WO2023177294A1 - Administration transmucosale de composés psychoactifs - Google Patents

Administration transmucosale de composés psychoactifs Download PDF

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Publication number
WO2023177294A1
WO2023177294A1 PCT/NL2023/050134 NL2023050134W WO2023177294A1 WO 2023177294 A1 WO2023177294 A1 WO 2023177294A1 NL 2023050134 W NL2023050134 W NL 2023050134W WO 2023177294 A1 WO2023177294 A1 WO 2023177294A1
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Prior art keywords
saccharinate
salt
psychoactive
ionic liquid
compound
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PCT/NL2023/050134
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English (en)
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Tobias POSTMA
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Plethora Therapeutics B.V.
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Publication of WO2023177294A1 publication Critical patent/WO2023177294A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C307/02—Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms

Definitions

  • 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 administration 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 administration 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 transmucosal administration of psychoactive compounds to a subject.
  • 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 are also disclosed.
  • Psychedelics 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 phenethylamine, 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-HT2A serotonin receptor in the central nervous system.
  • Psilocybin (a tryptamine derivative) is currently the most researched psychedelic, which unfortunately has a long-lasting pharmacological action.
  • the long-lasting pharmacological effects of psychedelics such as psilocybin and LSD are impractical and costly from a therapeutic perspective.
  • the FDA has recently designated breakthrough therapy status to the phenethylamine derivative 3,4-methylenedioxymethamphetamine (MDMA) for treatment of post-traumatic stress disorder (PTSD), and to the psychedelic tryptamine derivative psilocybin for treatment of major depressive disorder and treatment-resistant depression.
  • MDMA phenethylamine derivative 3,4-methylenedioxymethamphetamine
  • PTSD post-traumatic stress disorder
  • FDA breakthrough therapy designation expedites development and review of drugs that treat serious conditions and show clinical evidence that may significantly improve clinical endpoints over available therapies.
  • 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 dependence in subjects treated therewith. Intensifying scientific research efforts are directed to psychedelic tryptamines, focusing on their mechanisms of action, potential medical applications, formulations and chemical synthesis.
  • phenethylamine psychedelics are also intensifying, including a recent application 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).
  • PTSD post -traumatic stress disorder
  • Ketamine (RS)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone) is a non-classical psychedelic and a dissociative anaesthetic in the arylcyclohexylamine class of compounds. Similar to classical psychedelics, ketamine and related arylcyclohexylamines can cause hallucinations while additionally also inducing dissociation.
  • Ketamine was first reported to have fast-acting antidepressant effect in 2000, with significant reduction 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 suicidal patients.
  • Ketamine, and arylcyclohexylamine compounds in general have been found to possess NMDA receptor antagonistic, dopamine reuptake inhibitory, and/or p-opioid receptor agonistic properties, and have also been reported to enhance the function of the 5-HT2A serotonin receptor (Lin et al., Experimental & Molecular Medicine (2016) 50:47).
  • 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 administration (ingestion), sublingual and sublabial administration, buccal administration, (intra)nasal administration and injection (intravenous, intramuscular or subcutaneous).
  • injection is very efficient.
  • 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.
  • a more patient-friendly delivery route for psychoactive compounds would be either oral ingestion, 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 compared to injectables.
  • 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").
  • 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 delivery 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 traditional orally ingested forms and a higher bioavailability of the active compound.
  • psychoactive 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 gastrointestinal discomfort.
  • particularly the oral mucosal membranes have low enzymatic activity.
  • the propensity for psychoactive drug inactivation due to biochemical degradation is lower than for other administration routes.
  • oral and nasal transmucosal administration allows for the use of dosage forms which can be efficiently and painlessly administered and removed, and easily targeted.
  • the psychoactive compounds mentioned above 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.
  • taste masking compounds such as sweeteners or flavourings
  • sweeteners or flavourings are 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.
  • 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-dispersible coatings, wherein the orodispersible coating contains specific diluents and/or disintegrating agents.
  • WO1999015171A1 describes a formulation for nicotine that reduces the perception of local irritation by the addition of the local anaesthetics benzocaine or similar substances.
  • US 2004/0173224 Al discloses of salts nicotine with one or more of acesulfame-K, saccharin-Na and aspartame. The sweeteners are used to mask or eliminate the bitter taste of nicotine. The compounds can be used for oral administration of nicotine, for example in withdrawal from smoking. US 2004/0173224 Al does no mention any other compounds than nicotine.
  • CA 2341522A1 (equivalent WO 00/12067, cited in US 2004/0173224 Al) discloses saccharinate salts of orally administrable medicinal bases, specifically on-alkaloidal organic medicinal bases.
  • Several classes of such medicinal bases are broadly mentioned, among which psychopharmalogics, neurologies and anaesthetics. The only example provided concerns the anxiolytic compound buspirone saccharinate.
  • the purpose of the sweetener is masking the bitter taste of the medicinal bases.
  • US 2002/197381A1 describes 1:1 and 1:2 adducts of caffeine and acesulfame-H, wherein the bitter taste of caffeine is masked.
  • EP1703896B1 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 tolerability of the formulation by reducing the local irritation and the bitter drip.
  • a salt or ionic liquid represented by the general formula P + X _ , wherein P represents a psychoactive compound and X represents an artificial sweetener.
  • compositions comprising an ionic liquid or a salt of a prophylactically or therapeutically effective amount of psychoactive compound and an artificial sweetener.
  • Such compositions are particularly suitable for nasal, sublingual, sublabial or buccal administration 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 psychoactive compounds because of nausea, vomiting, malabsorption or dysphagia. They may further be attractive 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 administration via injection.
  • a dosage unit for oral or nasal transmucosal administration of a psychoactive compound to a subject wherein the transmucosal dosage unit comprises a salt or ionic liquid as defined herein.
  • 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, dissolved, 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.
  • the compositions and dosage units of the present disclosure may contribute to improved patient compliance and convenience.
  • 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.
  • one aspect of the invention relates to a salt or ionic liquid represented by the general formula (P + )(Xj, wherein P represents a psychoactive compound and X represents an artificial sweetener.
  • the ionic liquid or salt is of the formula ( P + )(X j, wherein P + is a cationic component of the ionic liquid or salt and X“ is an anionic component of the ionic liquid or salt.
  • 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 + )(Xj, 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 compound” or “an ionic liquid derived from an artificial sweetener and a psychoactive compound” refers to an ionic liquid represented by the general formula (P + )(Xj, wherein P represents the psychoactive compound and X represents the artificial sweetener.
  • the term "ionic liquid” refers to a salt having a melting point below 100 °C. Typically, 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).
  • 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 artificial 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., non-artificial and non-synthetic) sugar alcohol sweeteners such as sorbitol, xylitol, mannitol, erythritol, and lactitol.
  • reduced-calorie plant-derived (i.e., non-artificial and non-synthetic) sugar alcohol sweeteners such as sorbitol, xylitol, mannitol, erythritol, and lactitol.
  • 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.
  • ionic liquids and salts are also included in which the psychoactive compound has two or more different sweeteners as anion-forming components.
  • 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 2+ ) or magnesium (Mg 2+ ) cations.
  • a suitable cation such as alkali metals, such as sodium (Na + ) or potassium (K + ) cations, or alkaline earth metals, such as calcium (Ca 2+ ) or magnesium (Mg 2+ ) cations.
  • 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, including 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.
  • X represents an artificial sweetener compound
  • X- is selected from saccharinate, cyclamate, aspartate, alitame, neotame, and acesulfame, more preferably saccharinate, cyclamate, and acesulfame, most preferably saccharinate.
  • 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 compounds.
  • the terms “psychoactive compound” and “psychoactive agent” refer to a compound that changes functioning of the nervous system and results in alterations in perception, mood, consciousness, cognition, and/or behaviour .
  • the psychoactive compounds for use according to the present disclosure are selected from compounds that exert their effects primarily through activation of the serotonergic system, and in particular through activation of the 5-HT2A serotonin receptor in the central nervous system, and N- methyl-D-aspartate (NMDA) receptor antagonists.
  • NMDA N- methyl-D-aspartate
  • hallucinogens or hallucinogenic agents/compounds/substances
  • serotonergic hallucinogens typically have a psychedelic effect and are generally referred to as “psychedelics”
  • NMDA N-methyl-D-aspartate
  • the psychoactive compound is a hallucinogenic compound.
  • the psychoactive compound is a psychedelic or a dissociative compound, preferably a psychedelic compound.
  • the psychoactive compound is an amine-containing compound, i.e. comprising a primary, secondary or tertiary amine moiety.
  • 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 phencyclidine (PCP) derivatives.
  • 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 tryptamine derivatives, psychedelic phenethylamine derivatives, psychedelic ketamine derivatives, and psychedelic phencyclidine (PCP) derivative and wherein X represents an artificial sweetener.
  • the term “derivative” refers as used herein refers to compounds that are derived from the referenced compound by substitution with one or more functional groups and the maintain the same core structure as the compound from which they are derived.
  • the terms “tryptamine derivative”, “phenethylamine derivative”, “ketamine derivative”, and “phencyclidine derivative” are considered equivalent to the terms “substituted tryptamine”, “substituted phenethylamine”, “substituted ketamine”, and “substituted phencyclidine”. Examples of suitable tryptamine derivatives, phenethylamine derivatives, ketamine derivatives, and phencyclidine derivatives are described in detail below.
  • 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.
  • the invention concerns amongst other things the treatment of a disease or disorder.
  • 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 condition, for example arresting, reducing or delaying the development of the event, state, disorder or condition, 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.
  • the benefit to a patient to be treated may be either statistically significant or at least perceptible to the patient or to the physician.
  • compositions and methods described herein are of use for therapy and/or prophylaxis of the mentioned conditions.
  • 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 condition, for example for the purpose of reducing the chance of an event, state, disorder or condition occurring.
  • the outcome of the prophylaxis may be, for example, preservation of health or delaying the initiation 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 understood accordingly.
  • 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 different butyl isomers.
  • alkenyl includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl isomers.
  • Alkenyl 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.
  • alkoxy includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy isomers.
  • Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio and butylthio isomers.
  • Alkylthioalkyl denotes alkylthio substitution on alkyl. Examples of “alkylthioalkyl” include CH 3 SCH 2 , CH 3 SCH 2 CH 2 , CH 3 CH 2 SCH 2 , CH 3 CH 2 CH 2 CH 2 SCH 2 and CH 3 CH 2 SCH 2 CH 2 .
  • Alkylthioalkoxy denotes alkylthio substitution on alkoxy.
  • Cyanoalkyl denotes an alkyl group substituted with one cyano group. Examples of “cyanoalkyl” include NCCH 2 , NCCH 2 CH 2 and CH 3 CH(CN)CH 2 .
  • Alkylamino dialkylamino, and the like, are defined analogously to the above examples.
  • 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. Further, 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 F 3 C, CICH 2 , CF 3 CH 2 and CF 3 CCI 2 . The terms “haloalkoxy”, and the like, is defined analogously to the term “haloalkyl”.
  • haloalkoxy examples include CF 3 O-, CCI 3 CH 2 O-, HCF 2 CH 2 CH 2 O- and CF 3 CH 2 O-.
  • C1-C4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl (including various C4 isomers);
  • Cialkoxy-C 2 alkyl designates CH 3 OCH 2 CH 2 ;
  • Cialkoxy-C 2 alkyl designates, for example, CH 3 CH(OCH 3 )- or CH 3 OCH 2 CH 2 -.
  • the psychoactive compounds as disclosed herein can be present in the form of one of the isomers which are possible or as a mixture of these, for example in the form of pure isomers, such as antipodes and/or diastereomers, or as isomer mixtures, such as enantiomer mixtures, for example racemates, 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 configuration 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.
  • 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, cyclohexyl and the like.
  • 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, consisting 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 sulphur 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.
  • heterocycloalkyl as used herein includes reference to a saturated heterocyclic moiety 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.
  • 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 system but more often is monocyclic.
  • This term includes reference to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, quinolizidinyl and the like.
  • substituents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible.
  • amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. olefinic) bonds.
  • substituents described herein may themselves be substituted by any substituent, subject to the aforementioned restriction to appropriate substitutions as recognised by the skilled person.
  • the isomer having the lowest conformational energy may be preferred.
  • composition includes reference to a formulation comprising 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 pharmaceutical composition. Unless the context indicates otherwise, all references to a “formulation” herein are references to a pharmaceutical formulation.
  • product or “product of the invention” as used herein includes reference to any product containing a compound of the present invention. In particular, the term product relates to compositions and formulations containing a compound of the present invention, such as a pharmaceutical composition, for example.
  • terapéuticaally effective amount 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.
  • the psychoactive compound P is a tryptamine derivative represented by the general structure (I) wherein R la is selected from hydrogen, deuterium, Ci-C4alkyl, Ci-C4alkenyl, Ci.C4haloalkyl, C(O)R 13a , C(O)SR 13a , and C(O)NR 13a ;
  • R 2a and R 3a are independently selected from hydrogen, deuterium, halogen, and Ci-C4alkyl;
  • R 4a is selected from hydrogen, deuterium, halogen, Ci-C4alkyl, Ci-C4alkoxy, and Ci-C4alkylthio;
  • R 5a , R 6a , R 7a , R 8a and R 9a are independently selected from hydrogen, deuterium, hydroxyl, sulfhydryl, halogen, Ci-C4alkyl, OC(O)R 13a , SC(O)R 13a , and Ci-C4alkoxy;
  • R 10a and R lla are independently selected from hydrogen and deuterium, or
  • R 10a and R lla are independently selected from, optionally deuterated, Ci-C4alkyl, Ci-C4alkenyl, Ci-C4haloal- kyl, and Cs-Cgcycloalkyl;
  • R 12a is selected from hydrogen, deuterium, halogen, and Ci-C4alkyl
  • R 13a is selected from Ci-C4alkyl, Ci-C4alkenyl, Ci.C4haloalkyl, and Cs-Cgcycloalkyl.
  • R la is selected from hydrogen, deuterium, methyl and ethyl.
  • R 2a and R 3a are independently selected from hydrogen, deuterium, methyl and ethyl .
  • R 4a is selected from hydrogen, deuterium and Ci-C4alkyl, preferably hydrogen, methyl, ethyl, n-propyl and iso-propyl.
  • R 5a is selected from hydrogen, deuterium, hydroxyl, methyl and ethyl.
  • R 6a , R 7a , R 8a , R 9a are independently selected from hydrogen, deuterium, and Ci-C4alkyl, more preferably from hydrogen and methyl.
  • R 10a and R lla are independently selected from hydrogen, deuterium and Ci-C4alkyl, more preferably from methyl, ethyl, n-propyl and iso-propyl.
  • R 12a is selected from hydrogen, deuterium, methyl and ethyl.
  • R 13a is selected from hydrogen, deuterium, methyl and ethyl.
  • the psychoactive tryptamine compound P is a psychedelic substituted tryptamine compound.
  • the psychoactive tryptamine compound P is a psychedelic substituted tryptamine compound.
  • the psychoactive tryptamine compound P is selected from
  • N-methyl-N-ethyltryptamine N-methyl-N-ethyltryptamine, MET
  • the psychoactive compound P represents a psychoactive compound
  • the psychoactive compound P is a phenethylamine derivative represented by the general structure (II) wherein R lb ,R 2b , R 3b , and R 4b are independently selected from hydrogen and deuterium, or
  • R lb ,R 2b , R 3b , and R 4b are independently selected from, optionally deuterated, Ci-C4alkyl and Ci-C4alkenyl;
  • R 7b and R 8b are independently selected from hydrogen, deuterium, hydroxyl, Ci-C4alkyl, Ci-C4alkoxy and Ci- C4alkylthio; or
  • R 7b and R 8b together with the carbon atom to which they are attached form a 1-furan or 3-furan;
  • R 8b and R 9b together with the carbon atom to which they are attached form a dioxolane, 1-furan or 3-furan;
  • R 10b and R llb are independently selected from hydrogen, deuterium, hydroxyl, Ci-C4alkyl, Ci-C4alkoxy and
  • R 10b and R llb together with the carbon atom to which they are attached form a dioxolane, a 1-furan or a 3- furan.
  • R lb , R 2b , R 3b , and R 4b are independently selected from hydrogen, deuterium and Ci-C4alkyl, preferably hydrogen, methyl, ethyl, n-propyl and iso-propyl.
  • R 5b and R 6b are independently selected from hydrogen, deuterium and Ci-C4alkyl, preferably hydrogen and methyl.
  • R 7b , R 8b , R 9b , R 10b and R llb are independently selected from hydrogen, deuterium, hydroxyl, Ci-C4alkyl and Ci-C4alkoxy.
  • the psychoactive phenethylamine compound P is a dissociative substituted phenethylamine compound.
  • the psychoactive phenethylamine compound P is a psychedelic substituted phenethylamine compound.
  • the psychoactive phenethylamine compound P is selected from
  • DOI - l-(4-iodo-2,5-dimethoxyphenyl)-2-propanamine
  • the psychoactive compound P is a ketamine or phencyclidine derivative represented by the general structure (III) wherein
  • Ar represents a monocyclic or bicyclic aromatic or heteroaromatic group optionally substituted independently with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, Ci-C4alkyl, Cs-Cgcycloalkyl, Ci-C4alkenyl, Ci-C4alkynyl, Ci.C4haloalkyl, Ci-C4alkoxy, Ci- C4alkenyloxy, Ci-C4alkynyloxy, Ci-C4haloalkoxy, Ci-C4alkylthio, Ci-C4alkenylthio, Ci-C4haloalkylthio, Ci- C4al kylsulfinyl, Ci-C4-haloalkylsulfinyl, Ci-C4alkylsulfonyl, Ci-C4haloalkylsulfonyl, Ci-C4alkylcarbonyl, Ci-C 4alkoxy-C
  • R lc and R 2c are independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, Ci- C4alkyl, Ci-C4alkenyl, Cs-Cgcycloalkyl, Ci-C4alkynyl Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4alkenyloxy, Ci- C4alkynyloxy, Ci-C4haloalkoxy, Ci-C4alkylthio, Ci-C4alkenylthio, Ci-C4haloalkylthio, Ci-C4alkylsulfinyl, Ci- C4haloalkylsulfinyl, Ci-C4alkylsulfonyl, Ci-C4haloalkylsulfonyl, Ci-C4alkylcarbonyl, Ci-C4alkoxy-Ci-C4alkyl, Ci- C4alkoxycarbonyl, Ci-C4alk
  • R lc and R 2c together with the N to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring optionally including 1 to 2 additional ring heteromoieties selected from O, S, S(O), SO2, 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-C4 alkyl and Ci-C4-alkoxy.
  • R lc and R 2c are independently selected from hydrogen, deuterium, hydroxyl, Ci-C4-alkyl, Ci-C4-alkenyl, Ci-C4-haloalkyl, and Ci-C4-alkoxy.
  • R lc and R 2c together with the N to which they are attached form a pyrrolidinyl, piperidyl or morpholyl ring.
  • Ar is selected from phenyl, 2-pyridinyl, 2-thienyl, 3-thienyl, m-methoxyphenyl, m-ethoxyphenyl, m-chlorophenyl, o-chlorophenyl, benzothiophen-2-yl, 2-methyl-4-hydroxyphenyl, m- fluorophenyl, o-fluorophenyl, p-fluorophenyl, m-hydroxyphenyl, p-hydroxyphenyl, o-hydroxyphenyl, m- tolyl, o-tolyl, p-tolyl, o-trifluoromethylpheny, p-bromophenyl and 3,4-methylenedioxyphenyl.
  • the psychoactive ketamine or phencyclidine compound P is a dissociative substituted ketamine or phencyclidine compound.
  • the psychoactive ketamine or phencyclidine compound P is a psychedelic substituted ketamine or phencyclidine compound.
  • the psychoactive ketamine or phencyclidine compound P is selected from
  • the compounds as defined above include the (S)-enantiomers, (R)- enantiomers and racemic mixtures thereof.
  • ketamine may refer to (5)-(+)-ketamine (or “esketamine”) or (7?)-(-j-ketamine (or “arketamine”), or to a racemic mixture thereof.
  • 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 psychoactive compound.
  • the invention relates to an anionic liquid comprising a saccharinate, cyclamate, or acesulfame anion and a cation of a psychoactive compound.
  • the invention relates to a saccharinate, cyclamate, or acesulfamate salt or an ionic liquid of a tryptamine, phenethylamine, ketamine or phencyclidine as disclosed herein.
  • Exemplary ionic liquids or salts according to the present disclosure are N-[2-(lH-indol-3-yl)ethyl]-N- propyl-l-propanamine cyclamate, N-[2-(lH-indol-3-yl)ethyl]-N-propyl-l-propanamine acesulfame, 2-(lH- indol-3-yl)-N,N-dimethylethanamine saccharinate, 2-(lH-indol-3-yl)-N,N-dimethylethanamine cyclamate, 2- (lH-indol-3-yl)-N,N-dimethylethanamine acesulfame, 2-(lH-indol-3-yl)-N,N-diethylethanamine saccharinate, 2-(lH-indol-3-yl)-N,N-diethylethanamine cyclamate, 2-(l(lH
  • exemplary ionic liquids or salts according to the present disclosure are l-(l-benzofuran-5-yl)- N-methyl-2-propanamine saccharinate, l-(l-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-l- yl)oxy]phenyl ⁇ ethanamine saccharinate, 2- ⁇ 3,5-dimethoxy-4-[(2-methyl-2-propen-l- yl)oxy]phenyl ⁇ ethanamine cyclamate, 2- ⁇ 3,5-dimethoxy-4-[(2-methyl-2-propen-l-yl)oxy]phenyl ⁇ ethanamine acesulfame, 2-amino-l-(4-bromo-2,5-dimethoxyphenyl)ethanol
  • exemplary ionic liquids or salts are 2-(methylamino)-2- phenylcyclohexan-l-one saccharinate, 2-(methylamino)-2-phenylcyclohexan-l-one cyclamate, 2- (methylamino)-2-phenylcyclohexan-l-one acesulfame, 2-(2-fluorophenyl)-2-(methylamino)cyclohexan-l- one saccharinate, 2-(2-fluorophenyl)-2-(methylamino)cyclohexan-l-one cyclamate, 2-(2-fluorophenyl)-2- (methylamino)cyclohexan-l-one acesulfame, l-(l-(m-tolyl)cyclohexyl)piperidine saccharinate, l-(l-(m- tolyl)cyclohexyl)piperidine cyclamate,
  • DPT dipropyltryptamine
  • MET methylethyltryptamine
  • DCK deschloroketamine
  • the above psychoactive compounds are used in an amount sufficient to produce their desired prophylactic or curative efficacy.
  • the active ingredient content per dose unit may vary widely, and depends on a variety of factors including the type of active ingredient, condition being treated, total treatment period, age, weight and sex of the subject taking the medication, etc.
  • the active ingredient is used in an amount of 0.05 to 95 percent by weight based on the weight of the dosage unit.
  • 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 sufficient or a larger dose is required for the active ingredient to produce its prophylactic or therapeutic effects.
  • 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 acceptable salt thereof (such as HCI, fumarate or succinate) with a solution of the artificial sweetener, typically 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.
  • a pharmaceutically acceptable salt thereof such as HCI, fumarate or succinate
  • 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.
  • the psychoactive compound is provided in the form of a pharmaceutically acceptable salt thereof, such as its HCI, fumarate, succinate, etc. salt
  • a pharmaceutically acceptable salt thereof such as its HCI, fumarate, succinate, etc. salt
  • 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.
  • a dosage unit for the transmucosal administration of a psychoactive compound to a subject wherein the transmucosal dosage unit comprises a salt or an ionic liquid of an artificial sweetener and a psychoactive compound as disclosed herein.
  • the transmucosal dosage unit comprises a salt or ionic liquid represented by the general formula P + X _ , wherein P represents a psychoactive compound and X represents an artificial sweetener.
  • the dosage unit is configured for the oral transmucosal administration of a psychoactive compound to a subject.
  • the dosage unit is configured for the nasal transmucosal administration of a psychoactive compound to a subject.
  • 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 combination thereof.
  • sublingual refers to the pharmacological route of administration by which an active compound is held under the tongue
  • uccal refers to the pharmacological 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 compound 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.
  • nasal transmucosal administration or “intranasal transmucosal administration” refers to administration through the nasal mucosa of an active compound for the purpose of systemic delivery of said active compound.
  • the active compound is provided to the nasal cavity and contacted with the mucous membranes lining the nose.
  • the nasal mucous membranes possess a relatively large surface area, a porous epithelial membrane, and extensive vascularization, thus enabling rapid onset of the therapeutic or prophylactic effect.
  • the transmucosal dosage unit is a buccal transmucosal dosage unit.
  • the transmucosal dosage unit is a sublingual transmucosal dosage unit.
  • the transmucosal dosage unit is a sublabial transmucosal dosage unit.
  • the transmucosal dosage unit is a nasal or intranasal transmucosal dosage unit.
  • 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, aqueous 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 diluent, 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 peanut oil, liquid paraffin or olive oil.
  • the oral transmucosal dosage units according to the present invention are provided in the form of solid or semi-solid dosage units, especially in the form of tablets, capsules, cachets, pellets, pills, powders or granules.
  • 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.
  • 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, colouring agents and preserving agents. Said dosage units may suitably contain one or more non-toxic pharmaceutically acceptable excipients.
  • Suitable excipients may be, for example, disintegrants such as microcrystalline cellulose, methylcellulose, 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, colloidal silicon dioxide and talc; and lubricating agents, such as magnesium stearate, stearic acid, magnesium lauryl sulphate and sodium lauryl sulphate, or tal
  • Tablets may be uncoated or may be (partially) coated by known techniques to tune disintegration and adsorption by the oral mucosal membranes. Additional excipients may be included or combined, but are not limited to, the following: flavorings, sweeteners, colorants, preservatives, mucosal penetration enhancers, anti-oxidants, binders, buffers, thickening agents, mucoadhesive agents, salts, effervescent bases and emulsifiers.
  • super-disintegrants may be added to facilitate rapid disintegration of the dosage unit.
  • 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 croscarmellose sodium (CCS); as well as 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.
  • crospovidone cross-linked polyvinyl-N-pyrrolidone, PVP
  • chitin/chitosan-silicon dioxide coprecipitate INDION 414
  • the dosage unit for oral transmucosal administration is a rapidly disintegrating 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.
  • 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 anaesthetics, isotonizing agents, adsorption inhibitors (such as Tween 80), solubility enhancing agents (such as cyclodextrins and derivatives thereof), wetting agents (such as sodium acetate, sodium lactate), absorptionpromoting polymers (synthetic polymers or natural polymers such as processed collagen, chitin, chitosan).
  • 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 anaesthetics, isotonizing agents, adsorption inhibitors (such as Tween 80), solub
  • Syrups and elixirs may be formulated with additional sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavouring or a colouring agent. Other ingredients are added to the composition of the dosage form of the invention to provide particular properties.
  • 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.
  • the present disclosure relates to a salt or ionic liquid represented by the general formula P + X _ , wherein P represents a psychoactive compound and X represents an artificial sweetener, for use as a medicament.
  • 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 as a medicament.
  • 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 subject, wherein said method comprises transmucosal administration to said subject of the dosage unit.
  • 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.
  • 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 mammal suffering from a psychiatric disease or disorder.
  • the pharmaceutical formulation or transmucosal dosage unit according to the invention is administered via buccal, sublingual, sublabial or nasal transmucosal administration.
  • 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.
  • 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 subjects who are unable to tolerate oral ingestion, or intramuscular or intravascular injection of psychoactive compounds.
  • the compounds and compositions of the present disclosure are particularly advantageous 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.
  • a method for reducing mucosal irritation in a subject upon nasal, sublingual, sublabial or buccal administration of a psychoactive compound to the subject comprises providing the psychoactive compound as a salt or ionic liquid of an artificial 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.
  • 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.
  • Mucosal irritation can be assessed quantitatively by a so-called Slug Mucosal Irritation (SMI) assay.
  • SMI Slug Mucosal Irritation
  • 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 procedure that quantifies the mucus produced by a slug following a series of contact periods with a test compound, which correlates to mucosal irritation in humans.
  • the tested psychoactive compounds were purchased in their free-base or HCI salt form or synthesized using known procedures.
  • DIPT diisopropyltryptamine
  • the indole route is a three-step process, which is similar to the synthesis of psilocin and related tryptamine psychedelics (Scheme 1).
  • 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 compounds.
  • Tryptamine hydrochloride (0.5 mmol) was dissolved in 250pL deionized water.
  • Sodium cyclamate (0.5 mmol) was dissolved in 250pL deionized water.
  • the tryptamine HCI solution was added to the sodium cyclamate solution and vigorously shaken.
  • Tryptamine cyclamate formed immediately as an ionic liquid, which collected in the bottom of the container.
  • the aqueous layer was decanted and the ionic liquid washed twice with 500pL deionized water. The ionic liquid was dried overnight under vacuum at room temperature. Tryptamine cyclamate was obtained as a cream colored solid in 57% yield.
  • Saccharin (0.5 mmol) and Tryptamine freebase (0.5 mmol) were dissolved in ImL THF under mild heating at 40°C and shaken vigorously. This mixture was added to 5mL MTBE and shaken vigorously.
  • Tryptamine saccharinate formed immediately.
  • the organic solvent was decanted and tryptamine saccharinate was washed 3 times with fresh MTBE (ImL) and dried under vacuum at room temperature. Tryptamine saccharinate was obtained as a yellow flaky solid in 92% yield.
  • Tryptamine acesulfamate formed immediately.
  • the organic solvent was decanted and tryptamine acesulfamate was washed 3 times with fresh MTBE (ImL) and dried under vacuum at room temperature. Tryptamine acesulfamate was obtained as a yellow waxy solid in 84% yield.
  • DPT hydrochloride 0.5 mmol was dissolved in 500pL deionized water.
  • DPT hydrochloride 0.5 mmol was dissolved in 500pL deionized water.
  • Acesulfame potassium (0.5 mmol) was dissolved in 500pL 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 500pL deionized water. The solid was dried overnight under vacuum at room temperature. DPT acesulfamate was obtained as a cream colored solid in 75% yield.
  • Saccharin (0.5 mmol) was dissolved in 500pL THF under mild heating at 40°C.
  • Methylethyltryptamine (MET) fumarate (0.5 mmol) was suspended in 500pL MTBE.
  • MET Methylethyltryptamine
  • 500pL MTBE 0.5 mmol
  • 500pL MTBE saturated aqueous NaHCOs
  • the organic layer was allowed to separate, collected and added to the saccharin THF solution.
  • An additional portion of 500pL 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 500pL 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 immediately as an ionic liquid.
  • the organic solvent was decanted and MET saccharinate was washed 3 times with fresh MTBE (ImL) and dried under vacuum at room temperature. MET saccharinate was obtained as a pale yellow ionic liquid in 92% yield.
  • Saccharin (0.5 mmol) was dissolved in 500pL THF under mild heating at 40°C.
  • 5- methoxymethylisopropyltryptamine (5-MeO-MIPT) hydrochloride (0.5 mmol) was suspended in 500pL MTBE.
  • To the MTBE suspension 1 mL saturated aqueous NaHCOs 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 500pL 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 500pL 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 5-MeO-MIPT saccharinate was washed 3 times with fresh MTBE (ImL) and dried under 1 vacuum at room temperature.
  • 5-MeO-MIPT saccharinate was obtained as a colorless ionic liquid in 96% yield.
  • a third portion of 500pL 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 5mL 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 (ImL) and dried under vacuum at room temperature.
  • 4-HO-MET saccharinate was obtained as an ionic liquid that crystallized upon standing in 81% yield.
  • Saccharin (0.5 mmol) was dissolved in 500pL THF under mild heating at 40°C.
  • 5-(2- methylaminopropyl)benzofuran (5-MAPB) hydrochloride (0.5 mmol) was suspended in 500pL MTBE.
  • To the MTBE suspension 1 mL saturated aqueous NaHCOs 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, collected and added to the saccharin THF solution. An additional portion of 500pL 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 500pL 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-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 temperature.
  • 5- MAPB saccharinate was obtained as a yellow ionic liquid in 87% yield.
  • Example 11 Preparation of deschloroketamine (DCK) saccharinate
  • Saccharin 0.5 mmol
  • DCK deschloroketamine
  • hydrochloride 0.5 mmol racemate
  • To the MTBE suspension ImL saturated aqueous NaHCOs 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 500pL 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.
  • Saccharin (0.5 mmol) was dissolved in 500pL THF under mild heating at 40°C.
  • 2- Fluorodeschloroketamine (2-FDCK) hydrochloride (0.5 mmol) racemate was suspended in 500pL MTBE.
  • ImL saturated aqueous NaHCOs 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, collected and added to the saccharine THF solution.
  • An additional portion of 500pL 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.
  • Saccharin (0.5 mmol) was dissolved in 500pL THF under mild heating at 40°C.
  • 3- Methylphencyclidine (3-Me-PCP) hydrochloride (0.5 mmol) racemate was suspended in 500pL MTBE.
  • ImL saturated aqueous NaHCOs 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 500pL 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.
  • Mucosal irritation was assessed using a Slug Mucosal Irritation (SMI) assay.
  • SMI Slug Mucosal Irritation
  • the SMI assay was developed at the Laboratory of Pharmaceutical Technology at the University of Ghent in an effort to reduce testing on vertebrates. 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 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 membranes. 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 (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 paper 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 SMI assay. Only slugs without macroscopic injuries were used for an assay. The slugs were transferred 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 pl PBS to avoid dehydration.
  • PBS phosphate buffered saline
  • 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 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.
  • 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 pl test sample in individual petri dishes. The slugs were kept in the petri dish for a 15-minute contact period (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.
  • CP contact period
  • the mucus production was calculated per CP by dividing the quantity 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 mucus 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 positive control >17.5% to be valid.
  • Table 1 Mucosal irritation classification for Total Mean Mucus Production (TMP) with SMI assay 15

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Abstract

La présente divulgation concerne des composés psychoactifs, tels que des composés psychédéliques, des formulations pharmaceutiques et des unités de dosage pour l'administration transmucosale de composés psychoactifs, comprenant un sel d'édulcorant ou un liquide ionique d'édulcorant d'un composé psychoactif. Les composés, formulations et unités de dosage selon l'invention sont avantageusement utilisés dans un procédé d'administration nasale, buccale, sublabiale ou sublinguale d'un composé psychoactif, tel qu'un composé psychédélique à un sujet. La divulgation concerne également des composés, des formulations et des compositions destinés à être utilisés en tant que médicament dans un procédé de traitement prophylactique ou curatif d'un sujet souffrant d'une maladie ou d'un trouble psychiatrique.
PCT/NL2023/050134 2022-03-18 2023-03-16 Administration transmucosale de composés psychoactifs WO2023177294A1 (fr)

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US3492131A (en) 1966-04-18 1970-01-27 Searle & Co Peptide sweetening agents
WO1999015171A1 (fr) 1997-09-25 1999-04-01 Pharmacia & Upjohn Ab Compositions de nicotine et leur procede de formulation
CA2341522A1 (fr) 1998-08-27 2000-03-09 Bristol-Myers Squibb Company Nouvelle forme saline pharmaceutique
US20020197381A1 (en) 2001-06-25 2002-12-26 Andreas Burgard Caffeine complexes with enhanced taste, process for their preparation and their use
US20040173224A1 (en) 2000-03-20 2004-09-09 Andreas Burgard Nicotine salts having improved taste, process for their preparation and their use
US20070134331A1 (en) 2005-12-14 2007-06-14 Les Laboratoires Servier Orodispersible pharmaceutical composition for oromucosal or sublingual administration of agomelatine
EP1703896B1 (fr) 2004-01-14 2008-12-17 Franciscus Wilhelmus Henricus Maria Merkus Compositions pharmaceutiques contenant du midazolam dans une concentration elevee
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GB901919A (en) * 1959-02-12 1962-07-25 Upjohn Co Therapeutic compositions comprising alpha-alkyl-tryptamines
US3492131A (en) 1966-04-18 1970-01-27 Searle & Co Peptide sweetening agents
WO1999015171A1 (fr) 1997-09-25 1999-04-01 Pharmacia & Upjohn Ab Compositions de nicotine et leur procede de formulation
CA2341522A1 (fr) 1998-08-27 2000-03-09 Bristol-Myers Squibb Company Nouvelle forme saline pharmaceutique
WO2000012067A1 (fr) 1998-08-27 2000-03-09 Bristol-Myers Squibb Company Nouvelle forme saline pharmaceutique
US20040173224A1 (en) 2000-03-20 2004-09-09 Andreas Burgard Nicotine salts having improved taste, process for their preparation and their use
US20020197381A1 (en) 2001-06-25 2002-12-26 Andreas Burgard Caffeine complexes with enhanced taste, process for their preparation and their use
EP1703896B1 (fr) 2004-01-14 2008-12-17 Franciscus Wilhelmus Henricus Maria Merkus Compositions pharmaceutiques contenant du midazolam dans une concentration elevee
US20070134331A1 (en) 2005-12-14 2007-06-14 Les Laboratoires Servier Orodispersible pharmaceutical composition for oromucosal or sublingual administration of agomelatine
AU2012238330B1 (en) * 2010-10-26 2013-04-11 Ix Biopharma Ltd Fast Dissolving Solid Dosage Form
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