NL2031331B1

NL2031331B1 - Transmucosal delivery of a short-acting psychedelic compound

Info

Publication number: NL2031331B1
Application number: NL2031331A
Authority: NL
Inventors: Postma Tobias
Original assignee: Plethora Therapeutics B V
Priority date: 2022-03-18
Filing date: 2022-03-18
Publication date: 2023-09-29
Also published as: WO2023177295A1

Abstract

The present disclosure relates to a short—acting psychedelic compound, pharmaceutical formulations and dosage units for the transmucosal delivery of the psychedelic compound. The compound, formula— tions and dosage units according to the invention are advantageously employed in a method for the na— sal, buccal, sublabial, or sublingual administration of a psychedelic compound to a subject. Also dis— closed are compounds, formulations and compositions for use as a medicament in a method of prophy— lactically or curatively treating a subject suffering from a psychiatric disease or disorder.

Description

P335499NL 1

TRANSMUCOSAL DELIVERY OF A SHORT-ACTING PSYCHEDELIC COMPOUND

Field of the invention

[001] The present invention is in the field of psychoactive compounds. More specifically, it relates to transmucosal administration of a short-acting psychedelic compound and to dosage units for the trans- mucosal administration of the psychedelic compound. 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 a short-acting psychedelic compound to a subject in need thereof. The inven- tion further relates to a method for reducing mucosal irritation in a composition for nasal, sublingual, sublabial or buccal transmucosal administration of a short-acting psychedelic compound to a subject.

Also disclosed are compounds and compositions for use as a medicament in a method of prophylacti- cally 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 mediated by the same activation of the 5-HT24 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 psychedelic tryptamine de- rivative psilocybin for treatment of major depressive disorder and treatment-resistant depression. FDA

P335499NL 2 breakthrough designation expedites development and review 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 and chemical synthesis.

[008] The short-acting psychedelic N,N-dipropyltryptamine (DPT) is a promising psychedelic com- pound for the treatment of mental health disorders. The psychedelic activity of DPT is between 2-3 hours, which can significantly reduce the time of psychedelic therapy sessions. DPT has been used par- enterally in humans in early clinical trials in the 60s-70s.

[009] DPT is known to have low oral bioavailability due to extensive first-pass metabolism. Oral ad- ministration of DPT at high doses (2250mg) has been reported, albeit with great interpersonal variation in effects. Oral delivery of tryptamine psychedelics can become more predictable when used in combi- nation with a mono-amine oxidase inhibitor (“MAOVY”, e.g., moclobemide). However, the combination of a tryptamine psychedelic and an MAO! typically leads to undesirable side effects, such as intense nau- sea, vomiting and a pronounced prolongation of psychoactivity.

[010] Therefore, DPT is often administered in injectable dosage forms. However, injection is invasive and not patient-friendly, especially considering that psychedelic-assisted therapy is strongly influenced by set and setting, i.e. starting a psychedelic-assisted therapy session with an injection can cause anxiety or trigger phobias in some patients and may negatively impact the therapeutic outcome.

[011] A more patient-friendly delivery route for DPT compounds would be transmucosal absorption in the oral cavity (sublingual, sublabial or buccal) or intranasal transmucosal absorption, as these are gen- erally painless, non-invasive, patient-friendly administration routes.

[012] Oral or nasal transmucosal drug delivery, i.e. the administration of psychedelic 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, psychedelic 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.

P335499NL 3

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

[013] 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. Thus, transmucosal delivery of DPT to subjects would be less invasive and preferable.

[014] Unfortunately, there are considerable barriers to transmucosal delivery of DPT, as psychedelic tryptamine compounds, in particular the free base and their common salt forms - i.e., hydrochloride, fumarate or succinate salts - are generally known to cause irritation of the oral and nasal mucous mem- brane. This mucosal irritation may manifest itself with pain, with increased redness, with lesions like ul- cers, 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.

[015] These possible side-effects related to mucosal irritation upon nasal or oral transmucosal admin- istration of DPT limits its potential application in terms of choice of formulation options and concentra- tion ranges. This in turn may result in low patient acceptability and compliance of an otherwise promis- ing short-acting psychedelic agent.

[016] 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.

[017] US2007/134331A1 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 disinte- grating agents.

[018] Mucous membrane irritation has also been attempted to be controlled by the addition of desen- sitizing pharmaceutical agents, such as local anaesthetics. WO1999/015171A1 describes a formulation for nicotine that reduces the perception of local irritation by the addition of the local anaesthetics ben- zocaine or similar substances.

[019] 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

P335499NL 4 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.

[020] 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 reduces flexibility in selection of active ingredient con- centration ranges and suitable additives, and increases the complexity of manufacture of the dosage form.

[021] 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 DPT without causing one or more of the above-described undesirable side-effects, (ii) that provide broad flexibility in the choice of concentration ranges, dosage forms and associated additives and (iii) that may be administered in a con- venient and reliable manner, thus improving patient acceptability and therapy adherence.

Summary of the Invention

[022] The inventors have unexpectedly discovered that a saccharinate salt of N,N-dipropyltryptamine (DPT) shows a strong reduction of mucosal irritation upon the nasal, buccal, sublabial or sublingual ad- ministration thereof.

[023] Thus, in a first aspect of the present disclosure, there is provided the saccharinate salt of N,N- dipropyltryptamine (DPT).

[024] The compound of the present invention is represented by the general formula PX, wherein P represents N,N-dipropyltryptamine (DPT) and X represents saccharine.

[025] Surprisingly, it was found that the saccharinate salt of N,‚N-dipropyltryptamine (DPT) is capable of effective nasal or oral transmucosal delivery of DPT without causing the irritation of the nasal or oral mucosa that may typically be observed for intranasal, buccal, sublabial and sublingual administration of

DPT.

[026] Thus, in another aspect there is provided a pharmaceutical formulation comprising the sac- charinate salt of N,N-dipropyltryptamine. Typically such a formulation further comprises a pharmaceuti- cally acceptable carrier, excipient, and/or diluent.

[027] Such compositions are particularly suitable for nasal, sublingual, sublabial or buccal administra- tion of DPT. They are particularly suitable for administration to subjects who are unable to tolerate oral ingestion of DPT because of nausea, vomiting, malabsorption or dysphagia. They may further be attrac- tive for patients who cannot receive parenterally administrated DPT because of the lack of venous ac- cess or the presentation of typical contraindications for psychedelic drug administration via injection.

P335499NL

[028] Accordingly, in a further aspect there is provided a transmucosal drug delivery dosage unit for oral or nasal transmucosal administration of DPT to a subject, wherein the transmucosal drug delivery dosage unit comprises the saccharinate salt of N,N-dipropyltryptamine (DPT).

[029] The present dosage units for transmucosal administration of DPT to a subject, which can be dis- 5 integrated, dissolved, or suspended by saliva in the mouth or nasally administered can provide signifi- cant benefits to the subjects treated with DPT.

[030] Without wishing to be bound to theory, it is the inventors’ belief that the formation of a sac- charinate salt of DPT impacts its solubility, dissolution rate and pH properties, resulting in a synergy that enables DPT to be effectively used in transmucosal delivery.

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

General Description of the Invention

[032] Accordingly, one aspect of the invention relates to the saccharinate salt of N,N-dipropyltrypta- mine (DPT).

[033] The compound of the present invention is represented by the general formula PX, wherein P represents N,N-dipropyltryptamine (DPT) and X represents saccharine.

[034] The salt is of the formula (P*)(X), wherein P* is a cationic component of the salt and X™ is an ani- onic component of the salt. The formula (P*)(X’} is meant to encompass a cationic component (P*) having any valency of positive charge, and an anionic component (X"} having any valency of negative charge, provided that the charge contributions from the cationic portion and anionic portion are counterbal- anced in order for charge neutrality to be preserved in the salt. More specifically, the formula (P(X) is meant to encompass the more generic formula (P*),(X™),, wherein the variables a and b are, inde- pendently, non-zero integers, and the subscript variables x and y are, independently, non-zero integers, such that a-y=b-x.

[035] N,N-dipropyltryptamine (“DPT”; IUPAC name N-[2-(1H-indol-3-yl}lethyl-N-propylpropan-1- amine) is a compound having the chemical structure

P335499NL 6

Lr

A\ xs

[036] DPT is a close synthetic homolog of the endogenous human trace neurotransmitter and potent psychedelic compound N,N-dimethyltryptamine (DMT). However, DMT acts with high intensity for only a few minutes, which limits the suitability of psychedelic-assisted therapy. DPT has a potent psychedelic action lasting typically between 2-3 hours, which falls within the required range. Both animal behav- ioural studies and receptor binding studies strongly suggest that DPT acts as an agonist for the 5-HT14 and 5-HT2a receptors, whereby psychedelic action of DPT is mediated primarily by agonism of the 5-HT2a receptor.

[037] Saccharine is an acidic artificial sweetener having the following structure ©

A

7

Ne ©

[038] As used herein, the term “saccharinate salt of N,N-dipropyltryptamine” is considered synony- mous to “N,N-dipropyltryptamine saccharinate” “DPT saccharinate” or “DPT-Sac”.

[039] 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, 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

P335499NL 7 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.

[040] 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.

[041] 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.

[042] 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.

[043] 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.

[044] Inthe practice of the present disclosure, the N,N-dipropyltryptamine saccharinate is used in an amount sufficient to produce its desired prophylactic or curative therapeutic efficacy. The active ingredi- ent content per dose unit may vary widely, and depends on a variety of factors including the type of ac- tive ingredient, condition being treated, total treatment period, age, weight and sex of the subject tak- ing the medication, etc. In typical cases, the N,N-dipropyitryptamine saccharinate 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

P335499NL 8 individual active ingredient, its amount may be increased or decreased within the above range in an ad- equate manner depending on, among others, 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.

[045] There are several known synthetic routes for the chemical synthesis of N,N-dipropyltryptamine (DPT). The synthesis of DPT may 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, and is pre- sented in Scheme 1: o. © oN N oxalyl chloride 0 dipropylamine 0 LiAIH,

CD ER \ . \ > \

N Et,0 N N dioxane N

Scheme 1: Synthesis of DPT from indole.

[046] An alternative route starts from tryptamine and alkyl halide and provides DPT in a single syn- thetic step as presented in Scheme 2. In this process, purification of the end product DPT may be more complicated due to the presence of starting material and partially substituted tryptamine; however, this is offset by the simplicity of a single synthetic step.

NH, 7 propyl iodide,

DIPEA

\ en N

N . N

H isopropanol H

Scheme 2: Synthesis of DPT from tryptamine via alkylation.

[047] Variations of the synthesis of DPT using either the indole or the tryptamine route are known and are primarily variations of the solvents in which the reactions take place.

[048] Another feasible route to dialkylated tryptamines is reductive amination of tryptamine with an aldehyde as presented in Scheme 3. Sodium cyanoborohydride (NaBH3CN) is the preferred reducing agent, as reaction with sodium borohydride or sodium triacetoxyborohydride typically gives rise to sig- nificant side reactions and reduced yield.

P335499NL 9

NH, NaBHsCN U acetic acid propionaldehyde of Za cf

N methanol N

Scheme 3: Synthesis of DPT from tryptamine via reductive amination.

[049] The N,N-dipropyltryptamine saccharinate compound as disclosed herein can be prepared by methods known in the art, wherein said methods generally involve the steps of - providing a solution comprising N‚N-dipropyltryptamine; - providing a solution comprising saccharine; - mixing the solution comprising N,N-dipropyliryptamine and the solution comprising saccharine under agitation and optional heating to obtain an organic layer comprising the N,N-dipropyltryptamine sac- charinate as a salt; - separating the N,N-dipropyltryptamine saccharinate salt from the organic layer; and - optionally further purifying the N,N-dipropyltryptamine saccharinate salt.

[050] If the N‚N-dipropyltryptamine starting material is provided in the form of a pharmaceutically ac- ceptable salt thereof, such as its HCl, fumarate, succinate, etc. salt, it is generally required to first extract the free-base form by saturated by mild heating (around 40 °C) in aqueous NaHCO:; or other suitable base under vigorous agitation. The resulting organic layer is then typically separated, collected and com- bined with the artificial sweetener solution.

[051] When reductive amination is used to prepare DPT the crude purity is typically high, which ad- vantageously allows to directly form the saccharinate salt as part of the reaction work-up, followed by recrystallization to obtain a high purity DPT saccharinate product. Thus, DPT synthesis and direct for- mation of a saccharinate salt in a single step followed by purification via recrystallization greatly simpli- fies the process.

[052] In another aspect of the present disclosure there is provided a dosage unit for the transmucosal administration of N,N-dipropyltryptamine to a subject, comprising a therapeutically effective amount of

N,N-dipropyltryptamine, wherein N,N-dipropyltryptamine is present as a salt represented by the general formula P*X, wherein P represents N,N-dipropyltryptamine and X represents saccharine. Thus, in an em- bodiment there is provided a transmucosal dosage unit comprising a therapeutically effective amount of

N,N-dipropyltryptamine saccharinate.

[053] In one embodiment, the dosage unit is configured for the oral transmucosal administration of

N,N-dipropyitryptamine saccharinate to a subject.

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[054] in one embodiment, the dosage unit is configured for the nasal transmucosal administration of

N,N-dipropyltryptamine saccharinate to a subject.

[055] As used herein, “oral transmucosal administration” refers to administration through the oral mucosa of the 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 the active compound diffuses is held under the tongue; “buccal” administration 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 dif- fuses through the oral mucosa and enter directly into the bloodstream.

[056] As used herein, “nasal transmucosal administration” or “intranasal transmucosal administra- tion” refers to administration through the nasal mucosa of the 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.

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

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

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

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

[061] Examples of dosage unit forms for oral transmucosal administration of N,N-dipropyltryptamine saccharinate according to the present disclosure include tablets, soft gelatine capsules, including solu- tions used in soft gelatine capsules, aqueous or oil suspensions, emulsions, pills, lozenges, troches, syr- ups, elixirs and the like. Formulations for oral transmucosal use may also be presented as rapidly-dis- solving hard capsules wherein N,N-dipropyltryptamine saccharinate is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft capsules wherein N,N-di- propyltryptamine saccharinate is mixed with water or an oil medium, such as peanut 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, especially in the form of tablets, capsules, cachets, pellets, pills, powders or granules.

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[062] Non-limiting examples of dosage units for (intranasal transmucosal administration of N,N-di- propyltryptamine saccharinate according to the present disclosure include sprays, inhalers, nebules, drops, droplets, suspensions, creams, gels and ointments.

[063] The dosage units of the present disclosure may be prepared according to any method known in the art 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.

[064] In case of e.g. tablets, these excipients may be, for example, inert diluents, such as calcium car- bonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disinte- grating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatine or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be (partially) coated by known techniques to tune disintegration and adsorption by the oral muco- sal membranes.

[065] 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), sodium starch glycolate, 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 croscar- mellose 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-sup- porting/disintegration-enhancing agent such as sucrose and mannitol.

[066] Intranasal formulations may, in addition to N,N-dipropyitryptamine saccharinate, contain sol- vents 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, isotonis- ing agents, adsorption inhibitors (such as Tween 80), solubility enhancing agents (such as cyclodextrins and derivatives thereof), wetting agents (such as sodium acetate, sodium lactate), absorption-promoting polymers (synthetic polymers or natural polymers such as processed collagen, chitin, chitosan).

[067] 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.

[068] In one embodiment, a tablet, preferably a rapidly disintegrating tablet, for sublingual or buccal administration comprising N,N-dipropyltryptamine saccharinate is provided.

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[069] An exemplary composition comprising a rapidly disintegrating DPT saccharinate tablet that can be used for sublingual and buccal application is presented in Table 1.

Table 1: DPT saccharinate rapidly disintegrating tablet

Component Compound

Glidant Colloidal silicon dioxide

[070] This exemplary rapidly disintegrating tablet contains as active psychedelic compound DPT sac- charinate. A typical dose for DPT-assisted therapy is between 30 mg to about 150 mg, more preferably between 50 mg to about 120 mg, and most preferably between 70 mg to about 100 mg DPT, based on the DPT free base. This rapidly disintegrating tablet preferably contains between 50 mg to about 150 mg, and most preferably between 75 mg to about 100 mg DPT saccharinate per tablet. This allows for increased flexibility in the dosing regime, i.e., using two tablets between 75 mg to about 100 mg DPT saccharinate will have the additional benefit of increasing the mucosal absorption area by using both the right and left cheek mucosa.

[071] Exemplary super-disintegrants for use in a DPT saccharinate rapidly disintegrating tablet formu- lation are sodium starch glycolate and croscarmellose sodium, preferably croscarmellose sodium. Super- disintegrants may be added to the formulation in an amount between 1 to 25 percent, preferably be- tween 2 to 20 percent, more preferably between 5 to 15 percent, and most preferably between 10 to 14 percent of the final tablet weight.

[072] One or more fillers may be added to the formulation to obtain the desired tablet weight. An ex- emplary filler in a DPT saccharinate disintegrating tablet formulation is spray dried mannitol. Mannitol may be added in an amount between 5 to about 75 percent, more preferably between 10 to about 50 percent and most preferably between, 15 to about 35 percent of the final tablet weight. [073} Glidant may be added to the exemplary DPT saccharinate rapidly disintegrating tablet formula- tion in an amount between 0.1 to 10 percent, preferably between 0.1 to 6 percent, more preferably be- tween 1 to 4 percent, and most preferably between 2 to 3 percent of the final tablet weight. A preferred glidant for a DPT saccharinate disintegrating tablet formulation is colloidal silicon dioxide.

[074] An exemplary lubricant for use in the DPT saccharinate rapidly disintegrating tablet formulation is magnesium stearate. Magnesium stearate may be added to the formulation in an amount between

P335499NL 13 0.1 to 5 percent, more preferably between 0.5 to 3 percent, and most preferably between 1 to about 2 percent of the final tablet weight.

[075] Another exemplary composition comprising a rapidly disintegrating DPT saccharinate tablet that can be used for sublingual and buccal application is presented in Table 2.

Table 2: DPT saccharinate disintegrating tablet formulation

[076] The formulation of Table 2 comprises sodium bicarbonate as a base. Without wishing to be bound to theory, it is presumed that addition of a base will transform a portion of DPT saccharinate into the DPT free hase, which can more efficiently cross the mucosal membrane. Moreover, reaction of DPT saccharinate with an effervescent base such as sodium bicarbonate will release a small quantity of car- bon dioxide, which may act as a mucosal penetration enhancer.

[077] Further examples of bases that can be used in this formulation include sodium bicarbonate, so- dium carbonate, potassium bicarbonate, potassium carbonate, calcium hydroxide, magnesium hydrox- ide and magnesium oxide. The base and can be added to the formulation in any desirable amount, such as in equimolar amounts or in excess to DPT saccharinate.

[078] in addition to the effervescent base, a pharmaceutically acceptable acid, such as citric acid may be added in order to increase the effervescent effect of the base.

[079] The exemplified rapidly disintegrating DPT saccharinate tablet for buccal and sublingual trans- mucosal application can be manufactured by any known method. Typically, the components of the for- mulation are charged in a V-blender, or other low-shear blender, and tableted via direct compression.

The tablets are shaped into the appropriate dimensions for comfortable oromucosal application. For ex- ample, the tablets typically do not exceed 12 mm in diameter, preferably not exceed 10 mm and most preferably not exceed 8 mm in diameter. Typically, the thickness of the tablets does not exceed 5 mm, preferably does not exceed 3.5 mm. Taking the preferred dose range of DPT saccharinate into account, the total weight of the tablet is typically from 100 mg to about 500 mg, and preferably between 150 to

P335499NL 14 about 200 mg. Specific DPT saccharinate rapidly disintegrating tablet compositions of the formulations are found in the examples.

[080] in one embodiment, a nasal spray comprising N,N-dipropyltryptamine saccharinate is provided.

Typically such a nasal spray formulation further comprises one or more components selected from sol- vents, surfactants, pH-controlling agents and viscosity-controlling agents.

[081] In one embodiment, a nasal powder comprising N,N-dipropyltryptamine saccharinate is pro- vided. In a nasal powder dosage form the N,N-dipropyltryptamine saccharinate is typically contained in a medical device that can disperse a micronized powder of N,N-dipropyltryptamine saccharinate into the nasal cavity. The nasal cavity is known to efficiently absorb psychedelic substances directly into the bloodstream while fully avoiding first-pass metabolism.

[082] 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 before. The present method is particularly suitable for treating mammals, especially humans.

[083] Accordingly, in one aspect the present disclosure relates to salt represented by the general for- mula PX, wherein P represents N,N-dipropyltryptamine and X represents saccharine, for use as a me- dicament.

[084] In another aspect the present disclosure relates to a pharmaceutical formulation comprising a salt represented by the general formula PX, further comprising a pharmaceutically acceptable carrier, excipient, and/or diluent, wherein P represents N,N-dipropyltryptamine and X represents saccharine, for use as a medicament.

[085] in another aspect the present disclosure relates to a dosage unit comprising a salt represented by the general formula PX, wherein P represents N,N-dipropyitryptamine and X represents saccharine, for use as a medicament.

[086] More specifically, the present disclosure relates to a dosage unit comprising N,N-dipropyltrypta- mine saccharinate, for use in a method of prophylactically or curatively treating a subject.

[087] In an embodiment, the N,N-dipropyltryptamine saccharinate salt, the formulation comprising such a salt or the dosage unit according to the present invention is used as a medicament in the prophy- lactic or curative treatment of migraine, cluster headaches and traumatic brain injury.

[088] In an embodiment, the N,N-dipropyltryptamine saccharinate salt, the formulation or the dosage unit according to the present invention is used as a medicament in a method of prophylactically or cura- tively treating a mammal suffering from a psychiatric disease or disorder.

[089] In an embodiment, the psychiatric disorder or disease is selected from depression (including mild depression, major depressive disorder, and treatment-resistant depression), obsessive compulsive

P335499NL 15 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.

[090] The present compound, formulation and dosage units are particularly suitable for administra- tion to subjects who are unable to tolerate oral ingestion, or intramuscular or intravascular injection of

N,N-dipropyltryptamine. The compounds and compositions of the present disclosure are particularly ad- vantageous in preventing or reducing irritation of the oral or nasal mucosal membranes that is associ- ated with the (intranasal, sublingual, sublabial or buccal administration of N,N-dipropyltryptamine sac- charinate.

[091] Hence, in another aspect there is provided a method for reducing mucosal irritation in a subject upon nasal, sublingual, sublabial or buccal administration of N,N-dipropyltryptamine to the subject, wherein said method comprises providing N,N-dipropyltryptamine in the form of its saccharinate salt.

More specifically, said method comprises administering N,N-dipropyltryptamine as a salt represented by the general formula P*X', wherein P represents N,N-dipropyltryptamine and X represents saccharine.

[092] 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.

[093] 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.

[094] 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 help provide a full description of the invention. The examples are intended to be illustrative and not lim- itative of the present invention.

P335499NL 16

Examples

Example 1: Synthesis of dipropyltryptamine (DPT) saccharinate

[095] Tryptamine (1 g, 6.25 mmol} was dissolved in anhydrous methanol (100 mL) followed by addi- tion of acetic acid (1.43 mL, 25 mmol) and cooled to 0°C while stirring under argon. Sodium cyanoboro- hydride (786 mg, 12.5 mmol) was added to the methanol solution and followed by the dropwise addi- tion of a solution of propionaldehyde {1.08 ml, 15 mmol} in anhydrous methanol (75 mL). Following ad- dition, the reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The re- action was quenched by addition of 0.5M aqueous NaHCO; (100 mL) and concentrated under vacuum to remove methanol. The mixture was extracted with MTBE (3 x 50 mL), the organic layer washed with sat.

NaHCO3, brine, dried over Na25O, and concentrated under vacuum. The pale brown oil was dissolved in

MTBE (6 ml) and a solution of saccharin {1.15 g, 6.25 mmol} in THF (6 ml) was added. DPT saccharinate formed immediately as a white solid and was triturated with MTBE (3 x 10 mL). The solid was recrystal- lized from acetone (15 mL), washed with cold acetone and dried under vacuum. DPT saccharinate was obtained as white crystals in 69% yield (1.85g, 4.3 mmol} with a purity >99% (HPLC).

Example 2: Formulation Examples

[096] The example formulations were prepared by mixing the composition ingredients, except magne- sium stearate, using low-shear blending. After initial blending of 5 minutes, magnesium stearate was added and blended for an additional 2 minutes. The DPT saccharinate rapidly disintegrating tablets were prepared by direct compression using 2 tons of force. Flat round rapidly disintegrating tablets were ob- tained with a diameter of 8 mm.

Table A: Composition of DPT saccharinate rapidly disintegrating tablet

Component Quantity (mg/tablet)

DPT saccharinate 75.0

Croscarmellose sodium 20.0

Mannitol 50.0

Colloidal silica 3.0

Magnesium stearate 2.0

Total tablet weight 150.0 mg

P335499NL 17

Table B: Composition of DPT saccharinate rapidly disintegrating tablet

Component Quantity (mg/tablet)

DPT saccharinate 100.0

Croscarmellose sodium 20.0

Mannitol 50.0

Colloidal silica 3.0

Magnesium stearate 2.0

Total tablet weight 175.0 mg

Table C: Composition of DPT saccharinate rapidly disintegrating tablet

Component Quantity (mg/tablet)

DPT saccharinate 75.0

Sodium starch glycolate 15.0

Mannitol 55.0

Colloidal silica 3.0

Magnesium stearate 2.0

Total tablet weight 150.0 mg

Table D: Composition of DPT saccharinate disintegrating tablet with effervescent base

Component Quantity (mg/tablet)

DPT saccharinate 75.0

Croscarmellose sodium 20.0

Sodium bicarbonate 20.0

Mannitol 55.0

Colloidal silica 3.0

Magnesium stearate 2.0

Total tablet weight 175.0 mg

P335499NL 18

Table E: Composition of DPT saccharinate disintegrating tablet with effervescent base

Component Quantity (mg/tablet)

DPT saccharinate 100.0

Croscarmellose sodium 20.0

Sodium bicarbonate 25.0

Mannitol 25.0

Colloidal silica 3.0

Magnesium stearate 2.0

Total tablet weight 175.0 mg

Table F: Composition of DPT saccharinate disintegrating tablet with effervescent base

Component Quantity (mg/tablet)

DPT saccharinate 75.0

Sodium starch glycolate 15.0

Sodium bicarbonate 20.0

Mannitol 60.0

Colloidal silica 3.0

Magnesium stearate 2.0

Total tablet weight 175.0 mg

Table G: Composition of DPT saccharinate disintegrating tablet with non-effervescent base

Component Quantity (mg/tablet)

DPT saccharinate 75.0

Croscarmellose sodium 20.0

Calcium hydroxide 20.0

Mannitol 55.0

Colloidal silica 3.0

Magnesium stearate 2.0

Total tablet weight 175.0 mg

P335499NL 19

Table H: Composition of DPT saccharinate disintegrating tablet with non-effervescent base

Component Quantity (mg/tablet)

DPT saccharinate 100.0

Croscarmellose sodium 20.0

Calcium hydroxide 25.0

Mannitol 25.0

Colloidal silica 3.0

Magnesium stearate 2.0

Total tablet weight 175.0 mg

Table I: Composition of DPT saccharinate disintegrating tablet with non-effervescent water insoluble base

Component Quantity {mg/tablet)

DPT saccharinate 75.0

Croscarmellose sodium 20.0

Magnesium oxide 20.0

Mannitol 55.0

Colloidal silica 3.0

Magnesium stearate 2.0

Total tablet weight 175.0 mg

Table J: Composition of DPT saccharinate disintegrating tablet with non-effervescent base

Component Quantity (mg/tablet)

DPT saccharinate 75.0

Sodium starch glycolate 15.0

Calcium hydroxide 20.0

Mannitol 60.0

Colloidal silica 3.0

Magnesium stearate 2.0

Total tablet weight 175.0 mg

P335499NL 20

Table K: Composition of DPT saccharinate disintegrating tablet

Component Quantity (mg/tablet)

DPT saccharinate 75.0

Croscarmellose sodium 20.0

Citric acid 15.0

Sodium bicarbonate 20.0

Mannitol 30.0

Colloidal silica 3.0

Magnesium stearate 2.0

Total tablet weight 175.0 mg

Table L: Composition of DPT saccharinate disintegrating tablet

Component Quantity (mg/tablet)

DPT saccharinate 100.0

Croscarmellose sodium 20.0

Citric acid 15.0

Sodium bicarbonate 25.0

Mannitol 10.0

Colloidal silica 3.0

Magnesium stearate 2.0

Total tablet weight 175.0 mg

Table M: Composition of DPT saccharinate disintegrating tablet

Component Quantity (mg/tablet)

DPT saccharinate 75.0

Sodium starch glycolate 15.0

Citric acid 15.0

Sodium bicarbonate 20.0

Mannitol 35.0

Colloidal silica 3.0

Magnesium stearate 2.0

Total tablet weight 175.0 mg

P335499NL 21

Example 3: Slug Mucosal Irritation assay

[097] 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 SMI assay without the need of a large number of vertebrates, such as rabbits in the invasive Draize test.

[098] 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

[099] 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

[100] 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 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.

SMI Assay

[101] 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 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

P335499NL 22 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 N: Mucosal irritation classification for Total Mean Mucus Production (TMP) with SMI assay.

[102] The mucosal irritation of tryptamine and the psychedelic dipropyltryptamine (DPT) saccharinate were evaluated in an SMI assay. Hydrochloride salts are the most commonly used in psychedelics and were therefore used as a comparison against the saccharinate (Sac) salt.

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

[104] The results from the SMI assay clearly show a reduction of mucous membrane irritation when the saccharinate salt of tryptamine is used. Tryptamine hydrochloride is a severe mucous membrane ir- ritant and its saccharinate salt reduces the mucous membrane irritation to moderate. Tryptamine is a

P335499NL 23 non-psychoactive model for tryptamine psychedelics with similar physicochemical properties and differs from most psychedelic tryptamines by having no alkyl substitution on the amine functionality.

[105] The psychedelic tryptamine DPT showed a significant reduction in mucous membrane irritation when its saccharinate salt was used, i.e. no mucous membrane irritation was observed whereas its hy- drochloride salt was found to be a severe irritant.

Claims

CONCLUSIONS

1. A salt with the general formula PX, where P stands for N,N-dipropyltryptamine and X for saccharin,

A pharmaceutical formulation comprising the salt of claim 1, further comprising a pharmaceutically acceptable carrier, excipient and/or diluent.

3, A dosage unit for transmucosal administration of N,N-dipropyltryptamine to a subject, comprising a therapeutically effective amount of N,N-dipropyltryptamine, wherein N,N-dipropyltryptamine is present as a salt represented by the general formula PX, wherein P stands for N,N-dipropyltryptamine and X for saccharin.

The transmucosal dosage unit of claim 3, wherein the transmucosal dosage unit is an oral transmucosal dosage unit.

The transmucosal dosage unit of claim 4, wherein the transmucosal dosage unit is a buccal transmucosal dosage unit.

The transmucosal dosage unit of claim 3, wherein the transmucosal dosage unit is a sublingual transmucosal dosage unit.

The transmucosal dosage unit of claim 4, wherein the transmucosal dosage unit is a sublabial transmucosal dosage unit.

The transmucosal dosage unit of claim 4, wherein the dosage unit is a nasal transmucosal dosage unit.

A salt according to claim 1 or a pharmaceutical formulation according to claim 2 for use as a medicament.

A transmucosal dosage unit according to any one of claims 3-8 for use as a medicament.

A salt according to claim 1, a pharmaceutical formulation according to claim 2, or a transmucosal dosage unit according to claims 3-8, for use in a method of prophylactic or curative treatment of a subject suffering from a psychiatric disease or disorder.

Salt for use according to claim 11, pharmaceutical formulation for use according to claim 11, or transmucosal dosage unit for use according to claim 11, 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 addiction, 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 2.

The method of claim 13, wherein said pharmaceutical formulation is administered via nasal transmucosal administration.

The method of claim 13, wherein said pharmaceutical formulation is administered via buccal transmucosal administration.

The method of claim 13, wherein said pharmaceutical formulation is administered via sublingual transmucosal administration.

The method of claim 13, wherein said pharmaceutical formulation is administered via sublabial transmucosal administration.

18. A method of reducing mucosal irritation in a subject by nasal, sublingual, sublabial or buccal administration of N,N-dipropyltryptamine to the subject, the method involving the administration of N,N-dipropyitryptamine as a salt represented by the general formula P*X, where P represents N,N-dipropyltryptamine and X represents saccharin.

A rapidly disintegrating tablet for sublingual, sublabial or buccal administration comprising the salt of claim 1.

A tablet according to claim 19, further comprising an effervescent base, preferably selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium hydroxide, magnesium hydroxide and magnesium oxide.

A nasal spray comprising the salt of claim 1.

A nasal powder comprising the salt of claim 1.

A method for the preparation of a salt according to claim 1, comprising the steps of - providing a solution comprising N,N-dipropyltryptamine; - providing a solution comprising saccharin; - mixing the solution comprising N,N-dipropyltryptamine and the solution comprising saccharin under agitation and possibly heating to obtain an organic layer comprising the N,N-dipropyltryptamine saccharinate as salt - separating the N,N -dipropyltryptamine saccharinate salt of the organic layer; and - optionally further purifying the N,N-dipropyltryptamine saccharinate salt.