ketamine while lowering the osmolality to an acceptable range. This results in a final solution with an osmolality closer to physiological osmolality (and closer to isotonicity), thus reducing potential pain and irritation at the injection site without compromising deliverable ketamine. This is important because SC pump reservoirs have volumetric capacity limitations for patient convenience and product dynamics. Therefore, it is not feasible to reduce the concentration of ketamine without compromising the available dosage. The volume of drug delivered can also affect pain, irritation, and reaction at the injection site; therefore, maintaining a small injection volume via continuous infusion can further reduce irritation. This product is therefore expected to reduce local tissue irritation and side effects compared to standard formulations and administration routes in several ways, potentially including lower injection volumes, administration as a continuous infusion and / or low-dose bolus (e.g., lower than other current low-dose bolus approaches), and reduced osmolality and pH to more closely approximate the physiological pH of the target delivery tissue.

[0365] Example 7. Reducing tonicity through the use of novel divalent, trivalent, and higher salts of ketamine

[0366] explanation:

[0367] The use of divalent and trivalent ketamine salts can reduce the osmolality of the final solution relative to the use of monovalent salts such as HCl, HBr, etc. For example, ketamine hemifumarate contains 2 moles of ketamine per mole of fumarate, or 0.5 osmoles of fumarate for every 1 osmole of ketamine (1.5 osmole equivalents per salt complex). The total dissolved particles in the solution are therefore reduced relative to ketamine HCl (2 osmole equivalents vs. 1.5 osmole equivalents). Additionally, trivalent salts such as citrate can theoretically form a 1:3 molar ratio (e.g., 1 mole of citric acid can react with up to 3 moles of ketamine, thus requiring 0.33 osmoles of citrate for every osmole of ketamine, potentially reducing the osmole equivalents by 2 in a standard ketamine-HCl solution compared to 1.33 osmoles in a ketamine-citrate solution). While pKa limitations may actually result in less than 3 equivalents of ketamine being solubilized per mole of trivalent acid, the use of such trivalent anion complexes offers functional advantages, such as the ability to solubilize more than 2 molar equivalents of ketamine. Finally, the same argument can be made for SBE-β-CD (e.g., Captisol), which contains an average of about 6 to about 7 sulfonic acid moieties per molecule. Thus, one mole of SBE-β-CD with a degree of sulfonic acid side chain substitution of 7 can be used. BE-β-CD-acid (such as Captisol®-acid) can protonate 7 moles of ketamine, or 0.14 osmoles of Captisol® would be required for each osmole of ketamine (e.g., 1.14 total osmolar equivalents). Other potential polyvalent anions to consider in this aspect of our formulation innovation description include, but are not limited to, sulfate, tartrate, glutarate, succinate, maleate, malonate, and other SBE-β-CDs with various degrees of substitution (although preferably 6-7, such as Captisol®), and various additional anionic cyclodextrins with varying degrees of substitution, such as carboxymethyl-β-CD, succinyl-β-CD, 2-carboxyethyl-β-CD, β-CD-phosphate, beta-β-sulfate, sulfoethyl-β-CD, and SBE-β-CD.

[0368] These described techniques may enable the development of ketamine products with higher concentrations than standard ketamine HCl products without increasing the tonicity of the solution, a property that would reasonably be expected to enhance subcutaneous tissue tolerance. Similarly, comparably concentrated ketamine formulations can be prepared with lower osmolality and, therefore, a more acceptable tonicity range for subcutaneous injection. Such formulations are expected to reduce the osmolality of the ketamine solution relative to equivalent concentrations of standard ketamine HCl formulations, and in some cases, even further compared to lower concentrations of ketamine HCl, thereby enabling larger dose delivery and / or greater comfort to patients. The reduced osmolality, combined with other features of the formulation, such as increased pH (e.g., less acidic solutions), small continuous infusion volumes, and small bolus volumes, is expected to reduce tissue irritation and / or injection site pain and / or noxious irritation, as discussed herein.

[0369] Example 8. Efficacy and Safety Study of Ketamine in Participants with Major Depressive Disorder

[0370] Detailed Description: The purpose of this study is to evaluate the efficacy of ketamine as an antidepressant therapy, where ketamine (administered as a subcutaneous (SC) injection of 100 milligrams (mg) on days 1, 28, and 56 of a 12-week double-blind treatment period) is compared with placebo on depressive symptoms, as measured by the Hamilton Depression Rating Scale (HDRS) total score, based on the change from baseline to 12-week endpoints. The study will be conducted in participants diagnosed with major depressive disorder (MDD), who have a suboptimal response to current standard oral antidepressant therapy, and who have been screened for high-sensitivity C-reactive protein (hsCRP) levels >= 0.300 milligrams per deciliter (mg / dL) (International System of Units (SI) 3.00 mg / L). A cohort of subjects with hsCRP levels < 0.300 mg / dL will also be enrolled, thereby enabling a better understanding of the relationship between CRP changes and clinical change.

[0371] [Table 6-1]

[0372] [Table 6-2]

[0373] [Table 6-3]

[0374] [Table 6-4]

[0375] [Table 6-5]

[0376] [Table 6-6]

[0377] Example 9. Efficacy and Safety Study of Ketamine in Participants with Acute Post-Surgical Pain

[0378] Detailed Description: The purpose of this study is to evaluate the efficacy of ketamine as a therapy for postoperative pain, where ketamine (administered as a subcutaneous (SC) injection of up to 100 milligrams (mg) for up to 10 days during a double-blind treatment period) is compared with opioid standard of care based on the primary endpoint of change from baseline to day 3 in pain symptoms as measured by the Numeric Pain Rating Scale (NPRS) total score in participants diagnosed with acute postoperative pain (POP). Secondary endpoints include PROMIS Pain Intensity Scale, PROMIS Physical Function, Patient Global Impression of Change (PGIC), cumulative opioid use, and cumulative analgesic use.

[0379] [Table 7-1]

[0380] [Table 7-2]

[0381] Example 10. Preparation of ketamine formulation for subcutaneous injection

[0382] Currently available ketamine HCl is known to cause local tissue site irritation when injected subcutaneously. Symptoms may include erythema, pruritus, swelling, and pain, potentially resulting in sterile abscesses. This is thought to be due to the acidic pH (~4), high osmolality, the presence of ketamine itself, or a combination of these factors.

[0383] Ketamine formulations suitable for subcutaneous injection were prepared according to the general protocol shown in Scheme 1. Using the protocol provided herein, stable, highly concentrated ketamine solutions were prepared with near-physiological osmolality (~300 mOsm / kg) and pH ~5.5. The resulting formulated ketamine is expected to offer numerous advantages over other known formulations, including reduced injection site pain and other symptoms such as erythema, pruritus, and swelling, as well as a reduced likelihood of developing sterile abscesses.

[0384] [ka] Scheme 1

[0385] Experimental Procedures for Preparation of Bulk Drug Substance (BDS)

[0386] HPLC-grade solvents were used throughout all procedures unless otherwise noted. Materials were obtained from the commercial suppliers indicated and used as received unless otherwise noted. Equivalence points were determined by titration with 0.5 M sodium hydroxide, and data were analyzed on a Prism 8.

[0387] Captisol®: Purchased from Ligand Pharmaceuticals, Inc. (pharmaceutical grade). Water content was verified by Karl Fischer analysis (6.5%). Captisol® is a form of polysulfobutylated β-cyclodextrin sodium, with an average of 6.5 sulfobutyl groups per molecule and an average mW of 2,163.

[0388] Ketamine HCl: Purchased from Spectrum Chemical and used without further purification. Free base ketamine was prepared from the HCl salt using concentrated sodium hydroxide and isolated by vacuum filtration according to the protocol described below.

[0389] Synthesis of Captisol® Acid: Amberlite IR120 Hydrogen [Sigma-Aldrich (06428-1KG, Lot #BCBZ3814)] resin (198 g, 4.4 meq / g, 20 equivalents) was soaked in HPLC-grade water (400 mL) for 5 minutes and packed into a column (40 mm diameter). The resin was washed with two column volumes of HPLC-grade water and thoroughly dried by applying compressed air for 10 minutes before the sample was applied. A 15% Captisol® solution (90 mL) was applied to the column and allowed to flow by gravity into an Erlenmeyer flask. Once gravity flow ceased, the remaining volume was eluted using compressed air for 10 minutes. The eluate was frozen at -20°C, lyophilized, and further dried under high vacuum (<0.01 mmHg) for 3 hours. Every hour, the solid was removed from the vacuum, crushed, and then placed back under vacuum. The final moisture content of the solid (5.80%) was determined by Karl Fischer titration. The resulting white, free-flowing, glossy solid (5.6 g) was stored at -20°C in a foil-wrapped scintillation vial.

[0390] [ka]

[0391] Ketamine free base: Ketamine hydrochloride (3.0 g, 10.9 mmol) was dissolved in dH2O (100 mL). 2 M NaOH was added with stirring until a cloudy white precipitate formed. Excess base was added so that the added base did not cause further precipitation. After standing for 20 minutes, the precipitate was collected by gravity filtration, washed with 300 mL of HPLC-grade water, and dried under vacuum. The recovered yield of precipitated free base was 2.0 g. Purity was confirmed by HPLC, and water content by Karl Fischer analysis. Identity was determined by NMR and GC-MS.

[0392] Dissolution of S-ketamine from racemic ketamine free base using tartaric acid. R,S-Ketamine free base (500 mg, 2.10 mmol) was dissolved in acetone (6.1 mL), and L-(+)-tartaric acid (315 mg, 2.10 mmol) was added. dH2O (400 μL) was added, and the mixture was heated to a boil. The solution was cooled to room temperature and then to 4 °C, where it crystallized into long, white crystalline needles. The solid was collected (400 mg) and recrystallized once from acetone:water (8:1) at room temperature to form needle-like crystals (crop 1 = 270 mg). Specific rotation α = +74.47 (water, 25 °C). Literature α = +68.9 (water). S-ketamine tartrate was dissolved in dH2O and basified with excess 2 M NaOH to form a white precipitate. The solid was collected by filtration, washed with HPLC-grade water, and dried in vacuo to give S-ketamine free base (100 mg, 0.42 mmol) as a white fluffy solid.

[0393] Synthesis of ketamine-Captisol® drug substance BB105 (96 mg / mL ketamine). Captisol® acid (698 mg, water corrected 753 mg, for a 14% w / v final concentration) was dissolved in HPLC-grade water (4 mL) in a test tube using a Teflon stir bar. The solution was stirred vigorously, and racemic ketamine free base (480 mg) was added via a spatula in ~20-40 mg portions, allowing each portion to dissolve completely before adding the next. The solids were shaken as needed to facilitate dissolution. Once addition was complete, benzethonium chloride (5 mg, final concentration 0.1%) was added, followed by 2 M sodium hydroxide in small portions until the pH rose to 5.5 (initial starting pH 1.39). A total of 146 μL was required. Once complete, the solution was carefully transferred to a volumetric flask and brought to a volume of 5 mL. The solution was syringe filtered through a 0.45 μM nylon filter, stored in a test tube under ambient air, and wrapped in aluminum foil. A portion of the volume was lyophilized to produce a white tablet solid, which was crushed into a stable white powder (ket-cap). The resulting ket-cap powder did not visibly discolor or deliquesce, even after standing on a lab bench under ambient conditions for several weeks. The powder was easily reconstituted with water. Osmolality readings were taken immediately after preparation (average 465 mOsm / kg vs. 293 mOsm / kg for control 0.9% saline).

[0394] Synthesis of ketamine-Captisol® drug substance BB106 (70 mg / mL ketamine). Captisolic acid (5.20% moisture, 10.0 g active, 10.066 g moisture corrected, for a final 10% w / v) was dissolved in HPLC water (7.0 mL) in a test tube with a Teflon stir bar. The solution was stirred using a magnetic stir plate, and racemic ketamine free base (700 mg) was carefully added portionwise (~50-70 mg portions) via a spatula, shaking as needed to promote complete dissolution. Once the mixture was homogenous, the next portion was added one at a time. After ketamine addition, benzethonium chloride (10.0 mg, for a final concentration of 0.1%) was added, and the solution was titrated with small portions of 2 M NaOH (163 μL, final) to reach a target pH of 5.5 (final pH 5.51). The solution was then carefully transferred and diluted to a final volume of 10 mL in a volumetric flask and pH (pH 5.51). The solution was filtered through a 0.22 μM nylon sterile filter and stored in a sealed vial at room temperature in the dark (foil). Osmolality readings were taken immediately after preparation (average 299 mOsm / kg vs. 287.6 mOsm / kg for control 0.9% saline).

[0395] Preparation of S-ketamine-captisol drug substance BB107 (70 mg / mL S-ketamine). Captisolic acid (5.20% moisture, 100 mg active, 106.2 mg moisture corrected for a final 10% w / v) was dissolved in 0.75 mL of HPLC water in a test tube with a stir bar. The solution was stirred, and S-ketamine free base (70.1 mg) was added portionwise (~50-70 mg portions) via a spatula while shaking. Once the mixture was homogenous, the next portion was added. After the ketamine addition, a solution of benzethonium chloride (10 mg / mL, 100 μL, 1.0 mg, 0.1%) was added, and the solution was titrated with portions of 2 M NaOH (15 μL, final) to reach a pH of 5.5 (final pH 5.59). The complex was diluted to 1.0 mL and an osmolality reading was taken (307.6 mOsm / kg average vs. 293.3 mOsm / kg for 0.9% saline). The solution was sealed, covered with foil, and stored at room temperature.

[0396] One benefit of the above-described ketamine formulation process is the resulting osmolality. A summary of the final properties of the formulations prepared above is provided in Table 3 below. Prepared in this manner, BDS solution BB105 had an osmolality of ∼440 mOsmol / kg. The solution's osmolality was then further reduced by using a target concentration of 70 mg / mL instead of 96 mg / mL. This provides an isotonic solution that corresponds to 0.9% isotonic saline and closely matches the salt content of its intended use, i.e., human tissue, which has an osmolality of approximately ∼290 mOsm / kg. Thus, BB105 and BB106 offer improved pH and osmolality relative to standard ketamine HCl products of comparable strength and potency. Furthermore, the osmolality of the BB105 and BB106 formulations made by the methods provided herein is 465 and 299, respectively, dramatically lower than the conventional combination of ketamine HCl and Captisol®, which is 1252. Indeed, achieving an osmolality that is one-third to one-quarter that of the conventional combination of ketamine and Captisol® would meaningfully improve clinical utility and safety.

[0397] [Table 8]

[0398] Furthermore, the more neutral pH (pH ∼5.5) of formulations BB105, BB106, and BB107, compared to solution ketamine HCl itself (pH ∼3.6), indicates that the formulations of the present invention are better suited to maintaining non-ionized ketamine in solution. While ketamine HCl solutions are known to exhibit precipitation at high pHs around 5.5, the formulations of the present invention exhibit no precipitation at all. Because ketamine's pKa is ∼7.5, the stability of the formulations of the present invention at a pH of 5.5 indicates that approximately 1% of the non-ionized ketamine remains soluble.

[0399] The ketamine formulations provided herein have also been observed to be stable over significant periods of time. Visual inspection revealed no visible precipitation of BB105 or BB106 after >4 months of storage. No degradation of ketamine was observed by HPLC. Thus, the formulations provided herein demonstrate greater stability and retention of ketamine in solutions at higher pH compared to standard ketamine or ketamine HCl of comparable concentrations titrated to comparable pHs.

[0400] Example 11. Safety and Tolerability Study of Subcutaneous Ketamine Formulations in Yorkshire Pigs

[0401] Objective: The purpose of this study was to compare the visual and microscopic effects of two different formulations of ketamine—commercially available ketamine HCl and BB106—after a single subcutaneous (SC) injection into porcine skin tissue.

[0402] Description: Currently available ketamine HCl is known to cause local tissue site irritation when injected subcutaneously. Symptoms may include erythema, pruritus, swelling, and pain, and may result in sterile abscesses. This is thought to be due to the acidic pH (~4), high osmolality, the presence of ketamine itself, or a combination of these factors. BB106 is designed to partially reduce injection site side effects.

[0403] Yorkshire pigs have a skin histology that is very similar to human skin, and this breed is often used in animal testing to predict human skin.

[0404] Animals: The test population consists of Yorkshire pigs weighing approximately 30-40 kg. The animals are not fasted prior to testing.

[0405] The formulations used in this study are provided in Table 4.

[0406] [Table 9]

[0407] Test Device: The test ketamine formulation will be delivered using an infusion device (e.g., a Valeritas V-Go® 40 pump). The infusion device will deliver at a basal infusion rate of 0.01667 mL / hr. The infusion device will be filled with the test article by laboratory personnel on the day of administration prior to dosing, according to instructions provided by the manufacturer. The dosing schedule used in this study is provided in Table 5.

[0408] [Table 10]

[0409] protocol:

[0410] Six pigs are each administered two different ketamine preparations at two different locations. Four doses are administered using 70 mg / mL USP ketamine, with two doses at 72 and 120 hours, four doses using 100 mg / mL USP ketamine, with two doses at 72 and 120 hours, and four doses using BB106, with two additional doses at 72 and 168 hours. Three pumps are run at a baseline rate of 0.01667 ml / hr for 72 hours. After 72 hours, the needle is retracted by an automatic button on the pump to terminate the infusion. The pumps are then removed, visually inspected, and skin biopsies are taken at each infusion site. After an additional 48 hours, or 120 hours after the start of infusion, excisional skin biopsies are taken at each infusion site. At the same starting time, the three pumps will dispense at a baseline rate of 0.01667 ml / hr for 120 hours. At 120 hours post-infusion, the needles of these devices will be retracted, the pumps removed, a visual inspection performed, and a skin tissue biopsy performed at each injection site. Field personnel will ensure adequate spatial separation from other injection / biopsy sites.

[0411] The infusion pump's baseline flow rate is 0.01667 mL / hr. This flow rate is maintained for the entire treatment period without intervention by the field personnel, except for daily refills of the device reservoir. No bolus infusions are administered by the field personnel.

[0412] The injection device is filled with 0.7 mL of test article. This volume nearly completely fills the device reservoir, which is 0.76 mL. The device is refilled daily to ensure continuous administration. The device is adhered to the pig's upper flank by removing the adhesive backing cover according to treatment location assignment, ensuring spatial separation from other injection / biopsy sites.

[0413] At the end of the administration period and after device removal, field personnel will perform a visual assessment of the injection site and record their observations. Observations should focus on the injection site and adjacent skin tissue. Visual inspection will include, but is not limited to, an assessment of swelling or erythema using qualitative descriptions such as mild / moderate / severe, and measurements of the length and width (mm) of any tissue impaction from the injection site. Digital photographs will be taken at each visual observation.

[0414] Upon device removal at 72 and 120 hours after initiation of dosing, field personnel will collect a 2.5 cm x 2.5 cm square biopsy after removal of the infusion device and visual inspection. The depth of the excision should be approximately 1.5-2.0 cm, down to the first layer of muscle tissue. The biopsy will include the injection site of the actual needle insertion.

[0415] After collection, biopsy samples are prepared according to the following protocol: Place specimens in 10% neutral buffered formalin to protect them from freezing (ensure proper insulation during transport if these are being transported to areas of the country where freezing may be a concern). Place the skin specimen on a cardboard piece and allow it to sit for a few minutes before fixative submersion in formalin (it will stick to the cardboard, helping to maintain spatial orientation). Field personnel must ensure that the specimen is fully submerged in formalin (either by fully submerging the cardboard piece or by placing gauze or paper towels over the specimen to aid in ensuring submersion). Ensure that the ratio of tissue volume to formalin volume is at least 10:1. If multiple biopsy sites are being taken, it is recommended to use separate containers for each biopsy (i.e., common biopsy containers containing formalin) and ensure that each is clearly labeled.

[0416] Pathology: After sample preparation, the following assessments are made and findings recorded: spongiosis; superficial and / or deep perivascular inflammation; perifollicular or (more broadly including follicles and sweat glands) periadnexal inflammation; infiltrating inflammatory cell types, e.g., neutrophils, eosinophils, lymphocytes, histiocytes, plasma cells; dermal edema; interface changes; vasculitis, panniculitis, necrosis of epidermal, adnexal structures, or fat; additional findings may be recorded and / or graded at the pathologist's discretion. A standard ordinal grading scale (0-4) is used, where 0 = absent and 4 = marked.

[0417] Hypothesis: The BB106 formulation is expected to demonstrate a reduced incidence and / or severity of signs of injection site injury compared to the ketamine HCl formulation. Specifically, compared to the ketamine HCl formulation, we expect a reduced incidence or severity of epidermal necrosis and / or edema, eosinophil and / or perivascular cell infiltration into the dermis, inflammation, necrosis, and / or hemorrhage of subcutaneous tissue, and / or skeletal muscle necrosis or inflammation near the injection site.

[0418] Example 12. Suggested administration conditions for administration of subcutaneous ketamine formulations

[0419] The subcutaneous ketamine formulations provided herein can be used in a variety of dosage strengths for the treatment of various indications. The following are non-limiting examples of potential dosing schedules for the different strengths of ketamine formulations provided herein for specific indications / uses:

[0420] The ketamine formulations listed in the following administration schedules are administered using an infusion device capable of delivering the formulation at the indicated flow rate and, if necessary, a specified bolus amount. For each administration schedule, the number of bolus additions of ketamine formulation that can be delivered to the patient per hour is indicated by the "Bolus Options / Hour" field, typically 2-3 bolus options per hour. The "Initial Bolus" refers to the amount of ketamine formulation delivered at the beginning of the administration schedule. Each administration schedule includes both a "low" and a "high" schedule, which may be selected or modified by a healthcare professional. Furthermore, the administration schedules provided below are intended to be delivered and followed for the indicated period, typically 4-24 hours.

[0421] The indications specified in the following dosing schedules are merely suggestive, and the dosing schedules are not limited to those indications. The "postoperative pain dosing profile" refers to the administration of ketamine after a medical procedure (e.g., a surgical procedure) to relieve pain during the short- to medium-term recovery period, although other indications may conform to the same or similar dosing profile. The "battlefield pain dosing profile" refers to the administration of ketamine after a traumatic injury (e.g., a battlefield wound) to relieve a subject's pain for a relatively short period of time, although the dosing schedules provided below may be used for other indications.

[0422] Formulations BB105, BB106, and BB107 refer to the formulations described in Example 10 above. The concentrations of ketamine and Captisol® in each formulation and the pH of the formulations are provided below in Table 6. All formulations additionally have 0.1% benzethonium chloride as a preservative.

[0423] [Table 11]

[0424] Table 7 below provides an exemplary post-operative pain dosing profile using the BB106 subcutaneous ketamine formulation over a 24 hour period at both low and high dose strengths.

[0425] [Table 12]

[0426] Table 8 below provides an exemplary post-operative pain dosing profile using the BB106 subcutaneous ketamine formulation over an 18 hour period at both low and high dose strengths.

[0427] [Table 13]

[0428] Table 9 below provides an exemplary post-operative pain dosing profile using the BB105 subcutaneous ketamine formulation over a 24 hour period at both low and high dose strengths.

[0429] [Table 14]

[0430] Table 10 below provides an exemplary post-operative pain dosing profile using the BB105 subcutaneous ketamine formulation over an 18 hour period at both low and high dose strengths.

[0431] [Table 15]

[0432] Table 11 below provides an exemplary battlefield pain dosing profile using the BB106 subcutaneous ketamine formulation over a 4 hour period at both low and high dose strengths.

[0433] [Table 16]

[0434] Table 12 below provides an exemplary battlefield pain dosing profile using the BB106 subcutaneous ketamine formulation over an 8 hour period at both low and high dose strengths.

[0435] [Table 17]

[0436] Table 13 below provides an exemplary battlefield pain dosing profile using the BB107 subcutaneous ketamine formulation over a 4 hour period at both low and high dose strengths.

[0437] [Table 18]

[0438] Table 14 below provides an exemplary battlefield pain dosing profile using the BB107 subcutaneous ketamine formulation over an 8 hour period at both low and high dose strengths.

[0439] [Table 19]

[0440] Table 15 below provides an exemplary battlefield pain dosing profile using the BB107 subcutaneous ketamine formulation over a 24 hour period at both low and high dose strengths.

[0441] [Table 20]

[0442] Table 16 below provides an exemplary battlefield pain dosing profile using the BB107 subcutaneous ketamine formulation over an 18 hour period at both low and high dose strengths.

[0443] [Table 21]

[0444] Although the present disclosure has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the disclosure. Accordingly, the disclosure is limited only by the following claims.

Claims

1. A pharmaceutical composition, the pharmaceutical composition comprising: (i) Structural formula (I) 【Chemistry 1】 or an enantiomer, a mixture of enantiomers or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and (ii) at least one pharmaceutically acceptable excipient, and (iii) sulfobutylether-beta-cyclodextrin (SBEBCD) containing a plurality of acidic functional groups, at least two of the plurality of acidic functional groups being deprotonated counterions to the protonated forms of a plurality of the compounds of structural formula (I); the pharmaceutical composition has, in solution, a reduced osmolality compared to a composition comprising a salt of SBEBCD and a salt of the compound of structural formula (I); A pharmaceutical composition wherein the molar ratio of SBEBCD to the compound of formula (I) is from about 1:2 to about 1:

10.

2. The pharmaceutical composition described in claim 1, wherein the pharmaceutical composition is in a form for administration or administration by subcutaneous injection.

3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a molar ratio of SBEBCD to the compound of formula (I) of from about 1:4 to about 1:

10.

4. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a molar ratio of SBEBCD to the compound of formula (I) of from about 1:4 to about 1:

8.

5. A pharmaceutical composition described in any one of claims 1 to 4, wherein the pharmaceutical composition further comprises a base, a buffer solution, or a combination thereof.

6. A pharmaceutical composition described in any one of claims 1 to 5, wherein the pharmaceutical composition further comprises an emulsifier, a surfactant, a solubilizer, a cosolvent, or a combination thereof.

7. The compound of formula (I) is represented by the structural formula (IA) 【Chemistry 2】 or an enantiomer, a mixture of enantiomers or an isotopic variant thereof, or a solvate or hydrate thereof, During the ceremony, The pharmaceutical composition of claim 1, wherein X − is a counter ion.

8. The pharmaceutical composition of claim 7, wherein the compound of structural formula (IA), or its enantiomer, mixture of enantiomers or isotopic variant, or its solvate or hydrate, is partially ionized or fully ionized.

9. The pharmaceutical composition of claim 7, wherein the SBEBCD is present in an amount of about 50 mg / mL to about 600 mg / mL.

10. A pharmaceutical composition described in any one of claims 7 to 9, wherein the pharmaceutical composition further comprises a base, a buffer solution, or a combination thereof.

11. A pharmaceutical composition described in any one of claims 7 to 10, wherein the pharmaceutical composition further comprises an emulsifier, a surfactant, a solubilizer, an emulsifier, a co-solvent, or a combination thereof.

12. A pharmaceutical composition described in any one of claims 1 to 11, wherein the pharmaceutical composition has a pH of about 4.5 to about 6.

5.

13. A pharmaceutical composition described in any one of claims 1 to 12, wherein the pharmaceutical composition has a weight molar osmolality of from about 250 mOsm / kg to about 850 mOsm / kg.

14. A pharmaceutical composition according to any one of claims 1 to 13, wherein the compound of formula (I) or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate or hydrate, has a concentration of from about 20 mg / mL to about 150 mg / mL.

15. A pharmaceutical composition according to any one of claims 1 to 14, wherein the compound of formula (I) or its enantiomer, mixture of enantiomers, or isotopic variant, or its solvate or hydrate, has a concentration of from about 50 mg / mL to about 105 mg / mL.

16. A pharmaceutical composition described in any one of claims 1 to 15, wherein the pharmaceutical composition further contains a preservative.

17. The pharmaceutical composition of claim 16, wherein the preservative is benzethonium chloride.

18. The pharmaceutical composition of claim 17, wherein the benzethonium chloride is present in an amount from about 0.1 mg / mL to about 0.5 mg / mL.

19. Use of a pharmaceutical composition in the manufacture of a medicament for treating pain, said pharmaceutical composition comprising: (i) Structural formula (I) 【Transformation 3】 or an enantiomer, a mixture of enantiomers or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; (ii) a sulfobutylether-beta-cyclodextrin (SBEBCD) containing a plurality of acidic functional groups, at least two of the plurality of acidic functional groups being deprotonated counterions to the protonated forms of a plurality of the compounds of structural formula (I); the pharmaceutical composition has a reduced osmolality compared to a composition comprising a salt of SBEBCD and the salt of the compound of structural formula (I); The pharmaceutical composition has a molar ratio of SBEBCD to the compound of formula (I) of from about 1:2 to about 1:

10.

20. The use described in claim 19, wherein the pain is acute pain or chronic pain.

21. Use of a pharmaceutical composition in the manufacture of a medicament for treating a psychiatric, cognitive, or neurological disorder, said pharmaceutical composition comprising: (i) Structural formula (I) 【Chemistry 4】 or an enantiomer, a mixture of enantiomers or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof; (ii) sulfobutyl-ether-beta-cyclodextrin (SBEBCD) containing a plurality of acidic functional groups, at least two of the plurality of acidic functional groups being deprotonated counterions to the protonated forms of a plurality of the compounds of structural formula (I); the pharmaceutical composition has a reduced osmolality compared to a composition comprising a salt of SBEBCD and the salt of the compound of structural formula (I); The pharmaceutical composition has a molar ratio of SBEBCD to the compound of formula (I) of from about 1:2 to about 1:

10.

22. The use of claim 21, wherein the compound of formula (I) or its enantiomer, mixture of enantiomers or isotopic variant, or a pharmaceutically acceptable salt, solvate or hydrate thereof, is administered by bolus injection or by infusion pump.

23. A method for preparing a pharmaceutical composition, said method comprising: The free acid form of a complexing agent containing at least one acidic functional group and structural formula (I) 【Transformation 5】 or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof, or a solvate or hydrate thereof, wherein said compound of structural formula (I) is in its free base form and said complexing agent containing at least one acidic functional group is sulfobutyl-ether-beta-cyclodextrin (SBEBCD).

24. The method of claim 23, wherein the pharmaceutical composition has a molar ratio of complexing agent to compound of formula (I) of from about 1:4 to about 1:

8.

25. The method described in claim 23 or 24, wherein the pharmaceutical composition has a weight molar osmolality of less than about 500 mOsm / kg.

26. The method of any one of claims 23 to 25, wherein the pharmaceutical composition has a concentration of the compound of formula (I) of at least about 20 mg / mL.

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