NL2031332B1 - Transmucosal delivery of psychoactive compounds - Google Patents

Abstract

The present disclosure relates to psychoactive, such as psychedelic compounds, pharmaceutical formu— lations and dosage units for the transmucosal delivery of psychoactive compounds, comprising a sweet— ener salt or sweetener ionic liquid of a psychoactive compound. The compounds, formulations and dos— age units according to the invention are advantageously employed in a method for the nasal, buccal, sublabial, or sublingual administration of a psychoactive, such as a psychedelic compound to a subject. Also disclosed are compounds, formulations and compositions for use as a medicament in a method of prophylactically or curatively treating a subject suffering from a psychiatric disease or disorder.

Description

P335394NL 1

TRANSMUCOSAL DELIVERY OF PSYCHOACTIVE COMPOUNDS

Field of the invention

[001] The present invention is in the field of psychoactive compounds. More specifically, it relates to transmucosal administration of psychoactive compounds and to dosage units for the transmucosal ad- ministration of psychoactive compounds. The transmucosal dosage units according to the invention are advantageously employed as a medicament for use in the nasal, sublingual, sublabial or buccal admin- istration of psychoactive compounds to a subject in need thereof. The invention further relates to a method for reducing mucosal irritation in a composition for nasal, sublingual, sublabial or buccal trans- mucosal administration of psychoactive compounds to a subject. Also disclosed are compounds and compositions for use as a medicament in a method of prophylactically or curatively treating a subject suffering from a psychiatric disease or disorder.

Background of the Invention

[002] Psychoactive compounds, including psychedelics and hallucinogens, are undergoing a revival with a very strong increase in scientific research and pharmaceutical development of the compounds to treat mental health disorders. Classical psychedelics are a group of substances that are based on phene- thylamine, lysergamide (including lysergic acid diethylamide, LSD) or tryptamine structural scaffolds.

Even though their structural scaffolds are different, the main mechanism for psychedelic action in these compounds is primarily mediated by the same activation of the 5-HT.a serotonin receptor in the central nervous system.

[003] Psilocybin (a tryptamine derivative) is currently the most researched psychedelic, which unfortu- nately has a long-lasting pharmacological action. The long-lasting pharmacological effects of psychedel- ics such as psilocybin and LSD are impractical and costly from a therapeutic perspective.

[004] Short-acting psychedelics have similar pharmacological effects in a shorter time frame and offer significant practical benefits for hallucinogenic- or psychedelic-assisted therapy of mental health disor- ders.

[005] Psychedelics were intensely studied between the 1950s and early 1970s as potential models for and treatments of neuropsychiatric disorders. Following the early 1970s, international governmental intervention and regulation ground psychedelic research to an almost complete halt. After decades of little clinical and pharmaceutical research, there is a strong renewed interest in psychedelics as potential treatments for neuropsychiatric disorders

[006] The FDA has recently designated breakthrough therapy status to the phenethylamine derivative 3,4-methylenedioxymethamphetamine (MDMA) for treatment of post-traumatic stress disorder (PTSD),

P335394NL 2 and to the psychedelic tryptamine derivative psilocybin for treatment of major depressive disorder and treatment-resistant depression. FDA breakthrough therapy designation expedites development and re- view of drugs that treat serious conditions and show clinical evidence that may significantly improve clinical endpoints over available therapies.

[007] The psychedelic tryptamines are of major interest due to their high clinical potential, the large number of psychedelic substances available in this class, their benign safety profile and the lack of de- pendence in subjects treated therewith. Intensifying scientific research efforts are directed to psyche- delic tryptamines, focusing on their mechanisms of action, potential medical applications, formulations and chemical synthesis.

[008] Research towards phenethylamine psychedelics is also intensifying, including a recent applica- tion for clinical trials using mescaline (3,4,5-trimethoxyphenethylamine). The phenethylamine derivative

MDMA, also referred to as an entactogen and psychedelic, is currently undergoing phase-3 clinical trials for treatment of post-traumatic stress disorder (PTSD).

[009] In the broader category of psychoactive substances that are increasingly being used to treat neuropsychiatric disorders, ketamine and its derivatives are becoming increasingly relevant. Ketamine {(RS)-2-(2-chlorophenvyl)-2-(methylamino)cyclohexanone) is a non-classical psychedelic and a dissocia- tive anaesthetic in the arylcyclohexylamine class of compounds. Similar to classical psychedelics, keta- mine and related arylcyclohexylamines can cause hallucinations while additionally also inducing dissoci- ation. Ketamine was first reported to have fast-acting antidepressant effect in 2000, with significant re- duction of depressive symptoms after infusion of ketamine (Berman et al, Biol. Psychiatry 2000, 47 (4), 351-354). Since then, many studies have demonstrated the safety and efficacy of ketamine treatment of depression. The rapid-onset antidepressant effect can be especially useful in acute cases, such as for sui- cidal patients. Ketamine, and arylcyclohexylamine compounds in general, have been found to possess

NMDA receptor antagonistic, dopamine reuptake inhibitory, and/or p-opioid receptor agonistic proper- ties, and have also been reported to enhance the function of the 5-HT, serotonin receptor (Lin et al.,

Experimental & Molecular Medicine (2018) 50:47).

[010] In principle, these psychoactive compounds may be administered to a subject in need of such a psychoactive agent in a variety of ways. The most common administration routes include oral admin- istration (ingestion), sublingual and sublabial administration, buccal administration, (intra)nasal admin- istration and injection (intravenous, intramuscular or subcutaneous). Of these administration routes, injection is very efficient. However, injection is invasive and not patient-friendly, especially considering that psychoactive-assisted therapy is strongly influenced by set and setting, i.e. starting a psychoactive- assisted therapy session with an injection can cause anxiety or trigger phobias in some patients and may negatively impact the therapeutic outcome.

P335394NL 3

[011] A more patient-friendly delivery route for psychoactive compounds would be either oral inges- tion, absorption in the oral cavity (sublingual, sublabial or buccal) or intranasal application, as these are generally painless, non-invasive, patient-friendly administration routes, and in addition allow a great flexibility for the manufacturer in the design of inexpensive and easy to produce dosage forms as com- pared to injectables.

[012] However, the use of orally ingested forms such as pills and capsules can be disadvantageous, because these must first undergo first-pass hepatic metabolism and thus may produce a slower onset of the pharmacological effect and/or reduce the amount of active compound ending up in the subject's systemic circulation (“low bioavailability”). Due to this strong first-pass metabolism, oral administration of many psychoactive compounds requires high doses in order to reach therapeutically effective plasma levels. In some cases, the first-pass metabolism is so extensive that it is not possible to reach therapeuti- cally effective plasma levels with oral ingestion. These high doses may result in unwanted effects such as gastrointestinal (GI) tract disturbances.

[013] Oral or nasal transmucosal drug delivery, i.e. the administration of psychoactive compounds through the sublingual, sublabial, buccal or nasal mucosa, is an alternative method for systemic drug de- livery that does not suffer from the aforementioned problems. Due to the high oral and nasal mucosal vascularity, buccally, sublabially- or sublingually-delivered drugs can gain direct access to the systemic circulation and bypass the hepatic first-pass metabolism, resulting in a faster onset of action than tradi- tional orally ingested forms and a higher bioavailability of the active compound. In addition, psychoac- tive compounds administered via the nasal, sublingual, sublabial or buccal route are not exposed to the acidic environment of the gastrointestinal tract and will likely cause considerably less nausea or gastro- intestinal discomfort. Moreover, particularly the oral mucosal membranes have low enzymatic activity.

Hence, the propensity for psychoactive drug inactivation due to biochemical degradation is lower than for other administration routes.

[014] Since the oral and nasal mucosal membranes of subjects are highly accessible, oral and nasal transmucosal administration allows for the use of dosage forms which can be efficiently and painlessly administered and removed, and easily targeted.

[015] However, psychoactive compounds are generally known to cause irritation of the oral and nasal mucous membrane. This mucosal irritation may manifest itself with pain, with increased redness, with lesions like ulcers, erosion or blisters, with itching, dryness, crusting, cracking or bleeding, as a burning, tingling or stinging sensation, or any combination thereof, upon administration of the compound to a nasal, buccal, sublabial and/or sublingual cavity of a subject.

[016] These possible side-effects related to mucosal irritation upon nasal or oral transmucosal admin- istration of psychoactive compounds limit the application possibilities in terms of scope of choice of

P335394NL 4 psychoactive compounds and administrable concentration range of psychoactive compound, and result in poor patient acceptability and low therapy compliance.

[017] The use of taste masking compounds, such as sweeteners or flavourings, is unlikely to have any perceptible effect on mucous membrane irritation as the chemosensitive pathways that transmit taste are different from those involved in sensing of pain and localized irritation in general,

[018] US2007134331A1 is concerned with sublingual formulations of the anti-depressant agomelatine necessitated by the low oral bioavailability of the drug. Mucous membrane irritation caused by agomelatine is controlled by providing a formulation comprising a central core comprising agomelatine and excipients that allow an oro-dispersible formulation to be obtained, and one or more oro-dispersi- ble coatings, wherein the orodispersible coating contains specific diluents and/or disintegrating agents.

[019] Mucous membrane irritation has also been attempted to be controlled by the addition of desen- sitizing pharmaceutical agents, such as local anaesthetics. WO1999015171A1 describes a formulation for nicotine that reduces the perception of local irritation by the addition of the local anaesthetics ben- zocaine or similar substances.

[020] EP170389681 disclosed a method to reduce nasal mucous membrane irritation in a high dosage intranasal midazolam spray. Due to the high dosage required, considerable irritation to the mucous membranes and a bitter tasting drip in the back of the throat had to be resolved. Lowering the pH of the nasal spray solution allowed for an increased concentration of midazolam and therefore a smaller spray volume could be applied to the nasal cavity. The smaller area exposed to the drug increased the tolera- bility of the formulation by reducing the local irritation and the bitter drip.

[021] The solutions provided in the publications described above are aimed at the application of spe- cific administration vehicles or the addition of specific pharmaceutical agents. They are therefore limited to the choice of specific dosage forms, requiring specific external and/or internal materials such as wall materials, hydrogels and further additives. This further limits the choice of active compounds suitable for use with these administration vehicles, and increases the complexity of manufacture of the dosage form.

[022] As will be apparent from the above, there is an unmet need in the art for formulations and dos- age forms (i) that can be used for the oral or nasal transmucosal delivery of psychoactive compounds without causing undesirable side-effects, (ii) that provide a wide choice in psychoactive compounds and concentrations to be incorporated therein, (iii) that provide broad flexibility in the choice of dosage form and associated additives and (iv) that can be administered in a convenient and reliable manner, thus im- proving patient acceptability and therapy adherence.

Summary of the Invention

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[023] The inventors have unexpectedly discovered that salts and ionic liquids formed from psychoac- tive compounds and artificial sweeteners show a strong reduction of mucosal irritation upon the nasal, buccal, sublabial or sublingual administration thereof,

[024] Thus, in a first aspect of the present disclosure, there is provided a salt or ionic liquid repre- 5 sented by the general formula P’X, wherein P represents a psychoactive compound and X represents an artificial sweetener.

[025] Surprisingly, it was found that such salts and ionic liquids derived from a psychoactive com- pound and an artificial sweetener are capable of effective nasal or oral transmucosal delivery of the ac- tive compounds without causing the irritation of the nasal or oral mucosa that may typically be ob- served for intranasal, buccal, sublabial and sublingual administration of such compounds.

[026] Thus, in another aspect there is provided a composition comprising an ionic liquid or a salt of a prophylactically or therapeutically effective amount of psychoactive compound and an artificial sweet- ener.

[027] Such compositions are particularly suitable for nasal, sublingual, sublabial or buccal administra- tion of a wide variety of psychoactive compounds, in particular psychoactive compounds that suffer from poor oral bioavailability and/or that require rapid onset of the desired biological effect. They are particularly suitable for administration to subjects who are unable to tolerate oral ingestion of psychoac- tive compounds because of nausea, vomiting, malabsorption or dysphagia. They may further be attrac- tive for patients who cannot receive parenterally administrated psychoactive medication because of the lack of venous access or the presentation of typical contraindications for psychoactive drug administra- tion via injection.

[028] Accordingly, in a further aspect there is provided a dosage unit for oral or nasal transmucosal administration of a psychoactive compound to a subject, wherein the transmucosal dosage unit com- prises a salt or ionic liquid as defined herein.

[029] The compositions presented by the present disclosure allows for a great flexibility in the choice of psychoactive compounds, such as those compounds that have a low oral bioavailability or those which can be administered only by injection. The present dosage units that can be disintegrated, dis- solved, or suspended by saliva in the mouth or nasally administered can provide significant benefits to the patient populations as described herein, as well as other subjects who prefer the convenience of easily administrable dosage forms, that do not require water for ingestion or injections. As such, the compositions and dosage units of the present disclosure may contribute to improved patient compli- ance and convenience.

[030] Without wishing to be bound to theory, it is the inventors’ belief that the formation of sweet- ener salts or ionic liquids of the psychoactive compounds impacts their solubility, dissolution rate and

P335394NL 6 pH properties, resulting in a synergy that enables the psychoactive compounds to be effectively used in transmucosal administration.

[031] Another aspect of the invention relates to a method for reducing mucosal irritation in a subject upon nasal or oral transmucosal administration of a psychoactive compound to the subject, wherein said method comprises providing the psychoactive compound as a salt or ionic liquid as disclosed herein.

General Description of the Invention

[032] Accordingly, one aspect of the invention relates to a salt or ionic liquid represented by the gen- eral formula (P*)(X'), wherein P represents a psychoactive compound and X represents an artificial sweetener,

[033] The ionic liquid or salt is of the formula (P*)(X), wherein P" is a cationic component of the ionic liquid or salt and X7 is an anionic component of the ionic liquid or salt, The formula (P*)}(X") is meant to encompass a cationic component {P*) having any valency of positive charge, and an anionic component (X7) having any valency of negative charge, provided that the charge contributions from the cationic por- tion and anionic portion are counterbalanced in order for charge neutrality to be preserved in the ionic liquid or solid salt. More specifically, the formula (P*)(X"} is meant to encompass the more generic for- mula (P*2),(X®)x, wherein the variables a and b are, independently, non-zero integers, and the subscript variables x and y are, independently, non-zero integers, such that a-y=b-x.

[034] Thus, as used herein, the term “a salt of an artificial sweetener and a psychoactive compound” or “a salt derived from artificial sweetener and a psychoactive compound” refers to a salt represented by the general formula (P*}(X'), wherein P represents the psychoactive compound and X represents the artificial sweetener; likewise, the term “an ionic liquid of an artificial sweetener and a psychoactive com- pound” or “an ionic liquid derived from an artificial sweetener and a psychoactive compound” refers to an ionic liquid represented by the general formula (P*)(X'), wherein P represents the psychoactive com- pound and X represents the artificial sweetener.

[035] As used herein the term “ionic liquid” refers to a salt having a melting point below 100 °C. Typi- cally, the ionic liquids of the present disclosure have a melting point below room temperature, and are therefore liquid at normal temperature and pressure, i.e. 20 °C and 1 atm (abs).

[036] As used herein the term “artificial sweetener” refers to a compound that provides a sweet taste like that of sugar while providing significantly less food energy than sugar-based sweeteners. Such artifi- cial sweeteners are also known as “synthetic sweeteners”, “non-nutritive sweeteners” or “low-calorie sweeteners” or “zero-calorie sweeteners”. The term does not include reduced-calorie plant-derived (i.e,

P335394NL 7 non-artificial and non-synthetic) sugar alcohol sweeteners such as sorbitol, xylitol, mannitol, erythritol, and lactitol.

[037] Suitable sweeteners according to the present disclosure are all sweeteners which can form a salt with the respective psychoactive compound with formation of an at least singly negatively charged ion.

According to the invention, ionic liquids and salts are also included in which the psychoactive compound has two or more different sweeteners as anion-forming components.

[038] in one embodiment, the sweetener is an acidic sweetener, i.e. a sweetener that is capable of donating one or more protons to form its corresponding anion; as used herein, this definition includes those sweeteners that are normally present in the form of a salt with a suitable cation, such as alkali metals, such as sodium (Na*) or potassium (K*) cations, or alkaline earth metals, such as calcium (Ca?) or magnesium (Mg*) cations.

[039] Non-limiting examples of suitable artificial sweeteners are those that are known in the art as anion-forming sweeteners and are in widespread use in foodstuffs as safe non-nutritive sweeteners, in- cluding saccharin, cyclamate, and acesulfame. They further include dipeptide based sweeteners such as

L-aspartic acid derived sweeteners, including aspartame, alitame, neotame, and materials described in

U.S. Pat. No. 3,492,131; N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-a-aspartyl}-L-phenylalanine 1- methyl ester, N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methyl-butyl}-L-a-aspartyi}-L-phenylalanine 1- methyl ester, N-[N-[3-(3-methoxy-4-hydroxyphenyl}-propyl}-L-a-aspartyl]-L-phenylalanine 1-methyl es- ter, and mixtures thereof; other examples include trichloro-sucrose (sucralose}, neohesperidine DC, thaumatin, glycyrrhizin, mogroside IV, mogroside V, and cyclocarioside 1.

[040] Preferable, in the salt or ionic liquid represented by the general formula P*, wherein X repre- sents an artificial sweetener compound, X is selected from saccharinate, cyclamate, aspartate, alitame, neotame, and acesulfame, more preferably saccharinate, cyclamate, and acesulfame, most preferably saccharinate.

[041] Suitable psychoactive compounds for formation of the ionic liquids or salts with an artificial sweetener are in principle all therapeutically (prophylactically or curatively) effective psychoactive com- pounds.

[042] As used herein the terms “psychoactive compound” and “psychoactive agent” refer to a com- pound that changes functioning of the nervous system and results in alterations in perception, mood, consciousness, cognition, and/or behaviour .

[043] In an embodiment, the psychoactive compounds for use according to the present disclosure are selected from compounds that exert their effects primarily through activation of the serotonergic sys- tem, and in particular through activation of the 5-HT.a serotonin receptor in the central nervous system, and N-methyl-D-aspartate (NMDA) receptor antagonists. These specific categories of psychoactive

P335394NL 8 compounds are generally known as “hallucinogens” or “hallucinogenic” agents/compounds/substances, whereby the serotonergic hallucinogens typically have a psychedelic effect and are generally referred to as “psychedelics”, and the N-methyl-D-aspartate (NMDA) receptor antagonists typically have dissocia- tive effects and are generally referred to as “dissociatives”.

[044] Thus, in an embodiment, the psychoactive compound is a hallucinogenic compound.

[045] Ina particular embodiment, the psychoactive compound is a psychedelic or a dissociative com- pound, preferably a psychedelic compound.

[046] In an embodiment, the psychoactive, preferably psychedelic, compounds for use according to the present disclosure are selected from the group consisting of psychoactive tryptamine derivatives, psychoactive phenethylamine derivatives, psychoactive ketamine derivatives, and psychoactive phency- clidine (PCP) derivatives.

[047] Thus, in an embodiment, there is provided a salt or an ionic liquid represented by the general formula P*X, wherein P represents a compound selected from the group consisting of psychedelic tryp- tamine derivatives, psychedelic phenethylamine derivatives, psychedelic ketamine derivatives, and psy- chedelic phencyclidine (PCP) derivative and wherein X represents an artificial sweetener.

[048] The term “derivative” refers as used herein refers to compounds that are derived from the ref- erenced compound by substitution with one or more functional groups and the maintain the same core structure as the compound from which they are derived. As such, the terms “tryptamine derivative”, “phenethylamine derivative”, “ketamine derivative”, and “phencyclidine derivative” are considered equivalent to the terms “substituted tryptamine”, “substituted phenethylamine”, “substituted keta- mine”, and “substituted phencyclidine”. Examples of suitable tryptamine derivatives, phenethylamine derivatives, ketamine derivatives, and phencyclidine derivatives are described in detail below.

[049] The compounds in the classes of tryptamine derivatives, phenethylamine derivatives, ketamine derivatives, and phencyclidine derivatives as described herein are characterized by having a primary, secondary or tertiary amine moiety and one or more monocyclic or bicyclic aromatic moieties.

[050] The invention concerns amongst other things the treatment of a disease or disorder. The term “treatment”, and the therapies encompassed by this invention, include the following and combinations thereof: (1) hindering, e.g. delaying initiation and/or progression of, an event, state, disorder or condi- tion, for example arresting, reducing or delaying the development of the event, state, disorder or condi- tion, or a relapse thereof in case of maintenance treatment or secondary prophylaxis, or of at least one clinical or subclinical symptom thereof; (2} preventing or delaying the appearance of clinical symptoms of an event, state, disorder or condition developing in an animal (e.g. human) that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or sub- clinical symptoms of the state, disorder or condition; and/or (3) relieving and/or curing an event, state,

P335394NL 9 disorder or condition {e.g., causing regression of the event, state, disorder or condition or at least one of its clinical or subclinical symptoms, curing a patient or putting a patient into remission). The benefit to a patient to be treated may be either statistically significant or at least perceptible to the patient or to the physician. It will be understood that a medicament will not necessarily produce a clinical effect in each patient to whom it is administered; thus, in any individual patient or even in a particular patient popula- tion, a treatment may fail or be successful only in part, and the meanings of the terms “treatment” and “prophylaxis” and of cognate terms are to be understood accordingly. The compositions and methods described herein are of use for therapy and/or prophylaxis of the mentioned conditions.

[051] The term “prophylaxis” includes reference to treatment therapies for the purpose of preserving health or inhibiting or delaying the initiation and/or progression of an event, state, disorder or condi- tion, for example for the purpose of reducing the chance of an event, state, disorder or condition occur- ring. The outcome of the prophylaxis may be, for example, preservation of health or delaying the initia- tion and/or progression of an event, state, disorder or condition. It will be recalled that, in any individual patient or even in a particular patient population, a treatment may fail, and this paragraph is to be un- derstood accordingly.

[052] As used herein, the term "alkyl", used either alone or in compound words such as "alkylthio" or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the dif- ferent butyl isomers. "Alkenyl” includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl isomers. “Alkeny!” also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. "Alkynyl” includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2- propynyl and the different butynyl isomers.

[053] The term "alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy isomers. “Alkenyloxy” includes straight-chain or branched alkenyloxy moieties. Exam- ples of "alkenyloxy" include H,C=CHCH,0, (CH3HC=CHCH20, (CH3)CH=CHCH,O, (CH3)CH=C{CH3)CH,0 and

CH,=CHCH,CH,0. "Alkynyloxy" includes straight-chain or branched atkynyloxy moieties. Examples of “at kynyloxy" include HC=CCH,0, CH3C=CCH20 and CH3C=CCH2CH:0.

[054] “Alkylthio" includes branched or straight-chain alkylthio moieties such as methyithio, ethylthio, and the different propyithio and butylthio isomers. "Alkylthioalkyl” denotes alkylthio substitution on al- kyl. Examples of “alkylthioalkyl" include CH3SCH,;, CH3SCH2CH,, CHsCH2SCH>, CH3CH2CH2CH2SCH2 and

CH3CH2SCH;CH:.

[055] “Alkylthioalkoxy" denotes alkylthio substitution on alkoxy. "Cyanoalkyl" denotes an alkyl group substituted with one cyano group. Examples of "cyanoalky!" include NCCH;, NCCH,CH, and

CH3CH(CN)CH..

[056] "Alkylamino", "dialkylamino", and the like, are defined analogously to the above examples.

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[057] The term "halogen", either alone or in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" includes fluorine, chlorine, bromine or iodine. Fur- ther, when used in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" or "alkyl substituted with halogen" include FC, CICH,,

CF3CH; and CF3CCk. The terms "haloalkoxy”, and the like, is defined analogously to the term "haloalkyl".

Examples of "haloalkoxy” include CF30-, CCl3CH20-, HCF2CH2CH20- and CF3CH;0-. "Alkylcarbonyl" de- notes a straight-chain or branched alkyl moieties bonded to a C(=0) moiety. Examples of ”alkylcarbonyl!" include CH;C(=0}-, CH3CH,CH,C(=0}- and (CH3HCHC{=O)}-. Examples of ”alkoxycarbony!" include

CH30C(=0}-, CH3CH,0C(=0)-, CH3CH2CH20C{=0}-, (CH3HCHOC(=0)- and the different butoxycarbonyl iso- mers.

[058] The number of carbon atoms in a substituent group is indicated by the "C-C/” prefix where i and j are numbers from 1 to 4. For example, C;-C; alkylsulfonyl designates methylsulfonyl through butyl- sulfonyl (including various Ca isomers); Ci1alkoxy-Caalkyl designates CH3OCH.CH,; Cialkoxy-Caalkyl desig- nates, for example, CH3CH(OCH:3)- or CH3OCH;CH>-.

[059] The psychoactive compounds as disclosed herein can be present in the form of one of the iso- mers which are possible or as a mixture of these, for example in the form of pure isomers, such as an- tipodes and/or diastereomers, or as isomer mixtures, such as enantiomer mixtures, for example race- mates, diastereomer mixtures or racemate mixtures, depending on the number, absolute and relative configuration of asymmetric carbon atoms which occur in the molecule and/or depending on the config- uration of non-aromatic double bonds which occur in the molecule; the invention relates to the pure isomers and also to all isomer mixtures which are possible and is to be understood in each case in this sense hereinabove and hereinbelow, even when stereochemical details are not mentioned specifically in each case.

[060] The term “cycloalkyl” as used herein includes reference to an alicyclic moiety having 3, 4,5 or 6 carbon atoms. The group may be a bridged or polycyclic ring system. More often cycloalkyl groups are monocyclic. This term includes reference to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclo- hexyl and the like.

[061] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, con- sisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of nitrogen, oxygen, phosphorus and sulphur. The heteroatom(s) nitrogen, oxygen, phosphorus and sul- phur 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.

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[062] The term "heterocycloalkyl” as used herein includes reference to a saturated heterocyclic moi- ety having 3, 4, 5, 6 or 7 ring carbon atoms and 1, 2, 3, 4 or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulphur. For example, a heterocycloalkyl may comprise 3, 4, or 5 ring carbon atoms and 1 or 2 ring heteroatoms selected from O, N, P, and S. The group may be a polycyclic ring sys- tem but more often is monocyclic. This term includes reference to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyt, pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyt, morpholinyl, thiomorpholinyl, quinolizidinyl and the like.

[063] It will, of course, be understood that substituents are only at positions where they are chemi- cally possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible. For example, amino or hy- droxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. ole- finic) bonds. Additionally, it will of course be understood that the substituents described herein may themselves be substituted by any substituent, subject to the aforementioned restriction to appropriate substitutions as recognised by the skilled person.

[064] Where steric issues determine placement of substituents on a group, the isomer having the low- est conformational energy may be preferred.

[065] Where a compound, moiety, process or product is described as “optionally” having a feature, the disclosure includes such a compound, moiety, process or product having that feature and also such a compound, moiety, process or product not having that feature. Thus, when a moiety is described as “op- tionally substituted”, the disclosure comprises the unsubstituted moiety and the substituted moiety.

[066] Where two or more moieties are described as being “independently” or “each independently” selected from a list of atoms or groups, this means that the moieties may be the same or different. The identity of each moiety is therefore independent of the identities of the one or more other moieties.

[067] The term “pharmaceutical formulation” as used herein includes reference to a formulation com- prising at least one active compound and optionally one or more additional pharmaceutically acceptable ingredients, for example a pharmaceutically acceptable carrier. Where a pharmaceutical formulation comprises two or more active compounds, or comprises at least one active compound and one or more additional pharmaceutically acceptable ingredients, the pharmaceutical formulation is also a pharma- ceutical composition. Unless the context indicates otherwise, all references to a “formulation” herein are references to a pharmaceutical formulation.

[068] The term “product” or “product of the invention” as used herein includes reference to any prod- uct containing a compound of the present invention. In particular, the term product relates to composi- tions and formulations containing a compound of the present invention, such as a pharmaceutical com- position, for example.

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[069] The term “therapeutically effective amount” as used herein refers to an amount of a drug, or pharmaceutical agent that, within the scope of sound pharmacological judgment, is calculated to (or will) provide a desired therapeutic response in a mammal (animal or human). The therapeutic response may for example serve to cure, delay the progression of or prevent a disease, disorder or condition.

[070] in an embodiment, in the salt or ionic liquid represented by the general formula P*X, wherein P represents a psychoactive compound, the psychoactive compound P is a tryptamine derivative repre- sented by the general structure (1)

R10

R7 WN _ R1 1

R5 R® R9

R* R®

N R12

R3 N

R2 R!7 0 wherein R'is selected from hydrogen, deuterium, C1-Caatkyl, C:-C aalkenyl, C1.C shaloatkyl, C{O)R®,

C(O)SR™, and C(O]NR!3;

R? and R? are independently selected from hydrogen, deuterium, halogen, and C:-C4alkyl;

Ris selected from hydrogen, deuterium, halogen, C:-Caalkyl, C:-C satkoxy, and C1-Caalkylthio;

R5, R6, R7, R3 and R° are independently selected from hydrogen, deuterium, hydroxyl, sulfhydryl, halogen,

C:-Caalkyl, OC(O)R?3, SC(O)R®, and C:-C salkoxy;

RY and R* are independently selected from hydrogen and deuterium, or

R1° and R?? are independently selected from, optionally deuterated, C1-Caalkyl, C1-C salkenyl, Ci-Cshaloal- kyl, and Cs-Cscycloatkyl;

Ris selected from hydrogen, deuterium, halogen, and C:-Caalkyl; and

RE is selected from C:-Caalkyl, C:-C alkenyl, C:-C4haloalkyl, and C:-Cscycloalkyl.

[071] Preferably, in this embodiment, R? is selected from hydrogen, deuterium, methyl and ethyl.

[072] Preferably, in this embodiment, R? and R3 are independently selected from hydrogen, deuter- ium, methyl and ethyl,

[073] Preferably, in this embodiment, R* is selected from hydrogen, deuterium and C:-Caalkyl, prefera- bly hydrogen, methyl, ethyl, n-propyl and iso-propyl.

[074] Preferably, in this embodiment, R® is selected from hydrogen, deuterium, hydroxyl, methyl and ethyl.

[075] Preferably, in this embodiment, RS, R/, R$, R° are independently selected from hydrogen, deuter- ium, and C:1-Caalkyl, more preferably from hydrogen and methyl.

P335394NL 13

[076] Preferably, in this embodiment, R1° and R™ are independently selected from hydrogen, deuter- ium and C:-Caalkyl, more preferably from methyl, ethyl, n-propyl and iso-propyl. [0771 Preferably, in this embodiment, R¥ is selected from hydrogen, deuterium, methyl and ethyl.

[078] Preferably, in this embodiment, R* is selected from hydrogen, deuterium, methyl and ethyl. [0791 in an embodiment, the psychoactive tryptamine compound P is a psychedelic substituted tryp- tamine compound.

[080] in an embodiment, the psychoactive tryptamine compound P is a psychedelic substituted tryp- tamine compound.

[081] in a particularly preferred embodiment, the psychoactive tryptamine compound P is selected from - N-[2-(1H-indol-3-yl)ethyl]-N-propyl-1-propanamine (dipropyltryptamine, DPT) - 2-(1H-indol-3-yl}-N,N-dimethylethanamine (dimethyltryptamine, DMT) - 2-(1H-indol-3-yl}-N,N-diethylethanamine (diethyltryptamine, DET) - 2-(1H-indol-3-yl)-N,N-diisopropylethanamine {diisopropyltryptamine, DiPT) - 3-[2-(dimethylamino)ethyl}-1H-indol-4-of (psilocin, 4-HO-DMT) - 3-[2-(diisopropylamino)ethyl}-1H-indol-4-ol (4-hydroxy-N,N-diisopropyltryptamine, 4-HO-DiPT) - 3-(2-(dimethylamino)ethyl}-1H-indoi-4-yl-acetate (4-acetoxy-N,N-dimethyltryptamine, 4-AcO-DMT) - 3-[2-(diisopropylamino)ethyl}-1H-indol-4-yl-acetate (4-acetoxy-N,N-diisopropyltryptamine, 4-AcO-DiPT) - N-ethyl-2-(1H-indol-3-yl}-N-methylethanamine (N-methyl-N-ethyltryptamine, MET) - 3-{2-[ethyl(methyl)aminolethyl}-1H-indol-4-ol {4-hydroxy-N-methyl-N-ethyltryptamine, 4-HO-MET) - 3-[2-(diethylamino}ethyl]-1H-indol-4-01 {4-hydroxy-N,N-diethyltryptamine, 4-HO-DET) - 3-[2-(dipropylamino)ethyl}-1H-indol-4-ol (4-hydroxy-N,N-dipropyitryptamine, 4-HO-DPT) - 3-{2-[isopropyl{methyljamino]ethyl}-1H-indol-4-ol (4-hydroxy-N-methyl-N-isopropyltryptamine, 4-HO-

MiPT) - 3-[2-(diethylamino}ethyl]-1H-indol-4-ylacetate (4-acetoxy-N,N-diethyltryptamine, 4-AcO-DET) - 3-{2-lisopropyl{methyl}amino]ethyli}-1H-indol-4-yl-acetate (4-acetoxy-N-methyl-N-isopropyltryptamine, 4-AcO-MiPT) - 2-(5-methoxy-1H-indoi-3-yl)-N,N-dimethylethanamine (5-methoxydimethyltryptamine, 5-MeO-DMT) - 2-(5-methoxy-1H-indol-3-yl}-N,N-diisopropylethanamine (5-methoxydiisoproyltryptamine, 5-MeO-

DiPT) - 5-Methoxy-N-methyl-N-(1-methylethyl)-1H-indole-3-ethanamine (5-methoxymethylisopropyltrypta- mine, 5-MeO-MiPT) - alpha-methyltryptamine (a-MT).

P335394NL 14

[082] in another embodiment, in the salt or ionic liquid represented by the general formula PX, wherein P represents a psychoactive compound, the psychoactive compound P is a phenethylamine de- rivative represented by the general structure (II)

R7 R6 RS i

R+ R3

R® R11

R10 (th) wherein RLR?, R3, and R* are independently selected from hydrogen and deuterium, or

RL,R?, R?, and R* are independently selected from, optionally deuterated, C1-Csalkyl and C;-C satkenyl;

R5 and RS are independently selected from hydrogen, deuterium, hydroxyl, C1-C4alkyl and C;-C satkenyl; or

R5 and R® together with the carbon atom to which they are attached form a C=0 group;

R7 and RE are independently selected from hydrogen, deuterium, hydroxyl, C1-Caalkyl, C:1-C 4alkoxy and

Ci-Caalkylthio; or

R7 and R3 together with the carbon atom to which they are attached form a 1-furan or 3-furan;

R? is selected from hydrogen, deuterium, halogen, €:1-C 4alkoxy, C:-Caalkytthio, C:-C4alkenyloxy, C:-

Caalkenylthio, C:-C shaloalkyl, and Cs-Cscycloalkyl; or

R3 and R° together with the carbon atom to which they are attached form a dioxolane, 1-furan or 3-fu- ran;

RY and R* are independently selected from hydrogen, deuterium, hydroxyl, Ci-Caalkyl, C1-C 4alkoxy and

C1-Caalkylthio; or

RY and R* together with the carbon atom to which they are attached form a dioxolane, a 1-furan or a 3- furan.

[083] Preferably, in this embodiment, Rt, R?, R3, and R* are independently selected from hydrogen, deuterium and C:-C4alkyl, preferably hydrogen, methyl, ethyl, n-propyl and iso-propyl.

[084] Preferably, in this embodiment, R® and R® are independently selected from hydrogen, deuterium and C:1-C4alkyl, preferably hydrogen and methyl.

[085] Preferably, in this embodiment, R7, R®, R®, R1 and RY are independently selected from hydro- gen, deuterium, hydroxyl, C:-Caalkyt and C:1-C aalkoxy.

[086] In an embodiment, the psychoactive phenethylamine compound P is a dissociative substituted phenethylamine compound.

P335394NL 15

[087] in an embodiment, the psychoactive phenethylamine compound P is a psychedelic substituted phenethylamine compound.

[088] in a particularly preferred embodiment, the psychoactive phenethylamine compound P is se- lected from - 1-(1-benzofuran-5-yl}-N-methyl-2-propanamine (5-(2-methylaminopropyl)benzofuran, “5-MAPB”), - 2-{3,5-dimethoxy-4-[(2-methyl-2-propen-1-yljoxylphenyllethanamine (4-methallyloxy-3,5-dimethoxy- phenethylamine, “methallylescaline ”), - 2-amino-1-(4-bromo-2,5-dimethoxyphenyljethanl-one{“8k-2C-B"), - 2-amino-1-(4-bromo-2,5-dimethoxyphenyljethanot (“BOH-2C-B”}, and - 1-(4-iodo-2,5-dimethoxyphenyl})-2-propanamine (“DOI”) - N-methyl-1-(3,4-methylenedioxyphenyl)propan-2-amine (3,4-methylenedioxymethamphetamine,

MDMA) - 1-(1,3-benzodioxol-5-yl}propan-2-amine (3,4-methylenedioxyamphetamine, “MDA”) - 2-(4-bromo-2,5-dimethoxyphenyl)ethanamine (“2C-B”) - 2-(4-iodo-2,5-dimethoxyphenyl)ethanamine (“2C-1") - 3,4,5-trimethoxyphenethylamine (mescaline); and - 2,5-dimethoxy-4-{propylsulfanyl) phenethylamine (“2C-T-7").

[089] In yet another embodiment, in the salt or ionic liquid represented by the general formula P*X, wherein P represents a psychoactive compound, the psychoactive compound P is a ketamine or phency- clidine derivative represented by the general structure (i)

R! R?

NJ

N Ar ® > (mn) wherein

A represents CH: or C=0;

B represents CH, C=O or CHCR3. wherein R; is hydroxyl, halogen, C1-C-alkyl or C1-Ca-haloalkyl;

Ar represents a monocyclic or bicyclic aromatic or heteroaromatic group optionally substituted inde- pendently with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-Caalkyl, C3-Cscycloalkyt, C:-C alkenyl, C1-C aalkynyl, Ci.C haloalkyl, C:-C salkoxy, C1-Caalkenyloxy,

C1-Caalkynyloxy, C1-C4haloalkoxy, C:1-Caalkylthio, Ci-Caalkenylthio, C1-Cahaloalkylthio, C1-Caalkylsulfinyl,

P335394NL 16

C1-Ca4-haloalkylsulfinyl, C1-Caalkylsulfonyl, C1-C4haloalkylsulfonyl, C:-Caalkylcarbonyl, €1-C salkoxy-C:1-Caal- kyl, C:-Caalkoxycarbonyl, C:-Caalkoxy-C:1-Crcarbonyl, and C:-CsalkylcarbonyloxyC1-C4alkyl;

R! and R? are independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C:-

Caalkyl, C:1-C jatkenyl, C3-Cscycloalkyl, C:-C aalkynyl C1-C shaloalkyl, C:-C salkoxy, Ci-Csalkenyloxy, C:1-Caal- kynyloxy, C:-C4haloalkoxy, C:-Caalkylthio, C1-Caalkenylthio, C1-C4haloalkylthio, Ci-Caalkylsulfinyl, C:-

Cahaloalkylsulfinyl, C1-Ca4alkylsulfonyl, C:1-Cahaloalkylsulfonyl, C1-Caalkylcarbonyl, C1-C 4alkoxy-C1-C 4alkyl,

C1-Caalkoxycarbonyl, C:1-Caalkoxy-C1-C4-carbonyt, and C:1-CaalkylcarbonyloxyCi-Caalkyl; or

R! and R? together with the N to which they are attached form a 5-, 6-, or 7-membered hetero- cyclic ring optionally including 1 to 2 additional ring heteromoieties selected from O,S, S(O), S02, and N, wherein said 5-, 6-, or 7-membered heterocyclic ring is optionally substituted independently with one or more substituents selected from halogen, amino, hydroxyl, cyano, C1-Ca alkyl and C:-C4-alkoxy.

[090] In one embodiment, R and R? are independently selected from hydrogen, deuterium, hydroxyl,

Ci-Cs-alkyl, C:-Ca-alkenyl, Ci-Cs-haloalkyl, and Ci-C s-alkoxy.

[091] In one embodiment R+ and R? together with the N to which they are attached form a pyrroli- dinyl, piperidyl or morpholyt ring.

[092] In one embodiment, Ar is selected from phenyl, 2-pyridinyl, 2-thienyl, 3-thienyl, m-methoxy- phenyl, m-ethoxyphenyl, m-chlorophenyl, o-chlorophenyl, benzothiophen-2-yl, 2-methyl-4-hydroxy- phenyl, m-fluorophenyl, o-fluorophenyt, p-fluorophenyl, m-hydroxyphenyt, p-hydroxyphenyt, o-hydroxy- phenyl, m-tolyl, o-tolyl, p-tolyl, o-trifluoromethylpheny, p-bromophenyl and 3,4-methylenedioxyphenyl.

[093] In one embodiment, the psychoactive ketamine or phencyclidine compound P is a dissociative substituted ketamine or phencyclidine compound.

[094] In one embodiment, the psychoactive ketamine or phencyclidine compound P is a psychedelic substituted ketamine or phencyclidine compound.

[095] in one embodiment, the psychoactive ketamine or phencyclidine compound P is selected from - 2-{methylamino}-2-phenylcyclohexan-1-0ne (deschloroketamine, DCK) - 2~(2-chlorophenyl)-2-{methylamino)cyclohexan-1-one (ketamine) - 2-(2-fluorophenyl}-2-{methylamino)cyclohexan-1-one (2-fluorodeschloroketamine, 2-FDCK) - 1-(1-{m-tolyl)cyclohexyl) piperidine (3-methylphencyclidine, 3-Me-PCP).

[096] Wherever appropriate, the compounds as defined above include the (S)-enantiomers, (R)-enan- tiomers and racemic mixtures thereof. For example, “ketamine” may refer to {S}-{+}-ketamine (or “es- ketamine”) or {R}-{~}-ketamine {or “arketaming”}, or to a racemic mixture thereof.

[097] In an embodiment, the invention relates to a saccharinate, cyclamate, or acesulfame salt of a psychoactive compound, i.e. wherein the anion portion is derived from saccharine, cyclamic acid or a cyclamate salt, or an acesulfame salt such as acesulfame-K, and the cation portion is derived from

P335394NL 17 psychoactive compound. In an embodiment, the invention relates to an anionic liquid comprising a sac- charinate, cyclamate, or acesulfame anion and a cation of a psychoactive compound. In some embodi- ments, the invention relates to a saccharinate, cyclamate, or acesulfamate salt or an ionic liquid of a tryptamine, phenethylamine, ketamine or phencyclidine as disclosed herein.

[098] Preferred ionic liquids or salts according to the present disclosure are N-[2-(1H-indol-3-yl)ethyl]-

N-propyl-1-propanamine cyclamate, N-[2-(1H-indol-3-yl)ethyl]-N-propyl-1-propanamine acesulfame, 2- (1H-indol-3-yl}-N,N-dimethylethanamine saccharinate, 2-(1H-indol-3-yl}-N,N-dimethylethanamine cyclamate, 2-{1H-indol-3-yl}-N,N-dimethylethanamine acesulfame, 2-(1H-indol-3-yl}-N,N- diethylethanamine saccharinate, 2-(1H-indol-3-yl}-N,N-diethylethanamine cyclamate, 2-{(1H-indo}-3-yl}-

N,N-diethylethanamine acesulfame, 2-(1H-indol-3-yl)-N,N-diisopropylethanamine saccharinate, 2-(1H- indol-3-yl)-N,N-diisopropylethanamine cyclamate, 2-(1H-indol-3-yl}-N,N-diisopropylethanamine acesulfame, 3-[2-(dimethylamino)ethyl]-1H-indol-4-ol saccharinate, 3-[2-(dimethylamino)ethyl]-1H- indol-4-ol cyclamate, 3-[2-(dimethylamino)ethyl}-1H-indol-4-ol acesulfame, 3-[2- {diisopropylamino)ethyl}-1H-indol-4-ol saccharinate, 3-[2-(diisopropylamino)ethyl]-1H-indol-4-ol cyclamate, 3-[2-{diisopropylamino}ethyl]-1H-indol-4-0l acesulfame, 3-[2-(dimethylamino)ethyl]-1H- indol-4-yl-acetate saccharinate, 3-[2-(dimethylamino}ethy!]-1H-indol-4-yl-acetate cyclamate, 3-{2- (dimethylamino)ethyl]-1H-indol-4-yl-acetate acesulfame, 3-[2-(diisopropylamino)ethyi}-1H-indol-4-yl- acetate saccharinate, 3-[2-{diisopropylamino}ethyl]-1H-indol-4-yl-acetate cyclamate, 3-{2- (diisopropylamino)ethyl}-1H-indol-4-yl-acetate acesulfame, N-ethyl-2-(1H-indol-3-yl}-N- methylethanamine saccharinate, N-ethyl-2-(1H-indol-3-yl}-N-methylethanamine cyclamate, N-ethyl-2- (1H-indol-3-yl)-N-methylethanamine acesulfame, 3-{2-[ethyl{methyl}amino]ethyl}-1H-indol-4-ol saccharinate, 3-12-[ethyl(methyl}aminolethyl}-1H-indol-4-0l cyclamate, 3-{2-[ethyl{methyl}aminolethyl}- 1H-indol-4-ol acesulfame, 3-[2-(diethylamino)ethyl}-1H-indol-4-ol saccharinate, 3-[2- {diethylamino)ethyl}-1H-indol-4-ol cyclamate, 3-[2-(diethylamino)ethyl}-1H-indol-4-ol acesulfame, 3-{2- (dipropylamino)ethyl}-1H-indol-4-ol saccharinate, 3-[2-(dipropylamino}ethyl]-1H-indol-4-0l cyclamate, 3- [2-(dipropylamino}ethyl]-1H-indol-4-ol acesulfame, 3-{2-[isopropyl(methyl}aminolethyl}-1H-indol-4-ol saccharinate, 3-{2-{isopropyl{methyl}aminolethyi}-1H-indol-4-ol cyclamate, 3-{2- [isopropyi{methyl)amino]ethyi}-1H-indol-4-ol acesuifame, 3-[2-(diethylamino}ethyi]-1H-indol-4-yl- acetate saccharinate, 3-{2-(diethylamino)ethyl]-1H-indol-4-yl-acetate cyclamate, 3-{2- (diethylamino)ethyl]-1H-indoi-4-yl-acetate acesulfame, 3-{2-[isopropyl{methyl}amino]ethyi}-1H-indol-4- yl-acetate saccharinate, 3-{2-[isopropyl(methyl)amino]ethyl}-1H-indol-4-yl-acetate cyclamate, 3-{2- [isopropyi{methyl)amino]ethyi}-1H-indol-4-yl-acetate acesulfame, 2-(5-methoxy-1H-indol-3-yl}-N,N- dimethylethanamine saccharinate, 2-(5-methoxy-1H-indol-3-yl}-N,N-dimethylethanamine cyclamate, 2- (5-methoxy-1H-indol-3-yi)-N,N-dimethylethanamine acesulfame, 2-(5-methoxy-1H-indol-3-yl}-N,N-

P335394NL 18 diisopropylethanamine saccharinate, 2-(5-methoxy-1H-indol-3-yl}-N,N-diisopropylethanamine cyclamate, 2-{5-methoxy-1H-indol-3-yl}-N,N-diisopropylethanamine acesulfame, 5-methoxy-N-methyl-

N-(1-methylethyl)-1H-indole-3-ethanamine saccharinate, 5-methoxy-N-methyl-N-(1-methylethyl)-1H- indole-3-ethanamine cyclamate, and 5-methoxy-N-methyl-N-(1-methylethyl)-1H-indole-3-ethanamine acesulfame.

[099] Also preferred ionic liquids or salts according to the present disclosure are 1-(1-benzofuran-5- yl)-N-methyl-2-propanamine saccharinate, 1-(1-benzofuran-5-yl}-N-methyl-2-propanamine cyclamate, 1- {1-benzofuran-5-yl}-N-methyl-2-propanamine acesulfame, 2-{3,5-dimethoxy-4-[(2-methyl-2-propen-1- yl)oxylphenyllethanamine saccharinate, 2-{3,5-dimethoxy-4-[(2-methyl-2-propen-1- yl)oxy]phenyllethanamine cyclamate, 2-{3,5-dimethoxy-4-[(2-methyl-2-propen-1- yl)oxylphenyllethanamine acesulfame, 2-amino-1-{4-bromo-2,5-dimethoxyphenyt)ethanol saccharinate, 2-amin0-1-(4-bromo-2,5-dimethoxyphenyl}ethanol cyclamate, 2-amino-1-(4-bromo-2,5- dimethoxyphenyljethanol acesulfame, 1-{4-iodo-2,5-dimethoxyphenyl}-2-propanamine saccharinate, 1- {4-iodo-2,5-dimethoxyphenyl}-2-propanamine cyclamate, 1-(4-iodo-2,5-dimethoxyphenyl}-2- propanamine acesulfame, N-methyl-1-(3,4-methylenedioxyphenyl)propan-2-amine saccharinate, N- methyl-1-(3,4-methylenedioxyphenyl)propan-2-amine cyclamate, N-methyi-1-(3,4- methylenedioxyphenyl)propan-2-amine acesulfame, 1-(1,3-benzodioxol-5-yl}propan-2-amine saccharinate, 1-(1,3-benzodioxol-5-yl}propan-2-amine cyclamate, 1-(1,3-benzodioxol-5-yl)propan-2- amine acesulfame, 2-(4-bromo-2,5-dimethoxyphenyl)ethanamine saccharinate, 2-(4-bromo-2,5- dimethoxyphenyllethanamine cyclamate, 2-(4-bromo-2,5-dimethoxyphenyl}ethanamine acesulfame, 2- (4-iodo-2,5-dimethoxyphenyl)ethanamine saccharinate, 2-(4-iodo-2,5-dimethoxyphenyl}ethanamine cyclamate, 2-{4-iodo-2,5-dimethoxyphenyl)ethanamine acesulfame, 3,4,5-trimethoxyphenethylamine saccharinate, 3,4,5-trimethoxyphenethylamine cyclamate, 3,4,5-trimethoxyphenethylamine acesulfame, 2,5-dimethoxy-4-(propylsulfanyl}phenethylamine saccharinate, 2,5-dimethoxy-4- (propylsulfanyijphenethylamine cyclamate, and 2,5-dimethoxy-4-(propylsuifanyl)phenethylamine acesulfame.

[100] Further preferred ionic liquids or salts according to the present disclosure are 2-(methylamino)- 2-phenylcyclohexan-1-one saccharinate, 2-(methylamino)-2-phenylcyclohexan-1-one cyclamate, 2- (methylamino}-2-phenylcyclohexan-1-one acesulfame, 2-(2-fluorophenyl)-2-(methylamino)cyclohexan- 1-one saccharinate, 2-(2-fluorophenyl}-2-(methylamino)cyciohexan-1-one cyclamate, 2-(2- fluorophenyl)-2-(methylamino)cyciohexan-1-one acesulfame, 1-(1-(m-tolyl)cyclohexyl}piperidine saccharinate, 1-(1-{m-tolyl)cyclohexyl)piperidine cyclamate, 1-(1-(m-tolyl}cyclohexyl)piperidine acesulfame, 2-(2-chlorophenyl)-2-(methylamino)cyciohexan-1-one saccharinate, 2-(2-chlorophenyi}-2-

P335394NL 19 (methylaminojcyclohexan-1-one cyclamate, and 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one acesulfame.

[101] Particularly preferred ionic liquids or salts according to the present disclosure are - dipropyltryptamine (DPT) cyclamate - dipropyltryptamine (DPT) acesulfamate - methylethyltryptamine (MET) saccharinate - 5-methoxydimethyltryptamine (5-MeO-DMT) saccharinate - 5-methoxymethylisopropyltryptamine (5-MeO-MIPT) saccharinate - 4-hydroxy-methylethyltryptamine (4-HO-MET) saccharinate - 5-(2-methylaminopropyl)benzofuran (5-MAPB) saccharinate - deschloroketamine (DCK) saccharinate - 2-fluorodeschloroketamine (2-FDCK) saccharinate - 3-methylphencyclidine (3-Me-PCP) saccharinate - 4-hydroxy-N-methyl-N-isopropyltryptamine (4-HO-MiPT) saccharinate.

[102] inthe practice of the present disclosure, the above psychoactive compounds are used in an amount sufficient to produce their desired prophylactic or curative efficacy. The active ingredient con- tent per dose unit may vary widely, and depends on a variety of factors including the type of active in- gredient, condition being treated, total treatment period, age, weight and sex of the subject taking the medication, etc. In typical cases, the active ingredient is used in an amount of 0.05 to 95 percent by weight based on the weight of the dosage unit. For each individual active ingredient, its amount may be increased or decreased within the above range in an adequate manner depending on the type of active ingredient and the purpose of therapy or, in other words, depending on whether a small dose is suffi- cient or a larger dose is required for the active ingredient to produce its prophylactic or therapeutic ef- fects.

[103] The salts or ionic liquids of a sweetener and a psychoactive compound as disclosed herein can be prepared by methods known in the art, wherein said methods generally involve the steps of mixing a solution of the psychoactive compound in its free-base form or in the form of a pharmaceutically ac- ceptable salt thereof (such as HCl, fumarate or succinate) with a solution of the artificial sweetener, typi- cally in an organic solvent, followed by vigorous agitation of the resulting solution to produce an organic layer containing the salt or ionic liquid of the sweetener and the psychoactive compound. The salt or ionic liquid of the sweetener and the psychoactive compound can be isolated from the organic layer by known work-up, crystallization and/or purification steps.

[104] If the psychoactive compound is provided in the form of a pharmaceutically acceptable salt thereof, such as its HCl, fumarate, succinate, etc. salt, it is also possible to first extract the free-base

P335394NL 20 form by mild heating (around 40 °C) in aqueous NaHCO; or other suitable base under vigorous agitation.

The resulting organic layer containing the psychoactive compound in its free-base form is then typically separated, collected and combined with the artificial sweetener solution as described above.

[105] In another aspect of the present disclosure there is provided a dosage unit for the transmucosal administration of a psychoactive compound to a subject, wherein the transmucosal dosage unit com- prises a salt or an ionic liquid of an artificial sweetener and a psychoactive compound as disclosed herein. Thus, there is provided a transmucosal dosage unit, wherein the transmucosal dosage unit com- prises a salt or ionic liquid represented by the general formula P’X, wherein P represents a psychoactive compound and X represents an artificial sweetener.

[106] In one embodiment, the dosage unit is configured for the oral transmucosal administration of a psychoactive compound to a subject.

[107] In one embodiment, the dosage unit is configured for the nasal transmucosal administration of a psychoactive compound to a subject.

[108] As used herein, “oral transmucosal administration” refers to administration through the oral mucosa of an active compound for the purpose of systemic delivery of said active compound, wherein the oral administration route is selected from sublingual, sublabial and buccal administration, or a com- bination thereof. As used herein, “sublingual” refers to the pharmacological route of administration by which an active compound is held under the tongue; “buccal” administration refers to the pharmacolog- ical route of administration by which the active compound is held or applied in the buccal area, i.e. in the cheek; “sublabial” refers to the pharmacological route of administration by which the active com- pound is placed between the lip and the gingiva (gum). In all cases, the active compound diffuses through the oral mucosa and enters directly into the bloodstream.

[109] As used herein, “nasal transmucosal administration” or “intranasal transmucosal administra- tion” refers to administration through the nasal mucosa of an active compound for the purpose of sys- temic delivery of said active compound. Herein, the active compound is provided to the nasal cavity and contacted with the mucous membranes lining the nose. The nasal mucous membranes possess a rela- tively large surface area, a porous epithelial membrane, and extensive vascularization, thus enabling rapid onset of the therapeutic or prophylactic effect.

[110] In one embodiment, the transmucosal dosage unit is a buccal transmucosal dosage unit.

[111] In one embodiment, the transmucosal dosage unit is a sublingual transmucosal dosage unit.

[112] In one embodiment, the transmucosal dosage unit is a sublabial transmucosal dosage unit.

[113] In one embodiment, the transmucosal dosage unit is a nasal or intranasal transmucosal dosage unit.

P335394NL 21

[114] Examples of dosage unit forms for oral transmucosal administration according to the present disclosure include tablets, soft gelatine capsules, including solutions used in soft gelatine capsules, aque- ous or oil suspensions, emulsions, pills, lozenges, troches, films, chewing gums, syrups, elixirs and the like. Formulations for oral transmucosal use may also be presented as rapidly-dissolving hard capsules wherein the salt or ionic liquid of a sweetener and the active compound is mixed with an inert solid dilu- ent, for example calcium carbonate, calcium phosphate or kaolin, or as soft capsules wherein the salt or ionic liquid of a sweetener and the active compound is mixed with water or an oil medium, such as pea- nut oil, liquid paraffin or olive oil. In a particularly preferred embodiment, the oral transmucosal dosage units according to the present invention are provided in the form of solid or semi-solid dosage units, es- pecially in the form of tablets, capsules, cachets, pellets, pills, powders or granules.

[115] Non-limiting examples of dosage units for (intra)nasal transmucosal administration according to the present disclosure include sprays, inhalers, nebules, drops, droplets, suspensions, powders, creams, gels and ointments.

[116] The dosage units of the present disclosure may be prepared according to any method known in the for the manufacture of pharmaceutical compositions and such units may contain one or more agents selected from the group consisting of {additional} sweetening agents, flavouring agents, colour- ing agents and preserving agents. Said dosage units may suitably contain one or more non-toxic pharma- ceutically acceptable excipients.

[117] Suitable excipients may be, for example, disintegrants such as microcrystalline cellulose, methyl- cellulose, hydroxypropyl cellulose, starch, pregelatinized starch, hydroxypropyl starch, sodium starch glycolate, sodium alginate and chitosan hydrochloride; fillers such as microcrystalline cellulose, starch, sucrose, dextrose, lactose, maltose, dextrin, cyclodextrins, isomalt and mannitol; inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents, such as alginic acid; binding agents, such as gelatine or acacia; glidants such as corn starch, col- loidal silicon dioxide and talc; and lubricating agents, such as magnesium stearate, stearic acid, magne- sium lauryl sulphate and sodium lauryl sulphate, or talc. Tablets may be uncoated or may be (partially) coated by known techniques to tune disintegration and adsorption by the oral mucosal membranes. Ad- ditional excipients may be included or combined, but are not limited to, the following: flavorings, sweet- eners, colorants, preservatives, mucosal penetration enhancers, anti-oxidants, binders, buffers, thicken- ing agents, mucoadhesive agents, salts, effervescent bases and emulsifiers.

[118] If desired, so-called super-disintegrants may be added to facilitate rapid disintegration of the dosage unit. Examples of super-disintegrants are crospovidone (cross-linked polyvinyl-N-pyrrolidone,

PVP), chitin/chitosan-silicon dioxide coprecipitate, INDION 414, modified karaya gum (MKG), C-TAG (co- grinded treated agar), C-TGG (co-grinded treated guar gum) and croscarmeliose sodium (CCS); as well as

P335394NL 22 two-component freeze-dried frameworks comprising a water-soluble polymer matrix material such as gelatine, dextran, alginate or maltodextrin combined with a matrix-supporting/disintegration-enhancing agent such as sucrose and mannitol.

[119] In one embodiment, the dosage unit for oral transmucosal administration is a rapidly disinte- grating tablet, comprising the salt or ionic liquid of a sweetener and the active compound, and one or more additives selected from (super)disintegrants, fillers, glidants and lubricants.

[120] intranasal formulations may, in addition to the salt or ionic liquid of the psychoactive agent, contain solvents such as water and alcohol, additives such as polyols, surface-active agents, solubilizing agents and chelating agents, pH control agents (such as sodium hydroxide or citric acid), local anaesthet- ics, isotonizing agents, adsorption inhibitors (such as Tween 80), solubility enhancing agents (such as cy- clodextrins and derivatives thereof), wetting agents (such as sodium acetate, sodium lactate), absorp- tion-promoting polymers (synthetic polymers or natural polymers such as processed collagen, chitin, chitosan).

[121] Syrups and elixirs may be formulated with additional sweetening agents, such as glycerol, sorbi- tol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavouring or a colour- ing agent. Other ingredients are added to the composition of the dosage form of the invention to pro- vide particular properties.

[122] Another aspect of the present disclosure relates to a method of prophylactically or curatively treating a subject, said method comprising transmucosal administration to said subject of the present compound or dosage unit as described herein. The present method is particularly suitable for treating mammals, especially humans.

[123] Accordingly, in one aspect the present disclosure relates to a salt or ionic liquid represented by the general formula PX, wherein P represents a psychoactive compound and X represents an artificial sweetener, for use as a medicament.

[124] in another aspect the present disclosure relates to a dosage unit comprising a salt or an ionic liquid represented by the general formula PX, wherein P represents a psychoactive compound and X represents an artificial sweetener, for use as a medicament.

[125] More specifically, the present disclosure relates to a dosage unit comprising a salt or an ionic liquid represented by the general formula P*X, wherein P represents a psychoactive compound and X represents an artificial sweetener, for use in a method of prophylactically or curatively treating a sub- ject, wherein said method comprises transmucosal administration to said subject of the dosage unit.

[126] In an embodiment, the salt or ionic liquid, the formulation or the dosage unit according to the present invention is used as a medicament in the prophylactic or curative treatment of migraine, cluster headaches and traumatic brain injury.

P335394NL 23

[127] in an embodiment, the salt or ionic liquid, the formulation or the dosage unit according to the present invention is used as a medicament in a method of prophylactically or curatively treating a mam- mal suffering from a psychiatric disease or disorder.

[128] in an embodiment, the psychiatric disorder or disease is selected from depression (including mild depression, major depressive disorder, and treatment-resistant depression), obsessive compulsive disorder, panic and anxiety disorders, explosive behaviour disorder, post-traumatic stress disorder, schizophrenia, substance addiction, anorexia nervosa, binge eating disorder, bulimia nervosa, psychosis, autism spectrum disorders, developmental disorders, gambling disorder, and personality disorders.

[129] The salt and ionic liquids derived from an artificial sweetener and a psychoactive compound and oral dosage units comprising such salts or ionic liquids are particularly suitable for administration to sub- jects who are unable to tolerate oral ingestion, or intramuscular or intravascular injection of psychoac- tive compounds. The compounds and compositions of the present disclosure are particularly advanta- geous in preventing or reducing irritation of the oral or nasal mucosal membranes that is associated with the (intra)nasal, sublingual, sublabial or buccal administration of psychoactive compounds.

[130] Hence, in another aspect there is provided a method for reducing mucosal irritation in a subject upon nasal, sublingual, sublabial or buccal administration of a psychoactive compound to the subject, wherein said method comprises providing the psychoactive compound as a salt or ionic liquid of an arti- ficial sweetener and said psychoactive compound. More specifically, said method comprises providing the psychoactive compound as a salt or ionic liquid represented by the general formula P*X, wherein P represents the psychoactive compound and X represents an artificial sweetener.

[131] As used herein, the term “mucosal irritation” refers to one or more of pain, increased redness, lesions like ulcers, erosion or blisters, thickening of the mucosal epithelium, pruritus (itching), crusting, parakeratosis, inflammation, and a burning, tingling or stinging sensation in at least a part of the oral mucosal membranes.

[132] Mucosal irritation can be assessed quantitatively by a so-called Slug Mucosal irritation (SMI) as- say. The SMI assay was developed at the Laboratory of Pharmaceutical Technology at the University of

Ghent in an effort to reduce testing on vertebrates; see for example Aedriaans et al., Toxicol. Vitr. 2008, 22 (5), 1285-1296. Mucosal irritation can readily be assessed using an SMI assay without the need of a large number of vertebrates, such as rabbits in the invasive Draize test. The SMI assay is a simple proce- dure that quantifies the mucus produced by a slug following a series of contact periods with a test com- pound, which correlates to mucosal irritation in humans.

[133] The present invention will be further explained, illustrated, and described in the following exam- ples of the present invention. The examples demonstrate the utility and/or function of the invention and

P335394NL 24 help provide a full describe of the invention. The examples are intended to be illustrative and not limita- tive of the present invention,

Examples

Synthesis of ionic liquids and salts of psychoactive compounds

[134] The tested psychoactive compounds were purchased in their free-base or HCl salt form or syn- thesized using known procedures. For example, the synthesis of diisopropyltryptamine (DIPT) can start either from indole or from tryptamine. The indole route is a three-step process, which is similar to the synthesis of psilocin and related tryptamine psychedelics (Figure 1). o © 0 wl vl oxalyl chloride 0 diisopropylamine 0 LiAIH,

OD hata \ eee \ ie A

N Et,O N N dioxane N

Figure 1: Synthesis of DiPT from indole

[135] An alternative route starts from tryptamine, and DIPT is obtained in a single synthetic step (Fig- ure 2).

NH, ee isopropyl iodide,

DIPEA

N A\

N isopropanol N

Figure 2: Synthesis of DiPT from tryptamine

[136] The formation of the sweetener ionic liquids and salts from the psychoactive compounds can be conveniently made from the freebase or from the hydrochloride salt or other common salts of said com- pounds.

Sweetener Salt and lonic Liquid Formation Examples

Example 1 — Preparation of tryptamine cyclamate

[137] Tryptamine hydrochloride (0.5 mmol) was dissolved in 250uL deionized water. Sodium cycla- mate (0.5 mmol) was dissolved in 250uL deionized water. The tryptamine HCI solution was added to the sodium cyclamate solution and vigorously shaken. Tryptamine cyclamate formed immediately as an

P335394NL 25 ionic liquid, which collected in the bottom of the container. The aqueous layer was decanted and the ionic liquid washed twice with 500uL deionized water. The ionic liquid was dried overnight under vac- uum at room temperature. Tryptamine cyclamate was obtained as a cream colored solid in 57% yield.

Example 2 — Preparation of tryptamine saccharinate

[138] Saccharin (0.5 mmol) and Tryptamine freebase (0.5 mmol} were dissolved in 1mL THF under mild heating at 40°C and shaken vigorously. This mixture was added to 5mL MTBE and shaken vigor- ously. Tryptamine saccharinate formed immediately. The organic solvent was decanted and tryptamine saccharinate was washed 3 times with fresh MTBE (1mL} and dried under vacuum at room temperature.

Tryptamine saccharinate was obtained as a yellow flaky solid in 92% yield.

Example 3 — Preparation of tryptamine acesulfamate

[139] Acesulfame (0.5 mmol) and Tryptamine freebase (0.5 mmol) were dissolved in 1mL THF under mild heating at 40°C and shaken vigorously. This mixture was added to 5mL MTBE and shaken vigor- ously. Tryptamine acesulfamate formed immediately. The organic solvent was decanted and tryptamine acesulfamate was washed 3 times with fresh MTBE (1mL) and dried under vacuum at room tempera- ture. Tryptamine acesulfamate was obtained as a yellow waxy solid in 84% yield.

Example 4 — Preparation of dipropyitryptamine (DPT) cyclamate

[140] Dipropyltryptamine (DPT) hydrochloride (0.5 mmol) was dissolved in 500ulL deionized water. So- dium cyclamate (0.5 mmol) was dissolved in 500uL deionized water. The DPT hydrochloride solution was added to the sweetener salt solution and vigorously shaken. The liquid was decanted and the solid washed twice with 500uL deionized water. The solid was dried overnight under vacuum at room tem- perature. DPT cyclamate was obtained as a cream coloured solid in 58% yield.

Example 5 — Preparation of dipropyltryptamine (DPT) acesulfame

[141] Dipropyltryptamine (DPT) hydrochioride (0.5 mmol) was dissolved in 500ulL deionized water.

Acesulfame potassium (0.5 mmol} was dissolved in 500ul deionized water. The DPT hydrochloride solu- tion was added to the sweetener salt solution and vigorously shaken. The liquid was decanted and the solid washed twice with 500uL deionized water. The solid was dried overnight under vacuum at room temperature. DPT acesulfamate was obtained as a cream colored solid in 75% yield.

P335394NL 26

Example 6 — Preparation of methylethyltryptamine (MET) saccharinate

[142] Saccharin (0.5 mmol} was dissolved in 500uL THF under mild heating at 40°C. Methylethyltrypta- mine (MET) fumarate (0.5 mmol) was suspended in 500uL MTBE. To the MTBE suspension 1 mL satu- rated aqueous NaHCO3 was added and the container was vigorously shaken under mild heating at 40°C to extract MET freebase. The organic layer was allowed to separate, collected and added to the saccha- rin THF solution. An additional portion of 500pL MTBE was added to the aqueous layer and shaken vig- orously. The organic layer was allowed to separate, collected and added to the saccharin THF solution. A third portion of 500uL MTBE was added to the aqueous layer and shaken vigorously. The organic layer was allowed to separate, collected and added to the saccharin THF solution. The container containing the sweetener and psychedelic freebase was shaken vigorously and MET saccharinate formed immedi- ately as an ionic liquid. The organic solvent was decanted and MET saccharinate was washed 3 times with fresh MTBE (1mL)} and dried under vacuum at room temperature. MET saccharinate was obtained as a pale yellow ionic liquid in 92% yield.

Example 7 — Preparation of 5-Methoxydimethyltryptamine (5-MeO-DMT) saccharinate

[143] Saccharin (0.5 mmol) was dissolved in 500uL THF under mild heating at 40°C. 5-Methoxydime- thyltryptamine (5-MeO-DMT) freebase (0.5 mmol} was dissolved in 500uL MTBE under mild heating at 40°C. The psychedelic freebase solution was added to the sweetener THF solution and shaken vigor- ously. 5-MeO-DMT saccharinate formed immediately as an ionic liquid that collected in the bottom of the container. The organic solvent was decanted and 5-MeO-DMT saccharinate was washed 3 times with fresh MTBE (1mL) and dried under vacuum at room temperature. 5-MeO-DMT saccharinate was obtained as a yellow to light pink ionic liquid in 98% yield.

Example 8 — Preparation of 5-methoxymethylisopropyltryptamine (5-MeO-MIPT) saccharinate

[144] Saccharin (0.5 mmol) was dissolved in 500uL THF under mild heating at 40°C. 5-methoxymethyli- sopropyltryptamine (5-MeO-MIPT) hydrochloride (0.5 mmol} was suspended in 500uL MTBE. To the

MTBE suspension 1 mL saturated aqueous NaHCO; was added and the container was vigorously shaken under mild heating at 40°C to extract 5-MeO-MIPT freebase. The organic layer was allowed to separate, collected and added to the saccharin THF solution. An additional portion of 500uL MTBE was added to the aqueous layer and shaken vigorously. The organic layer was allowed to separate, collected and added to the saccharin THF solution. A third portion of 500uL MTBE was added to the aqueous layer and shaken vigorously. The organic layer was allowed to separate, collected and added to the saccharin THF solution. The container containing the sweetener and psychedelic freebase was shaken vigorously and 5-MeO-MIPT saccharinate formed immediately as an ionic liquid. The organic solvent was decanted and

P335394NL 27 5-MeO-MIPT saccharinate was washed 3 times with fresh MTBE (1ml) and dried under vacuum at room temperature. 5-MeO-MIPT saccharinate was obtained as a colorless ionic liquid in 96% yield.

Example 9 — Preparation of 4-hydroxy-methylethyltryptamine (4-HO-MET) saccharinate

[145] Saccharin (0.5 mmol} was dissolved in 500uL THF under mild heating at 40°C. 4-hydroxy-meth- ylethyltryptamine (4-HO-MET) hydrochloride (0.5 mmol) was suspended in 500uL MTBE: THF (1:1, viv).

To the suspension 1 mL saturated aqueous NaHCO; was added and the container was vigorously shaken under mild heating at 40°C to extract 4-HO-MET freebase. The organic layer was allowed to separate, collected and added to the sweetener THF solution. An additional portion of 500uL MTBE: THF was added to the aqueous layer and shaken vigorously. The organic layer was allowed to separate, collected and added to the sweetener THF solution. A third portion of 500uL MTBE: THF was added to the aqueous layer and shaken vigorously. The organic layer was allowed to separate, collected and added to the sweetener THF solution. The mixture containing the sweetener and psychedelic freebase was added to 5mbL MTBE and shaken vigorously. 4-HO-MET saccharinate formed as an ionic liquid that collected in the bottom of the container. The organic solvent was decanted and the psychedelic sweetener salt was washed 3 times with fresh MTBE (1mL) and dried under vacuum at room temperature. 4-HO-MET sac- charinate was obtained as an ionic liquid that crystallized upon standing in 81% yield.

Example 10 — Preparation of 5-(2-methylaminopropyl)benzofuran (5-MAPB) saccharinate

[146] Saccharin (0.5 mmol) was dissolved in 500uL THF under mild heating at 40°C. 5-(2-methyla- minopropyli}benzofuran (5-MAPB) hydrochloride (0.5 mmol} was suspended in 500uL MTBE. To the

MTBE suspension 1 mi saturated aqueous NaHCO; was added and the container was vigorously shaken under mild heating at 40°C to extract 5-MAPB freebase. The organic layer was allowed to separate, col- fected and added to the saccharin THF solution. An additional portion of 500uL MTBE was added to the aqueous layer and shaken vigorously. The organic layer was allowed to separate, collected and added to the saccharin THF solution. A third portion of 500uL MTBE was added to the aqueous layer and shaken vigorously. The organic layer was allowed to separate, collected and added to the saccharin THF solu- tion. The container containing the sweetener and psychedelic freebase was shaken vigorously and 5-

MAPB saccharinate formed immediately as an ionic liquid. The organic solvent was decanted and 5-

MAPB saccharinate was washed 3 times with fresh MTBE (imL} and dried under vacuum at room tem- perature. 5-MAPB saccharinate was obtained as a yellow ionic liquid in 87% yield.

P335394NL 28

Example 11 — Preparation of deschloroketamine (DCK} saccharinate

[147] Saccharin (0.5 mmol} was dissolved in 500uL THF under mild heating at 40°C. Deschloroketa- mine (DCK) hydrochloride (0.5 mmol) racemate was suspended in 500uL MTBE. To the MTBE suspension 1mL saturated aqueous NaHCO; was added and the container was vigorously shaken under mild heating at 40°C to extract the DCK freebase. The organic layer was allowed to separate, collected and added to the saccharine THF solution. An additional portion of 500uL MTBE was added to the aqueous layer and shaken vigorously. The organic layer was allowed to separate, collected and added to the saccharine

THF solution. A third portion of 500ul MTBE was added to the aqueous layer and shaken vigorously. The organic layer was allowed to separate, collected and added to the saccharine THF solution. The con- tainer containing the saccharine and DCK freebase was shaken vigorously and DCK saccharinate salt pre- cipitated immediately. The organic solvent was decanted and DCK saccharinate was washed 3 times with fresh MTBE (1mL) and dried under vacuum. DCK saccharinate was obtained as colorless crystals in 91% yield.

Example 12 — Preparation of 2-fluorodeschloroketamine (2-FDCK} saccharinate

[148] Saccharin (0.5 mmol} was dissolved in 500uL THF under mild heating at 40°C. 2-Fluorodeschloro- ketamine (2-FDCK) hydrochloride (0.5 mmol} racemate was suspended in 500uL MTBE. To the MTBE suspension ImL saturated aqueous NaHCO; was added and the container was vigorously shaken under mild heating at 40°C to extract the 2-FDCK freebase. The organic layer was allowed to separate, col- fected and added to the saccharine THF solution. An additional portion of 500uL MTBE was added to the aqueous layer and shaken vigorously. The organic layer was allowed to separate, collected and added to the saccharine THF solution. A third portion of 500uL MTBE was added to the aqueous layer and shaken vigorously. The organic layer was allowed to separate, collected and added to the saccharine THF solu- tion. The container containing the saccharine and 2-FDCK freebase was shaken vigorously and 2-FDCK saccharinate precipitated immediately. The organic solvent was decanted and 2-FDCK saccharinate was washed 3 times with fresh MTBE (1mL)} and dried under vacuum. 2-FDCK saccharinate was obtained as colorless crystals in 90% yield.

Example 13 — Preparation of 3-methyiphencyclidine (3-Me-PCP) saccharinate

[149] Saccharin (0.5 mmol) was dissolved in 500uL THF under mild heating at 40°C. 3-Methylphency- clidine (3-Me-PCP} hydrochloride (0.5 mmol) racemate was suspended in 500uL MTBE. To the MTBE sus- pension 1mL saturated aqueous NaHCO; was added and the container was vigorously shaken under mild heating at 40°C to extract the 3-Me-PCP freebase. The organic layer was allowed to separate, collected and added to the saccharine THF solution. An additional portion of 500uL MTBE was added to the

P335394NL 29 aqueous layer and shaken vigorously. The organic layer was allowed to separate, collected and added to the saccharine THF solution. A third portion of 500uL MTBE was added to the aqueous layer and shaken vigorously. The organic layer was allowed to separate, collected and added to the saccharine THF solu- tion. The container containing the saccharine and 3-Me-PCP freebase was shaken vigorously and 3-Me-

PCP saccharinate precipitated immediately. The organic solvent was decanted and the 3-Me-PCP sac- charinate salt was washed 3 times with fresh MTBE (1mL)} and dried under vacuum. 3-Me-PCP sac- charinate was obtained as colorless crystals in 97% yield.

Slug Mucosal Irritation assay

[150] Mucosal irritation was assessed using a Slug Mucosal Irritation (SMI) assay. The SMI assay was developed at the Laboratory of Pharmaceutical Technology at the University of Ghent in an effort to re- duce testing on vertebrates. Mucosal irritation can readily be assessed using an SM! assay without the need of a large number of vertebrates, such as rabbits in the invasive Draize test.

[151] The SMI assay is a simple procedure that quantifies the mucus produced by a slug following a series of contact periods with a test compound. There is a demonstrated relation between an increase in mucus production and increased stinging, itching and burning sensations in human mucous mem- branes. The mucosal irritation is classified as none, mild, moderate and severe irritation and expressed in the SMI as the percentage of the slug body weight (Table 1).

Slugs

[152] Slugs (Arion lusitanicus} were collected in a park in the south of the Netherlands. The slugs were kept at 18-20°C in plastic containers, with ventilation holes in the lid, and the bottom covered with pa- per tissue wetted with phosphate buffered saline (PBS) at pH 7.4. Acclimatization was performed by keeping the slugs in the plastic containers for at least 1 week and fed with lettuce, cucumber, carrots, and commercial cat food. Test slugs weighing between 3 to 6 g were selected and isolated 2 days prior to an SMH assay. Only slugs without macroscopic injuries were used for an assay. The slugs were trans- ferred to a plastic box covered with paper tissue and wetted with PBS. During the 2-day isolation period, the slugs were not fed and the body wall of the slugs was wetted daily with 300 ul PBS to avoid dehydra- tion.

Test samples

[153] The test samples were prepared in 2mL centrifuge tubes using 10% (wt/vol} test compound in

PBS. The compound was powdered with a mortar and pestle (in the case of waxy/oily compounds only

P335394NL 30 weighted), PBS was added and the mixture was vortexed for 3 minutes. PBS was used as the negative control and 1% (wt/vol) benzalkonium chloride (BAC) as the positive control.

SM! Assay

[154] Mucosal irritation was evaluated for the test compounds and the negative and positive controls.

The assay was performed by placing 3 slugs, not used in previous experiments, per compound on 100 pi test sample in individual petri dishes. The slugs were kept in the petri dish for a 15-minute contact pe- riod (CP) and subsequently transferred to a new individual petri dish onto a paper tissue wetted with 1.5mL PBS. The slugs were kept in the petri dish for a 60-minute rest period followed by another CP. In total 3 CPs per slug were used. Before and after each 15-minute CP the weight of the slug, and the petri dish with test slurry were recorded. The mucus production was calculated per CP by dividing the quan- tity of mucus produced by the starting weight of the slug before each CP. The total mucus production per slug was obtained by adding up the mucus production for each of the three CPs. The total mean mu- cus production (TMP) per compound was calculated by taking the mean of the 3 slugs, and is expressed as the percentage of the slug body weight. The negative control must have a TMP <5.5% and the posi- tive control 217.5% to be valid.

Table 1: Mucosal irritation classification for Total Mean Mucus Production (TMP) with SMI assay®®

[155] The mucosal irritation of tryptamine and the psychedelic dipropyltryptamine (DPT) salts were evaluated in an SMI assay. Hydrochloride salts are the most commonly used in psychedelics and were therefore used as a comparison against the sweetener salts (cyclamate (Cyc), acesulfamate (Ace) and saccharinate (Sac)).

P335394NL 31

[156] Table 2: SMI assay of tryptamine and DPT salts * 10% in PBS for tryptamine and psychedelic salts ** positive control — 1% BAC and negative control - PBS

[157] The results from the SMI assay clearly show a reduction of mucous membrane irritation when sweetener salts of the tryptamine derivatives are used. Tryptamine hydrochloride is a severe mucous membrane irritant and the sweetener salts Cyc and Ace reduce the mucous membrane irritation to moderate. Tryptamine is a non-psychoactive model for tryptamine psychedelics with similar physico- chemical properties and differs from most psychedelic tryptamines by having no alkyl substitution on the amine functionality.

[158] The psychedelic tryptamine DPT showed a significant reduction in mucous membrane irritation when sweetener salts were used (HCl > Cyc > Ace).

P335394NL 32

[159] Table 3: SMI assay of psychedelic tryptamine salts

[160] * 10% in PBS for tryptamine and psychedelic salts ** Positive control — 1% BAC and negative control — PBS

[161] The results in table 3 show significant reduction of mucous membrane irritation upon formation of a saccharinate salt of psychedelic tryptamines. All psychedelic tryptamine hydrochloride salts that were tested are severe mucous membrane irritants. Besides hydrochloride, fumarate and succinate psy- chedelic tryptamine salts were shown to be severe irritants as well.

P335394NL 33

[162] Table 4: SMI assay of psychedelic phenethylamine salts

Mucosal irritation 5-MAPB - Sac 8.6 +0.5

BOH-2C-B Sac 5,9 1.3

Negative control” | <5.5 * 10% in PBS for tryptamine and psychedelic salts ** Positive control — 1% BAC and negative control — PBS *** Very severe irritant, only 2 contact periods were used

[163] All tested psychedelic phenethylamine HCl and fumarate salts were found to be severe mucous membrane irritants, whereas the psychedelic phenethylamine saccharinate salts were only mild irri- tants. These results demonstrate that the formation of a saccharinate salt significantly reduces mucosal irritation. The reduction in mucosal irritation with phenethylamines further broadens the applicability of this invention.

Claims (27)

CONCLUSIONS 1. A salt or an ionic liquid with the general formula P'X, where P stands for a psychoactive compound and X for an artificial sweetener. The salt or ionic liquid of claim 1, wherein P is a psychoactive compound mediated primarily by activation of the 5-HT2A serotonin receptor in the central nervous system or by N-methyl-D-aspartate (NMDA) receptor antagonists. A salt or ionic liquid according to claim 1, wherein P is a psychoactive compound selected from tryptamine, phenethylamine, ketamine and phencyclidine psychoactive compounds. A salt or ionic liquid according to any one of claims 1-3, wherein the psychoactive compound is a hallucinogenic compound. A salt or ionic liquid according to any one of the preceding claims, wherein the psychoactive compound is a psychedelic or dissociative compound. A salt or ionic liquid according to any one of the preceding claims, wherein the psychoactive compound is a psychedelic compound. 7. Salt or ionic liquid according to any one of the preceding claims, wherein 8. Salt or ionic liquid according to any one of the preceding claims, wherein 9. Salt or ionic liquid according to any one of the preceding claims, wherein the salt or ionic liquid represented by the general formula P - 5-methoxydimethyltryptamine (5-MeO-DMT) saccharinate - 5-methoxymethylisopropyltryptamine (5-MeO-MIPT) saccharinate - 5-methoxydiisoproyltryptamine (5-MeO-DiPT) saccharinate - 4-hydroxy-methylethyltryptamine (4-HO-MET) saccharinate - 4-hydroxy-N,N-diethyltryptamine (4-HO-DET} saccharinate - 4- hydroxy-N,N-dipropyltryptamine (4-HO-DPT) saccharinate -4-acetoxy-N,N-diethyltryptamine (4-AcO-DET) saccharinate - 4-acetoxy-N-methyl-N-isopropyltryptamine (4- AcO-MiPT) saccharinate - 5-(2-methylaminopropyl)benzofuran {5-MAPB) saccharinate - deschloroketamine (DCK} saccharinate - 2-fluorodeschloroketamine (2-FDCK} saccharinate - 3-methylphencyclidine (3-Me-PCP ) saccharinate - 4-hydroxy-N-methyl-N-isopropyltryptamine (4-HO-MiPT) saccharinate; and - alpha-methyltryptamine (α-MT) saccharinate. A method for the preparation of a salt or an ionic liquid according to any one of the preceding claims, comprising the steps of - providing a solution of the psychoactive compound; - providing a solution of the artificial sweetener; - mixing the solution of the psychoactive compound and the solution of the artificial sweetener under agitation and possibly heating to obtain an organic layer containing the salt or ionic liquid; - separating the salt or ionic liquid from the organic layer; and - possibly further purifying the salt or ionic liquid, A pharmaceutical formulation comprising the salt or ionic liquid of any one of claims 1 to 9, further comprising a pharmaceutically acceptable carrier, excipient and/or diluent. 12. A dosage unit for transmucosal administration of a psychoactive compound to a subject, comprising a therapeutically effective amount of the psychoactive compound, the psychoactive compound being present as a salt or ionic liquid, represented by the general formula PX, where P is the psychoactive represents a compound and X represents an artificial sweetener. The transmucosal dosage unit of claim 12, wherein the transmucosal dosage unit is an oral transmucosal dosage unit. The transmucosal dosage unit of claim 13, wherein the transmucosal dosage unit is a buccal transmucosal dosage unit. The transmucosal dosage unit of claim 13, wherein the transmucosal dosage unit is a sublingual transmucosal dosage unit. The transmucosal dosage unit of claim 13, wherein the transmucosal dosage unit is a sublabial transmucosal dosage unit. The transmucosal dosage unit of claim 12, wherein the dosage unit is a nasal transmucosal dosage unit. A pharmaceutical formulation according to claim 11 for use as a medicament. A transmucosal dosage unit according to any one of claims 12-17, for use as a medicament. A pharmaceutical formulation according to claim 11, or a transmucosal dosage unit according to claim 12, for use in a method for the prophylactic or curative treatment of a person suffering from a psychiatric disease or disorder. A pharmaceutical formulation for use according to claim 20, or transmucosal dosage unit for use according to claim 20, wherein the psychiatric disease or disorder is selected from depression, obsessive compulsive disorder, panic and anxiety disorders, explosive behavior disorder, post-traumatic stress disorder, schizophrenia, substance abuse disorder, anorexia nervosa, binge eating disorder, bulimia nervosa, psychosis, autism spectrum disorders, developmental disorders, and personality disorders. A method of prophylactically or curatively treating a psychiatric disease or disorder, the method comprising administering to a subject a therapeutically effective amount of a pharmaceutical formulation according to claim 11. The method of claim 22, wherein said pharmaceutical formulation is administered via nasal transmucosal administration. The method of claim 22, wherein said pharmaceutical formulation is administered via buccal transmucosal administration. The method of claim 22, wherein said pharmaceutical formulation is administered via sublingual transmucosal administration. The method of claim 22, wherein said pharmaceutical formulation is administered via sublabial transmucosal administration. 27. A method of reducing mucosal irritation in a subject following nasal, sublingual, sublabial or buccal administration of a psychoactive compound to the subject, the method comprising administering the psychoactive compound as a salt or ionic liquid represented by the general formula P *X includes where P represents the psychoactive compound and X represents an artificial sweetener.