Cucurbituril compositions

Abstract

The disclosure provides compositions and method for reducing the concentration of a toxic agent in the body of a patient by administering to the patient a therapeutically effective amount of a composition comprising a cucurbituril compound and an organic amine. The compositions of cucurbituril compounds with organic amines have improved solubility, stability and / or other beneficial properties.

Description

347495.46276CUCURBITURIL COMPOSITIONS

[0001] This invention was made with government support under grant no. U01DA053054 awarded by the National Institute of Health. The government has certain rights in the invention.FIELD

[0002] The present disclosure provides organic amine salts of cucurbituril compounds having improved solubility, stability and / or other beneficial properties. The present disclosure also provides methods and compositions for lowering the amount of a toxic agent in a patient by administering to the patient an effective amount of the cucurbituril composition.BACKGROUND

[0003] Drug overdose, intoxication and addiction are major social issues that affects all aspects of society. An epidemic of opioid use disorders and of fatal overdose due to the illicit use of heroin and fentanyl are a growing concern worldwide. Over 100,000 overdose deaths were reported in the 12-month period ending in April 2021, with the large majority of the overdose deaths due to synthetic opioids, mostly fentanyl and its analogs.(http: / / www.cdc.gov / nchs / nvss / vsrr / drug-overdose-data.htm). Alarmingly, potent fentanyl analogs such as carfentanil, cyclopropyl fentanyl, (±)-cis-3 -methyl fentanyl, and furanyl fentanyl have been used as adulterants in illicit drugs, which have resulted in many fatal overdose cases.

[0004] There is also an urgent need for a safe and rapidly acting reversal agent for methamphetamine. Methamphetamine (meth) is the fastest growing drug of abuse in the U.S., representing over 200,000 annual emergency room (ER) visits, with deaths quadrupling since 2015 (9356 deaths in 2017 alone), yet no current therapeutics are available for treating meth intoxication. Meth induces excessive, rapid, and sustained (serum half-life t% ~10hr) stimulation of the sympathetic nervous system, responsible for a recognizable adrenergic toxi drome consisting of both behavioral (psychomotor agitation) and physiological (tachycardia, hypertension, mydriasis, and diaphoresis) components. Meth intoxication can cause cardiovascular and other complications; 20% of ER visits require hospital admission. The current standard of care for meth intoxication is to treat the symptoms only. A reversal181440027agent for meth that normalizes both the behavioral and physiological components would minimize complications, improve patient outcomes, and reduce mortality.

[0005] Xylazine is increasingly being found in the US illicit drug supply and linked to overdose deaths. There has been an increase in the number of reports, alerts, and advisories from public health agencies indicating that xylazine is being abused in combination with other drugs of abuse, such as fentanyl, cocaine, and heroin, and is causing significant harm. People who use illicit drugs may not be aware of the presence of xylazine. The DEA has seized xylazine and fentanyl mixtures in 48 of 50 states, and the DEA reported that approximately 23% of fentanyl powder and 7% of fentanyl pills seized by the DEA in 2022 contained xylazine.

[0006] Importantly, many drugs of abuse, such as methamphetamine and xylazine, do not respond to available reversal agents like naloxone. There remains a need for methods and compositions for the treatment of patients suffering from drug overdose or drug intoxication.SUMMARY

[0007] The present disclosure provides compositions and methods for addressing these and other circumstances wherein it is desirable to reverse the effect of one or more toxic agents, including but not necessarily limited to drugs of abuse.

[0008] In one aspect, the disclosure provides a method of reducing the concentration of a toxic agent in the body of a patient by administering to the patient a therapeutically effective amount of a composition comprising a cucurbituril compound and an organic amine, particularly as an organic amine salt and / or complex of the cucurbituril. In embodiments, the composition comprises a cucurbituril compound and an amino acid or an amino acid derivative. The toxic agent may be a drug of abuse, such as methamphetamine, cocaine, fentanyl or a fentanyl analog such as carfentanil, xylazine, or combinations thereof. The organic amine may be an aliphatic amine, cyclic amine, aromatic amine, amino sugar, amino acid, amino acid derivative, or combinations thereof. The amino acid may be one or more of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, serine, arginine, cysteine, glutamine, glycine, proline, and tyrosine; and particularly is one or more of arginine, glutamic acid, proline, phenylalanine, histidine, lysine, aspartic acid, and tryptophan, or a combination thereof; and particularly is arginine. In an embodiment, the cucurbituril compound is Compound A and the amino acid is arginine, glutamic acid, proline, aspartic acid,2181440027phenylalanine, histidine, lysine, tryptophan, or a combination thereof. In an embodiment, the cucurbituril compound is Compound A and the amino acid is arginine.

[0009] In embodiments the molar ratio of the cucurbituril compound to the organic amine is from about 2: 1 to about 1 :6, or is from about 1 : 1 to about 1 :4, or is from about 1 :2 to about 1 :4. In further embodiments, the molar ratio of the cucurbituril compound to the amino acid, or amino acid derivative, is from about 2: 1 to about 1 :6, or is from about 1 : 1 to about 1 :4, or is from about 1 :2 to about 1 :4. In embodiments the molar ratio of the cucurbituril compound to the amino acid, or amino acid derivative, is about 1:4. In embodiments, the sequestering agent is the tetra-arginine salt of Compound A.

[0010] In one aspect, the disclosure provides a pharmaceutical dosage form that comprises a cucurbituril compound, an organic amine, and a pharmaceutically acceptable carrier. The cucurbituril compound and the organic amine together may be present in the compositions as an organic amine salt of the cucurbituril compound. In an embodiment, the disclosure provides a pharmaceutical dosage form that comprises a cucurbituril compound, an amino acid or an amino acid derivative, and a pharmaceutically acceptable carrier. The cucurbituril compound and the amino acid together may be present in the compositions as an amino acid salt of the cucurbituril compound.

[0011] In one embodiment, the dosage form is an aqueous solution that is suitable for injection into a patient comprising (i) a cucurbituril compound, (ii) an organic amine (such as an amino acid or an amino acid derivative), (iii) optionally, a buffering agent, and (iv) optionally a tonicity agent. The cucurbituril compound and an organic amine are preferably present in the form of an organic amine salt and / or complex of the cucurbituril compound. The dosage form may be for intramuscular injection (IM) or intravenous injection (IV).

[0012] In another embodiment, the dosage form is a solid for reconstitution comprising (i) a cucurbituril compound, (ii) an organic amine (such as an amino acid or an amino acid derivative), (iii) optionally, a buffering agent, and (iv) optionally a tonicity agent. In another embodiment, the dosage form is an oral dosage form comprising (i) a cucurbituril compound, (ii) an organic amine (such as an amino acid or an amino acid derivative), and (iii) one or more pharmaceutically acceptable carriers. The cucurbituril compound and an organic amine are preferably present in the form of an organic amine salt and / or complex of the cucurbituril compound. The oral dosage form may be a liquid dosage form for oral ingestion.3181440027BRIEF DESCRIPTION OF THE FIGURES

[0013] Figure 1 shows the overlaid IR spectra of Na»Arg»Comp. A (top), Na4 Comp. A (middle), and arginine (bottom). The spectra of Na»Arg»Comp. A has peaks that overlap with justNa4 Comp. A (1050 and 1200 cm-1) and arginine (1600-1700 cm-1), indicating a mixed salt had been made.

[0014] Figure 2 shows the IR spectra of Compound A tetrasodium salt (Fig. 2A) and Compound A tetra-arginine salt (Fig, 2B).

[0015] Figure 3 shows the NMR spectrum of the Compound A tetra-arginine salt with an ethylene carbonate reference standard.

[0016] Figure 4 shows the HLPC charts for the quantification of arginine in Compound A tetra-arginine salt.

[0017] Figure 5 shows the % recovery of unmetabolized methamphetamine in urine after administration of Compound A tetra-arginine salt to rats by IV (Fig. 5 A) and by IM injection (Fig. 5B).

[0018] Figure 6 shows the plasma concentration of Compound A (free acid) over time following administration of Compound A tetra-arginine salt or Compound A tetrasodium salt by IV (Fig. 6A) and by IM injection (Fig. 6B).

[0019] Figure 7 shows the plasma concentration of Compound A (free acid) over time following administration of Compound A tetra-arginine salt by IM injection in dogs.DETAILED DESCRIPTION

[0020] There is an urgent need for therapeutics that facilitate the removal of toxic agents from a patient’s body, particularly in the context of drug abuse and overdose. A new class of drugs, acyclic cucurbiturils, represent a promising technology for lowering the concentration of toxic agents, including drugs of abuse, in a patient suffering from high exposure to the toxic agent, such as drug overdose.

[0021] In one embodiment, the compositions and methods use a cucurbituril compound for reversing intoxication or overdose from methamphetamine, fentanyl, xylazine of combinations thereof. Since methamphetamine intoxication cases often involve a high level of methamphetamine inside the patient, therapeutic doses of the cucurbituril compound may be sufficiently high in order for sufficient reversal of intoxication upon the first administration. Although cucurbituril compounds may have a relatively high limit of solubility, the high therapeutic dose means that increasing the solubility is of interest for4181440027reducing the burden of administration via a decrease in the volume required to achieve a therapeutic dose. Additionally, the cucurbituril compounds may be used in other cases of drug intoxication outside of methamphetamine. In these cases, a potential higher dose may facilitate the cucurbituril compound in sequestering drugs with a lower binding affinity. This capability is of particular interest for cases of polysubstance abuse, where it is highly beneficial to remove each of the drugs of abuse from a patient’s system. In embodiments, the compositions and methods use a cucurbituril for reversing intoxication from a combination of methamphetamine and fentanyl, or a combination of fentanyl and xylazine.

[0022] The inventors have found an enhancement in the solubility of cucurbituril compounds using organic amine ion complexes / salts of the cucurbituril compound, and particularly amino acid ion complexes / salts of the cucurbituril compound. The resulting complex improves the solubility of the cucurbituril compound in two cases: (1) it increases the maximum possible solubility of the cucurbituril in water, and particularly saline, water-for-inj ection, Ringer’s solution, dextrose solution (e.g., D5W), and the like, and / or (2) increases the longevity of a solution (physical stability) of the cucurbituril over time.Additionally, the inclusion of an organic amine guest, and particularly an amino acid guest, in the binding pocket of the cucurbituril may reduce non-specific, off-target binding. For the organic amine complexes with the cucurbituril compound, the organic amine can act both as a counterion and as a guest-host in order to improve solubility and solution stability, and optionally to reduce off-target binding of the cucurbituril.

[0023] The compositions and methods provided in this disclosure use a cucurbituril compound, and particularly Compound A, to facilitate and accelerate the clearance of one or more toxic agents from the body of a patient. The composition comprising the cucurbituril compound is administered to the patient, particularly by injection, and sequesters the toxic agent in the plasma compartment of blood and removes it from the patient’s body. The now ‘inactive’ toxic agent is eliminated from the body by filtration in the kidney. Rapid sequestration and clearance of the toxic agent may rapidly reverse its effects, with the reversal effect starting immediately after administration, to lower the level of toxic agent in the body. Alternatively or additionally, the composition comprising the cucurbituril compound is administered orally to the patient, and sequesters the toxic agent in the gastrointestinal tract, reducing, slowing and / or preventing absorption into the blood, and removes it from the patient’s body.5181440027

[0024] The improved solubility of the organic amine cucurbituril complex facilitates the use of the sequestering agent in intramuscular (IM) injections. Particularly in the case of acute intoxication or overdose of the patient, a responder or other emergency personnel may be unable to readily or easily fit an IV injection into patient. IM administration allows for quick dosing with low risk to the patient and the responder. For improved IM administration, the organic amine cucurbituril complex shows high solubility and stability, to provide a high concentration, in a low volume dose. Additionally, for IM administration, the organic amine cucurbituril complex shows good bioavailability (relative to IV) and rapid appearance in the plasma compartment. The IM administration of the organic amine cucurbituril complex shows good tolerability at the injection site and low local toxicity. Higher concentration for the IM administration (as compared to IV) due to the improved solubility is particularly beneficial for reducing the burden of administration of IM injection by a decrease in the volume per injection for the effective dose.

[0025] The terms “subject,” “host,” “patient,” and “individual” are used interchangeably herein to refer to any mammalian subject for whom the therapy provided herein is desired, particularly humans.

[0026] As used herein, the term “soluble” refers to the ability of the cucurbituril compound to form a homogenous aqueous solution.

[0027] As used herein, the term “stable” refers to the ability of the cucurbituril compound to be maintained as a homogenous aqueous solution, for example, without precipitation or the appearance of solids.Toxic agents

[0028] The compositions and methods provided in this disclosure are particularly suitable for the treatment of patients suffering from exposure to, ingestion of, or administration (including self-administration) of a toxic agent, by lowering the amount of the toxic agent by sequestration by the cucurbituril compound.

[0029] A toxic agent refers to any agent which may be present in the body of a patient that is capable of causing the illness or death of the patient when present at sufficient levels. Toxic agents may include some medicines that are helpful in low doses, but are harmful or poisonous in larger amounts. In some embodiments, the toxic agent is a pharmaceutical drug or is a drug of abuse.6181440027

[0030] As used herein, the term “drug of abuse” is intended to mean any substance the excessive consumption or administration of which can result in intoxication, overdose, or a diagnosis of substance dependence or substance abuse (e.g., substance use disorder). Drugs of abuse include, without limitation, psychoactive drugs such as amphetamine-type stimulants, barbiturates, opioids, benzodiazepines, and psychedelics. Drug of abuse include, but are not limited to, cocaine, amphetamines, methamphetamine, methylphenidate, xylazine, heroin, codeine, hydrocodone, oxycodone, marijuana(cannabis), methadone, opioids, fentanyl, carfentenil, fentanyl analogs, ayahuasca, CNS depressants, N,N-dimethyltryptamine (DMT), gamma-hydroxybutyrate (GHB), hallucinogens, inhalants, ketamine, khat, kratom, lysergic acid diethylamide (LSD), MDMA (molly / ecstasy), mescaline (peyote), dextromethorphan, loperamide, PCP, psilocybin, rohypnol, salvia, synthetic cannabinoids, synthetic cathinones (bath salts), mephedrone, nicotine, extroamphetamine, dexmethylphenidate, or any combination thereof. Furthermore, drugs of abuse can include, but are not necessarily limited to those drugs listed by the National Institute of Health (NIH) and the National Institute of Drug Abuse (NIDA).

[0031] In embodiments, the drug of abuse may be a stimulant phenethylamine, including amphetamine, methamphetamine, methylphenidate, cathinone, methcathinone, and the like. In other embodiments, the drug of abuse may be an opioid, including fentanyl or a fentanyl analog such as carfentanil. In further embodiments, the drug of abuse comprises a combination of a stimulant phenethylamine, such as methamphetamine, and fentanyl or a fentanyl analog. In further embodiments, the drug of abuse comprises a combination of fentanyl, or a fentanyl analog such as carfentanil, and xylazine, or a combination of methamphetamine and xylazine, or a combination of fentanyl, methamphetamine and xylazine.

[0032] The term “fentanyl analog” refers to a molecule that has been designed to mimic the pharmacological effects of fentanyl. Exemplary fentanyl analogs include 3 -allylfentanyl, alfentanil, acrylfentanyl, acetylfentanyl, brifentanil, butyrfentanyl, 2,2'-difluorofentanyl, carfentanil, crotonylfentanyl, cyclopentylfentanyl, cyclopropyl fentanyl, (±)-cis-3 -methyl fentanyl, furanyl fentanyl, 3-fluorofentanyl, 3-furanylfentanyl, 3 -methylbutyrfentanyl, 3-methylfentanyl, 3-methylfuranylfentanyl, 3 -methylthiofentanyl, 3-phenylpropanoylfentanyl, 4-fluorobutyrfentanyl, 4-chloroisobutyrylfentanyl, 4-fluoroisobutyrfentanyl, 4-fluorofentanyl, para-fluorofuranylfentanyl, para-chlorofuranylfentanyl, ortho-methylfuranylfentanyl, 4-phenylfentanyl, lofentanil, 4-methoxybutyrfentanyl, para-hydroxy-butyrylfentanyl, 4-7181440027methylphenethylacetylfentanyl, a-methylacetylfentanyl, a-methylbutyrfentanyl, a-methylbutyrfentanyl, a-methylthiofentanyl, benzodioxolefentanyl, benzoylfentanyl, butyrfentanyl, isobutyrylfentanyl, isofentanyl, methoxyacetylfentanyl, sufentanil, paratolylfentanyl, 3 -methylfentanyl, a-methylfentanyl, mefentanyl, mirfentanil, remifentanil, phenaridine, ohmefentanyl, trefentanil, and the like.

[0033] Alpha-2 adrenergic agonists may mimic the effects of the hormone norepinephrine. Examples of alpha-2 adrenergic agonists include xylazine, guanabenz, guanfacine, and clonidine. In embodiments, the alpha-2 adrenergic agonist is xylazine. Xylazine is often used in combination with illicit substances, knowingly or unknowingly, but may also be abused alone. Additionally, published case reports have demonstrated that xylazine has been used in drug-facilitated crimes to induce sleep. Fatalities involving xylazine have been reported. The known doses of xylazine that produce toxicity and fatality in humans vary from 40 to 2400 mg. However, most overdose deaths linked to xylazine involved additional substances such as: fentanyl, heroin, benzodiazepines, alcohol, gabapentin, methadone, prescription opioids, and cocaine. Xylazine and fentanyl drug mixtures place users at a higher risk of suffering a fatal drug poisoning. Because xylazine is not an opioid, naloxone does not reverse its effects.Cucurbituril compound

[0034] In the compositions and methods provided herein, one or more cucurbituril compounds is administering to the patient in an amount sufficient to reduce the level of the toxic agent in the patient’s body. In some embodiments, the cucurbituril compounds may simultaneously lower the level of multiple toxic agents present in the patient’s body.

[0035] Cucurbiturils are a class of macrocyclic compounds based on oligomers of glycoluril, its analogues and derivatives. Cucurbiturils can be used to form complexes with other molecules and are useful as sequestering agents. This property makes cucurbiturils an attractive candidate for the entrapment and removal of chemical agents.

[0036] In embodiments of the compositions and methods provided in this disclosure, the cucurbituril compound has a structure of formula I:8181440027or a pharmaceutically acceptable salt thereof, wherein:each R1Aand R1Dis independently selected from hydrogen, halogen, -OH, Ci-Ce alkyl, 2 to 6 membered heteroalkyl, C3-C6 cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-L-S(O)viX1, -O-L-CO2X1, and -O-L-POviX1;each R1Band R1Cis independently selected from hydrogen, halogen, -OH, Ci-Ce alkyl, 2 to 6 membered heteroalkyl, C3-C6 cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-L-S(O)viX1, -O-L-CO2X1, and -O-L-POviX1; or additionally or alternatively, two R1AR1B, R1Cand R1Dattached on the same phenyl ring at adjacent positions, together with atoms to which they are attached, are joined to form a fused C6-C12 aryl, 5 to 12 membered heteroaryl, or 5 to 7 membered heterocycle, which are optionally substituted with 1 to 3 substituents independently selected halogen, -OH, -NH2, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl;each L is independently selected from a single bond, Ci to Ce alkylene, or C2 to Ce alkenylene;each R3Aand R3Bis independently selected from hydrogen, halogen, -OH, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl;each R4Aand R4Bis independently selected from hydrogen, halogen, -OH, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl;each vl is independently selected from 2 or 3; andeach X1is independently selected from selected from H, -OH, Ci-Ce alkyl, alkali metal cation, quaternary ammonium cation, or an organic amine cation; and preferably at least one X1is an organic amine cation, and particularly an amino acid cation.

[0037] In embodiments, R1Bis hydrogen, halogen, -OH, Ci-Ce alkyl, 2 to 6 membered heteroalkyl, C3-C6 cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl. In embodiments, R1Bis hydrogen, halogen, -OH, or Ci-Ce alkyl, and particularly R1Bis hydrogen or halogen.9181440027

[0038] In embodiments, R1Cis hydrogen, halogen, -OH, Ci-Ce alkyl, 2 to 6 membered heteroalkyl, C3-C6 cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl. In embodiments, R1Cis hydrogen, halogen, -OH or Ci-Ce alkyl, and particularly, R1Cis hydrogen or halogen.

[0039] In embodiments, R1Band R1Care hydrogen.

[0040] Additionally or alternatively, R1AandR1B, attached on the same phenyl ring, together with atoms attached thereto, may be joined to form a C6-C12 aryl, or 5 to 12 membered heteroaryl. In embodiments, R1AandR1B, attached on the same phenyl ring, together with atoms attached thereto, join to form phenyl. In embodiments, R1Aand R1B, attached on the same phenyl ring, together with atoms attached thereto, join to form naphthyl. In embodiments, R1AandR1B, attached on the same phenyl ring, together with atoms attached thereto, join to form pyridyl.

[0041] In embodiments, R1BandRlc, attached on the same phenyl ring, together with atoms attached thereto, join to form C6-C12 aryl, or 5 to 12 membered heteroaryl. In embodiments, R1Band R1C, attached on the same phenyl ring, together with atoms attached thereto, join to form phenyl. In embodiments, R1BandRlc, attached on the same phenyl ring, together with atoms attached thereto, join to form naphthyl. In embodiments, R1Band R1C, attached on the same phenyl ring, together with atoms attached thereto, join to form pyridyl.

[0042] In embodiments, RlcandR1D, attached on the same phenyl ring, together with atoms attached thereto, join to form C6-C12 aryl, or 5 to 12 membered heteroaryl. In embodiments, R1Cand R1D, attached on the same phenyl ring, together with atoms attached thereto, join to form phenyl. In embodiments, R1CandR1D, attached on the same phenyl ring, together with atoms attached thereto, join to form naphthyl. In embodiments, R1Cand R1D, attached on the same phenyl ring, together with atoms attached thereto, join to form pyridyl.

[0043] In embodiments, the C6-C12 aryl or 5 to 12 membered heteroaryl, which are formed by two of R1A, R1B, R1Cand R1Dattached on the same phenyl ring, may be substituted with one or more substituents, e.g., halogen, -OH, -NH2, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

[0044] In embodiments, each R1Aand R1Dare the same and are selected from -O-L-S(O)viXJ, -O-L-CO2X1, and -O-L-POviX1. In further embodiments, each R1Band R1Care H, or adjacent R1Band R1Care taken together to form a substituted or unsubstituted phenyl.10181440027

[0045] In embodiments, each L independently selected from -(CH2)ni-, wherein each nl is independently selected from 0 to 5.

[0046] In embodiments, R3Ais hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R3Ais C1-C3 alkyl, and particularly methyl.

[0047] In embodiments, R3Bis hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R3Bis C1-C3 alkyl, and particularly methyl.

[0048] In embodiments, R3Aand R3Bare both hydrogen. Alternatively, R3Aand R3Bmay both be methyl. In embodiments, one of R3Aand R3Bis hydrogen and the other is methyl.

[0049] In embodiments, R4Ais hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R4Ais C1-C3 alkyl, and particularly methyl. In embodiments, R4Ais H.

[0050] In embodiments, R4Bis hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R4Bis C1-C3 alkyl, and particularly methyl. In embodiments, R4Bis hydrogen.

[0051] In embodiments, each R4Aand R4Bis hydrogen. Alternatively, each R4Aand R4Bmay be methyl. In embodiments, one of R4Aand R4Bis hydrogen and the other is methyl.

[0052] In embodiments, each R3Aand R3Bis independently C1-C3 alkyl and R4Aand R4Bare hydrogen, and particularly, each R3Aand R3Bare methyl and each R4Aand R4Bare hydrogen.

[0053] In embodiments, each X1is independently selected from selected from H, -OH, alkali metal cation, quaternary ammonium cation, or an organic amine cation; and preferably at least one X1is an organic amine cation; or two X1are organic amine cations; or three X1are organic amine cations; or each X1is an organic amine cation; and more preferably at least one X1is an amino acid cation; or two X1are amino acid cations; or three X1are amino acid cations; or each X1is an amino acid cation.

[0054] In another aspect, the cucurbituril compounds used in the compositions and methods of this disclosure have the structure of formula (I-a):11181440027or a pharmaceutically acceptable salt thereof. R1A, R1D, R3A, R3B, R4A, and R4Bare as described herein.

[0055] In embodiments, R3Ais hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R3Ais C1-C3 alkyl, and particularly methyl.

[0056] In embodiments, R3Bis hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R3Bis C1-C3 alkyl, and particularly methyl.

[0057] In embodiments, R3Aand R3Bare both hydrogen. Alternatively, R3Aand R3Bmay both be methyl. In embodiments, one of R3Aand R3Bis hydrogen and the other is methyl.

[0058] In embodiments, R4Ais hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R4Ais C1-C3 alkyl, and particularly methyl. In embodiments, R4Ais H.

[0059] In embodiments, R4Bis hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R4Bis C1-C3 alkyl, and particularly methyl. In embodiments, R4Bis hydrogen.

[0060] In embodiments, each R4Aand R4Bis hydrogen. Alternatively, each R4Aand R4Bmay be methyl. In embodiments, one of R4Aand R4Bis hydrogen and the other is methyl.

[0061] In embodiments, each R3Aand R3Bis independently C1-C3 alkyl and R4Aand R4Bare hydrogen, and particularly, each R3Aand R3Bare methyl and each R4Aand R4Bare hydrogen.

[0062] In embodiments, each R1Aand R1Dis neutral. In embodiments, each R1Aand R1Dis in an ionic salt form.

[0063] In embodiments, each R1Aand R1Dare the same or different and are selected from -O-L-S(O)viXJ, -O-L-CO2X1, and -O-L-POviX1.

[0064] In embodiments, each L independently selected from -(CH2)ni-, wherein each nl is independently selected from 0 to 5.

[0065] In embodiments, R1Ais -O-(CH2)niS(O)viX1. In embodiments, R1Ais -O-(CH2)niCO2X1. In embodiments, R1Ais -O-(CH2)niPOviX1. In embodiments, each nl is 0. In embodiments, each nl is 1. In embodiments, each nl is 2. In embodiments, each nl is 3. In embodiments, each nl is 4. In embodiments, each nl is 5. In embodiments, each vl is 2. In embodiments, each vl is 3.

[0066] In embodiments, R1Dis -O-(CH2)niS(O)viX1. In embodiments, R1Dis -O-(CH2)niCO2X1. In embodiments, R1Dis -O-(CH2)niPOviX1. In embodiments, each nl is 0.12181440027In embodiments, each nl is 1. In embodiments, each nl is 2. In embodiments, each nl is 3. In embodiments, each nl is 4. In embodiments, each nl is 5. In embodiments, each vl is 2. In embodiments, each vl is 3.

[0067] In embodiments, R1Aand R1Dattached to the same phenyl ring may be same or different. In embodiments, R1Aand R1Aattached to the different phenyl rings may be same or different. In embodiments, R1Dand R1Dattached to the different phenyl rings may be same or different.

[0068] In embodiments, each R1Aand R1Dattached to the same phenyl ring is independently -O-(CH2)niS(O)viX1. In embodiments, each R1Aand R1Aattached to the different phenyl rings is independently -O-(CH2)niS(O)viX1. In embodiments, each R1Dand R1Dattached to the different phenyl rings is independently -O-(CH2)niS(O)viX1.

[0069] In embodiments, each X1is independently selected from selected from H, -OH, alkali metal cation, quaternary ammonium cation, or an organic amine cation; and preferably at least one X1is an organic amine cation; or two X1are organic amine cations; or three X1are organic amine cations; or each X1is an organic amine cation; and more preferably at least one X1is an amino acid cation; or two X1are amino acid cations; or three X1are amino acid cations; or each X1is an amino acid cation.

[0070] In another aspect, the cucurbituril compounds used in the compositions and methods of this disclosure have the structure of formula (I-b):or a pharmaceutically acceptable salt thereof. R1Aand R1Dare as described herein.

[0071] In embodiments, each R1Aand R1Dis neutral. In embodiments, each R1Aand R1Dis in an ionic salt form.

[0072] In embodiments, each R1Aand R1Dare the same or different and are selected from -O-L-S(O)viXJ, -O-L-CO2X1, and -O-L-POviX1.

[0073] In embodiments, each L is independently selected from -(CH2)ni-, wherein each nl is independently selected from 0 to 5.13181440027

[0074] In embodiments, R1Ais -O-(CH2)niS(O)viX1. In embodiments, R1Ais -O-(CH^niCChX1. In embodiments, R1Ais -O-(CH2)niPOviX1. In embodiments, each nl is 0. In embodiments, each nl is 1. In embodiments, each nl is 2. In embodiments, each nl is 3. In embodiments, each nl is 4. In embodiments, each nl is 5. In embodiments, each vl is 2. In embodiments, each vl is 3.

[0075] In embodiments, R1Dis -O-(CH2)niS(O)viX1. In embodiments, R1Dis -O-(CH2)niCO2X1. In embodiments, R1Dis -O-(CH2)niPOviX1. In embodiments, each nl is 0. In embodiments, each nl is 1. In embodiments, each nl is 2. In embodiments, each nl is 3. In embodiments, each nl is 4. In embodiments, each nl is 5. In embodiments, each vl is 2. In embodiments, each vl is 3.

[0076] In embodiments, R1Aand R1Dattached to the same phenyl ring may be same or different. In embodiments, R1Aand R1Aattached to the different phenyl rings may be same or different. In embodiments, R1Dand R1Dattached to the different phenyl rings may be same or different.

[0077] In embodiments, each R1Aand R1Dattached to the same phenyl ring is independently -O-(CH2)niS(O)viX1. In embodiments, each R1Aand R1Aattached to the different phenyl rings is independently -O-(CH2)niS(O)viX1. In embodiments, each R1Dand R1Dattached to the different phenyl rings is independently -O-(CH2)niS(O)viX1.

[0078] In embodiments, each X1is independently selected from selected from H, -OH, alkali metal cation, quaternary ammonium cation, or an organic amine cation; and preferably at least one X1is an organic amine cation; or two X1are organic amine cations; or three X1are organic amine cations; or each X1is an organic amine cation; and more preferably at least one X1is an amino acid cation; or two X1are amino acid cations; or three X1are amino acid cations; or each X1is an amino acid cation.

[0079] In another aspect, the cucurbituril compounds used in the compositions and methods of this disclosure have the structure of formula (I-c):14181440027or a pharmaceutically acceptable salt thereof. X1and nl are as described herein.

[0080] In embodiments, each X1are same or different. In embodiments, each X1is independently H, alkali metal cation, quaternary ammonium cation, or an organic amine cation, and preferably at least one X1is an organic amine cation; or two X1are organic amine cations; or three X1are organic amine cations; or each X1is an organic amine cation; and more preferably at least one X1is an amino acid cation; or two X1are amino acid cations; or three X1are amino acid cations; or each X1is an amino acid cation.

[0081] In embodiments, each nl is 0 to 5. In embodiments, each nl is 1 to 5. In embodiments, each nl is 2 to 5. In embodiments, each nl is 3 to 5. In embodiments, each nl is 4 or 5.

[0082] In another aspect, the cucurbituril compounds used in the compositions and methods of this disclosure have the structure of formula (I-A):or a pharmaceutically acceptable salt thereof. Each X is independently H, alkali metal cation (e.g., Li+, Na+, K+, or Cs+), quaternary ammonium cation, or an organic amine cation; and preferably at least one X is an organic amine cation; or two X are organic amine cations; or three X are organic amine cations; or each X is an organic amine cation; and more preferably at least one X is an amino acid cation; or two X are amino acid cations; or three X are amino acid cations; or each X is an amino acid cation.

[0083] In another aspect, the cucurbituril compounds used in the compositions and methods of this disclosure is Compound A, having the following structure:15181440027or a pharmaceutically acceptable salt thereof. The Compound A salt may comprise alkali metal cation (e.g., Li+, Na+, K+, or Cs+), quaternary ammonium cation, or an organic amine cation; and preferably at least one organic amine cation; or two organic amine cations; or three organic amine cations; or four organic amine cations; and more preferably at least one amino acid cation; or two amino acid cations; or three amino acid cations; or four amino acid cations.

[0084] In another aspect, the cucurbituril compounds used in the compositions and methods of this disclosure have the structure of formula (Il-a):or a pharmaceutically acceptable salt thereof. R1A, R1D, R3A, R3B, R4A, and R4Bare as described herein.

[0085] In embodiments, R3Ais hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R3Ais C1-C3 alkyl, and particularly methyl.

[0086] In embodiments, R3Bis hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R3Bis C1-C3 alkyl, and particularly methyl.

[0087] In embodiments, R3Aand R3Bare both hydrogen. Alternatively, R3Aand R3Bmay both be methyl. In embodiments, one of R3Aand R3Bis hydrogen and the other is methyl.

[0088] In embodiments, R4Ais hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R4Ais C1-C3 alkyl, and particularly methyl. In embodiments, R4Ais H.

[0089] In embodiments, R4Bis hydrogen or substituted or unsubstituted C1-C3 alkyl. In embodiments, R4Bis C1-C3 alkyl, and particularly methyl. In embodiments, R4Bis hydrogen.16181440027

[0090] In embodiments, each R4Aand R4Bis hydrogen. Alternatively, each R4Aand R4Bmay be methyl. In embodiments, one of R4Aand R4Bis hydrogen and the other is methyl.

[0091] In embodiments, each R3Aand R3Bis independently C1-C3 alkyl and R4Aand R4Bare hydrogen, and particularly, each R3Aand R3Bare methyl and each R4Aand R4Bare hydrogen.

[0092] In embodiments, each R1Aand R1Dis neutral. In embodiments, each R1Aand R1Dis in an ionic salt form.

[0093] In embodiments, each R1Aand R1Dare the same or different and are selected from -O-L-S(O)viXJ, -O-L-CO2X1, and -O-L-POviX1.

[0094] In embodiments, each L independently selected from -(CH2)ni-, wherein each nl is independently selected from 0 to 5.

[0095] In embodiments, R1Ais -O-(CH2)niS(O)viX1. In embodiments, R1Ais -O-(CH2)niCO2X1. In embodiments, R1Ais -O-(CH2)niPOviX1. In embodiments, each nl is 0. In embodiments, each nl is 1. In embodiments, each nl is 2. In embodiments, each nl is 3. In embodiments, each nl is 4. In embodiments, each nl is 5. In embodiments, each vl is 2. In embodiments, each vl is 3.

[0096] In embodiments, R1Dis -O-(CH2)niS(O)viX1. In embodiments, R1Dis -O-(CH2)niCO2X1. In embodiments, R1Dis -O-(CH2)niPOviX1. In embodiments, each nl is 0. In embodiments, each nl is 1. In embodiments, each nl is 2. In embodiments, each nl is 3. In embodiments, each nl is 4. In embodiments, each nl is 5. In embodiments, each vl is 2. In embodiments, each vl is 3.

[0097] In embodiments, R1Aand R1Dattached to the same phenyl ring may be same or different. In embodiments, R1Aand R1Aattached to the different phenyl rings may be same or different. In embodiments, R1Dand R1Dattached to the different phenyl rings may be same or different.

[0098] In embodiments, each R1Aand R1Dattached to the same phenyl ring is independently -O-(CH2)niS(O)viX1. In embodiments, each R1Aand R1Aattached to the different phenyl rings is independently -O-(CH2)niS(O)viX1. In embodiments, each R1Dand R1Dattached to the different phenyl rings is independently -O-(CH2)niS(O)viX1.

[0099] In embodiments, each X1is independently selected from selected from H, -OH, alkali metal cation, quaternary ammonium cation, or an organic amine cation; and preferably17181440027at least one X1is an organic amine cation; or two X1are organic amine cations; or three X1are organic amine cations; or each X1is an organic amine cation; and more preferably at least one X1is an amino acid cation; or two X1are amino acid cations; or three X1are amino acid cations; or each X1is an amino acid cation.

[0100] In another aspect, the cucurbituril compounds used in the compositions and methods of this disclosure have the structure of formula (Il-b) :or a pharmaceutically acceptable salt thereof. R1Aand R1Dare as described herein.

[0101] In embodiments, each R1Aand R1Dis neutral. In embodiments, each R1Aand R1Dis in an ionic salt form.

[0102] In embodiments, each R1Aand R1Dare the same or different and are selected from -O-L-S(O)viXJ, -O-L-CO2X1, and -O-L-POviX1.

[0103] In embodiments, each L independently selected from -(CH2)ni-, wherein each nl is independently selected from 0 to 5.

[0104] In embodiments, R1Ais -O-(CH2)niS(O)viX1. In embodiments, R1Ais -O-(CH2)niCO2X1. In embodiments, R1Ais -O-(CH2)niPOviX1. In embodiments, each nl is 0. In embodiments, each nl is 1. In embodiments, each nl is 2. In embodiments, each nl is 3. In embodiments, each nl is 4. In embodiments, each nl is 5. In embodiments, each vl is 2. In embodiments, each vl is 3.

[0105] In embodiments, R1Dis -O-(CH2)niS(O)viX1. In embodiments, R1Dis -O-(CH2)niCO2X1. In embodiments, R1Dis -O-(CH2)niPOviX1. In embodiments, each nl is 0. In embodiments, each nl is 1. In embodiments, each nl is 2. In embodiments, each nl is 3. In embodiments, each nl is 4. In embodiments, each nl is 5. In embodiments, each vl is 2. In embodiments, each vl is 3.

[0106] In embodiments, R1Aand R1Dattached to the same phenyl ring may be same or different. In embodiments, R1Aand R1Aattached to the different phenyl rings may be same or different. In embodiments, R1Dand R1Dattached to the different phenyl rings may be same or different.18181440027

[0107] In embodiments, each R1Aand R1Dattached to the same phenyl ring is independently -O-(CH2)niS(O)viX1. In embodiments, each R1Aand R1Aattached to the different phenyl rings is independently -O-(CH2)niS(O)viX1. In embodiments, each R1Dand R1Dattached to the different phenyl rings is independently -O-(CH2)niS(O)viX1.

[0108] In embodiments, each X1is independently selected from selected from H, -OH, alkali metal cation, quaternary ammonium cation, or an organic amine cation; and preferably at least one X1is an organic amine cation; or two X1are organic amine cations; or three X1are organic amine cations; or each X1is an organic amine cation; and more preferably at least one X1is an amino acid cation; or two X1are amino acid cations; or three X1are amino acid cations; or each X1is an amino acid cation.

[0109] In another aspect, the cucurbituril compounds used in the compositions and methods of this disclosure have the structure of formula (II-c):or a pharmaceutically acceptable salt thereof. X1and nl are as described herein.

[0110] In embodiments, each X1are same or different. In embodiments, each X1is independently H, alkali metal cation, quaternary ammonium cation or an organic amine cation, and preferably at least one X1is an organic amine cation; or two X1are organic amine cations; or three X1are organic amine cations; or each X1is an organic amine cation; and more preferably at least one X1is an amino acid cation; or two X1are amino acid cations; or three X1are amino acid cations; or each X1is an amino acid cation.[OHl] In embodiments, each nl is 0 to 5. In embodiments, each nl is 1 to 5. In embodiments, each nl is 2 to 5. In embodiments, each nl is 3 to 5. In embodiments, each nl is 4 or 5.

[0112] In another aspect, the cucurbituril compounds used in the compositions and methods of this disclosure have the structure of formula (II-B):19181440027

[0113] or a pharmaceutically acceptable salt thereof. Each X is independently H, alkali metal cation (e.g., Li+, Na+, K+, or Cs+), quaternary ammonium cation, or an organic amine cation; and preferably at least one X is an organic amine cation; or two X are organic amine cations; or three X are organic amine cations; or each X is an organic amine cation; and more preferably at least one X is an amino acid cation; or two X are amino acid cations; or three X are amino acid cations; or each X is an amino acid cation.

[0114] In another aspect, the cucurbituril compounds used in the compositions and methods of this disclosure is Compound B, having the following structure:or a pharmaceutically acceptable salt thereof. The Compound B salt may comprise alkali metal cation (e.g., Li+, Na+, K+, or Cs+), quaternary ammonium cation, or an organic amine cation; and preferably at least one organic amine cation; or two organic amine cations; or three organic amine cations; or four organic amine cations; and more preferably at least one amino acid cation; or two amino acid cations; or three amino acid cations; or four amino acid cations.

[0115] Cucurbituril compounds may be prepared according to the methods of U.S. App No. 15 / 417,785 (US 2017 / 0137431); International application PCT / US2023 / 077486, entitled Methods of Synthesis for Cucurbituril Compounds; each of which is incorporated herein by reference in their entirety.

[0116] In preferred embodiment, for each of the cucurbituril compounds provided above (i.e., compounds of the formulas I, I-a, I-b, I-c, I-A, Il-a, Il-b, II-c, II-B, Compound A and Compound B), the compound is present as an organic amine salt, and particularly as an amino acid salt or amino acid derivative salt. The amino acid may be selected from the group comprising histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine,20181440027tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, serine, arginine, cysteine, glutamine, glycine, proline, and tyrosine. In embodiments, the amino acid is one or more of arginine, glutamic acid, proline, aspartic acid, phenylalanine, histidine, lysine, and tryptophan; or the amino acid is one or more of arginine, histidine, lysine, tryptophan; and particularly the amino acid is arginine. In embodiments, the cucurbituril amino acid salt is a mixed salt, wherein the other cation is alkali metal cation (e.g., Li+, Na+, K+, or Cs+), or quaternary ammonium cation. The salts may have the general formulas: cucurbituril / AA / 3X, cucurbituril / 2AA / 2X, cucurbituril / 3 AA / X, or cucurbituril / 4AA; wherein AA is an amino acid or amino acid derivative, and X is H or a cation selected from alkali metal cation or quaternary ammonium cation. In a particular embodiment, the cucurbituril compound is Compound A, the cation is Na+, and the amino acid is arginine.

[0117] The 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.

[0118] The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups and branched-chain alkyl groups. The alkyl may include a designated number of carbons (e.g., Ci-Cio means one to ten carbons). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term alkylene refers to alkyl groups that are bivalent and include, for example -CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, and the like.

[0119] The term “alkenyl” refers to a linear or branched hydrocarbyl having at least one carbon-carbon double bond and including straight-chain and branched-chain alkenyl groups. Examples of alkenyl groups (e.g., “C2-C6 alkenyl”) includes vinyl, 1 -propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3 -pentenyl, and the like. When the compound of the present disclosure contains an alkenyl group, the compound may exist as the E-form, the Z-form, or any mixture thereof. The term alkenylene refers to alkenyl group that is bivalent, and includes, for example, -CH=CH-, -C(CH3)=CH-, -CH2CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, -CH=CHCH=CH-, -CH2CH2CH2CH=CH-, -CH2CH=CHCH=CH-, -CH2CH2CH=CHCH2-, -CH2CH2CH2CH2CH=CH-, -CH2CH2CH=CHCH=CH-, and the like.21181440027

[0120] The term “alkynyl” refers to a linear or branched hydrocarbyl having at least one carbon-carbon triple bond and including straight-chain and branched-chain alkynyl groups. Examples of alkenyl groups (e.g., “C2-C6 alkynyl”) includes ethynyl, propynyl, and the like.

[0121] The term “cycloalkyl” refers to saturated, carbocyclic groups having from 3 to 9 carbons in the ring and including a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH2)w, where w is 1, 2, or 3).Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.

[0122] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: -O-C1-C6 alkyl, -O-C2-C6 alkenyl, -O-C2-C6 alkynyl, -S-Ci-C6alkyl, -S-C2-C6 alkenyl, -S-C2-Ce alkynyl, -NH-Ci-Ce alkyl, -NH-C2-C6 alkenyl, -NH-C2-C6 alkynyl, -N-(Ci-Ce alkyl)2, -S(O)-C1-C6alkyl, -S(O)-C2-C6alkenyl, -S(O)-C2-C6alkynyl, -S(O)2-Ci-C6alkyl, -S(O)2-C2-C6alkenyl, -S(O)2-C2-C6alkynyl, -Ci-C6alkyl-O-Ci-C6alkyl, -Ci-C6alkyl-S-Ci-C6alkyl, -C1-C6 alkyl-NH-Ci-Ce alkyl, -Ci-C6alkyl-N-(Ci-C6alkyl)2, -Ci-C6alkyl-S(O)-Ci-C6alkyl, -Ci-Ce alkyl-S(O)2-Ci-Ce alkyl, and more particularly include, but are not limited to:— CH2— o— CH3, — CH2— NH— CH3, — CH2— CH2— N(CH3)— CH3, — CH2— s— CH3, — S(O)— CH3, — CH2— S(O)2— CH3, — Si(CH3)3, — O— CH3, or — O— CH2— CH3. Up to two or three heteroatoms may be consecutive, such as, for example, — CH2 — NH — OCH3and — CH2 — O — Si(CH3)3. The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one carbon-carbon double bond. The term “heteroalkynyl,” by itself or in combination with another term,22181440027means, unless otherwise stated, a heteroalkyl including at least one carbon-carbon triple bond.

[0123] The term “cycloalkenyl” as used herein is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. In embodiments, monocyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 9 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon-carbon double bond), but not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, bicyclic cycloalkenyl rings are bridged or fused bicyclic rings.

[0124] The term “heterocycle,” “heterocyclyl” or “heterocyclic” as used herein, means a monocyclic, bicyclic, or multicyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6, 7 or 8 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, S, Si, and P where the ring is saturated or unsaturated, but not aromatic. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. Representative examples of bicyclic heterocycles include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-l-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro- IH-indolyl, and octahydrobenzofuranyl. The heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic or bicyclic ring system.

[0125] The term "aryl" as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heteroaromatics" or "heteroaryl". The term “aryl” also includes 7- to 14-membered polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic (including heteroaryl), e.g., the23181440027other cyclic rings can be fused cycloalkyls, cycloalkenyls, aryls, heteroaryl and / or heterocyclic groups. Single-ring heteroaryl groups may have from 1 to 3 ring heteroatoms and fused polycyclic heteroaryl groups may have from 1 to 5 ring heteroatoms, wherein the ring heteroatoms are selected from N, O and S.

[0126] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, — CH2CH2CH2CH2 — . Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0127] It will be understood that "substituted", "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Exemplary substituents as used herein means a group selected from oxo, halogen, — CN, — OH, — NH2, — COOH, — CONH2, — NO2, — SH, SCI k --SO3H, --SO4H, --SO2NH2, ---NHNH2, --ONH2, ---NHC(O)NHNH ,— NHC(O)NH2, — NHSO2H, — NHC(O)H, — NHC(O)OH, — NHOH, — OCF3, — OCCI3, — OCBr3, — OCI3, — OCHF2, — OCHCh, — OCHBn, — OCHI2, — OCH2F, — OCH2CI, — OC LBr, — OCH2I, alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., Ce-Cioaryl, Cioaryl, or phenyl), or heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and these alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be optionally substituted with at least one substituents. For example, in the cucurbituril compounds disclosed herein, each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl and heterocycle may be optionally substituted with 1 to 4 substituents selected from the foregoing substituents.

[0128] A quaternary ammonium cation as used herein is has the structure+N(R)4, wherein each R is independently selected from alkyl, cycloalkyl, aryl, aralkyl and heteroaryl, each of24181440027which may be optionally substituted. The quaternary ammonium cations, for example, may have the structure+N(CI-6 alkyl)4, wherein each of the Ci-6 alkyl group boned to the nitrogen is independently selected.

[0129] The terms “a” or “an” as used in herein means one or more. In addition, the phrase “substituted with a[n],” as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C1-C20 alkyls, and / or one or more unsubstituted 2 to 20 membered heteroalkyls.

[0130] Certain compounds provided in this disclosure may exist in particular geometric or stereoisomeric forms. The disclosure contemplates all such compounds, including cis- and / ra / z.s-i somers, R- and 5-enantiomers, diastereomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included in this invention.

[0131] The term "pharmaceutically-acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds disclosed herein and inorganic and organic basic addition salts of the compounds disclosed herein. When compounds of the present invention 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 salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds 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 like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like.25181440027Organic amines

[0132] In the compositions of this disclosure, the cucurbituril compound is combined with one or more organic amines. The cucurbituril compound and the organic amine are preferably present as an organic amine salt and / or complex of the cucurbituril compound. In one aspect, the disclosure provides a pharmaceutical dosage form that comprises a cucurbituril compound and an organic amine (for example, as an organic amine salt of the cucurbituril compound). The addition of the organic amine with the cucurbituril compound enhances the solubility of the cucurbituril compound, and may additionally enhance the stability of the resulting solution. Additionally, the complex / salt of the cucurbituril compound with the organic amine may be used to improve off-target binding of the cucurbituril compound.

[0133] Organic amines are nitrogen-containing organic compounds derived from ammonia (NH3) in which one or more hydrogen atoms are replaced by a carbon-based group, wherein each amine group may be independently primary, secondary, tertiary, or quaternary. The organic amine may be an aliphatic amine, cyclic amine, aromatic amine, amino sugar, amino acid, amino acid derivative, or combinations thereof. Aliphatic amines have an amine nitrogen atom bonded to one or more alkyl groups, which may be substituted or unsubstituted, and include alkyl mono-, di-, and tri-amines such as diethylamine, ethylenediamine, and diethylenetriamine; alcohol amines such as ethanol amine, and the like. Cyclic amines are organic amines that include an amine nitrogen as one of the ring atoms, and includes substituted or unsubstituted morpholines, pyrrolidines, piperdines, and the like. Aromatic amines are organic amines that include an amine nitrogen as one of the ring atoms, and includes substituted or unsubstituted imidazoles, pyrroles, oxazoles, and the like. Amino sugars are sugars, and particularly monosaccharides, where one or more hydroxyl (-OH) groups are replaced by amino (-NH2) group(s), such as glucosamine, glucamine, and the like.

[0134] In the compositions, the molar ratio of the cucurbituril compound to the organic amine, may be from about 2: 1 to about 1 :6, or from about 1 : 1 to about 1 :4, or from about 1 :2 to 1 :4. In embodiments, the molar ratio of the cucurbituril compound to the organic amine is about 1:4.

[0135] In the compositions, the molar ratio of Compound A to the organic amine may be from about 2: 1 to about 1 :6, or from about 1 : 1 to about 1 :4, or from about 1 :2 to 1 :4. In embodiments, the molar ratio of Compound A to the organic amine is about 1 :4. In embodiments, the composition comprises a tetra organic amine salt of Compound A.26181440027

[0136] In the compositions, the molar ratio of Compound B to the organic amine may be from about 2: 1 to about 1 :6, or from about 1 : 1 to about 1 :4, or from about 1 :2 to 1 :4. In embodiments, the molar ratio of Compound B to the organic amine is about 1 :4. In embodiments, the composition comprises a tetra organic amine salt of Compound B.

[0137] In embodiments, the cucurbituril organic amine salt is a mixed salt, wherein the other cation is alkali metal cation (e.g., Li+, Na+, K+, or Cs+), or quaternary ammonium cation. The salts may have the general formulas: cucurbituril / OA / 3X, cucurbituril / 2OA / 2X, cucurbituril / 3OA / X, or cucurbituril / 4OA; wherein OA is an organic amine, and X is H or a cation selected from alkali metal cation or quaternary ammonium cation.

[0138] In an embodiment, the disclosure provides a pharmaceutical dosage form that comprises a cucurbituril compound and an amino acid or an amino acid derivative. The addition of the amino acid with the cucurbituril compound enhances the solubility of the cucurbituril compound, and may additionally enhance the stability of the resulting solution. Additionally, the complex of the cucurbituril compound with the amino acid may be used to improve off-target binding of the cucurbituril compound.

[0139] Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. The preferred amino acids for use in the compositions are alpha-amino acids having the L-configuration. Unless otherwise stated herein, the amino acids recited in this disclosure are L-amino acids. The amino acids include one or more of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, serine, arginine, cysteine, glutamine, glycine, proline, and tyrosine. In embodiments, the amino acid is one or more of arginine, proline, glutamic acid, phenylalanine, aspartic acid, histidine, lysine, and tryptophan; or the amino acid is one or more of arginine, proline, glutamic acid, aspartic acid, lysine, histidine, and tryptophan; and particularly the amino acid is arginine.

[0140] Alternatively, an amino acid derivative may be used in the compositions and methods of this disclosure. An amino acid derivative is a chemically modified amino acid which has an N-acetyl group, a carboxyl amide group, or a carboxyl ester group. As would be understood by a person skilled in the art, an amino acid derivative having an N-acetyl group has the chemical formula CH3C(=O)-NH-CHR-CO2H, where R is the amino acid side chain, particularly a side chain of the naturally occurring, proteinogenic amino acids. An amino acid derivative having a carboxyl amide group has the chemical formula H2N-CHR-CO-NH2. An amino acid derivative having a carboxyl ester group has the chemical formula27181440027H2N-CHR-CO-O-alkyl, wherein alkyl has 1, 2, 3 or 4 carbon atoms, for example methyl or ethyl.

[0141] In other embodiments, the amino acid derivative may be a dipeptide. The preferred amino acids for use in the dipeptide are alpha-amino acids having the L-configuration. The amino acids of the dipeptide may be the same or different and may be selected from histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, serine, arginine, cysteine, glutamine, glycine, proline, and tyrosine. The dipeptide may be chemically modified with an N-acetyl group, a carboxyl amide group, or a carboxyl ester group. Such a modified dipeptide may have the formula CH3C(=O)-NH-CHR-CO2-NH-CHR-CO2H, H2N-CHR-CO2-NH-CHR-CO-NH2 or H2N-CHR-CO2-NH-CHR-CO-O-alkyl, in which each side chain R may be the same or different, and is particularly selected from the side chains of the naturally occurring, proteinogenic amino acids; and alkyl has 1, 2, 3 or 4 carbon atoms, for example methyl or ethyl. Exemplary dipeptides are alanine-glycine and methyl L-a-aspartyl-L-phenylalaninate (aspartame).

[0142] In the compositions, the molar ratio of the cucurbituril compound to the amino acid, or amino acid derivative, may be from about 2: 1 to about 1 :6, or from about 1 : 1 to about 1 :4, or from about 1 :2 to 1 :4. In embodiments, the molar ratio of the cucurbituril compound to the amino acid, or amino acid derivative is about 1 :4.

[0143] In the compositions, the molar ratio of Compound A to the amino acid, or amino acid derivative, may be from about 2: 1 to about 1 :6, or from about 1 : 1 to about 1 :4, or from about 1 :2 to 1 :4. In embodiments, the molar ratio of Compound A to the amino acid, or amino acid derivative is about 1 :4. In embodiments, the composition comprises a tetra amino acid salt of Compound A.

[0144] In the compositions, the molar ratio of Compound B to the amino acid, or amino acid derivative, may be from about 2: 1 to about 1 :6, or from about 1 : 1 to about 1 :4, or from about 1 :2 to 1 :4. In embodiments, the molar ratio of Compound B to the amino acid, or amino acid derivative is about 1 :4. In embodiments, the composition comprises a tetra amino acid salt of Compound B. Preferred amino acid salts of Compound B include proline, glutamic acid, aspartic acid, lysine, histidine, and arginine.

[0145] In the compositions, the molar ratio of Compound A to arginine may be from about 2: 1 to about 1 :6, or from about 1 : 1 to about 1 :4, or from about 1 :2 to 1 :4. In embodiments, the molar ratio of Compound A to arginine is about 1 :4. In embodiments, the composition comprises a tetraarginine salt of Compound A.28181440027

[0146] In embodiments, the cucurbituril amino acid salt is a mixed salt, wherein the other cation is alkali metal cation (e.g., Li+, Na+, K+, or Cs+), or quaternary ammonium cation. The salts may have the general formulas: cucurbituril / AA / 3X, cucurbituril / 2AA / 2X, cucurbituril / 3 AA / X, or cucurbituril / 4AA; wherein AA is an amino acid or amino acid derivative, and X is H or a cation selected from alkali metal cation or quaternary ammonium cation.

[0147] The inventors have found an enhancement in properties of cucurbituril compounds using the complexes with organic amines, and particularly amino acids or amino acid derivatives. The complexes are salts of the cucurbituril compounds with the organic amine(s). It is believed that the organic amine may bind in the cavity of cucurbituril compound forming a guest-host complex. For these complexes with the cucurbituril compound, the organic amine may act both as a counterion and as a guest-host, i.e., occupying the binding cavity of the cucurbituril compound. The resulting complex may show improved properties as compared to the cucurbituril compound or its salts. In embodiments, the complex is a tetra amino acid salt of the cucurbituril compound; or the complex is a tetra amino acid salt of Compound A or Compound B; or the complex is the tetra arginine salt of Compound A or Compound B.

[0148] For example, the complex may show improved solubility of the cucurbituril compound. The organic amine complex, and particularly the amino acid or derivative complex, may improve the solubility of the cucurbituril compound in two cases: (1) it may increase the maximum solubility of the cucurbituril compound in water and / or (2) it may increase the longevity of a solution (physical stability) of the cucurbituril compound over time.

[0149] Additionally, the inclusion of the organic amine, and particularly an amino acid or derivative, in the binding cavity of the cucurbituril compound may reduce non-specific, off-target binding. Each organic amine may have a different binding constant when it occupies the cavity of a cucurbituril compound. The organic amine will be displaced from the cavity when the complex encounters a potential guest molecule that binds more tightly in the cavity. A guest molecule having a lower binding constant will be replaced in the cavity of the cucurbituril compound by a different guest molecule having a higher binding constant.Accordingly, potential off-target quest molecules that have a lower binding constant than the organic amine that is part of the complex with the cucurbituril compound will not displace the organic amine, and will not be bound by the cucurbituril compound. Concurrently, the29181440027organic amine is selected to have a lower binding constant than the intended target (i.e., the toxic agent) which is intended for removal from the patient.Administration of the cucurbituril compound-organic amine complex

[0150] The composition comprising a cucurbituril compound and an organic amine, particularly an amino acid or an amino acid derivative, can be included in pharmaceutical compositions for administration to the patient. The pharmaceutical compositions of the disclosure may further include a pharmaceutically acceptable carrier, excipient, or diluent.

[0151] The term “pharmaceutical composition” as used herein refers to a composition containing a cucurbituril compound and an organic amine, particularly an amino acid or an amino acid derivative, formulated with a pharmaceutically acceptable carrier, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disorder in a patient. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gel cap, syrup, or solution); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); for intramuscular administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intramuscular use); or in any other formulation described herein.

[0152] The term “pharmaceutically acceptable carrier” as used herein refers to a carrier which is physiologically acceptable to a treated mammal (e.g., a human) while retaining the therapeutic properties of the cucurbituril compound, with which it is administered. One exemplary pharmaceutically acceptable carrier is physiological saline. Other physiologically acceptable carriers and their formulations are known to one skilled in the art and described, for example, in Remington's Pharmaceutical Sciences (18thedition, A. Gennaro, 1990, Mack Publishing Company, Easton, Pa.), incorporated herein by reference.

[0153] Pharmaceutical compositions containing the cucurbituril compound and an organic amine, particularly an amino acid or an amino acid derivative, in some embodiments are prepared as solutions, dispersions in glycerol, liquid polyethylene glycols, and any combinations thereof in oils, in solid dosage forms, dosage forms comprising nanoparticles, dosage forms comprising microparticles, polymeric dosage forms, or any combinations thereof.

[0154] A pharmaceutically acceptable excipient is, in some examples, an excipient described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986). Non-limiting examples of suitable excipients include a buffering agent, a30181440027preservative, a stabilizer, a binder, a compaction agent, a lubricant, a chelator, a dispersion enhancer, a disintegration agent, a flavoring agent, a sweetener, a coloring agent.

[0155] In some embodiments an excipient is a buffering agent. Non-limiting examples of suitable buffering agents include sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate, and calcium bicarbonate. As a buffering agent, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide and other calcium salts or combinations thereof is used, in some embodiments, in a pharmaceutical composition of the present disclosure.

[0156] In some embodiments an excipient comprises a preservative. Non-limiting examples of suitable preservatives include antioxidants, such as alpha-tocopherol and ascorbate, and antimicrobials, such as parabens, chlorobutanol, and phenol. In some examples, antioxidants further include but are not limited to EDTA, citric acid, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), sodium sulfite, p-amino benzoic acid, glutathione, propyl gallate, cysteine, methionine, ethanol and N-acetyl cysteine. In some instances preservatives include validamycin A, TL-3, sodium ortho vanadate, sodium fluoride, N-a-tosyl-Phe-chloromethylketone, N-a-tosyl-Lys-chloromethylketone, aprotinin, phenylmethyl sulfonyl fluoride, diisopropylfluorophosphate, kinase inhibitor, phosphatase inhibitor, caspase inhibitor, granzyme inhibitor, cell adhesion inhibitor, cell division inhibitor, cell cycle inhibitor, lipid signaling inhibitor, protease inhibitor, reducing agent, alkylating agent, antimicrobial agent, oxidase inhibitor, or other inhibitor.

[0157] In some embodiments a pharmaceutical composition as described herein comprises a binder as an excipient. Non-limiting examples of suitable binders include starches, pregelatinized starches, gelatin, polyvinylpyrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, and combinations thereof. The binders used in a pharmaceutical formulation are, in some examples, selected from starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and 31181440027synthetic gums; gelatine; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol and water or any combinations thereof.

[0158] In some embodiments a pharmaceutical composition as described herein comprises a lubricant as an excipient. Non-limiting examples of suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil. The lubricants that are used in a pharmaceutical formulation, in some embodiments, are be selected from metallic stearates (such as magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc or a combination thereof.

[0159] In some embodiments a pharmaceutical formulation comprises a dispersion enhancer as an excipient. Non-limiting examples of suitable dispersants include, in some examples, starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.

[0160] In some embodiments a pharmaceutical composition as described herein comprises a disintegrant as an excipient. In some embodiments a disintegrant is a non-effervescent disintegrant. Non-limiting examples of suitable non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth. In some embodiments a disintegrant is an effervescent disintegrant. Non-limiting examples of suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.

[0161] In some embodiments an excipient comprises a flavoring agent. Flavoring agents incorporated into an outer layer are, in some examples, chosen from synthetic flavor oils and flavoring aromatics; natural oils; extracts from plants, leaves, flowers, and fruits; and combinations thereof. In some embodiments a flavoring agent can be selected from the 32181440027group consisting of cinnamon oils; oil of wintergreen; peppermint oils; clover oil; hay oil; anise oil; eucalyptus; vanilla; citrus oil such as lemon oil, orange oil, grape and grapefruit oil; and fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0162] In some embodiments an excipient comprises a sweetener. Non-limiting examples of suitable sweeteners include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as a sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; and sugar alcohols such as sorbitol, mannitol, sylitol, and the like.

[0163] In some instances, a pharmaceutical composition as described herein comprises a coloring agent. Non-limiting examples of suitable coloring agents include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), and external drug and cosmetic colors (Ext. D&C). Coloring agents can be used as dyes or their corresponding lakes.

[0164] In some instances, a pharmaceutical composition as described herein comprises a chelator. In some cases, a chelator is an antimicrobial or fungicidal chelator. Examples include, but are not limited to: ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA); a disodium, trisodium, tetrasodium, dipotassium, tripotassium, dilithium and diammonium salt of EDTA; a barium, calcium, cobalt, copper, dysprosium, europium, iron, indium, lanthanum, magnesium, manganese, nickel, samarium, strontium, or zinc chelate of EDTA; trans-1,2-diaminocyclohexane-N,N,N',N'-tetraaceticacid monohydrate; N,N-bis(2-hydroxyethyl)glycine; l,3-diamino-2-hydroxypropane-N,N,N',N'-tetraacetic acid; 1,3-diaminopropane-N,N,N',N'-tetraacetic acid; ethylenediamine-N,N'-diacetic acid; ethylenediamine-N,N'-dipropionic acid dihydrochloride; ethylenediamine-N,N'-bis(methylenephosphonic acid) hemihydrate; N-(2-hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid; ethylenediamine-N,N,N',N'-tetrakis(methylenephosponic acid); 0,0'-bis(2-aminoethyl)ethyleneglycol-N,N,N',N'-tetraacetic acid; N,N-bis(2-hydroxybenzyl)-ethylenediamine-N,N-diacetic acid; l,6-hexamethylenediamine-N,N,N',N'-tetraacetic acid; N-(2-hydroxyethyl)iminodiacetic acid; iminodiacetic acid; l,2-diaminopropane-N,N,N',N'-tetraacetic acid; nitrilotriacetic acid; nitrilotripropionic acid; the trisodium salt of nitrilotris(m ethylenephosphoric acid); 7, 19,30-trioxa- 1,4,10,13,16,22,27,33 -octaazabicyclo[l 1,11,1 l]pentatriacontane hexahydrobromide; or triethylenetetramine-N,N,N',N",N'",N'"-hexaacetic acid.33181440027

[0165] The pharmaceutical compositions of the cucurbituril compound and amino acid or derivative as described herein may be formulated for parenteral administration to the patient. In particular, the pharmaceutical compositions of the cucurbituril compound and amino acid will be suitable for administration by injection into the patient, including intravenous, intramuscular, subcutaneous, and intraperitoneal administration, and preferably will be suitable for intramuscular or intravenous administration.

[0166] In an embodiment, the dosage form is an oral dosage form comprising (i) a cucurbituril compound, (ii) an organic amine, and (iii) one or more pharmaceutically acceptable carriers. The oral dosage form may be a capsule or a tablet. Alternatively, the oral dosage form may be an orally administrable solution, suspension, or syrup.

[0167] In an embodiment, the dosage form is an oral dosage form comprising (i) a cucurbituril compound, (ii) an amino acid or an amino acid derivative, and (iii) one or more pharmaceutically acceptable carriers. The oral dosage form may be a capsule or a tablet. Alternatively, the oral dosage form may be an orally administrable solution, suspension, or syrup.

[0168] In another embodiment, the dosage form is an aqueous solution that is suitable for injection into a patient comprising (i) a cucurbituril compound, (ii) an organic amine, (iii) optionally, a buffering agent, and (iv) optionally a tonicity agent. In another embodiment, the dosage form is a solid for reconstitution comprising (i) a cucurbituril compound, (ii) an organic amine, (iii) optionally, a buffering agent, and (iv) optionally a tonicity agent.Preferably, the cucurbituril compound and the organic amine together are present in the compositions as an organic amine salt of the cucurbituril compound.

[0169] In another embodiment, the dosage form is an aqueous solution that is suitable for injection into a patient comprising (i) a cucurbituril compound, (ii) an amino acid, or an amino acid derivative, (iii) optionally, a buffering agent, and (iv) optionally a tonicity agent. In another embodiment, the dosage form is a solid for reconstitution comprising (i) a cucurbituril compound, (ii) an amino acid, or an amino acid derivative, (iii) optionally, a buffering agent, and (iv) optionally a tonicity agent. Preferably, the cucurbituril compound and the amino acid together are present in the compositions as an amino acid salt of the cucurbituril compound.

[0170] For parenteral administration in an aqueous solution, for example, the liquid dosage form may be suitably buffered if necessary and the liquid diluent rendered isotonic with sufficient saline or glucose. In this connection, sterile aqueous media that can be employed will be known to those of skill in the art in light of the present disclosure. For 34181440027example, one dosage is dissolved, in certain cases, in 1 mL to 20 mL of isotonic NaCl solution and either added to 100 mL to 1000 mL of a fluid, e.g., sodium-bicarbonate buffered saline, or injected at the proposed site of infusion.

[0171] The compositions may comprise a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The pharmaceutical compositions comprise a carrier which is a solvent or a dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and / or vegetable oils, or any combinations thereof. Proper fluidity may be maintained, for example, by the use of an agent, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms is brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, isotonic agents are included, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0172] In certain embodiments, sterile injectable solutions are prepared by incorporating a cucurbituril compound, in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. The compositions disclosed herein are, in some instances, formulated in a neutral or salt form. Upon formulation, the pharmaceutical compositions are administered, in some embodiments, in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.

[0173] In some embodiments, the cucurbituril compound or a pharmaceutically acceptable salt thereof is administered at about 0.05 mg / kg to 500 mg / kg. In some embodiments, sequestering agent is administered at about 0.05 mg / kg - 50 mg / kg, 50 - 60 mg / kg, 50 - 70 mg / kg, 50 - 80 mg / kg, 50 - 90 mg / kg, 50 - 100 mg / kg, 50 - 120 mg / kg, 50 - 140 mg / kg, 50 -160 mg / kg, 50 - 180 mg / kg, 50 - 200 mg / kg, 50 - 220 mg / kg, 50 - 240 mg / kg, 50 - 260 mg / kg, 50 - 280 mg / kg, 50 - 300 mg / kg, 50 - 350 mg / kg, 50 - 400 mg / kg, 50 - 450 mg / kg, 50 - 500 mg / kg, 60 - 70 mg / kg, 60 - 80 mg / kg, 60 - 90 mg / kg, 60 - 100 mg / kg, 60- 120 mg / kg, 60- 140 mg / kg, 60 - 160 mg / kg, 60 - 180 mg / kg, 60 - 200 mg / kg, 60 - 220 mg / kg, 60 - 24035181440027mg / kg, 60- 260 mg / kg, 60 - 280 mg / kg, 60 - 300 mg / kg, 60 - 350 mg / kg, 60 - 400 mg / kg, 60 -450 mg / kg, 60- 500 mg / kg, 80 - 90 mg / kg, 80 - 100 mg / kg, 80 - 120 mg / kg, 80 - 140 mg / kg, 80 - 160 mg / kg, 80 - 180 mg / kg, 80 - 200 mg / kg, 80 - 220 mg / kg, 80 - 240 mg / kg, 80 - 260 mg / kg, 80 - 280 mg / kg, 80 - 300 mg / kg, 80 - 350 mg / kg, 80 - 400 mg / kg, 80 - 450 mg / kg, 80 - 500 mg / kg, 100 - 120 mg / kg, 100 - 130 mg / kg, 100 - 140 mg / kg, 100 - 150 mg / kg, 100 -160 mg / kg, 100 - 180 mg / kg, 100 - 200 mg / kg, 100 -220 mg / kg, 100 - 240 mg / kg, 100 - 260 mg / kg, 100 - 280 mg / kg, 100 - 300 mg / kg, 100 - 350 mg / kg, 100 - 400 mg / kg, 100 - 450 mg / kg, 100 - 500 mg / kg, 140 - 160 mg / kg, 140 - 180 mg / kg, 140 - 200 mg / kg, 140 - 220 mg / kg, 140 - 240 mg / kg, 140 - 260 mg / kg, 140 - 280 mg / kg, 140 - 300 mg / kg, 140 - 350 mg / kg, 140 - 400 mg / kg, 140 - 450 mg / kg, 140 - 500 mg / kg, 160 - 200 mg / kg, 160 - 220 mg / kg, 160 - 240 mg / kg, 160 - 260 mg / kg, 160 - 280 mg / kg, 160 - 300 mg / kg, 160 - 350 mg / kg, 160 - 400 mg / kg, 160 - 450 mg / kg, 160 - 500 mg / kg, 180 - 200 mg / kg, 180 - 220 mg / kg, 180 - 240 mg / kg, 180 - 260 mg / kg, 180 - 280 mg / kg, 180 - 300 mg / kg, 180 - 350 mg / kg, 180 - 400 mg / kg, 180 - 450 mg / kg, 180 - 500 mg / kg, 200 - 220 mg / kg, 200 - 240 mg / kg, 200 - 260 mg / kg, 200 - 280 mg / kg, 200 - 300 mg / kg, 200 - 350 mg / kg, 200 - 400 mg / kg, 200 - 450 mg / kg, 200 - 500 mg / kg, 220 - 240 mg / kg, 220 - 260 mg / kg, 220 - 280 mg / kg, 220 - 300 mg / kg, 240 - 260 mg / kg, 240 - 280 mg / kg, 240 - 300 mg / kg, 240 - 350 mg / kg, 240 - 400 mg / kg, 240 - 450 mg / kg, 240 - 500 mg / kg, 260 - 280 mg / kg, 260 - 300 mg / kg, 280 - 300 mg / kg, 260 - 350 mg / kg, 260 - 400 mg / kg, 260 - 450 mg / kg, 260 - 500 mg / kg, 280 - 350 mg / kg, 280 - 400 mg / kg, 280 - 450 mg / kg, or 280 - 500 mg / kg.

[0174] In some embodiments, cucurbituril compound or a pharmaceutically acceptable salt thereof is administered at about at least 0.05 mg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 170 mg / kg, 180 mg / kg, 190 mg / kg, 200 mg / kg, 210 mg / kg, 220 mg / kg, 230 mg / kg, 240 mg / kg, 250 mg / kg, 260 mg / kg, 270 mg / kg, 280 mg / kg, 290 mg / kg, 300 mg / kg, 350 mg / kg, 400 mg / kg, 450 mg / kg, or 500 mg / kg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered at about less than 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 170 mg / kg, 180 mg / kg, 190 mg / kg, 200 mg / kg, 210 mg / kg, 220 mg / kg, 230 mg / kg, 240 mg / kg, 250 mg / kg, 260 mg / kg, 270 mg / kg, 280 mg / kg, 290 mg / kg, 300 mg / kg, 350 mg / kg, 400 mg / kg, 450 mg / kg, or 500 mg / kg.

[0175] In some embodiments, the cucurbituril compound or a pharmaceutically acceptable salt thereof can be administered at about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 536181440027mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg.

[0176] In embodiments, the organic amine salt (particularly, the amino acid salt) of the cucurbituril compound is administered to a patient in need thereof in an amount of from about 100 mg to about 600 mg, or from about 300 mg to about 500 mg (based on the free acid of the cucurbituril compound) by IM or IV injection, and particularly by IM. Each injectable IM dosage may have a volume of from about 0.5 ml to about 5 ml; or from about 0.5 ml to about 3 ml; or from about 1 ml to about 3 ml. For IM injection, if needed, the patient may be treated with multiple injections, which may be administered at different sites of injection.

[0177] In embodiments, the organic amine salt (particularly, the amino acid salt) of the cucurbituril compound is administered by IV infusion to a patient in need thereof in an amount of from 125 mg to 1700 mg (based on the free acid of the cucurbituril compound); or from 125 mg to 1200 mg; or from 500 mg to 1200 mg; or from 900 mg to 1100 mg. In embodiments, the cucurbituril compound is administered by IV infusion to the patient in an amount of about 125 mg, or about 500 mg, or about 1000 mg, based on the free acid or the cucurbituril. The total volume of the IV infusion to the patient may be from about 40 ml to about 300 ml; or from about 50 ml to about 150 ml. The IV infusion may be administered to the patient over a time of about 5 minutes to about 25 minutes; or over a time of about 7 minutes to about 15 minutes; or over a time of about 10 minutes.EXAMPLESExample 1

[0178] Table 1 shows that the maximum solubility of Compound A can increase depending on the additive and the molar ratio of that additive relative to Compound A tetra sodium salt. In this experiment, Compound A tetrasodium salt and the additive were37181440027measured into a vial at ratios according to Table 1. Water was added in 20-100 pL increments as the vials were constantly stirred until a clear solution was achieved. The final Compound A concentration was then back-calculated from the total volume of water added to each vial. Histidine at a 1:1 ratio and Arginine at a 1 :4 ratio of Compound A:additive achieved solubilities of 312 mg / mL and 418 mg / mL Compound A, respectively, for Compound A. These solutions were also physically stable for at least 20 hours at 20 °C. Compared to the tetrasodium salt of Compound A alone (Na4 Comp. A), which only reached 233 mg / mL Compound A and crystallized over night at 20 °C, having additives present, specifically arginine, increases the maximum amount of Compound A in solution.Table 1

[0179] Maximum solubility of Compound A can increase when certain additives are present. Compound A is soluble at 312 mg / mL when in solution with histidine at a molar ratio of 1 : 1 of Comp. A:histidine. The maximum solubility of Compound A is 418 mg / mL when arginine is present at molar ratios of Comp. A:arginine is 1 :4. When solutions were stored at 20 °C overnight, solutions with arginine were of higher concentration and more physically stable than Na»Comp. A alone.Example 2

[0180] The maximum solubility of cucurbiturils, Compound A and Compound B, in water were measured after the addition of a molar equivalent of an organic amine to the sodium salt of the cucurbituril. The results (reported as the amount of cucurbituril free acid; mg / ml) are provided in Table 2.38181440027Table 2Example 3

[0181] In addition to improved maximum solubility, amino acids may improve the physical stability of Compound A in solution. Table 3 summarizes the physical stability of 150-350 mg / mL Compound A tetrasodium salt solutions with different additives at varying molar ratios. Arginine as an additive stands out as it is able to maintain 350 mg / mL Compound A in solution for 24 hours at 12 °C when present at a molar ratio 1 :4 Comp. A:arginine. Another notable additive is methamphetamine, which can keep 150 mg / mL Comp. A in solution at 12 °C for over 1 month at a 1:1 ratio.39181440027Table 3Physical Stability of Comp. A Improves in the Presence of Certain Additives40181440027

[0182] Table 3 provides a summary of the physical stability of solutions at 150-350 mg / mL Compound A tetrasodium salt, prepared volumetrically, monitored at varying molar ratios of Comp. A:additive at 20 °C or 12 °C. A solution of 250 mg / mL Compound A with molar ratio 1 :4 Comp. A:arginine is physically stable at 20 °C for at least 1 week and at least 24 hours at 1 °C. Histidine, another amino acid additive, is able to help maintain Compound A in solution at concentrations 200 and 250 mg / mL at 20 °C. Both controls (200 mg / mL and 250 mg / mL Compound A with no additive) after 24 hours formed precipitate when stored at 20 °C. 150 mg / mL Compound A with methamphetamine at a 1 : 1 molar ratio, the solution is stable 12 °C for over 1 month. Na4 Comp. A starts forming crystals after 24 hours under the same conditions and concentration.

[0183] Table 4 provides the binding constant for Compound A tetrasodium salt at pH 7 for the additives tested from Table 3.Table 4

[0184] In summary, the 1:4 molar ratio of Comp. A: Arginine showed substantially improved solubility and stability in both these sets of experiments.Example 4

[0185] The Na»Arg»Comp. A ion pair was prepared via successive recrystallizations. In brief, Na4 Comp A was dissolved in concentrated arginine»HCl in water, and then ethanol was added to a 1:1 volume ratio with the arginine»HCl solution to cause precipitation of Compound A. This solution was then heated to dissolve the precipitate and allowed to cool and filtered, followed by recrystallization and washing with 1 : 1 water: ethanol. The resulting powder was analyzed and is summarized in Table 5. Osmolality and pH were measured for 200 mg / mL Na*Arg»Comp. A.

[0186] Overlaid IR spectra of Na4 Comp. A, Na»Arg»Comp. A, and arginine are shown in Figure 1. The spectra of Na»Arg»Comp. A has peaks that overlap with just Na»Comp. A (1050 and 1200 cm-1) and just arginine (1600-1700 cm-1), indicating the mixed salt has been made.41181440027Table 5

[0187] Ratios of arginine, sodium, and Comp. A in the recrystallized dry powder of Na*Arg*Comp. A were calculated based on results from elemental analysis and assay from quantitative NMR. This data indicates that the recrystallized material was a mixed salt between 1:3:1 and 2:2:1 Na:Arginine:Comp. A.

[0188] The maximum solubility of the Na*Arg*Comp. A powder was 470 mg / mL using the shake flask method. Compared to 222 mg / mL Compound A from Na4 Comp. A, the Na*Arg*Comp. A salt has 112% more Comp. A. A 350 mg / mL solution of the Na*Arg*Comp. A salt was stable for at least 5 days at 20 °C. This result is 133% higher than the solubility of Na4 Comp. A for 5 days (150 mg / mL). Additionally, a 250 mg / mL solution of Na* Arg* Comp. A was found to be stable for 5 days at 12 °C and overnight at 4 °C, both temperatures that showed solid formation for Na4 Comp. A.Example 5. Preparation of Compound A Tetra-arginine Salt

[0189] Ion exchange resin was washed and prepared for use according to the procedure provided by resin manufacturer. Exemplary suitable resins include Dowex G26 Hydrogen Form, Lanxess Lewatit PH 1601 Sodium Form, Purolite Cl 116PH Hydrogen Form. A solution of Compound A tetrasodium salt was passed through the resin bed and the resin was washed with water (3 V). Arginine free base solution was added until a pH of 7-8 was achieved and agitated for 30 minutes. Precipitation was performed with ethanol at 0 °C with a ratio of 1 :4 water:EtOH. 12.5 equivalents of resin to Compound A provided the highest sodium removal from the molecule. The IR spectra of the tetrasodium and tetra-arginine salts of Compound A are shown in Figures 2A and 2B, respectively.

[0190] Quantitative NMR was used to measure the arginine content in the Compound A tetra-arginine salt using ethylene carbonate as the reference standard. The arginine content in42181440027the Compound A tetra-arginine salt from NMR: 33.7% (theoretical arginine content from mass balance: 32.59%). The NMR of the Comp. A tetra-arginine salt is shown in Figure 3.

[0191] Arginine HLPC Quantification: HPLC was used to confirm the arginine content in the Compound A tetra-arginine salt from s calibration curve. The content of arginine in the Compound A tetra-arginine salt was determined as 28.65% (arginine content from mass balance: 28.56%)(Tailing Factor: 1.21). The HPLC curves are shown in Figure 4.

[0192] Improved temperature stability observed with Compound A tetra-arginine salt compared to Compound A tetrasodium salt, even at reduced temperatures. Compound A tetra-arginine salt was observed to form a stable aqueous solution at 4 °C at 300 mg / mL, remaining a clear, precipitate-free solution. In comparison, Compound A tetrasodium salt is only stable at room temperature at 100 mg / mL. When stored at 2-8 °C for a 1-3 hours Compound A tetrasodium salt (100 mg / mL) showed significant precipitation.Example 6. Binding of Compound A tetra-arginine salt

[0193] The binding constant was measured for the Compound A tetra-arginine salt for methamphetamine, fentanyl and xylazine and are reported in Table 6.Table 6: Binding constant for Comp. A salt for drugs of abuse

[0194] Compound A tetra-arginine salt has similar binding as Compound A tetrasodium salt for methamphetamine, fentanyl and xylazine.Example 7. Solubility Comparison if There is Residual Sodium (RK)

[0195] Solubility measurements were achieved by adding 500 mg to a 1 mL volumetric flask and filling with water.Table 7: Solubility at varying the levels of sodium to arginine> > > >>43181440027

[0196] The solubility of the Compound A salt increased when at least one equivalence of arginine is present, with the tetra-arginine salt showing greatly superior solubility over the tetrasodium salt. The tetrasodium salt solubility is limited to approximately 100 mg / mL (in 0.45% saline) or 200 mg / mL in WFI.Example 8

[0197] Salts / complexes of organic amines with cucurbiturils having a molar ratio of 4: 1 were prepared from the cucurbituril sodium salt by first removing the sodium salt by ion exchange, followed by addition of four molar equivalents of the organic amine. Ion exchange resin was washed with 5 V of water three times. The washed resin was soaked is an aqueous solution of the cucurbituril sodium salt for 1 hour. The cucurbituril solution was separated from the resin by filtration. 4 molar equivalents of the organic amino acid was added to the cucurbituril solution. The mixture was evaporated to dryness in a Rotovap. A large excess of the resulting compound was added into a volumetric flask and water was added to the line. The mixture was set aside for 1 day, followed by filtration of any precipitated material to provide a saturated solution. The amount of the organic amine cucurbituril salt in the saturated solution was determined and the maximum solubility was confirmed by HPLC. The maximum solubility (reported as the amount of cucurbituril free acid; mg / ml) for organic amine: cucurbituril salts having a ratio of 4:1 at room temperature is reported in Table 8.Table 8>44181440027Example 9: In Vivo Efficacy Rat - Renal Excretion of Methamphetamine in Rats

[0198] Study of methamphetamine excretion in Sprague Dawley rats with Jugular Vein Catheter given a single IM dose of Compound A tetra-arginine salt. The rats were treated and tested according to the parameters in Table 9. Urine was collected via metabolic cage.Table 9: Study Design

[0199] The measured excretion of methamphetamine in each cohort is provided in Table 10.45181440027Table 10: Renal Excretion of Analytes after Treatment with Comp. A tetra-Arg salt.

[0200] The intramuscular administration of Compound A tetra-arginine salt significantly increases the excretion of unmetabolized methamphetamine in urine. The % recovery of unmetabolized methamphetamine in urine after administration of Compound A tetra-arginine salt is shown in Figure 5A (IV, IM, t = 5 min) and Figure 5B (IM, t = 5, 60, 120 min).Compound A tetra-arginine salt was effective at increasing the renal excretion of methamphetamine when administered by IM and when administered by IV.Example 10. In Vivo PK and Tolerability in Rats

[0201] A study of the tolerability and pharmacokinetics of Compound A tetrasodium salt and Compound A tetra-arginine salt in male Sprague Dawley rats administered a single IM dose of the Compound A salt. The study parameters are provided in Table 11 (IV administration) and Table 12 (IM administration).Table 1146181440027Table 12

[0202] Rats were administered a single, fast push of IV or IM Compound A tetrasodium salt and Compound A tetra-arginine salt (formulated to a dose level of 141 or 300 mg / kg free acid). IV administrations were performed by a jugular vein catheter and IM administrations were performed by injection in the thigh.

[0203] The pharmacokinetic properties of Compound A tetrasodium salt and Compound A tetra-arginine salt when administered by IV are provided in Table 13.Table 13

[0204] Compound A tetra-arginine salt was well tolerated as single IV bolus in the rat model. Figure 6A shows the plasma concentration over time for the IV administrations. The results demonstrate that, in IV administration Compound A tetra-arginine salt is approximately bioequivalent to tetrasodium salt on AUC (systemic exposure).

[0205] The pharmacokinetic properties of Compound A tetrasodium salt and Compound A tetra-arginine salt when administered by IM are provided in Table 14.47181440027Table 14

[0206] Compound A tetra-arginine salt was well tolerated as single IM injection to the thigh in the rat model. Figure 6B shows the plasma concentration over time for the IM administrations. The results demonstrate that, in IM administration Compound A tetraarginine salt is bioequivalent to tetrasodium salt based on AUC (systemic exposure).

[0207] Subjects given a single, quick push IV (JVC) or IM (thigh) injection of either 141 mg / kg or 300 mg / kg based on Comp. A free acid (as Comp. A tetra arginine salt). Systemic exposure based on route of administration (IV dose compared to IV dose, and IM dose compared to IM dose) to Compound A, as shown by Cmax and AUCiast, appeared to increase with increasing dose in a dose-proportionate manner (i.e., systemic exposure appears to increase with a linear effect proportional to dose level).Example 11. Dose Escalating Study in Dog, Crossover - CRL

[0208] A dose escalating study, crossover, with dose escalation was performed in dogs (n=l male, 1 female) with washout between doses. Compound A tetra-arginine salt was administered by IM bolus to the hind limb from 50 mg / kg up to 300 mg / kg (free acid)(2x doses for Phase 3 and 4). The study parameters are provided in Table 15.Table 15aDose levels were based on Compound A free acid content.bDose volume was split equally between two injection sites, one in each hind limb (0.417 mL / kg / site for Phase 3; 0.5 mL / kg / site for Phase 4).48181440027

[0209] Response and tolerability were monitored, and plasma concentration was monitored up to 8 hrs post-dose. The IM injections were well tolerated in dogs, with only slight swelling after injection, and no adverse changes in clinical chemistry or urinalysis observed. Exposure to Compound A free acid, as determined by individual Cmax and AUCo-24hr values, was observed to increase with increasing dose in an approximate dose proportional manner. The plasma concentration of Compound A (free acid, pg / mL) over time is shown in Figure 7.49181440027

Claims

1. We Claim:

1. A method of reducing the concentration of a toxic agent in the body of a patient comprising administering to the patient a composition comprising a therapeutically effective amount of a cucurbituril compound and an organic amine, wherein the molar ratio of the cucurbituril compound to the organic amine is from about 2:1 to about 1:6, or is from about 1 : 1 to about 1 :4, or is from about 1 :2 to about 1 :4.

2. The method of claim 1, wherein the organic amine is selected from an aliphatic amine, cyclic amine, aromatic amine, amino sugar, amino acid, amino acid derivative, or combinations thereof.

3. The method of claim 1, wherein the organic amine is an amino acid or amino acid derivative.

4. The method according to any one of claims 1 to 3, wherein the cucurbituril compound and the organic amine, are an organic amine salt of the cucurbituril compound.

5. The method according to any one of claims 1 to 4, wherein the toxic agent is a drug of abuse.

6. The method of claim 5, wherein the toxic agent comprises methamphetamine.

7. The method of claim 5 or claim 6, wherein the toxic agent comprises fentanyl or a fentanyl analog.

8. The method of claim 7, wherein the fentanyl analog is carfentanil.

9. The method according to any one of claims 5 to 8, wherein the toxic agent comprises xyl azine.

10. The method according to any one of claims 1 to 9, wherein the cucurbituril compound has a structure of formula I:or a pharmaceutically acceptable salt thereof, wherein:50181440027each R1Aand R1Dis independently selected from hydrogen, halogen, -OH, Ci-Ce alkyl, 2 to 6 membered heteroalkyl, C3-C6 cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-L-S(O)viX1, -O-L-CO2X1, and -O-L-POviX1;each R1Band R1Cis independently selected from hydrogen, halogen, -OH, Ci-Ce alkyl, 2 to 6 membered heteroalkyl, C3-C6 cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-L-S(O)viX1, -O-L-CO2X1, and -O-L-POviX1; or additionally or alternatively, two R1AR1B, R1Cand R1Dattached on the same phenyl ring at adjacent positions, together with atoms to which they are attached, are joined to form a fused C6-C12 aryl, 5 to 12 membered heteroaryl, or 5 to 7 membered heterocycle, which are optionally substituted with 1 to 3 substituents independently selected halogen, -OH, -NH2, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl;each L is independently selected from a single bond, Ci to Ce alkylene, or C2 to Ce alkenylene;each R3Aand R3Bis independently selected from hydrogen, halogen, -OH, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl;each R4Aand R4Bis independently selected from hydrogen, halogen, -OH, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl;each vl is independently selected from 2 or 3; andeach X1is independently selected from selected from H, -OH, Ci-Ce alkyl, alkali metal cation, quaternary ammonium cation, or an organic amine cation; and preferably at least one X1is an organic amine cation.

11. The method according to claim 10, wherein at least one X1is an organic amine cation; or two X1are organic amine cations; or three X1are organic amine cations; or each X1is an organic amine cation.

12. The method according to claim 11, wherein at least one X1is an amino acid cation; or two X1are amino acid cations; or three X1are amino acid cations; or each X1is an amino acid cation.

13. The method according to any one of claims 1 to 10, wherein the cucurbituril compound has a structure of formula (I-a) or formula (Il-a):51181440027or a pharmaceutically acceptable salt thereof, wherein R1A, R1D, R3A, R3B, R4A, and R4Bare defined for formula I.

14. The method of claim 13, wherein the cucurbituril compound of formula (I-a) or formula (Il-a) is an amino acid salt comprising at least one amino acid cation; or two amino acid cations; or three amino acid cations; or four amino acid cations.

15. The method according to any one of claims 1 to 10, wherein the cucurbituril compound has the formula (I-b):or a pharmaceutically acceptable salt thereof, wherein R1Aand R1Dare as described for formula I.

16. The method of claim 12, wherein the cucurbituril compound of formula (I-b) is an amino acid salt comprising at least one amino acid cation; or two amino acid cations; or three amino acid cations; or four amino acid cations.

17. The method according to any one of claims 1 to 10, wherein the cucurbituril compound has the formula (I-c):52181440027or a pharmaceutically acceptable salt thereof, wherein each X1is independently H, alkali metal cation, quaternary ammonium cation or an amino acid cation, and preferably at least one X1is an amino acid cation; or two X1are amino acid cations; or three X1are amino acid cations; or each X1is an amino acid cation; and each nl is 0 to 5, or each nl is 2 to 5, or each nl is 3 to 5, or each nl is 4 or 5.

18. The method according to any one of claims 1 to 9, wherein the cucurbituril compound has the formula (I- A):or a pharmaceutically acceptable salt thereof, wherein each X is independently H, alkali metal cation, quaternary ammonium cation or an amino acid cation, and preferably at least one X is an organic amine cation; or two X are organic amine cations; or three X are organic amine cations; or each X is an organic amine cation.

19. The method of claim 18, wherein at least one X is an amino acid cation; or two X are amino acid cations; or three X are amino acid cations; or each X is an amino acid cation.

20. The method according to any one of claims 1 to 10, wherein the cucurbituril compound is Compound A, having the following structure:53181440027or a pharmaceutically acceptable salt thereof.

21. The method of claim 20, wherein Compound A is a salt comprising an alkali metal cation, quaternary ammonium cation, or an organic amine cation; and preferably comprises at least one organic amine cation; or two organic amine cations; or three organic amine cations; or four organic amine cations.

22. The method of claim 21, wherein Compound A is a salt comprising at least one amino acid cation; or two amino acid cations; or three amino acid cations; or four amino acid cations.

23. The method according to any one of claims 1 to 22, wherein the amino acid is one or more of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, serine, arginine, cysteine, glutamine, glycine, proline, and tyrosine.

24. The method according to any one of claims 1 to 23, wherein the amino acid is one or more of arginine, glutamic acid, phenylalanine, histidine, lysine and tryptophan.

25. The method according to any one of claims 1 to 24, wherein the amino acid is arginine.

26. The method according to any one of claims 1 to 25, wherein the cucurbituril compound is Compound A and the amino acid is arginine.

27. The method according to any one of claims 1 to 13, wherein the cucurbituril compound has the formula (Il-b) :54181440027or a pharmaceutically acceptable salt thereof, wherein R1Aand R1Dare as described for formula I.

28. The method of claim 27, wherein the cucurbituril compound of formula (Il-b) is an amino acid salt comprising at least one amino acid cation; or two amino acid cations; or three amino acid cations; or four amino acid cations.

29. The method of claim 27, wherein the cucurbituril compound has the formula (II-c):or a pharmaceutically acceptable salt thereof, wherein each X1is independently H, alkali metal cation, quaternary ammonium cation or an amino acid cation, and preferably at least one X1is an organic amine cation; or two X1are organic amine cations; or three X1are organic amine cations; or each X1is an organic amine cation; and each nl is 0 to 5, or each nl is 2 to 5, or each nl is 3 to 5, or each nl is 4 or 5.

30. The method of claim 29, wherein the cucurbituril compound has the formula (II-B):or a pharmaceutically acceptable salt thereof, wherein each X is independently H, alkali metal cation, quaternary ammonium cation or an amino acid cation, and preferably at least one X is an organic amine cation; or two X are organic amine cations; or three X are organic amine cations; or each X is an organic amine cation.

31. The method of claim 30, wherein at least one X is an amino acid cation; or two X are amino acid cations; or three X are amino acid cations; or each X is an amino acid cation.5518144002732. The method of claim 29, wherein the cucurbituril compound is Compound B, having the following structure:or a pharmaceutically acceptable salt thereof.

33. The method of claim 32, wherein Compound B is a salt comprising an alkali metal cation, quaternary ammonium cation, or an organic amine cation; and preferably comprises at least one organic amine cation; or two organic amine cations; or three organic amine cations; or four organic amine cations.

34. The method of claim 33, wherein Compound B is a salt comprising at least one amino acid cation; or two amino acid cations; or three amino acid cations; or four amino acid cations.

35. The method according to any one of claims 27 to 34, wherein the amino acid is one or more of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, serine, arginine, cysteine, glutamine, glycine, proline, and tyrosine.

36. The method according to any one of claims 1 to 35, wherein the molar ratio of the cucurbituril compound to the organic amine is or from about 1 : 1 to about 1 :4.

37. The method according to any one of claims 1 to 36, wherein the molar ratio of the cucurbituril to the organic amine is from about 1 :2 to about 1 :4.

38. The method according to any one of claims 1 to 37, wherein the molar ratio of the cucurbituril to the organic amine is about 1 :

439. The method according to any one of claims 1 to claim 38, wherein the cucurbituril compound salt has the formula cucurbituril / AA / 3X, cucurbituril / 2AA / 2X, cucurbituril / 3 AA / X, or cucurbituril / 4AA; wherein AA is an amino acid or amino acid56181440027derivative, and X is independently selected from H or a cation selected from alkali metal cation or quaternary ammonium cation.

40. The method according to any one of claims 1 to claim 26, wherein the cucurbituril amino acid salt is Compound A tetra-arginine salt.

41. The method according to any one of claims 1 to claim 40, wherein the composition is an aqueous solution comprising the therapeutically effective amount of a cucurbituril compound and the organic amine.

42. The method of claim 41, wherein the aqueous solution is administered to the patient in need thereof by intramuscular injection.

43. The method of claim 41, wherein the aqueous solution is administered to the patient in need thereof by intravenous injection.

44. A pharmaceutical dosage form comprising:a cucurbituril compound,an organic amine, anda pharmaceutically acceptable carrier;wherein the molar ratio of the cucurbituril compound to the organic amine is from about 2: 1 to about 1 :6, or is from about 1 : 1 to about 1 :4, or is from about 1 :2 to about 1 :

4.

45. The pharmaceutical dosage form of claim 44, wherein the organic amine is selected from an aliphatic amine, cyclic amine, aromatic amine, amino sugar, amino acid, amino acid derivative, or combinations thereof.

46. The pharmaceutical dosage form of claim 44 or 45, wherein the organic amine is an amino acid or amino acid derivative.

47. The pharmaceutical dosage form according to any one of claims 44 to 46, wherein the cucurbituril compound and the organic amine, are an organic amine salt of the cucurbituril compound.

48. The pharmaceutical dosage form according to any one of claims 44 to 47, wherein the cucurbituril compound has a structure of formula I:57181440027or a pharmaceutically acceptable salt thereof, wherein:each R1Aand R1Dis independently selected from hydrogen, halogen, -OH, Ci-Ce alkyl, 2 to 6 membered heteroalkyl, C3-C6 cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-L-S(O)viX1, -O-L-CO2X1, and -O-L-POviX1;each R1Band R1Cis independently selected from hydrogen, halogen, -OH, Ci-Ce alkyl, 2 to 6 membered heteroalkyl, C3-C6 cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, -O-L-S(O)viX1, -O-L-CO2X1, and -O-L-POviX1; or additionally or alternatively, two R1AR1B, R1Cand R1Dattached on the same phenyl ring at adjacent positions, together with atoms to which they are attached, are joined to form a fused C6-C12 aryl, 5 to 12 membered heteroaryl, or 5 to 7 membered heterocycle, which are optionally substituted with 1 to 3 substituents independently selected halogen, -OH, -NH2, substituted or unsubstituted Ci-Ce alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl;each L is independently selected from a single bond, Ci to Ce alkylene, or C2 to Ce alkenylene;each R3Aand R3Bis independently selected from hydrogen, halogen, -OH, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl;each R4Aand R4Bis independently selected from hydrogen, halogen, -OH, Ci-Ce alkyl, phenyl, substituted phenyl and 2 to 6 membered heteroalkyl;each vl is independently selected from 2 or 3; andeach X1is independently selected from selected from H, -OH, Ci-Ce alkyl, alkali metal cation, quaternary ammonium cation, or an organic amine cation; and preferably at least one X1is an organic amine cation.

49. The pharmaceutical dosage form of claim 48, wherein at least one X1is an organic amine cation; or two X1are organic amine cations; or three X1are organic amine cations; or each X1is an organic amine cation.5818144002750. The pharmaceutical dosage form of claim 48, wherein at least one X1is an amino acid cation; or two X1are amino acid cations; or three X1are amino acid cations; or each X1is an amino acid cation.

51. The pharmaceutical dosage form according to any one of claims 44 to 48, wherein the cucurbituril compound has a structure of formula (I-a) or formula (Il-a):or a pharmaceutically acceptable salt thereof, wherein R1A, R1D, R3A, R3B, R4A, and R4Bare defined for formula I.

52. The pharmaceutical dosage form of claim 51, wherein the cucurbituril compound of formula (I-a) or formula (Il-a) is an organic amine salt salt comprising at least one organic amine cation; or two organic amine cations; or three organic amine cations; or four organic amine cations.

53. The pharmaceutical dosage form of claim 51, wherein the cucurbituril compound of formula (I-a) or formula (Il-a) is an amino acid salt comprising at least one amino acid cation; or two amino acid cations; or three amino acid cations; or four amino acid cations.

54. The pharmaceutical dosage form according to any one of claims 44 to 53, wherein the cucurbituril compound has a structure of formula (I-b):59181440027or a pharmaceutically acceptable salt thereof, wherein R1Aand R1Dare as described for formula I.

55. The pharmaceutical dosage form of claim 54, wherein the cucurbituril compound of formula (I-b) is an amino acid salt comprising at least one amino acid cation; or two amino acid cations; or three amino acid cations; or four amino acid cations.

56. The pharmaceutical dosage form according to any one of claims 44 to 55, wherein the cucurbituril compound has a structure of formula (I-c):or a pharmaceutically acceptable salt thereof, wherein each X1is independently H, alkali metal cation, quaternary ammonium cation or an organic amine cation, and preferably at least one X1is an organic amine cation; or two X1are organic amine cations; or three X1are organic amine cations; or each X1is an organic amine cation; and each nl is 0 to 5, or each nl is 2 to 5, or each nl is 3 to 5, or each nl is 4 or 5.

57. The pharmaceutical dosage form according to any one of claims 44 to 56, wherein the cucurbituril compound has a structure of formula (I- A):60181440027or a pharmaceutically acceptable salt thereof, wherein each X is independently H, alkali metal cation, quaternary ammonium cation or an organic amine cation, and preferably at least one X is an organic amine cation; or two X are organic amine cations; or three X are organic amine cations; or each X is an organic amine cation.

58. The pharmaceutical dosage form according to any one of claims 47 to 57, wherein the cucurbituril compound is Compound A, having the following structure:or a pharmaceutically acceptable salt thereof.

59. The pharmaceutical dosage form of claim 58, wherein Compound A is a salt comprising an alkali metal cation, quaternary ammonium cation, or an organic amine cation; and preferably comprises at least one organic amine cation; or two organic amine cations; or three organic amine cations; or four organic amine cations.

60. The pharmaceutical dosage form of claim 58 or 59, wherein Compound A is a salt comprising at least one amino acid cation; or two amino acid cations; or three amino acid cations; or four amino acid cations.

61. The pharmaceutical dosage form according to any one of claims 44 to 60, wherein the organic amine is an amino acid selected from one or more of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, serine, arginine, cysteine, glutamine, glycine, proline, and tyrosine.6118144002762. The pharmaceutical dosage form according to any one of claims 44 to 61, wherein the organic amine is an amino acid selected from one or more of arginine, glutamic acid, phenylalanine, histidine, lysine and tryptophan.

63. The pharmaceutical dosage form according to any one of claims 44 to 62, wherein the amino acid is arginine.

64. The pharmaceutical dosage form according to any one of claims 44 to 63, wherein the cucurbituril compound is Compound A and the amino acid is arginine.

65. The pharmaceutical dosage form according to any one of claims 44 to claim 64, wherein the cucurbituril amino acid salt is Compound A tetra-arginine salt.

66. The pharmaceutical dosage form according to any one of claims 44 to 53, wherein the cucurbituril compound has the structure of formula (Il-b):or a pharmaceutically acceptable salt thereof, wherein R1Aand R1Dare as described for formula I.

67. The pharmaceutical dosage form of claim 66, wherein the cucurbituril compound of formula (Il-b) is an amino acid salt comprising at least one amino acid cation; or two amino acid cations; or three amino acid cations; or four amino acid cations.

68. The pharmaceutical dosage form of claim 66, wherein the cucurbituril compound has a structure of formula (II-c):62181440027or a pharmaceutically acceptable salt thereof, wherein each X1is independently H, alkali metal cation, quaternary ammonium cation or an amino acid cation, and preferably at least one X1is an organic amine cation; or two X1are organic amine cations; or three X1are organic amine cations; or each X1is an organic amine cation; and each nl is 0 to 5, or each nl is 2 to 5, or each nl is 3 to 5, or each nl is 4 or 5.

69. The pharmaceutical dosage form of claim 68, wherein the cucurbituril compound has a structure of formula (II-B):or a pharmaceutically acceptable salt thereof, wherein each X is independently H, alkali metal cation, quaternary ammonium cation or an amino acid cation, and preferably at least one X is an organic amine cation; or two X are organic amine cations; or three X are organic amine cations; or each X is an organic amine cation.

70. The pharmaceutical dosage form of claim 69, wherein at least one X is an amino acid cation; or two X are amino acid cations; or three X are amino acid cations; or each X is an amino acid cation.

71. The pharmaceutical dosage form of claim 69, wherein the cucurbituril compound is Compound B, having the following structure:63181440027or a pharmaceutically acceptable salt thereof.

72. The pharmaceutical dosage form of claim 71, wherein Compound B is a salt comprising an alkali metal cation, quaternary ammonium cation, or an organic amine cation; and preferably comprises at least one organic amine cation; or two organic amine cations; or three organic amine cations; or four organic amine cations.

73. The pharmaceutical dosage form of claim 71, wherein Compound B is a salt comprising at least one amino acid cation; or two amino acid cations; or three amino acid cations; or four amino acid cations.

74. The pharmaceutical dosage form according to any one of claims 66 to 73, wherein the amino acid is one or more of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, serine, arginine, cysteine, glutamine, glycine, proline, and tyrosine.

75. The pharmaceutical dosage form according to any one of claims 44 to 74, wherein the molar ratio of the cucurbituril compound to the organic amine is or from about 1 : 1 to about 1:4.

76. The pharmaceutical dosage form according to any one of claims 44 to 75, wherein the molar ratio of the cucurbituril to the organic amine is from about 1 :2 to about 1 :4.

77. The pharmaceutical dosage form according to any one of claims 44 to 75, wherein the molar ratio of the cucurbituril to the organic amine is from about 1 :4.

78. The pharmaceutical dosage form according to any one of claims 44 to claim 77, wherein the cucurbituril compound salt has the formula cucurbituril / AA / 3X, cucurbituril / 2AA / 2X, cucurbituril / 3 AA / X, or cucurbituril / 4AA; wherein AA is the amino acid cation, and X is independently selected from H or a cation selected from alkali metal cation or quaternary ammonium cation.6418144002779. The pharmaceutical dosage form according to any one of claims 44 to 78, wherein the dosage form is a solid for reconstitution into an injectable solution, the dosage form comprising the cucurbituril compound, the organic amine, optionally a buffering agent, and optionally a tonicity agent.

80. The pharmaceutical dosage form according to any one of claims 44 to claim 78, wherein the pharmaceutical dosage form is an aqueous solution comprising the therapeutically effective amount of the cucurbituril compound, the organic amine, optionally a buffering agent, and optionally a tonicity agent.

81. The pharmaceutical dosage form of claim 80, wherein the aqueous solution is for administration to a patient in need thereof by intramuscular injection.

82. The pharmaceutical dosage form of claim 81, wherein the dosage form comprises the cucurbituril compound in an amount of from about 100 mg to about 1000 mg, or from about 100 mg to about 600 mg, or from about 300 mg to about 500 mg (based on the free acid of the cucurbituril compound).

83. The pharmaceutical dosage form of claim 82, wherein each injectable IM dosage has a volume of from about 0.5 ml to about 5 ml; or from about 0.5 ml to about 3 ml; or from about 1 ml to about 3 ml.

84. The pharmaceutical dosage form of claim 80, wherein the aqueous solution is for administration to a patient in need thereof by intravenous injection.

85. The pharmaceutical dosage form of claim 84, wherein the dosage form comprises the cucurbituril compound in an amount of from 125 mg to 1700 mg; or from 125 mg to 1200 mg; or from 500 mg to 1200 mg; or from 900 mg to 1100 mg (based on the free acid of the cucurbituril compound).

86. The pharmaceutical dosage form of claim 85, wherein the volume of the dosage administered by IV infusion to the patient is from about 40 ml to about 300 ml; or from about 50 ml to about 150 ml.6518144002787. The pharmaceutical dosage form according to any one of claims 44 to 86, for use in a method of reducing the concentration of a toxic agent in the body of a patient.

88. The pharmaceutical dosage form of claim 87, wherein the toxic agent is a drug of abuse.

89. The pharmaceutical dosage form of claim 88, wherein the toxic agent comprises methamphetamine .

90. The pharmaceutical dosage form of claim 88 or 89, wherein the toxic agent comprises fentanyl or a fentanyl analog.

91. The pharmaceutical dosage form of claim 90, wherein the fentanyl analog is carfentanil.

92. The pharmaceutical dosage according to any one of claims 88 to 91, wherein the toxic agent comprises xylazine.66181440027

Images