WO2025087962A1

WO2025087962A1 - Pharmaceutical formulations comprising 5-meo-dmt and their therapeutic uses

Info

Publication number: WO2025087962A1
Application number: PCT/EP2024/079939
Authority: WO
Inventors: Dario DORNBIERER; Davor Kosanic; Milan SCHEIDEGGER; Robin VON ROTZ; Daniel CLAUSSEN
Original assignee: Reconnect Labs Ag
Current assignee: Reconnect Labs Ag
Priority date: 2023-10-23
Filing date: 2024-10-23
Publication date: 2025-05-01
Anticipated expiration: 2026-04-23

Abstract

The present invention relates to a composition comprising 5-methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof formulated by using templated carrier particles, as well as to a tablet, in particular a sublingual tablet, comprising the same. The compositions and in particular the tablets of the present invention are particularly useful in the treatment or prevention of psychiatric disorders.

Description

Pharmaceutical formulations comprising 5-MeO-DMT and their therapeutic uses

Field of the invention

Background of the invention

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring tryptamine that primarily acts as an agonist at the 5-HT1A and 5-HT2A receptors. Its affinity for the 5-HT1A subtype is highest. Subjective effects following 5-MeO-DMT administration include distortions in auditory and time perception, amplification of emotional states, and feelings of ego dissolution that usually are short-lasting, depending on the route of administration. Individual dose escalation of 5-MeO-DMT reliably induces a “peak” experience. Observational studies and surveys have suggested that single exposure to 5-MeO- DMT can cause rapid and sustained reductions in symptoms of depression, anxiety, and stress. 5-MeO- DMT has also been shown to stimulate neuroendocrine function, immunoregulation, and antiinflammatory processes, which may contribute to changes in mental health outcomes.

To date, only two clinical trials have been published on 5-MeO-DMT, demonstrating the safety of vaporized dosing up to 18 mg. Short duration of the 5-MeO-DMT experience and its rapid onset may render it more suitable for individual dose-finding strategies compared with longer-acting psychedelics. (Reckweg J, Mason NL, van Leeuwen C, Toennes SW, Terwey TH, Ramaekers JG. A Phase 1 , Dose- Ranging Study to Assess Safety and Psychoactive Effects of a Vaporized 5-Methoxy-N, N- Dimethyltryptamine Formulation (GH001) in Healthy Volunteers. Front Pharmacol. 2021 Nov 25;12:760671. doi: 10.3389/fphar.2021.760671. PMID: 34912222; PMCID: PMC8667866, Reckweg JT, van Leeuwen CJ, Henquet C, van Amelsvoort T, Theunissen EL, Mason NL, Paci R, Terwey TH, Ramaekers JG. A phase 1/2 trial to assess safety and efficacy of a vaporized 5-methoxy-N,N- dimethyltryptamine formulation (GH001) in patients with treatment-resistant depression. Front Psychiatry. 2023 Jun 20; 14:1133414. doi: 10.3389/fpsyt.2023.1133414. PMID: 37409159; PMCID: PMC10319409). There is an interest in the development of 5-MeO-DMT formulations for a range of medical indications, most notably depression.

5-MeO-DMT is known to be orally inactive as it is rapidly metabolized by monoamine oxidase enzymes in the gut and liver (Shen et al., 2010). Therefore, 5-MeO-DMT is usually administered parenterally through smoking or inhalation ofvapor or less commonly via intravenous, intramuscular, rectal, sublingual, or intranasal applications. Vaporization and smoking are the most popular routes of administration because these are relatively easy and accessible and well documented. Observational research has demonstrated that smoking/inhalation of 5-MeO-DMT vapor causes a very rapid onset of subjective effects, reaching peak effects in a matter of seconds. Other routes of administration, e.g. intramuscular, have also been explored.

Different formulations (smoked, vaped, IM, intranasal, intravenous) are characterized by high bioavailability of 5-MeO-DMT because they avoid first-pass metabolism, with intravenous formulations providing maximal (100%) bioavailability. IM, intravenous, intranasal, and vaped administration provide easy control of dose delivery as compared to smoking. IM and intranasal administration of 5-MeO-DMT produce a more gentle experience with a slower onset and longer duration, while smoked and vaporized administration provides fast onset of subjective experiences with high intensity and short duration.

Acute adverse effects include overwhelming emotions including fear/panic, sadness, anxiety, confusion, disembodiment, spatial and temporal disorientation, fatigue, crying, paranoia, trembling, muscle spasms/contractions, vomiting, nausea, headache, pressure on the chest or abdomen, respiratory depression, skin flushing and loss of body perception. Subacute effects include flashbacks, i.e. short reexperiencing of some of the subjective 5-MeO-DMT effects and reactivations, i.e. brief (in order of seconds) sensory disturbances such as flashes of light. Reactivations have been reported during the week after 5-MeO-DMT exposure and may occur more frequently after vaporization as compared to intramuscular administration. Due to the overwhelming characteristics of fast-acting delivery forms of 5- MeO-DMT, sometimes prolonged adverse reactions (e.g. dissociation/depersonalization, flashbacks, sleep disturbances, panic attacks) may occur in vulnerable individuals which require additional psychological support.

The magnitude of the experience is known to vary considerably between individuals, as about 20-30% of participants in 5-MeO-DMT ceremonies reported a low to medium psychedelic experience. This variability in psychedelic experience may have been caused by differences in doses administered at ceremonies, administration/inhalation techniques, and the actual concentration of 5-MeO-DMT used by different facilitators.

Certain serotonergic psychedelics (such as psilocybin or N,N-DMT) are currently being evaluated as adjunctive treatments for patients on SSRIs. In order to prevent serotonin syndrome and other safety concerns due to potential DDI (drug-drug interactions), precise control over the administered dose and exposure levels are needed for evaluating the safety and efficacy of combined 5-MeO-DMT treatment in patients with SSRIs.

Accordingly, there is a need for novel delivery technologies of 5-MeO-DMT with improved pharmacokinetic/pharmacodynamic properties that would allow for precise dosing, in particular individual dose escalation to achieve the desired therapeutic effects and with improved safety/tolerability profiles to avoid undesired side effects and prolonged adverse reactions in vulnerable individuals.

Document US 2021/393716 discloses certain composition comprising 5-methoxy-N,N-dimethyltryptamine formulated by using templated carrier particles such as SiC>2, maltodextrin or other excipients.

Document US 2022/071958 discloses 5-methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in treating a patient who is diagnosed with major depressive disorder.

Summary of the invention

The present inventors have developed a formulation of 5-Meo-DMT (5-methoxy-N,N-dimethyltryptamine) or its pharmaceutically acceptable salt that is characterized by advantageous properties, in particular improved pharmacokinetic/pharmacodynamic properties, including a slower onset of action compared to inhaled, insufflated or injected 5-MeO-DMT, and an extended plateau of acute therapeutic drug effects. Accordingly, the present invention is based, at least in part, on a surprising discovery of the present inventors that 5-MeO-DMT, when formulated using templated carrier particles, shows improved pharmacokinetic/pharmacodynamic properties and/or allows for reduced acute and subacute side effects. Moreover, the inventors surprisingly found, that 5-MeO-DMT, when formulated according to the present invention, displays a psychotropic effects that are unexpected for 5-MeO-DMT, including:

- Strong anxiolytic effects - Strong physical and mental relaxation

- Rapid induction of a state of mindfulness

- Rapid reduction of aversive emotions (e.g. distress, anger, irritability, nervousness)

- Rapid silencing of maladaptive ruminative thought patterns (e.g. worrying, obsessive-compulsive thoughts)

- Rapid reduction of maladaptive behavioral patterns (e.g. impulsivity, rigidity, cravings, aggression)

- Absence of changes in time and space perception

- Apart from mild bodily sensations, no changes in sensory perception (i.e. absence of hallucinatory effects)

- Minimal cognitive impairment, no changes in personal identity/integrity

- No cardiovascular challenges and overall favourable side effects profile (e.g. no respiratory depression, no muscle tremors/spasms/contractions or motor control loss, no dissociation/disembodiment or spatial disorientation, no vomiting)

As such, the present inventors suggest, that this format of delivering 5-MeO-DMT is particularly suited for administration in a minimal supportive setting (as it is the case for inhaled, insufflated or injected 5-MeO- DMT) and might be suited for home use. Moreover, it is argued, that the safety and tolerability profile of the present invention is suitable for self-administration by the patient at home. Compared to benzodiazepines or ketamine, 5-MeO-DMT has no addictive/abuse potential and is therefore particularly well suited for repeated-intermittent or daily chronic administration. It is further suggested, that the present invention represents a non-psychedelic, non-hallucinogenic neuroplastogen, that unfold its effects via a dual-mode of action:

1) Acute reduction of maladaptive emotional, cognitive or behavioral states such as anxiety, rumination, worrying, distress, aversive emotions, agitation, neuroticism, obsessive-compulsive behavior, impulsivity, addictive cravings, aggression, suicidal ideation, and

2) Disease-modifying properties via an induction of neuroplasticity through daily use, which supports learning and memory processes to overcome maladaptive neurobehavioral patters and facilitate adaptive changes by allowing the brain to establish new connections.

The present inventors conclude that this format of delivering 5-MeO-DMT has a favorable benefit-risk ratio and is particularly well suited for vulnerable patient populations compared to other delivery technologies or other approved drugs with similar modes of action (e.g. tranquillizers, benzodiazepines, antipsychotics, mood stabilizers, and dissociative drugs such as ketamine).

The invention will be summarized in the following embodiments. In a first embodiment, the present invention relates to a composition comprising 5-methoxy-N,N- dimethyltryptamine or a pharmaceutically acceptable salt thereof formulated by using templated carrier particles.

In a second embodiment, the present invention relates to a tablet comprising the composition of the present invention.

In a third embodiment, the present invention relates to the composition of the present invention for use as a medicament.

In a fourth embodiment, the present invention relates to the composition of the present invention for use in the treatment or prevention of a psychiatric or somatic disorder.

In a fifth embodiment, the present invention relates to use of the composition of the present invention for the manufacture of a medicament for the treatment or prevention of a psychiatric or somatic disorder.

In a sixth embodiment, the present invention relates to a method of treating a psychiatric or somatic disorder in a subject in need thereof, the method comprising the step of administering the composition of the present invention to said subject. It is to be understood that a therapeutically effective amount of the composition is to be administered.

Brief description of figures

The invention is further illustrated in the following Figures. It is to be noted that these are not meant to limit the scope of the invention in any way, which is defined by the hereto appended claims, but merely to illustrate the exemplary embodiments of the invention.

Fig. 1 presents SEM pictures which show 5-MeO-DMT tartrate loaded TIP with no signs of external crystallization, proving the incorporation of the API into the particles.

Fig. 2 presents XRPD profiles of loaded (grey) and unloaded microparticles (black). The signals are identical, suggesting that 5-MeO-DMT tartrate is in its amorphous form. Fig. 3 presents orodispersible tablet a 20mg (5-MeO-DMT tartrate); size 6x3mm; Hardness >70N; in- vitro disintegration time: <20s.

Fig. 4 presents the plot that depicts the subjective intensity profiles following the administration of 10mg, 20mg and 30mg of in 6 healthy volunteers (n=3 per dose condition).

Fig. 5 presents the plot that depicts the subjective intensity profiles following the administration of 20mg of in 4 healthy volunteers.

Fig. 6 presents 5-MeO-DMT plasma profiles in 4 healthy volunteers following the sublingual administration of 20mg of microencapsulated 5-MeO-DMT tartrate, according to the invention. The dosage form provides a fast absorption with low intersubject variability, with peak values between 10-30min post-administration. The profile suggests some sustained-release profile of the formula.

Fig. 7 presents the plasma profiles of 5-MeO-DMT‘s main metabolite 5-methoxyindole-3-acetic acid (5- MIAA) in 4 healthy volunteers following the sublingual administration of 20mg of microencapsulated 5-MeO-DMT tartrate. Bufotenine levels (not shown) were below LLOQ in most cases or 0.05 ng/ml in some cases.

Fig. 8 presents systolic (A; black lines) and diastolic (A; grey lines) blood pressure and heart rate (B; black lines) in 4 healthy volunteers following the sublingual administration of 20mg of microencapsulated 5-MeO-DMT tartrate. No relevant changes in blood pressure or heart rate were observed, despite a trend pointing towards an overall decrease, potentially associated with the deep physical and mental relaxation observed in the volunteers.

Fig. 9 presents the study plan for both experiments (discussed in panels A and B of the Figure, respectively) described in Example 2.

Fig. 10 presents Average blood plasma concentrations across study participants (N =4) for each dose condition. Demonstrated is a dose-response relationship of increasing total 5-MEO-DMT exposure (Cmax and elimination duration) with increasing dose. Error bars indicate standard error from the mean. Fig. 11 presents Trajectory of pharmacodynamics. A Average rating of acute subjective “Drug effect Intensity” across study participants (N=4) for each dose condition. Demonstrated is a general dose-response relationship of increasing average acute intensity of subjective drug effects with increasing dose without significantly extending the overall duration of acute effects. Error bars indicate standard error from the mean. Visual analogue scale (VAS) range of 0 (minimum) to 10 (maximum). B Relaxation. Average rating of acute subjective “Relaxation” across study participants (N=4) for each dose condition. Demonstrated is an increase in average acute subjective relaxation following drug intake which is preserved for an extended period. Error bars indicate standard error from the mean. Visual analogue scale (VAS) range of 0 (minimum) to 10 (maximum). C. Pleasantness. Average rating of acute subjective “Pleasantness” across study participants (N=4) for each dose condition. Demonstrated is an increase in average acute subjective pleasantness following drug intake which is preserved for an extended period. Error bars indicate standard error from the mean. Visual analogue scale (VAS) range of 0 (minimum) to 10 (maximum).

Fig. 12 presents Summarized pharmacodynamics. Area under the curve (AUG) was computed for several acute psychometrics to capture the overall shape of these subjective effects over time. AUG was calculated using trapezoidal approximation applied to the ratings provided by each study participant for all recorded time points. Demonstrated is a dose-response relationship of increasing median AUG for subjective acute drug effect intensity (“Intensity”) with increasing dose. We also show that the median value of participants' reported sense of being challenged by the drug effects (“Challenging”) do not increase proportionally with rated intensity. Also demonstrated is that RE02 has a therapeutic potential to attenuate states of irritability, anxiety, psychophysiological tension, and negative mood/rumi nation as evidenced by dose-proportional increases in subjective ratings of relaxation and pleasantness. This is indicated by the tendency for minimum AUG values of relaxation and pleasantness to be greater for 30mg than lower dose conditions.

Fig. 13 presents Dose-dependency of the Efficacy Index. To meaningfully assess the impact of dose on participants’ state of mind, a set of assessment instruments were combined to form the ‘Efficacy Index’. This is calculated by combining the total score for the following metrics: “Blissful State” (a dimension from the ‘11 dimensional altered states of consciousness scale’; 11 D-ASC), and the percentage change from pre-intake to post-intake for the Cognitive Flexibility questionnaire, Psychological Flexibility questionnaire, and the Well-being Index (WHO-5 questionnaire). For the Well-being Index the baseline was defined as prior to drug intake on the first study day. Demonstrated is that by increasing the dose we can increase the average cumulative positive psychological effects of these composite dimensions of efficacy.

Fig. 14 presents Favorable experiential profile for clinical use. Here presented is the average value of each dimension from the 11 dimensional altered state of consciousness scale (11 D-ASC) across study participants. This serves to visualize the subjective effects of this formulation more generally, and allows for the experiential profile or ‘fingerprint’ of the drug effects to be contrasted with existing or future formulations. With this formulation the present inventors demonstrate a strong effect of mean ‘blissfulness’, ‘insightfulness’ and ‘Spiritual experiences’ with increasing dose, while attenuating most of the commonly reported hallucinogenic effects for this class of compounds. Most notably, less favorable subjective experiences such as ‘Anxiety’, ‘Disembodiment’, or ‘Impaired Cognition and Control’ were not significantly elevated.

Detailed description of the invention

As mentioned before, in one embodiment the present invention relates to a composition comprising 5- methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof formulated by using templated carrier particles.

As understood herein, 5-methoxy-N,N-dimethyltryptamine is a compound according to formula (I):

It is also referred to as 5-MeO-DMT. 5-MeO-DMT is a methoxylated derivative of DMT. While most common psychedelics are believed to primarily elicit psychological effects through agonism of serotonin 5-HT2A receptors, 5-MeO-DMT shows 1000-fold greater affinity for 5-HT1A over 5-HT2A. In line with its affinity for 5-HT1 A receptors, 5-MeO-DMT is extremely potent at suppressing the firing of dorsal raphe 5- HT neurons. 5-MeO-DMT is being developed and evaluated for potential therapeutic effects in patients with Treatment-Resistant Depression (TRD). Biopharmaceutical company GH Research has sponsored a completed phase 1 study in healthy volunteers and phase 1/2 study in TRD patients where 87.5% of patients with TRD were brought into remission on day 7 in the phase 2 part of the study. Beckley Psytech in collaboration with King's College London research the safety and tolerability of intranasal 5-MeO-DMT in healthy subjects, in a phase 1 study.

Throughout the present description, reference is made to a salt of 5-MeO-DMT. Preferably, said salt is a pharmaceutically acceptable salt. The scope of the invention embraces all pharmaceutically acceptable salt forms of the compound of formula (I) which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-p henylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Preferred pharmaceutically acceptable salts of the compound of formula (I) include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt. A particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt. Accordingly, it is preferred that the compound of formula (I) is in the form of a fumarate salt, a maleate salt, an oxalate salt, a malate salt, a tartrate salt, and a mesylate salt. More preferably, the compound of formula (I) is in the form of a tartrate salt. However, the present invention also specifically encompasses relates to the compound of formula (I) in non-salt form. In one embodiment, the compound of formula (I) is in the form of a benzoate salt. Accordingly, as encompassed by the present invention, the compound of formula (I) may also be in a form of a benzoate salt.

Accordingly, in the composition of the present invention 5-methoxy-N,N-dimethyltrypatmine or a pharmaceutically acceptable salt thereof may be 5-methoxy-N,N-dimethyltrypatmine tartrate, 5-methoxy- N,N-dimethyltrypatmine hydrochloride, 5-methoxy-N,N-dimethyltrypatmine fumarate, 5-methoxy-N,N- dimethyltrypatmine maleate, 5-methoxy-N,N-dimethyltrypatmine oxalate, 5-methoxy-N,N- dimethyltrypatmine malate, or 5-methoxy-N,N-dimethyltrypatmine mesylate. It is particularly preferred that 5-methoxy-N,N-dimethyltrypatmine or a pharmaceutically acceptable salt thereof is 5-methoxy-N,N- dimethyltrypatmine tartrate.

In the composition of the present invention, 5-methoxy-N,N-dimethyltrypatmine or a pharmaceutically acceptable salt thereof is formulated by using templated carrier particles.

The term “carrier particle”, as used herein, refers to a material that is nontoxic or not substantially toxic to a subject, which can be used to improve a desired drug delivery property of a solid pharmaceutical composition. The carrier particle described herein has no or no substantial therapeutic effect upon administration to a subject unless it is loaded with a therapeutic agent. In some embodiments, the carrier particle described herein is pharmacologically inert unless it is loaded with a therapeutic agent. In some embodiments, the carrier particle described herein does not or not substantially dissolve in water. The desired drug delivery properties described herein of the solid pharmaceutical composition include, without limitation, effectiveness, safety, pharmacokinetic properties (e.g., bioavailability), physical stability, chemical stability, drug loading capacity, and/or disintegration time. In some embodiments, the desired drug delivery properties of a solid pharmaceutical composition are physical stability, drug loading capacity, and disintegration time. In some embodiments, the desired drug delivery properties of a solid pharmaceutical composition are high drug loading capacity of the solid pharmaceutical composition (e.g., the drug loading capacity of v/v >50%, >55%, >60%, >65%, >70%, >75%, >80%, preferably >60%, more preferably between 60%, and 85%), low disintegration time of the solid pharmaceutical composition (e.g., <15s, <14s, <13s, <12s, <11 s, <1 Os, preferably <1 Os) and/or physical stability (e.g., tablet hardness of >200N, >21 ON >220N, >230N, >240N, or >250N, for an 11 mm tablet or >40N, >50N, >60N for a 6mm tablet, preferably >50N for an 6mm tablet . A carrier particle according as described herein, can have any shape, preferably a carrier particle as described herein has a shape similar to that of a sphere, a spheroid, and/or a bead. Removal of the template material can result in at least one pore in the otherwise largely uniform structure. The carrier particle preferably can form a hollow structure in a dry environment. As such, the carrier particle described herein does not or not substantially collapse upon drying.

As referred to herein the carrier particles are templated carrier particles, preferably templated inverted particles, which also may be referred to as TIP particles. The technology of manufacturing and using TIP particles is described in detail in patent application PCT/EP2022/051799, which is incorporated herein by reference in its entirety.

Said templated inverted particles may also be referred to as carrier particles with secondary internal structure. As noted in PCT/EP2022/051799, the method for the production of carrier particles with secondary internal structures comprises the steps of a) combining a carrier material with a template material, wherein the carrier material forms a primary structure around the template material; b) transforming the template material; c) removing the transformed template material, and d) obtaining carrier particles with secondary internal structures. Accordingly, the present invention relates to an embodiment wherein the carrier particle (or carrier particles) are particle(s) with secondary internal structure.

Thus, preferably, the carrier particle (in particular the carrier particle with secondary internal structure) is obtainable or obtained by the steps of: a) combining a carrier material with a template material, wherein the carrier material forms a primary structure around the template material; b) transforming the template material; c) removing the transformed template material; and d) obtaining carrier particles with secondary internal structures.

Accordingly, it is preferred that in the composition of the present invention, templated carrier particles are templated inverted particles.

Preferably, in the composition of the present invention the templated carrier particles are loaded with 5- methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof in a ratio of at least 10 %w/w, more preferably between 10 and 20 %w/w, even more preferably about 15%w/w, yet again more preferably 15%w/w.

The term about, as used herein, when used in the context of a numerical value, preferably refers to that value ± 10% of said value, more preferably to that value ± 5% of said value, even more preferably to that value ± 1 % of said value, even more preferably to said value.

The carrier particles exhibit the desired drug delivery properties when produced with a template material that undergoes a transformation as described herein. Accordingly, whenever reference is made to carrier particles as described hereinabove, preferably the particles obtainable according to the method of production of carrier particles with secondary internal structure, as described hereinabove, are meant. The term “primary structure” as used herein, refers to the layer of a carrier material that encompasses the template material. In some embodiments, the primary structure comprises further structure elements (e.g., petals as) that increase the surface area of the carrier particle.

The term “secondary internal structure”, as used herein, refers to a hollow internal structure, wherein the internal surface of the hollow internal structure is dense in crystallization initiation points. Therefore, the secondary internal structure enables crystallization inside the carrier particle. It is to be understood that, preferably, said secondary internal structure, or in other words hollow internal structures, comprises at least one hollow cavity. Preferably said at least one hollow cavity is surrounded by a shell. In an exemplary embodiment, said shell is a porous hydroxyapatite shell.

Thus, the present invention relates to an embodiment, wherein the carrier particles are particles with hollow internal structure.

The term “carrier material”, as used herein, refers to a material or a mixture that comprises the raw material for the carrier particle as described herein. In some embodiments, the carrier material described herein is an inorganic salt or comprises an inorganic salt to a substantial degree. In some embodiments, the carrier material described herein is insoluble or poorly soluble in water. In some embodiments, the carrier material is dissolved in a solvent. In some embodiments, the carrier material or a precursor of the carrier material is a liquid. In some embodiments, the carrier material described herein is a non-polymer or comprises a non-polymer to a substantial degree.

The term “template material”, as used herein, refers to a solid material comprising particles suitable to serve as a template to enable the formation of the primary structure of the carrier particles. The particles in the template material preferably have the shape of a sphere, a spheroid, and/or a bead. In some embodiments, the template material described herein is a non-polymer or comprises a non-polymer to a substantial degree. In some embodiments, the template material described herein has a uniform or almost uniform particle size distribution. In some embodiments, the template material described herein has a distribution width (as defined by the formula: (D90 - D10)/D50)) of about <5, about <4.5, about <4, about <3.5, about <3, about <2.8, about <2.4, about <2, about <1.8, about <1.6, about <1.4, about <1.2, about <1 , about <0.9, about <0.8, about <0.7, about <0.6, about <0.5, about <0.4, about <0.3, about <0.2, or about <0.1 . As such the template material is any material that is transformable and has sufficient stability to hold the carrier material. To avoid the dissolution of the template material during the step of combining a carrier material with a template material, a template material poorly soluble in a combining liquid should be used. In some embodiments, the template material described herein, is poorly soluble in at least one organic solvent selected from the group of dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2-propanol, 1 -propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicon oils, gamma-Butyrolactone, and tetrahydrofuran. In some embodiments, the template material described herein, is poorly soluble in water. In some embodiments, the template material described herein, is poorly soluble in an aqueous solution comprising solubility altering agents (e.g. salt water). In some embodiments, the term “poorly soluble” as described herein refers to a solubility at 25°C of about <1 OOmg/L, <80mg/L, <60mg/L, <40mg/L, <20mg/L, <1 Omg/L, <9mg/L, <8mg/L, <7mg/L, <6mg/L, <5mg/L, <4mg/L, <3mg/L, <2mg/L, <1 mg/L, <0.9mg/L, <0.8mg/L, <0.7mg/L, <0.6mg/L, <0.5mg/L, <0.4mg/L, <0.3mg/L, <0.2mg/L, <1 OOpg/L, <90pg/L, <80pg/L, <70pg/L, <60pg/L, <50pg/L, <40pg/L, <30pg/L, <25pg/L or <20pg/L.

The template material described herein may comprise a salt. Preferably, if the the template material described herein comprises a salt, said salt is an organic salt. The template material described herein may be a carbonate salt or may comprise a carbonate salt to a substantial degree. Alternatively, or in addition to salt, the template material described herein may comprise a basic oxide.

The term “transforming”, as used herein, refers to changing the properties of the template material by at least one physical step and at least one chemical step that in combination enable removal of the template material. The physical step of “transforming” comprises providing energy to the material. The energy may be applied in form of a rise in temperature, and/or alteration of pressure. The physical step of “transforming” may induce an endothermic chemical reaction in the template material. The chemical step of “transforming” may comprise providing a chemical reactant to the template material. In such case, the reactant provided in the chemical step of “transforming” reacts with the template material but not or not substantially with the carrier material. The chemical reactant provided in the chemical step of “transforming” may be provided in liquid, dissolved, and/or gaseous form.

Accordingly, the carrier particles as described herein are carrier particles with secondary internal structures. In some embodiments, these secondary internal structures enable high drug loading, because, without being bound by theory, the carrier particles can be loaded with the drug inside the secondary internal structures and not only on the surface of the carrier particles. The loaded agent or drug can leave the carrier by diffusion through the porous carrier wall. In some embodiments, the carrier particles have certain stability at a target site (e.g., on the mucosa of a patient). Therefore, these carrier particles can remain at a target site (e.g., by adhesion to the mucosa) and enable specific drug delivery. The release rate of the loaded agent can be controlled by geometry of the template material and/or by diffusion rate modifiers such as disintegrants. Therefore, the unpleasant taste diffuses to a lesser extent to the locations of perceptions (e.g., the tongue).

The secondary internal structure described herein enables efficient drug loading on the inside of the carrier particle. Further, the secondary internal structure is accessible via pores e.g., for loading solvents. Accordingly, the carrier particle can be loaded with less effort and/or has a particularly high loading capacity. The carrier particle can have a particularly large surface area that is beneficial for interparticle forces. These interparticle forces act between the carrier particles in absence of water and increase the mechanical stability of carrier particle clusters. This increased mechanical stability reduces the need for additional stabilization material in the use of the carrier particles in pharmaceutical compositions such as solid pharmaceutical compositions, e.g., tablets. The interparticle forces acting between the carrier particles can be diminished by water enabling a low disintegration time of pharmaceutical compositions such as solid pharmaceutical compositions, e.g., tablets, comprising the carrier particle as described herein.

The carrier material is an inorganic material or consists primarily of inorganic material. The term “consists primarily of”, as used herein, in the context of a material refers to consisting of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% of the material.

Accordingly and preferably, the carrier material and the template material are inorganic salts or consist primarily of inorganic salts. The carrier particles as described herein with secondary internal structures that are beneficial to enhance one or more desired drug delivery properties.

In the process of producing said particles, the template material is preferably suspended in a liquid before combining a carrier material with a template material. The template material can be suspended in a combining liquid (e.g., water) under stirring in a reaction vessel. The set agitation speed ensures stable turbulent mixing to impede particle agglomeration, which enables the treatment of the particles individually.

Combining a carrier material with a template material may comprise adding the template material described herein and the carrier material described herein to a combining liquid. The combining liquid described herein is preferably at least one organic solvent selected from the group of dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2- propanol, 1 -propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicon oils, gamma- Butyrolactone, and tetrahydrofuran. Alternatively, the combining liquid described herein is water, or an aqueous solution comprising solubility altering agents (e.g. salt water).

To avoid dissolution of the template material during the step of combining a carrier material with a template material, an appropriate ratio of the amount of template material compared to the amount of the combining liquid should be used. This appropriate ratio depends on the solubility of the template material in the combining liquid. In some embodiments amount of the template material and combining liquid is chosen such that less than about 0.05%(w/w), less than about 0.04%(w/w), less than about 0.03%(w/w), less than about 0.02%(w/w), less than about 0.01%(w/w), less than about 0.0095%(w/w), less than about 0.009%(w/w), less than about 0.0085%(w/w), less than about 0.0008%(w/w), less than about 0.0075%(w/w), less than about 0.007%(w/w), less than about 0.0065%(w/w), less than about 0.06%(w/w), less than about 0.0055%(w/w), or less than about 0.005%(w/w) of the template material are dissolved in the combining liquid.

Combining a carrier material with a template material may comprise chemical precipitation, layering, and/or crystallization of the carrier material on the template material. The term “chemical precipitation”, as used herein, refers to the process of conversion of a chemical substance from a solution into a solid by converting the substance into an insoluble form.

Combining a precursor of the carrier material may form the carrier material in a chemical reaction with the surface of the template material. The soluble precursor of the carrier material described herein is preferably phosphoric acid.

The conversion grade is relevant wherein combining a precursor of the carrier material forms the carrier material in a chemical reaction with the surface of the template material. A too low conversion grade can cause particles with holes or broken shells, whereas a too high conversion can reduce the size of the inner cavity and produces more external crystals for example of dicalcium phosphate, which further converts to hydroxyapatite slabs. In some embodiments, the conversion grade described herein is between about 30% and about 60%, between about 35% and 55%, or between about 40% and about 50%.

The temperature during the chemical precipitation described herein can have a substantial influence on the material. For example, dicalcium phosphate as it is a less thermodynamically stable form than the hydroxyapatite. Therefore, too low temperatures and fast or uncontrolled orthophosphoric acid addition to calcium carbonate will trigger its precipitation and yield more dicalcium phosphate resulting in separate crystals that are more difficult to process. In some embodiments, the temperature during the chemical precipitation is about 60°C or higher, preferably between about 60°C and about 100°C, more preferably between about 70°C and about 95°C, more preferably between about 80°C and about 95°C.

A soluble precursor of the carrier material may be added in a solution to the template material and distributed on the template material by the addition of a reactant that converts the soluble precursor of the carrier material to the insoluble carrier material. The soluble precursor of the carrier material described herein is preferably sodium phosphate or calcium chloride (e.g., as Despotovic, R., et al., 1975, Calc. Tis Res. 18, 13-26).

The term “layering”, as used herein, refers to a technique for adding at least one layer of the carrier on the template material.

Any layering technique known in the art may be used (see, e.g., Decher, G. H. J. D., et al., 1992, Thin solid films, 210, 831-835; Donath, E., et al., 1998, Angewandte Chemie International Edition, 37(16), 2201-2205; Caruso, F, et al., 1998, Science, 282(5391), 1111-1114). In some embodiments, electrostatic interactions (e.g., as described in Decher, G. H. J. D., et al., 1992, Thin solid films, 210, 831-835), hydrogen bonding (e.g., as described in Such, G. K. et al., 2010, Chemical Society Reviews, 40(1), 19- 29), hydrophobic interactions (e.g., as described in Serizawa, T., Kamimura, S., et al., 2002, Langmuir, 18(22), 8381-8385), and/or covalent coupling (e.g., as described in Zhang, Y., et al., 2003, Macromolecules, 36(11), 4238-4240), electroplating and electrodeposition (e.g., as described in Chandran, R., Panda, S.K. & Mallik, A. A short review on the advancements in electroplating of CulnGaSe2 thin films. Mater Renew Sustain Energy 7, 6 (2018)) are exploited to prepare at least one layer on the template material, particularly to prepare multilayered films on the template material.

The term “crystallization”, as used herein, refers to the process of conversion of a chemical substance from a super-saturated solution.

The carrier material may be added in a super-saturated solution to the template material and distributed on the template material by the initiation of chemical precipitation. Combining a carrier material with a template material may comprise chemical precipitation and crystallization of the carrier material on the template material. Alternatively, combining a carrier material with a template material may comprise chemical layering and crystallization of the carrier material on the template material. Alternatively, combining a carrier material with a template material may comprises chemical precipitation and layering of the carrier material on the template material.

The chemical precipitation process can be carried out by pumping a solution of a precursor of the template material onto the carrier material or into the liquid comprising the carrier material. During this process, the carrier material can start growing (e.g., in the form of a crystalline lamellae structure) on the surface of template material and thus forming the stratum layer. In certain embodiments, the template material as described herein is converted to the carrier material. In certain embodiments, the template material as described herein is converted to at least about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% to the carrier material.

As it is understood herein, chemical precipitation, layering, and/or crystallization enable fine and/or uniform distribution of the carrier material on the template material. This fine and/or uniform distribution is considered to affect the formation of the secondary internal structures. Accordingly, the carrier particles produced as described herein exhibit particularly fine and/or uniform secondary internal structures by using chemical precipitation, layering, and/or crystallization of the carrier material on the template material.

As disclosed herein, transforming the template material may comprise heating to a temperature from about 600 °C to about 1200 °C, preferably about 600 to about 900°C, preferably about 600”C to 839°C, preferably about 650°C to about 700°C. Alternatively, transforming the template material may comprise heating to a temperature from 840 °C to 1200 °C. The conditions can be optimized to avoid interparticle condensation during the heating step, which can result in redispersability problems. While in some embodiments no further agents to avoid interparticle condensation need to be added, in other embodiments agents to avoid interparticle condensation (e.g., anti-sintering agents) are added during and/or before the heating step described herein. Such anti-sintering agents are described for example in Okada, M., et al., 2014, Journal of nanoparticle research, 16(7), 1-9.

The transformation of the template material described herein can be done at any suitable temperature or any suitable temperature range. To enable the transformation of the template material described herein the minimal suitable temperature for transformation is set at a certain temperature e.g., about 210°C (e.g., for silver and gold carbonate as the template material), about 840°C (e.g., for calcium carbonate as the template material), about 900°C, about 1000°C, or about 1200°C (e.g., for potassium and/or sodium carbonates as template material). The person skilled in the art can identify the appropriate minimal suitable temperature from the decomposition temperature of the template material. An increased temperature can shorten the transformation time, however, melting of the carrier material may have an undesired effect on the carrier particles such as incomplete carrier particle formation or reduced carrier particle hardness. To avoid melting of the carrier material, the maximal suitable temperature for the transformation of the template material described herein is set below the melting temperature of the carrier material. Deformation and/or loss of desired structures (e.g., petals on the surface of the carrier particles) that enhance the surface area of the carrier particles can already occur at temperatures below the melting temperature of the carrier material. Accordingly, the maximal suitable temperature for the transformation of the template material described herein is set preferably about 100°C, about 200°C, about 400°C, about 500°C, or about 600°C below the melting temperature of the carrier material.

As provided herein, transforming the template material may comprise heating to a temperature from about the decomposition temperature of the template material to about the melting temperature of the carrier material, preferably from about the decomposition temperature of the template material to about 400°C below the melting temperature of the carrier material, more preferably about the decomposition temperature of the template material to about 500°C below the melting temperature of the carrier material.

As provided herein, transforming the template material may comprise heating to a temperature from 840°C to 1600°C, preferably from 840°C to 1200°C, more preferably around 1100°C.

The duration of the heating for transforming the template material described herein depends on various factors such as the template material, the carrier material, the temperature range, particle size, and/or the desired carrier particle surface area. The duration of the heating for transforming the template material described herein may for example be about 1 hour. In certain embodiments, the duration of the heating for transforming the template material described herein is between about 5 min and about 24 h, about 10 min and about 12 h, 20 min and about 4 h.

The heating for transforming the template material described herein (e.g., to a temperature in a certain range, e.g., between 840 °C to 1200 °C or 600”C to 900°C) can be achieved by any heating pattern such as a linear increase of temperature or with one or more preheating steps. The preheating steps described herein may comprise keeping the temperature at a certain temperature level for a certain time before heating the template material to a temperature in a certain range, e.g., from 840 °C to 1200 °C or 600°C to 900°C. Preheating allows for example removal of undesired volatile components such as solvents.

As provided herein, the pressure may be reduced during the heating for transforming the template material to a temperature in a certain range, e.g., from 840 °C to 1200 °C. Alternatively, the pressure may be increased during the heating for transforming the template material to a temperature in a certain range, e.g., from 840 °C to 1200 °C.

The heating for transforming the template material may induce an endothermic chemical reaction. Accordingly, an inert substance (e.g., noble gas) may be supplied to avoid side reactions during the heating for the transforming the template material to a temperature in a certain range, e.g., from 840 °C to 1200 °C.

Alternatively, the heating for transforming the template material induces the evaporation of volatile fractions of the template material. The heating to a temperature in a certain range, e.g., from 840 °C to 1200 °C, may initiate the transformation of the template material but does not or not to the same extent alter the carrier material. This enables the removal of the transformed template material based on the altered properties. Lower temperature (e.g. about 600°C to about 839°C or 600°C to about 900°C) can be used to maintain the petals’ structure to a larger degree, which can increase the resulting tablet hardness.

In case the temperatures are higher than the recommended range, the fine petal structure of the particles is molten and is reduced, the flexibility of the petals is reduced; therefore, the hardness of the tablets produced with such overheated material is strongly reduced. Pharmaceutical compacts made with overheated material show capping and lamination and cannot be used comparably well in pharmaceutical formulations.

Accordingly, a heating step for the transformation of the template material enables the production of carrier particles with secondary internal structures that are beneficial to enhance one or more desired drug delivery properties.

As provided herein, the step of transforming the template material may comprise calcination.

The term “calcination”, as used herein, refers to heating a solid or a mixture comprising a solid to high temperatures (e.g., a temperature from 840 °C to 1200 °C or 600°C to 900°C) under the supply of air or oxygen to the solid or the mixture.

The calcination as described herein may induce decomposition of template material comprising a carbonate (e.g., carbonate salts such as calcium carbonate) to carbon dioxide. The calcination as described herein may induce decomposition of template material comprising a metallic carbonate to a metallic oxide, preferably to a basic oxide.

The calcination as described herein may induce the decomposition of hydrated template material by the removal of water. The calcination as described herein may also induce the decomposition of volatile matter in the template material.

Accordingly, the calcination step for the transformation of the template material may enable the production of carrier particles with secondary internal structures that are beneficial to enhance one or more desired drug delivery properties.

In certain embodiments, transforming the template material comprises a subsequent addition of water.

The subsequent addition of water transforms the template material in a chemical reaction but does not alter or unsubstantially alter the carrier material. This enables the removal of the transformed template material based on the altered properties. As it is to be understood herein, the subsequent addition of water as described herein will lead to said water reacting with a metallic oxide. Accordingly, the transformation step ay method comprise the addition of water to enable the production of carrier particles with secondary internal structures that are beneficial to enhance one or more desired drug delivery properties.

It is to be understood that the addition of water enables an exothermic reaction. The term “exothermic reaction”, as used herein, refers to a reaction for which the overall standard enthalpy change is negative. The subsequent addition of water, as described herein, transforms the template material in an exothermic chemical reaction but does not alter or unsubstantially alter the carrier material. This enables the removal of the transformed template material based on the altered properties.

The basic oxide described herein, is not toxic or unsubstantially toxic at the dose used as described herein. In some embodiments, the subsequent addition of water as described herein reacts with a basic oxide. In some embodiments, the subsequent addition of water as described herein reacts with at least one basic oxide selected from the group of lithium oxide, sodium oxide, potassium oxide, rubidium oxide, cesium oxide, magnesium oxide, calcium oxide, strontium oxide, barium oxide, and bismuth(lll) oxide. It is accordingly preferred that upon the subsequent addition of water as described herein said water reacts with magnesium oxide and/or calcium oxide.

The exothermic reaction as described herein can facilitate subsequent removal of the template material. The forces released during the exothermic reaction and/or the properties of the products of the exothermic reaction can decrease density and/or increase solubility. For example, the exothermic reaction of calcium oxide with a density of 3.34g/cm³ with water results in calcium hydroxide with a density of 2.21 g/cm³.

Accordingly, the addition of water through an exothermic reaction may support the secondary structure formation and facilitate subsequent template material removal.

As provided herein, removing the template material may comprise dissolution of the transformed template material to form secondary internal structures. The secondary internal structures can be formed by the removal of the transformed template material by dissolution in a solvent that dissolved the transformed template material but not the carrier material.

Alternatively, removing the template material may comprise dissolution of the transformed template material with water or an aqueous solution. The pH of the aqueous solution may be altered before the dissolution of the transformed template material to increase the solubility of the transformed template material or decrease the solubility of the carrier material in the aqueous solution.

Alternatively, removing the template material may comprise the dissolution of the transformed template with an organic solvent. The removal of the template material by dissolution is particularly mild to the carrier material. Therefore, this mild removal supports the maintenance of the primary carrier material structure and enables the formation of secondary internal structures that are particularly beneficial for crystallization during the drug loading process. Accordingly, removing the template material may comprise dissolution of the transformed template material supports the formation of the secondary internal structures.

As provided herein, the template material may comprise a metal carbonate. Preferably, the template material comprises at least one metal carbonate selected from the group of IJ2CO3, Li HCO3, Na2CO₃, NaHCOs, Na₃H(CO₃)2, MgCO₃, Mg(HCO₃)₂, AI₂(CO₃)₃, K₂CO₃, KHCO₃, CaC0₃, Ca(HCO₃)₂, MnC0₃, FeCOs, NiCOs, C112CO3, C11CO3, ZnCOs, Rb2COs, PdCOs, Ag2COs, CS2CO3, CsHCOs, BaCOs, and (BiO)₂CO₃.

As provided herein, the template material may comprise at least one metal selected from the group of Fe, Mg, Al, Mn, V, Ti, Cu, Ga, Ge, Ag, Au, Sm, U, Zn, Pt and Sn. In certain embodiments, the template material comprises at least one non-metal selected from the group of Si, S, Sb, I, and C.

Preferably, the template material comprises more than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% metal carbonate. Accordingly, and preferably, the template material comprises more than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% of at least one metal carbonate selected from the group of IJ2CO3, LiHCOs, Na₂CO₃, NaHCOs, Na₃H(CO₃)2, MgCOs, Mg(HCO₃)2, AI₂(CO₃)3, K2CO3, KHCO3, CaCOs, Ca(HCO3)2, MnCOs, FeCOs, NiCOs, CU2CO3, CuCOs, ZnCOs, Rb2CO3, PdCOs, Ag2COs, CS2CO3, CsHCOs, BaCOs, and (BiO)2CO3.

The template material may comprise magnesium carbonate, Accordingly and preferably, the template material comprises more than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% magnesium carbonate.

Alternatively or additionally, the template material may comprise calcium carbonate. Thus, preferably, the template material comprises more than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% calcium carbonate.

Preferably, the calcium carbonate as described herein comprises anhydrous calcium carbonate, complexes comprising calcium carbonate and/or hydrated calcium carbonate such as CaCOs W and/or calcium carbonate hexahydrate. The calcium carbonate as described herein is preferably anhydrous calcium carbonate.

The metal carbonates described herein can be used as a basis to produce a carrier material with distinct properties (e.g., an insoluble metal phosphate by a reaction of the metal carbonate with H3PO4) on the surface of the template material and can be transformed as described herein.

The carrier material may comprise at least one salt and/or complex selected from the group of calcium phosphate and magnesium phosphate. Accordingly, the carrier material preferably comprises at least one salt and/or complex of magnesium phosphate. Alternatively, the carrier material preferably comprises at least one salt and/or complex of calcium phosphate. Calcium phosphate and magnesium phosphate have a particularly low solubility in water and show a reasonable heat resistance. Furthermore, calcium phosphate and magnesium phosphate are typically pharmacologically inert and non-toxic. Therefore, calcium phosphate and magnesium phosphate are robust, non-toxic, and allow the transformation of the template material as described herein without decomposition.

Thus, the production of the carrier particles as described herein is particularly efficient when the carrier material comprises at least one salt and/or complex selected from the group of calcium phosphate and magnesium phosphate.

Preferably, in the composition of the present invention the carrier particles comprise calcium phosphate and/or magnesium phosphate. More preferably, the carrier particles as encompassed by the present invention comprise calcium phosphate.

Preferably, the calcium phosphate is present in the form of hydroxyapatite. As referred to herein, hydroxyapatite is a substance according to formula Ca5(OH)(PO4)3. Accordingly and preferably, the carrier particles as encompassed by the present invention comprise hydroxyapatite. Further preferably, the carrier particles as encompassed by the present invention further comprise calcium hydroxide.

Thus, preferably, the present invention relates to an embodiment, wherein the compositions of the present invention may be formulated by using carrier particles with secondary internal structures, wherein said carrier particles comprise hydroxyapatite and optionally comprise calcium hydroxide. Preferably, the content of the hydroxyapatite in said particle (not loaded with the composition) is at least 80% w/w, preferably at least 90% w/w, more preferably at least 95% w/w, even more preferably at least 99% w/w, even more preferably about 100% w/w.

As preferably it is to be understood herein, the term “carrier particles with secondary internal structures” may also be referred to as “carrier particles with hollow internal structures”.

The template material can have various structures, e.g., powder (e.g., a powder with D50 of about: 1 .9pm, 2.3pm, 3.2pm, 4.5pm, 5.5pm, 6.5pmo or 14pm; a powder with a particle size range of about: 1 to 100 pm, 100pm to 300pm or 300pm to 600pm) or nanoparticles.

Accordingly, the template material may comprise particles that have a diameter of 1 to 300 pm. Preferably, the template material comprises (or consists of) particles wherein about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 99% of the particles that have a diameter of 1 to 300 pm. In certain embodiments, the template material comprises particles that have a median diameter of about 1 to 300 pm, about 1 to 250 pm, about 1 to 200 pm, about 1 to 150 pm, about 1 to 100 pm, about 1 to 90 pm, about 1 to 80 pm, about 1 to 70 pm, about 1 to 60 pm, about 1 to 50 pm, about 1 to 40 pm, about 1 to 30 pm or about 1 to 20 pm.

In certain embodiments, the carrier particles have a diameter of 1 to 300 pm.

The particle size of the template material influences the diameter of the carrier particle. The particles of the template material may have about the same median diameter as the median diameter of the carrier particles. However, in the cases wherein the template material and the carrier material are combined by layering and/or crystallization as described herein, the carrier particle has a similar or larger median diameter compared to the template material. In turn, in the cases wherein the template material and the carrier material are combined by chemical precipitation as described herein, the carrier particle has a similar or smaller median diameter compared to the template material.

Particles of a certain size can be obtained by methods known in the art, including milling, sieving (see, e.g., Patel, R. P., et al., 2014, Asian Journal of Pharmaceutics (AJP), 2(4); DAVID, J., and PETER, R., 2006, Fundamentals of Early Clinical Drug Development: From Synthesis Design to Formulation, 247; US5376347A). Particle size and shape measurements can be made using any method known in the art, such as laser diffraction or in situ microscopy (Kempkes, M., Eggers, J., & Mazzotti, M., 2008, Chemical Engineering Science, 63(19), 4656-4675; Allen, T. (2013). Particle size measurement. Springer).

In some applications, a particular low carrier particle diameter is desired. In certain embodiments, the carrier particles have a diameter of about 1 to 20 pm, about 1 to 15 pm, about 1 to 10 pm, or about 1 to 5 pm for use in intrapulmonary administration and/or nasal administration. In some applications, a particular low carrier particle diameter is desired to increase the diffusion surface and accelerate the release of the loaded agent.

In some applications, a larger carrier particle diameter is desired to enhance the flowability of the carrier particles and to facilitate further processing. In certain embodiments, the carrier particles have a diameter of about 5 to 300 pm, about 10 to 250 pm, about 15 to 200 pm, or about 20 to 150 pm. The carrier particles may have a surface area between 15 m²/g to 400 m²/g or 30 m²/g to 400 m²/g. Accordingly and preferably, the carrier particles have a surface area between about 15 m²/g to 400 m²/g about 30 m²/g to 400 m²/g, about 50 m²/g to 350 m²/g, about 70 m²/g to 320 m²/g, about 90 m²/g to 300 m²/g or about 100 m2/g to 280 m²/g as measured by 5-point BET (Brunnauer-Emmet-Teller) surface area analysis with nitrogen as a gas.

Alternatively, the surface area of carrier particles can be measured by any method known in the art (see, e.g., Akashkina, L.V., Ezerskii, M.L., 2000, Pharm Chem J 34, 324-326; Bauer, J. F., 2009, Journal of Validation Technology, 15(1), 37-45). However, the BET method is preferred.

The surface area of the carrier particles can be altered e.g., by the particle size of the carrier material, the carrier material, and/or changing the surface structure by the parameters as described herein (e.g., heat, duration of heating).

Accordingly, the method for the production of carrier particles as described herein enables mechanical stability and disintegration capabilities if the carrier particles have a surface area between 15 m²/g to 400 m²/g, preferably 30 m²/g to 400 m²/g.

The carrier particle as described herein may be used as an adsorber. A greater specific surface of carrier particles described herein allows strong Van der Waals interactions once the particles are brought in contact. This effect results in higher tensile strength of the final dosage forms. These Van der Waals interactions can be diminished by the addition of water and support the disintegration of particle clusters.

The secondary internal structure of the particles as encompassed by the invention, may comprise pores having a diameter size in the range of > 0.2 m and < 1.5 pm. Thus preferably, the secondary internal structure comprises pores having a diameter size of about > 0.2 pm, about > 0.3 pm, about > 0.4 pm, about > 0.5 pm, about > 0.6 pm, about > 0.7 pm, about > 0.8 pm, about > 0.9 pm, about > 1 pm, about > 1.1 pm, about > 1.2 pm, about > 1.3 pm, or about 1.5 pm. Accordingly and preferably, the secondary internal structure comprises pores having a diameter size in the range of about > 0.2 pm to < 1.5 pm, about > 0.3 pm to < 1 .5 pm, about > 0.4 pm to < 1 .5 pm, about > 0.5 pm to < 1 .5 pm, about > 0.6 pm to < 1.5 pm, about > 0.7 pm to < 1.5 pm, about > 0.8 pm to < 1.5 pm, about > 0.9 pm to < 1.5 pm, about > 1 pm to < 1.5 pm, about > 1.1 pm to < 1.5 pm, about > 1.2 pm to < 1.5 pm or about > 1.3 pm to < 1 .5 pm. As it is to be understood herein, The pore size of carrier particles can be measured by any method known in the art (see, e.g. Markl, D. et al., 2018, International Journal of Pharmaceutics, 538(1- 2), 188-214).

The porous structure that can be formed by the method for the production of the carrier particles as described herein enables pores of a particularly large size. This large pore size facilitates drug loading on the carrier particle and accelerates drug release from the carrier particle. A pore size diameter greater than 90% of the diameter of the particles of the template material results in unstable carrier particles. Therefore, there is a maximal pore size which depends on the size particles of the template material.

Accordingly, in certain embodiments, the secondary internal structure comprises pores having a diameter size of about < 270 pm, about < 225 pm, about < 180 pm, about < 135 pm, about < 90 pm, about < 81 pm, about < 72 pm, about < 63 pm, about < 54 pm, about < 45 pm, about < 36 pm, about < 27 pm, or about < 18 pm diameter. Accordingly, the method for the production of the carrier particles as described herein, wherein the secondary internal structure comprises pores that have a certain diameter size, preferably as described herein, is particularly useful for the subsequent drug loading and drug release of the carrier particles produced as described herein.

The total volume of the secondary internal structures in the obtained carrier particles with secondary internal structures may be in the range of > 10% to < 90% of the particle volume as determined by image analysis of SEM-FIB and SEM of resin-embedded particles’ cross-section images. Alternative analytical methods to measure the volume ratio of the internal structure and particle include porosity calculation as a ratio of tapped bulk of the carrier material to the true crystalline density of the carrier material. The total volume of the secondary internal structures refers to the volume inside the particle inside that results from the removal of the template material. In certain embodiments, the total volume of the secondary internal structures described herein is the average internal volume of the carrier particles obtained as described herein.

As referred to herein, the total volume of the secondary internal structures described herein is preferably the median internal volume of the carrier particles obtained as described herein.

Accordingly, the total volume of the secondary internal structures in the obtained carrier particles with secondary internal structures may be more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 70%, or about 80% of the particle volume. Thus, preferably, the total volume of the secondary internal structures in the obtained carrier particles with secondary internal structures is more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 70%, or about 80% of the particle volume.

Accordingly, the total volume of the secondary internal structures in the obtained carrier particles with secondary internal structures is in the range of about > 10% - < 90%, about > 15% - < 90%, about > 20%- < 90%, about > 25%- < 90%, about > 30%- < 90%, about > 35% - < 90%, about > 40% - < 90%, about > 45% - < 90%, about > 50% - < 90%, about > 55% - < 90%, about > 60% - < 90%, about > 65% - < 90%, about > 70% - < 90%, about > 10% - < 80%, about > 15% - < 80%, about > 20%- < 80%, about

> 25%- < 80%, about > 30%- < 80%, about > 35% - < 80%, about > 40% - < 80%, about > 45% - < 80%, about > 50% - < 80%, about > 55% - < 80%, about > 60% - < 80%, about > 65% - < 80%, about

> 70% - < 80%, about > 10% - < 70%, about > 15% - < 70%, about > 20%- < 70%, about > 25%- < 70%, about > 30%- < 70%, about > 35% - < 70%, about > 40% - < 70%, about > 45% - < 70%, about > 50% - < 70%, about > 55% - < 70%, about > 60% - < 70%, about > 65% - < 70%, about > 10% - < 60%, about > 15% - < 60%, about > 20%- < 60%, about > 25%- < 60%, about > 30%- < 60%, about > 35% - < 60%, about > 40% - < 60%, about > 45% - < 60%, about > 50% - < 60%, about > 55% - < 60%, about

> 10% - < 50%, about > 15% - < 50%, about > 20%- < 50%, about > 25%- < 50%, about > 30%- < 50%, about > 35% - < 50%, about > 40% - < 50% or about > 45% - < 50% of the particle volume.

The carrier particle obtainable as described herein may have a loading capacity of > 72% v/v, > 70% v/v,

> 68% v/v, > 66% v/v, > 64% v/v, > 62% v/v, or > 60% v/v. In one embodiment, the carrier particle has a loading capacity of > 60% v/v. The term “loading capacity”, as used herein, refers to the volume of the carrier particle that can be used for loading of an agent compared to the volume of the whole carrier particle. Accordingly, a carrier particle with a loading capacity of 60% v/v can load an agent having 60% of the volume of the carrier particle. The volume of the carrier particle is calculated from the diameter of the carrier particle. Therefore, the volume of the internal structure is part of the volume of the carrier particle for this calculation.

As understood herein, an agent that is loaded on the carrier particle may be comprised of a loading solvent and the loading solvent is removed to complete loading. The agent to be loaded is dissolved in the loading solvent and put in contact with the carrier particle ensuring complete wetting of the latter. The loading solvent can be removed by method any solvent removal method known to the person skilled in the art. In some embodiments the loading solvent is removed by a method selected from the group of evaporation, vacuum-assisted evaporation, atmospheric drying, vacuum-freeze drying, freeze drying at atmospheric pressure, spray drying, spray drying in fluidized bed apparatus, microwave assisted drying, electrospray- assisted drying, dielectric drying, fluidized-bed assisted drug loading, and solvent-sorption method. In some embodiments, the solvent-sorption method comprises high shear granulation.

The choice of the appropriate loading solvent depends on solvent toxicity, solvent partial vapor pressure, properties of the agent to be loaded (e.g., pH-stability and/or solubility of the agent to be loaded) and/or properties of the carrier material. The loading solvent described herein may comprise at least one organic solvent, preferably at least one organic solvent selected from the group of dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2-propanol, 1 -propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicon oils, gamma-Butyrolactone, and tetrahydrofuran. Preferably, the loading solvent described herein is water. Some loading solvents such as water have high surface tension and may therefore require additional measures to support entering the pore(s) of the carrier particle as described herein despite the exceptionally large pore size. The loading solvent described herein may comprise at least one surface-active agent such as a tenside. Alternatively, the addition of the loading solvent may occur under increased pressure, to support the loading solvent by entering into the inside of the carrier particle.

Loading on and into the carrier particle as described herein may comprise the addition of an antisolvent that reduces the solubility of the agent to be loaded in the loading solvent. The antisolvent may be at least one antisolvent selected from the group of water, dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2-propanol, 1 -propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicon oils, gamma-Butyrolactone, and tetrahydrofuran.

The loading solvent may be removed by evaporation, e.g., by increased temperature and/or decreased pressure. The maximal temperature for the removal of the loading solvent depends on the heat stability of the loaded agent.

The carrier particles with secondary internal structures, as described herein, can be compacted to obtain compacted carrier particles. The term “compacted carrier matter”, as used herein, refers to clusters of more than one carrier particle with adhesive forces acting between the carrier particles.

The term “compacting”, as used herein, refers to applying pressure to more than one particle (e.g., carrier particle) to form compacted carrier matter, wherein the carrier particle at least partially remains adherent to each other upon release of the pressure. Techniques for compacting are known to the person skilled in the art (see, e.g., Odeku, 0. A. et al., 2007, Pharmaceutical Reviews, 5(2)). Examples of techniques for compaction include, without limitation tableting, roller compaction, slugging, briquetting and/or centrifugation.

The compacted carrier matter described herein is particularly stable and can be used for the obtainment of a particularly stable pharmaceutical composition. During compaction, the large surface areas of the carrier particles as described herein form strong interparticle Van Der Waals adhesion forces that enable mechanical stability. Upon intake, water enters between the particles (e.g., by capillary forces), the distance-dependent Van Der Waals adhesion forces diminish, and the compacted carrier matter disintegrates. Accordingly, the compacted carrier matter described herein show particular mechanical stability and/or fast disintegration time.

Accordingly and preferably, the carrier particles as described in the present invention are compacted.

It has been surprisingly found by the present inventors that the formulations of the compositions of the present invention formulated using carrier particles show improved bioavailability.

Thus, preferably, the present invention relates to an embodiment, wherein the composition comprising 5- methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof is formulated by using carrier particles with secondary internal structures (which may also be referred to as hollow internal structures), wherein the carrier particles are compacted, wherein said carrier particles comprise hydroxyapatite and optionally comprise calcium chloride. Preferably, the content of the hydroxyapatite in said particle (not loaded with the composition of the present invention) is at least 80% w/w, preferably at least 90% w/w, more preferably at least 95% w/w, even more preferably at least 99% w/w, even more preferably about 100% w/w.

Alternatively, in the composition of the present invention, the templated carrier particle may comprise a porous hydroxyapatite shell, at least one hollow cavity and calcium hydroxide. Preferably, the calcium hydroxide is present in a smaller amount than the hydroxyapatite, preferably wherein the amount of calcium hydroxide is at least 2 times, at least 5 times, at least 10 times, at least 50 times or at least 100 times smaller than the amount of hydroxyapatite. The ratios herein are given as w/w ratios.

It is to be understood that the secondary internal structure of the carrier particles, or, in other words, the hollow internal structure, can be embodied in a form of said particle comprising porous hydroxyapatite shell and at least one hollow cavity (preferably porous hydroxyapatite shell, at least one hollow cavity and calcium hydroxide).

It is particularly preferred that the templated inverted particles used in the suspension of the present invention are obtainable in the process comprising the steps of:

1. adding diluted orthophosphoric acid to the suspension of calcium carbonate in water, wherein the w/w ratio of orthophosphoric acid is from 0.15 to 0.2 (preferably 0.17),

2. calcinating the so obtained filtered solid at 900°C for 5 h,

3. repeating the steps of: i. suspending the so obtained particles in water, ii. stirring the so obtained suspension, and ill. decanting the supernatant upon particle sedimentation until the pH of the suspension is lower than 10.5, and

4. drying and sieving the obtained particles. An exemplary such process is provided in the Examples section.

In one embodiment of the present invention, the composition of the present invention further comprises at least one pharmaceutically acceptable carrier. The composition as referred to herein may also be referred to as a pharmaceutical composition of the present invention.

The term "pharmaceutically acceptable" indicates that the compound or composition, typically and preferably the salt or carrier, must be compatible chemically or toxicologically with the other ingredient(s), typically and preferably with the inventive composition, when typically and preferably used in a formulation or when typically and preferably used for treating the animal, preferably the human, therewith. Preferably, the term "pharmaceutically acceptable" indicates that the compound or composition, typically and preferably the salt or carrier, must be compatible chemically and toxicologically with the other ingredient(s), typically and preferably with the inventive composition, when typically and preferably used in a formulation or when typically and preferably used for treating the animal, preferably the human, therewith. It is noted that pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, 22^nd edition.

The pharmaceutically acceptable carrier of the (pharmaceutical) composition of the present invention is without limitation any pharmaceutically acceptable excipient, vehicle, adjuvant, additive, surfactant, desiccant or diluent. Suitable pharmaceutically acceptable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, hydroxy- propyl-methyl-cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter. Pharmaceutically acceptable carriers of the invention can be solid, semi-solid or liquid.

It is known to the skilled person that small molecule drugs can be administered through peroral route of administration, parenteral route of administration (including intravenous route of administration, intramuscular route of administration, and subcutaneous route of administration), nasal (or intranasal) route of administration, ocular route of administration, transmucosal route of administration (buccal route of administration, sublingual route of administration, vaginal route of administration, and rectal route of administration), inhalation route of administration and transdermal route of administration.

The dosage will depend on the route of administration, the severity of the disease, age and weight of the subject and other factors normally considered by the attending physician, when determining the individual regimen and dosage level for a particular patient or subject. The pharmaceutical composition of the present invention may be administered via any route, including parenteral, intramuscular, subcutaneous, topical, transdermal, intranasal, intravenous, sublingual or intrarectal administration.

Preferably, the pharmaceutical composition of the invention is a solid pharmaceutical composition, preferably a solid pharmaceutical composition for oral, sublingual, buccal, nasal, bronchial, rectal, urethral, and/or intravaginal administration, more preferably for oral, sublingual or buccal administration. In other words, the composition is adapted for oral, sublingual, buccal, nasal, bronchial, rectal, urethral, and/or intravaginal administration (or delivery), more preferably for oral, sublingual or buccal administration or delivery). In a particularly preferred embodiment of the invention, the composition is adapted for sublingual delivery (or administration).

Tablets, capsules or sachets for peroral administration are usually supplied in dosage units and may contain conventional excipients, such as binders, fillers, diluents, tableting agents, lubricants, detergents, disintegrants, colorants, flavors and wetting agents. Tablets may be coated in accordance to methods well known in the art. Suitable fillers include or are preferably cellulose, mannitol, lactose and similar agents. Suitable disintegrants include or are preferably starch, polyvinyl pyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include or are preferably, for example, magnesium stearate. Suitable wetting agents include or are preferably sodium lauryl sulfate. These solid oral compositions can be prepared with conventional mixing, filling or tableting methods. The mixing operations can be repeated to disperse the active agent in compositions containing large quantities of fillers. These operations are conventional.

The pharmaceutical composition of the invention may be prepared by mixing suitably selected and pharmaceutically acceptable excipients, vehicles, adjuvants, additives, surfactants, desiccants or diluents known to those well-skilled in the art, and can be suitably adapted for peroral, transmucosal, parenteral or topical administration. Typically and preferably the pharmaceutical composition of the invention is to be administered in the form of a tablet, orodispersible tablet, mucoadhesive film, lyophilizates, capsule, sachets, powder, granule, pellet, peroral or parenteral solution, suspension, suppository, ointment, cream, lotion, gel, paste and/or may contain liposomes, micelles and/or microspheres.

The pharmaceutical composition of the present invention may also be a liquid composition. Accordingly, the pharmaceutical composition of the present invention as liquid compositions for oral administration can be provided in the form of, for example, aqueous solutions, emulsions, syrups or elixirs or in the form of a dry product to be reconstituted with water or with a suitable liquid carrier at the time of use. The liquid compositions can contain conventional additives, such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non aqueous carriers (which can include edible oil), for example almond oil, fractionated coconut oil, oily esters, such as glycerin esters, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; penetration enhancer, for example dimethylsulfoxide (DMSO); pH buffer systems, for example phosphate buffer, carbonate buffer, citrate buffer, citrate-phosphate buffer and other pharmaceutically acceptable buffer systems; solubilizers, for example beta-cyclodextrin, and if desired, conventional flavors or colorants. Oral formulations may also include or may be formulated as conventional formulations, such as tablets or granules.

Oral formulations may optionally further include taste-masking components to optimize the taste perception of the oral formulation. Examples of such taste-masking components may be peppermint-, spearmint-, citrus-, licorice-, mint-, grape-, black currant- or eucalyptus-based flavorants known to those well-skilled in the art. Further taste-masking effect is provided by using the carrier particles, as described herein, in the composition of the present invention.

The form of dosage for intranasal administration may include solutions, suspensions or emulsions of the active compound in a liquid carrier in the form of nose drops. Suitable liquid carriers include water, propylene glycol and other pharmaceutically acceptable alcohols. For administration in drop form formulations may suitably be put in a container provided e.g. with a conventional dropper/closure device, e.g. comprising a pipette or the like, preferably delivering a substantially fixed volume of composition/drop. The dosage forms may be sterilized, as required. The dosage forms may also contain adjuvants such as preservatives, stabilizers, emulsifiers or suspending agents, wetting agents, salts for varying the osmotic pressure or buffers, as required. Buffer systems may include for example phosphate buffer, carbonate buffer, citrate buffer, citrate-phosphate buffer and other pharmaceutically acceptable buffer systems. Intranasal formulations may optionally further include smell-masking components to optimize the smell.

For parenteral administration, liquid dosage units can be prepared containing the inventive composition and a sterile carrier. The parenteral solutions are normally prepared by dissolving the compound in a carrier and sterilizing by filtration, autoclavation, before filling suitable vials or ampoules and sealing.

Adjuvants, such as local anesthetics, preservatives and buffering agents can be added to the pharmaceutical composition of the present invention. In order to increase stability, the pharmaceutical composition can be frozen after filling the vial and the water can be removed under vacuum. A surfactant or humectant can be advantageously included in the pharmaceutical composition in order to facilitate uniform distribution of the inventive composition.

Preferably, the composition or the pharmaceutical composition of the present invention is formulated as a tablet, preferably a sublingual tablet and/or an orodispersible tablet.

Accordingly, the present invention, in a further embodiment, relates to a tablet comprising the composition or the pharmaceutical composition of the present invention. Preferably, the tablet is a sublingual tablet.

Preferably, the tablet of the present invention, as referred to herein, comprises a dose of 5-methoxy-N,N- dimethyltryptamine or a pharmaceutically acceptable salt thereof corresponding to 5 to 40mg, more preferably 5 to 15 mg of 5-methoxy-N,N-dimethyltryptamine. Accordingly, the present invention, in one embodiment, relates to a tablet comprising the composition of the present invention, with dose of 5- methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof corresponding to 5 to 40 mg, more preferably 5 to 15 mg of 5-methoxy-N,N-dimethyltryptamine.

Preferably, to improve mucosal absorption of 5-MeO-DMT, before loading into the TIP particles, the 5- MeO-DMT tartrate is neutralized by addition of an equimolar amount of a base (e.g. NaOH, NaHCO3, etc.) to remove excessive protons from the formula. This avoids excessive amounts of protons when the tablets disintegrates in the oral cavity, which could lead to strong protonation of 5-MeO-DMT in the saliva and thus reduced mucosal absorption due to a positively charged amine function on the 5-MeO-DMT. Accordingly, in one embodiment the 5-MeO-DMT or its pharmaceutically acceptable salt is 5-MeO-DMT (i.e., 5-MeO-DMT in its salt-free form).

In a further embodiment, the present invention relates to the composition of the present invention or the pharmaceutical composition of the present invention for use as a medicament. In other words, the present invention also relates to use of the composition of the present invention or the pharmaceutical composition of the present invention in a manufacture of a medicament.

The medicament comprising the composition of the present invention or the pharmaceutical composition of the present invention can be used in the treatment of a number of diseases and disorders. The said diseases and disorders are preferably selected from the following: a) treatment of depression, depressive episode, major depressive disorder, dysthymia, double depression, seasonal affective disorder, treatment-resistant depression, depressive episodes in bipolar disorder, postpartum depression, premenstrual dysphoric disorder, and/or stress-related affective disorders, e.g. burnout or depression in patients with chronic somatic disorders; b) treatment of anxiety such as panic attacks, panic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, separation anxiety disorder, social phobia, specific phobia, substance- induced anxiety disorder; treatment of obsessive-compulsive disorder; treatment of body dysmorphic disorder, body schema disorders, body integrity dysphoria, and body integrity identity disorder; treatment of post-traumatic stress disorder, treatment of attachment disorders; and/or treatment of attention deficit disorders, such as attention-deficit hyperactivity disorder (ADHD), autism and autism-spectrum disorders, and/or impulse control disorder; c) treatment and prevention of substance-related and/or behavioral addictions (such as gambling, eating, digital media, exercise or shopping); treatment of substance addiction, drug dependence, tolerance, dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, caffeine, stimulants, research chemicals, hallucinogens, inhalants, nicotine, opioids, GHB, dissociatives (including ketamine, phencyclidine), sedatives, hypnotics or anxiolytics; treatment of smoking addiction; and/or as an agent to aid quitting smoking, d) as a support agent for psychotherapy and/or psychoanalysis; e) as a diagnostic aid for dysfunctions, and/or mental and somatic disorders. f) treatment of sexual dysfunction; g) treatment of neuroses; and/or as an agent for inducing deep relaxation; treatment of sleep disorders associated with acute or chronic stress, agitation, depression, excessive worry and rumination, hyperarousal and anxiety. h) as an agent for pharmacological induction of meditative states; and/or as an agent to support mindfulness-based therapies; i) treatment of tendency to aggressive behavior of the patient against himself and against other persons; treatment of suicidal ideation and prevention of suicidal behaviors; treatment of emotional dysregulation (e.g. personality disorders); and/or treatment of behavioral disorders including self-harming, psychophysiological tension/arousal, agitation and socially harmful behavior; j) treatment of alexithymia; and/or improvement of mentalization and social skills (e.g. in attachment/developmental disorders, autism spectrum disorders, personality disorders); k) as agent for stimulation of neuroendocrine function, as agent for stimulation of oxytocin release; as agent for stimulation of prolactin release; as agent for stimulation of cortisol release; l) as agent for treating monoamine dysfunction in the central nervous system; as agent for increasing serotonergic signaling in the central nervous system; and/or as agent for increasing dopaminergic and noradrenergic signaling in the central nervous system; m) as neuroprotective, neuroplastic and neuroregenerative agent; as agent to stimulate neurotrophic factors (BDNF and other neurotrophins); treatment of neurodegenerative disorders; treatment of movement disorders such as Parkinson’s disease and essential tremor; sleep and autonomic nervous system disorders; Alzheimer’s disease, frontotemporal dementia, Parkinson’s dementia, Lewy body dementia, multiple system atrophy and other types of dementia; as an agent to support stroke rehabilitation through angiogenesis and a reduction of infarct volume and neuronal cell death; treatment of neuronal damage due to excessive substance abuse; as anti-aging agent, regenerative agent, prevention and treatment of signs of aging; protection from free radical damage; and/or protection and improvement of damage by ionizing radiation; n) as appetite regulation agent; as weight loss agent; treatment and prevention of obesity; treatment of eating disorders including anorexia, bulimia, and binge eating disorder; activation of lipid metabolism and physiological fat burning; activation of carbohydrate metabolism; activation of physiological glycogen combustion; treatment and prevention of diabetes; and/or treatment of insulin resistance; o) treatment of inflammation; as agent to stimulate anti-inflammatory effects in the body and in the central nervous system; as agent to inhibit pro-inflammatory cytokine production; as agent to stimulate the release of anti-inflammatory cytokines; treatment of chronic low grade inflammation, treatment of autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis and other demyelinating diseases, type 1 diabetes mellitus, Guillain-Barre syndrome, and/or psoriasis; treatment of infectious diseases (preferably caused by fungi infection, helminth infection, or bacterial infection); treatment of ulcers, asthma, and bronchitis; and/or treatment of autoinflammatory diseases, including Crohn’s disease, and/or Behcet’s disease. p) stimulation of immune response; q) as an antineoplastic and antimetastatic agent; treatment and/or prevention of cancer, abnormal cell growth and mutation r) treatment and/or prevention of cardiovascular diseases; treatment of abnormal blood pressure and abnormal heart rate; as an agent to decrease blood pressure and heart rate s) treatment of pain, psychosomatic pain, cancer pain, intestinal pain, perimenstrual pain, migraine, posttraumatic headaches, cluster headaches and other types of headaches, chronic pain syndromes including complex regional pain syndrome, neuropathic pain, phantom pain, post mastectomy pain, post stroke pain, post-spinal cord injury pain, musculoskeletal pain, chronic lower back pain, rheumatic pain, osteoarthritis, joint stiffness, fibromyalgia, rheumatoid arthritis, and muscle cramps. t) women’s reproductive health such as premenstrual dysphoric disorder (PMDD), post-partum depression, premenstrual syndrome (PMS), and menopause. It is to be understood that the above list of diseases is only given as specific examples and is not to be interpreted as limiting the present invention. Among the above, the preferred one(s) are one or more selected from a), b), and c).

In a further embodiment, the present invention relates to the composition of the present invention, or the pharmaceutical composition of the present invention for use in the treatment and/or prevention of a psychiatric, psychosomatic or somatic disorder.

Accordingly, the present invention relates as well to use of the composition of the present invention or the pharmaceutical composition of the present invention for manufacture of a medicament for treatment and/or prevention of a psychiatric, psychosomatic or somatic disorder.

Further accordingly, in a further embodiment, the present invention relates to a method of treatment (and/or prevention) of a psychiatric, psychosomatic or somatic disorder, the method comprising the step of administering to the individual in need thereof of the composition of the present invention, or the pharmaceutical composition of the present invention. It is to be understood that the composition of the present invention or the pharmaceutical composition of the present invention is to be administered in a therapeutically effective amount.

The “treatment” of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only). The “treatment” of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject/patient suffering from the disorder or disease. Accordingly, the “treatment” of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, e.g., lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject/patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above). The treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief). The term “prevention” of a disorder or disease, as used herein, is also well known in the art. For example, a patient/subject suspected of being prone to suffer from a disorder or disease may particularly benefit from a prevention of the disorder or disease. The subject/patient may have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition. Such a predisposition can be determined by standard methods or assays, using, e.g., genetic markers or phenotypic indicators. It is to be understood that a disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient/subject (for example, the patient/subject does not show any clinical or pathological symptoms). Thus, the term “prevention” comprises the use of a compound of the present invention before any clinical and/or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.

Preferably, within the scope of the present invention, the psychiatric, psychosomatic or somatic disorder is a psychiatric or neurological disorder. Preferably, said psychiatric disorder is selected from depression, stress-related affective disorder, burnout, major depressive disorder, dysthymia, treatment-resistant depression, suicidal ideation, premenstrual dysphoric disorder (PMDD), post-partum depression, anxiety, post-traumatic stress disorder, addiction, eating disorder, body dysmorphic disorder, obsessive- compulsive disorder, and behavioral and personality disorders. Preferably, said neurological disorder is selected from chronic pain syndromes, neuropathic or phantom pain, migraine, cluster headaches and other types of headaches, multiple sclerosis and other demyelinating diseases, neuroinflammation, autonomic and neuroendocrine dysfunction, neuronal damage due to excessive substance abuse, Parkinson’s disease, Alzheimer’s disease and other types of dementia. Preferably, multiple sclerosis and other demyelinating diseases relates to multiple sclerosis. Preferably, Alzheimer’s disease and other types of dementia relate to Alzheimer’s disease.

In one embodiment of the invention, said neurological disorder is selected from chronic pain syndromes, neuropathic or phantom pain, migraine, cluster headaches and other types of headaches, preferably from chronic pain syndromes, and neuropathic or phantom pain. In this specific embodiment, it is particularly preferred that the compound of formula (I) is in a form of benzoate salt.

As understood herein, chronic pain syndromes include complex regional pain syndrome, fibromyalgia, osteoarthritis, rheumatic pain, rheumatoid arthritis, and chronic lower back pain. Accordingly, in one embodiment, the neurological disorder is chronic pain syndrome, preferably selected from complex regional pain syndrome, fibromyalgia, osteoarthritis, rheumatic pain, rheumatoid arthritis and chronic lower back pain. It is to be understood that in case of osteoarthritis and rheumatoid arthritis, when referred to as chronic pain syndromes, reference is preferably made to chronic pain associated with osteoarthritis (or, in other words, chronic pain caused by osteoarthritis) and chronic pain associated with rheumatoid arthritis (or, in other words, chronic pain caused by rheumatoid arthritis), respectively. Thus, in other words, in one embodiment, the neurological disorder is chronic pain syndrome, preferably selected from complex regional pain syndrome, fibromyalgia, chronic pain associated with osteoarthritis, rheumatic pain, chronic pain associated with rheumatoid arthritis, and chronic lower back pain.

In one embodiment of the invention, the psychiatric, psychosomatic or somatic disorder is selected from depression, depressive episode, major depressive disorder, dysthymia, double depression, seasonal affective disorder, treatment-resistant depression, depressive episodes in bipolar disorder, postpartum depression, premenstrual dysphoric disorder, stress-related affective disorders, e.g. burnout or depression in patients with chronic somatic disorders, panic attacks, panic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder; obsessive-compulsive disorder; body dysmorphic disorder, body schema disorders, body integrity dysphoria, body integrity identity disorder; post-traumatic stress disorder, attachment disorders; attention deficit disorders, such as attention-deficit hyperactivity disorder (ADHD), autism and autism-spectrum disorders, impulse control disorder, substance addiction, drug dependence, sexual dysfunction, sleep disorders associated with acute or chronic stress, agitation, depression, excessive worry and rumination, hyperarousal and anxiety, Parkinson’s disease, essential tremor; Alzheimer’s disease, frontotemporal dementia, Parkinson’s dementia, Lewy body dementia, multiple system atrophy, obesity; eating disorders including anorexia, bulimia, and binge eating disorder, inflammation, autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, type 1 diabetes mellitus, Guillain-Barre syndrome, psoriasis, Crohn’s disease, Behcet’s disease, infectious diseases, preferably caused by fungi infection, helminth infection, or bacterial infection; ulcers, asthma, and bronchitis.

Accordingly, preferably the psychiatric disorder is selected from depression, depressive episode, major depressive disorder, dysthymia, double depression, seasonal affective disorder, treatment-resistant depression, depressive episodes in bipolar disorder, postpartum depression, premenstrual dysphoric disorder, stress-related affective disorders, e.g. burnout or depression in patients with chronic somatic disorders, panic attacks, panic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder; obsessive-compulsive disorder; body dysmorphic disorder, body schema disorders, body integrity dysphoria, body integrity identity disorder; post-traumatic stress disorder, attachment disorders; attention deficit disorders, such as attention-deficit hyperactivity disorder (ADHD), autism and autism-spectrum disorders, impulse control disorder, substance addiction, drug dependence, sexual dysfunction, sleep disorders associated with acute or chronic stress, agitation, depression, excessive worry and rumination, hyperarousal and anxiety.

Preferably, the somatic or psychosomatic disorder is selected from Parkinson’s disease, essential tremor; Alzheimer’s disease, frontotemporal dementia, Parkinson’s dementia, Lewy body dementia, multiple system atrophy, obesity; eating disorders including anorexia, bulimia, and binge eating disorder, inflammation, autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, type 1 diabetes mellitus, Guillain-Barre syndrome, psoriasis, Crohn’s disease, Behcet’s disease, infectious diseases, preferably caused by fungi infection, helminth infection, or bacterial infection; ulcers, asthma, and bronchitis.

Preferably, when referring to the psychiatric, psychosomatic or somatic disorder, preferably the psychiatric disorder is meant. However, in one embodiment, the term psychiatric, psychosomatic or somatic disorder may also refer to psychosomatic or somatic disorder, preferably a somatic disorder.

The composition of the present invention upon administration to a subject, preferably a human subject, may cause anxiolytic effects. The composition of the present invention upon administration to a subject, preferably a human subject, may cause relaxation, in particular physical and mental relaxation. The composition of the present invention upon administration to a subject, preferably a human subject, may cause induction of a state of mindfulness, in particular rapid induction of a state of mindfulness (i.e. within 20 minutes of administration, preferably 10 minutes of administration, more preferably 5 minutes of administration). The composition of the present invention upon administration to a subject, preferably a human subject, may cause reduction of aversive emotions (e.g. distress, anger, irritability, nervousness), in particular rapid reduction of aversive emotions (i.e. within 20 minutes of administration, preferably 10 minutes of administration, more preferably 5 minutes of administration). The composition of the present invention upon administration to a subject, preferably a human subject, may cause silencing of maladaptive ruminative thought patterns (e.g. worrying, obsessive-compulsive thoughts), in particular rapid silencing of maladaptive ruminative thought patterns (i.e. within 20 minutes of administration, preferably 10 minutes of administration, more preferably 5 minutes of administration). The composition of the present invention upon administration to a subject, preferably a human subject, may cause reduction of maladaptive behavioral patterns (e.g. impulsivity, rigidity, cravings, aggression), in particular rapid reduction of maladaptive behavioral patterns (i.e. within 20 minutes of administration, preferably 10 minutes of administration, more preferably 5 minutes of administration).

At the same time, the composition of the present invention upon administration to a subject, preferably a human subject, preferably does not cause (or substantially does not cause) changes in time and space perception of said subject, changes in sensory perception of said subject (i.e. hallucinatory effects). The composition of the present invention upon administration to a subject, preferably a human subject, preferably causes at most minimal cognitive impairment, and/or causes no changes in personal identity/integrity of said subject. Furthermore, the composition of the present invention upon administration to a subject, preferably a human subject, preferably does not cause cardiovascular challenges, respiratory depression, muscle tremors/spasms/contractions, motor control loss, dissociation/disembodiment or spatial disorientation, and/or vomiting).

Within the scope of the present invention, 5-MeO-DMT, as comprised in the composition of the present invention or pharmaceutical composition of the present invention can be administered to a subject as a single bolus dose. Preferably, within said single bolus dose, the total dose of 5-MeO-DMT is between 5 mg and 60 mg (in case a salt or solvate of 5-MeO-DMT is administered, the amount is to be recalculated to account for the mg content of 5-MeO-DMT in said salt). The final dosage is preferably to be determined by the attending physician.

It is particularly preferred that a bolus dose of between 10 mg and 30 mg is administered. Accordingly, the bolus dose may be 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg. Particularly preferred doses are 10 mg, 20 mg or 30 mg. Alternatively, preferred bolus doses include doses between 40 and 60 mg. Accordingly, the bolus dose may be 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59 and 60. Particularly preferred bolus doses are 40 mg, 50 mg, and 60 mg.

Preferably, the bolus dose as referred to herein, is to be administered daily. It is to be understood that, preferably, the bolus dose is to be administered not more often than once a day. In one embodiment, the bolus dose is to be administered once every two days. In one embodiment, the bolus dose is to be administered once every three days. In one embodiment, the bolus dose is to be administered once every four days. In one embodiment, the bolus dose is to be administered once every five days. In one embodiment, the bolus dose is to be administered once a week. In one embodiment, the bolus dose is to be administered two times a week. In one embodiment, the bolus dose is to be administered three times a week.

Further within the scope of the present invention, 5-MeO-DMT, as comprised in the composition of the present invention, or pharmaceutical composition of the present invention can be administered to a subject incrementally. In other words, incremental administration refers to administering a substance to a subject as a plurality of doses (increments) with waiting time (intervals) between each two consecutive doses. During said intervals, preferably the subject may be examined to see if a further increment of the dose should be administered. The incremental dosing can be characterized by incremental dose, total dose and/or a number of increments, and intervals between the increments. It is preferred that each increment of 5-MeO-DMT is between 5 mg and 20 mg. Furthermore, it is preferred that the total dose of 5-MeO-DMT is between 10 mg and 100 mg, preferably 20 mg and 100 mg. More preferably, the total dose is between 10 and 60 mg, such as 10 mg, 20 mg, 30 mg, 40 mg, 50 mg and 60 mg. It is further preferred that the interval between the increments is between 2 and 20 minutes, preferably between 2 and 10 minutes.

Further embodiments of the present invention are disclosed in the following numbered items.

1. A composition comprising 5-methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof formulated by using templated carrier particles.

2. The composition of item 1 , wherein 5-methoxy-N,N-dimethyltrypatmine or a pharmaceutically acceptable salt thereof is 5-methoxy-N,N-dimethyltrypatmine tartrate.

3. The composition of item 1 , wherein 5-methoxy-N,N-dimethyltrypatmine or a pharmaceutically acceptable salt thereof is 5-methoxy-N,N-dimethyltrypatmine in its free-base form.

4. The composition of any one of items 1 to 3, wherein the templated carrier particles are templated inverted particles.

5. The composition of any one of items 1 to 4, wherein the templated carrier particles comprise calcium phosphate and/or magnesium phosphate.

6. The composition of any one of items 1 to 4, wherein the templated carrier particle comprises a porous hydroxyapatite shell, at least one hollow cavity and calcium hydroxide.

7. The composition of any one of items 1 to 6, wherein the templated carrier particles are loaded with 5-methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof in a ratio of 15%w/w.

8. The composition of any one of items 1 to 7, further comprising at least one pharmaceutically acceptable carrier.

9. The composition of any one of items 1 to 8, wherein the composition is adapted for sublingual delivery.

10. The composition of any one of items 1 to 8, wherein the composition is formulated as ODT, sublingual film or buccal spray.

11. A tablet comprising the composition of any one of items 1 to 9.

12. The tablet of item 11 , wherein the tablet is a sublingual tablet.

13. The tablet of item 11 or 12, with a dose of 5-methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof corresponding to 5 to 40 mg of 5-methoxy-N,N-dimethyltryptamine.

14. The composition of any one of items 1 to 10, for use as a medicament.

15. The composition of any one of items 1 to 10, for use in the treatment of a psychiatric, psychosomatic or somatic disorder.

16. The composition for use of item 15, wherein the psychiatric, psychosomatic or somatic disorder is selected from depression, depressive episode, major depressive disorder, dysthymia, double depression, seasonal affective disorder, treatment-resistant depression, depressive episodes in bipolar disorder, postpartum depression, premenstrual dysphoric disorder, stress-related affective disorders, e.g. burnout or depression in patients with chronic somatic disorders, panic attacks, panic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder; obsessive- compulsive disorder; body dysmorphic disorder, body schema disorders, body integrity dysphoria, body integrity identity disorder; post-traumatic stress disorder, attachment disorders; attention deficit disorders, such as attention-deficit hyperactivity disorder (ADHD), autism and autismspectrum disorders, impulse control disorder, substance addiction, drug dependence, sexual dysfunction, sleep disorders associated with acute or chronic stress, agitation, depression, excessive worry and rumination, hyperarousal and anxiety, Parkinson’s disease, essential tremor; Alzheimer’s disease, frontotemporal dementia, Parkinson’s dementia, Lewy body dementia, multiple system atrophy, obesity; eating disorders including anorexia, bulimia, and binge eating disorder, inflammation, autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, type 1 diabetes mellitus, Guillain- Barre syndrome, psoriasis, Crohn’s disease, Behcet’s disease, infectious diseases, preferably caused by fungi infection, helminth infection, or bacterial infection; ulcers, asthma, and bronchitis.

17. The composition for use of item 15 or 16, wherein the dose of 5-methoxy-N,N-dimethyltryptamine is between 5 and 100 mg.

18. The composition for use of item 17, wherein the 5-methoxy-N,N-dimethyltryptamine is administered as a single bolus dose, wherein the total dose is between 5mg and 60 mg.

19. The composition for use of item 17, wherein the 5-methoxy-N,N-dimethyltryptamine is administered at increments, wherein the interval between he increments is between 2 and 20 minutes, and wherein each increment is at a dose of between 5 mg and 20 mg, wherein the total dose of 5- methoxy-N,N-dimethyltryptamine is between 20 and 100 mg.

20. The composition for use of any one of items 14 to 19, wherein the composition is to be administered on a daily basis.

The invention will be illustrated in the following Examples. These however are not meant to limit the scope of protection, which is defined by the hereto appended claims.

Examples

Example 1 : A Sublingual Formulation of 5-MeO-DMT Tartrate incorporated in Template inverted particles (TIP) Table 1 : Calculation for 5-MeO-DMT tartrate loading on TIP

# of tablets Total @ 10 mg 5- 5-MeO-DMT tartrate unloaded _K. _nu ,_M1 ^dH2° Loading weight

MeO-DMT [g] TIP [g] ^{Na0H [al} [ml] [% w/w] upon freebase drying [g]

1 0.0169 0.0956 0.0018 0.1 15 0.1125

50 0.8438 4.7814 0.0916 5 15 5.6252

Procedure - Loading of neutralized 5-MeO-DMT tartrate on TIP (calculation see table 1)

1) Weigh 5-MeO-DMT tartrate (0.8438g) and place into 100ml beaker

2) Dissolve NaOH (0.0916g) in dH2O (5ml)

3) Add entire NaOH solution to the 5-MeO-DMT tartrate and stir at room temperature until fully dissolved

4) Weigh unloaded TIP powder (4.7814g) and place into crystallization dish (100ml)

5) Add the 5-MeO-DMT tartrate / NaOH solution dropwise to the TIP powder using a 10ml syringe. The powder is constantly stirred using a spatula. After adding 3ml of the solution, the powder is allowed to dry in a convection oven at 40°C for 2h to avoid over wetting of the powder. After that, the remaining solution (~2ml) is slowly added to the powder.

6) The powder is now dried overnight in the convection oven at 40 °C

The 5-MeO-DMT tartrate-loaded particles are shown on SEM images in Figure 1. Their XRPD profile is shown in Figure 2.

Table 2: Calculations powder blending for Tableting

# of tablets @ 10mg 5-MeO DMT

Loaded TIP [g] Ac-Di-Sol [g] Total [g] tartrate

1 0.113 0.006 0.118

50 5.625 0.281 5.906

Procedure - Powder blending and tablet compression

1) Loaded TIP powder (5.906g) and Ac-Di-Sol (0.281 g) are placed in a powder container and homogenized in a T urbula powder mixer for 10min. 2) Tablets are compacted using a Korsch compaction machine. Tablets a 16.9mg 5-MeO-DMT tartrate (corresp. 10mg freebase) are manufactured by adding 0.118g of the powder blend (loaded TIP + Ac-Di-Sol) into the tooling matrix and compressing.

Obtained tablets are shown in Figure 3.

Production of TIP particles

The TIP particles, as used herein, are obtainable according to the following procedure.

Dilution of 85% ortho-phosphoric acid:

• Pipetting 42 mL 85% ortho-phosphoric acid into a 150 mL volumetric flask

• Filling to the mark with water

Manufacturing of TIP S1 (Activation):

1 . Transfer 1200 mL of water into a three-neck flask (reactor)

2. Addition of 200 g of calcium carbonate (L600)

3. While stirring continuously at 400 rpm, the suspension is heated to 60°C using a heating plate.

4. The diluted acid is added dropwise to the reactor at a rate of 1 .5 mL/min.

5. Run the process for 100 min until the diluted phosphoric acid has been completely transferred into the reactor.

6. Filtration of the suspension

Manufacturing of TIP S2 (Calcination):

1 . Particles are transferred to the muffle oven

2. Calcination Options: a. Option 1 : Calcination at 900°C for 5 h b. Option 2: Calcination at 750°C for 8h (Three calcination and washing cycles)

Manufacturing of TIP (pH-controlled washing):

1. Calcinated particles are suspended in 10 L of water

2. Suspension is stirred for 5 min at 400 rpm

3. Stirrer is stopped and particle sedimentation for 7 min

4. Decanting of supernatant

5. Steps 2-4. Are repeated until the pH of the suspension is < 10.5. 6. Particles are dried and sieved

The particles as used herein are also known as G-TIP, i.e. Galvita Templated Inverted Particles, and are manufactured by Galvita AG (www.galvita.com), Munchensteinerstrasse 274A, 4053 Basel, Switzerland.

Example 2: PK/PD experiments

In a small pilot dose-finding PKPD study N=4 female or male subjects (25-45y, BMI 18.5-30) with no current or previous history of neurological or psychiatric disorder and no family history of Axis-I psychiatric disorder will be recruited. Depending on the response, up to three doses of sublingual 5-MeO-DMT are to be administered (10, 20, 30 mg) in an open-label, dose-escalating, multiple ascending dose design. During each session, safety assessments is to be conducted, including the monitoring of various vital parameters (blood oxygenation, ECG, temperature, blood pressure, and heart rate) and blood samples are to be collected throughout. The safety/tolerability and intensity of acute subjective drug effects are to be assessed and at the end of each session, the study physician assesses the mental and physical wellbeing of the participant and subsequently determines whether the next dose level can be safely administered. There is also the option to conduct up to 3 additional study days with escalating dose steps (up to a maximum of 60 mg), as long as there are no safety concerns for the individual test subjects up to 30 mg. For details on the study assessment, see Figure 9A.

Based on the pilot study, another N=15 healthy female and male subjects (25-45y, BM1 18.5-30) with no current or previous history of neurological or psychiatric disorder and no family history of Axis-I psychiatric disorder are to be recruited by medical screening. Escalating doses of 5-MeO-DMT are to be determined based on the results of the pilot study and administered sublingually on 4 different visits (doses [mg]: 0, low (10-30, e.g. 20), med (e.g. 30-50, e.g. 40), high (e.g. 50-70, e.g. 60)) with one week between each substance administration in a double blinded manner. Only the study physician knows the actual administration dose. Pharmacokinetic modeling, drug quantification and quality control is to be assured in collaboration with the Institute of Forensic Medicine (University of Zurich). The test days each last about 3 hours and take place over a period of about 3-4 weeks at the Psychiatric University Hospital. On all test days, before and after the pharmaceutical intervention, several validated questionnaires and interviews are assessed. Venous blood is taken at regular intervals for further PKPD analyses. For details on the study assessment, see Figure 9B. The results of the pilot study are shown in Figures 4 to 8. The collection and analysis of the PK (blood samples) and PD (psychometrics) assessments followed the same experimental procedures as described in more detail below (Example 3).

Example 3: Dose-escalation PKPD study

In an open-label, multiple ascending doses PKPD study N=4 healthy subjects (2 females, 2 males, 25- 45y, BM1 18.5-30) with no current or previous history of neurological or psychiatric disorder and no family history of Axis-I psychiatric disorder were recruited by medical screening at the Psychiatric University Hospital Zurich. Three ascending doses of sublingual 5-MeO-DMT were administered (10, 20, 30 mg) in an open-label, within-subject design on non-consecutive separate study days. On the study days, the tablets were sublingually administered by the participants on empty stomach (last meal > 10 hours; last drink > 90 mins) under the supervision of an experimenter. The drug was administered to the subject as a bolus dose. During each session of about 3 hours duration, safety assessments were conducted, including the monitoring of drug-induced adverse effects and vital parameters (blood oxygenation, ECG, temperature, blood pressure, and heart rate). Venous blood samples were collected at regular intervals for PK analyses. On all test days, before and after the pharmaceutical intervention, several validated questionnaires and interviews were conducted. The safety/tolerability and intensity of acute subjective drug effects were assessed during the acute drug experience and at the end of each session. Prior to advancing to the next dosage level, the study physician assessed the participant's mental and physical well-being. For details on the study assessment, see Figure 9A.

Psychometrics: At baseline (i.e. , only on the first substance day), the Affective Style Questionnaire (ASQ), Highly Sensitive Person-Long (HSP-L), and Mindfulness-related capabilities (MINDSENS) questionnaires were administered. Acute psychometrics were administered shortly before substance administration and at various time points during the drug experience. Using a visual analog scale the overall intensity of acute drug effects, challenging aspects of the experience, mental clarity, visuals, emotional state, pleasantness, relaxation, and bodily effects were assessed. To measure changes in psychological state from pre- to post-session the following scales were utilized: Psy-Flex questionnaire (Psy-Flex), Cognitive Flexibility Questionnaire (CFQ), WHO-5 Well-Being Index (WHO-5), Emotional Breakthrough Questionnaire (EBI), Watts Connectedness Scale (WCS), Challenging Experience Questionnaire (CEQ), Visual Transcendence Scale (VST), Altered States of Consciousness (5D-ASC). During the intervention study days, the questionnaires were filled out on a tablet computer. Often participants feel the need to talk about their experience, these conversations were conducted as semi-structured interviews after the sessions. Blood chemistry: Blood was sampled by placing a peripheral venous catheter (venflon) in the median cubital vein of the non-dominant arm. The intravenous line was kept patent with a slow drip (1 Oml/h) of saline (0.9 g NaCI/dL). Blood was sampled at various timepoints (see Figure 9A) throughout the experimental days of the study, whereby at each time point 8 ml (2 x 4 ml) were sampled using a BD Vacutainer system. After sampling, the blood is immediately centrifuged (1800 rpm, 150 min, 20°C) to obtain plasma, which then is distributed to Eppendorf tubes and immediately frozen and stored at -80°C.

5-MeO-DMT was purchased from Sigma Aldrich as a 1 mg/mL methanolic solution. For the sample preparation 200 pl of plasma were spiked with 50 pl internal standard (IS) mixture (500 ng/ml DMT-d6) and 50 pl methanol (MeOH). Proteins were precipitated by adding 400 pl of acetonitrile (ACN). The samples were shaken for 10 minutes and centrifuged for 5 min at 10'000 rpm. 350 pl of the supernatant was transferred into an auto-sampler vial, evaporated to dryness under a gentle stream of nitrogen at room temperature and reconstituted in 100 pl eluent-mixture (98:2, v/v). External calibrator and quality control (QC) samples were prepared accordingly, replacing the MeOH with calibrator or QC solution mixtures. The calibration ranges were 4-400 pM for 5-MeO-DMT. Samples were analysed on an ultra- high performance liquid chromatography (UHPLC) system (Thermo Fisher, San Jose, CA) coupled to a linear ion trap quadrupole mass spectrometer 5500 (Sciex, Darmstadt, Germany). The mobile phases consisted of a mixture of water (eluent A) and ACN (eluent B), both containing 0.1 % formic acid (v/v). Using a XSelect HSST RP-C18 column; 150 mm x 2.1 mm i.d; 2.5 pm particle size (Waters, Baden, Daettwil, Switzerland), the flow rate was set to 0.5 ml/min with the following gradient: starting conditions 95% eluent A, for 1 min, decreasing to 40% within 6.5 min, followed by a quick decrease to 5% within 0.5 min, holding for 1 min and returning to starting conditions for 1 .5 min, resulting in a total runtime of 9 min. The mass spectrometer was operated in positive electrospray ionization mode with scheduled multiple reaction monitoring. The following transitions of precursor ions to product ions were selected as quantifier (italic) and qualifier ions: 5-MeO-DMT m/z 219^58, m/z 219— >174, and m/z 219— >130.

PK/PD Results: PK profiles were quantified from 4 subjects that received three ascending doses of 10, 20, and 30 mg of 5-MeO-DMT formulated in TIP. Plasma concentration values (ng/ml) were quantified at 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 60, 90, 120, 180 and 240 minutes after drug administration. Data presented in Fig. 10 (adjust numbers) show a gradual onset and dose-proportional increase in exposure levels. Pharmacokinetic (PK) time courses align with pharmacodynamic (PD) profiles, demonstrating a general dose-response relationship wherein the average acute subjective drug effect intensifies with increasing doses without significantly prolonging the overall duration of these acute effects (Fig. 11). In correspondence with Example 2, an atypical experience profile was noted by participants in example 3, characterized primarily by profound mindfulness-type relaxation without hallucinogenic effects. This was unexpected, as some participants anticipated a typical psychedelic experience. Accordingly, the term "intensity" was considered less suitable for describing these acute drug effects, which were predominantly experienced as "serenitizing". Therefore, in example 3, new experiential dimensions such as relaxation, mental clarity, and emotional state were added to the assessments and we asked participants to rate the drug's intensity relative to these additional dimensions. This approach yielded high ratings for relaxation and pleasantness, and comparatively lower (adjusted) ratings for the overall intensity of the drug experience (see Fig 11 B and 11 C). Area under the curve (AUG) was computed for several acute psychometrics to capture the overall shape of these subjective effects over time (Fig. 12). AUG was calculated using trapezoidal approximation applied to the ratings provided by each study participant for all recorded time points. A dose-response relationship of increasing median AUG for subjective acute drug effect intensity (“Intensity”) with increasing dose was demonstrated. The median value of participants' reported sense of being challenged by the drug effects (“Challenging”) has been shown not to increase proportionally with rated intensity. Demonstrated was also that the formulation has a therapeutic potential to attenuate aversive emotions (i.e. states of irritability, anxiety, psychophysiological tension, and rumination) as evidenced by dose-proportional increases in subjective ratings of pleasantness and mindfulness-type relaxation without signs of sedation or reductions in mental clarity. This is indicated by the tendency for minimum AUG values of relaxation and pleasantness to be greater for 30 mg than lower dose conditions. Additionally, participants experienced enhanced levels of relaxation and pleasantness post-session with escalating doses of 5-MeO-DMT (see Fig 11 B and 110). This observation aligns with the idea that these beneficial "afterglow" effects represent a prolonged and therapeutically relevant response to drug exposure. It is important to note that these effects are distinct from the transient acute drug effects, which are sometimes erroneously attributed to efficacy in the literature.

Table 3.1. Favorable safety profile: Adverse events. During the acute drug effect period, study participants were invited to report any adverse events they had experienced for the given dose. The number of study participants reporting occurrences of each adverse event type are tabulated. We demonstrate that the frequency of common clinical adverse events is minimal, even with increasing dosages.

Table 3.2. Favorable safety profile: Challenging Experiences. After subjective drug effects had subsided, study participants completed the Challenging Experiences Questionnaire (CEQ). Single questionnaire items are scored on a scale of 0 (minimum) to 5 (maximum) and the ratings from all 26 items are summed to form the total score (“CEQ total”). The mean and standard deviation (std) values for each dose condition are tabulated, as well as the CEQ score as a percentage of the maximum possible score (“CEQ %”). We demonstrate that mean CEQ ratings do follow a dose-response relationship, but that even the highest dose elicits favorably minimal levels of reported challenge for study participants.

Safety/Tolerability Results: Sublingual doses of 10, 20, and 30 mg 5-MeO-DMT formulated in TIP demonstrated no safety concerns and were well tolerated by participants. During the acute drug effect period, study participants were invited to report any adverse events they had experienced for the given dose. After subjective drug effects had subsided, study participants completed the Challenging Experiences Questionnaire (CEQ). The frequency of common clinical adverse events is minimal, even with increasing dosages (Table 3.1), and even the highest dose elicits favorably minimal levels of reported challenge for study participants (Table 3.2). Evaluation of ECG, temperature and pulsoxymetry (assessed 5 times at each study day) did not yield any clinically relevant signals. Vital signs showed only mild, transient, and clinically non-significant elevations (BPsys [meanSD AeMax T+30min] = 17.25(24.62); BPdia [mean AeMax T+30min] = 2.00(10.23); HR [mean AeMax T+20min] = 1.85(8.63)).

Efficacy Results: It is demonstrated that 5-MeO-DMT formulated in TIP can increase the average cumulative positive psychological effects of surrogate markers of efficacy (Fig. 13). To meaningfully assess the impact of dose on participants’ state of mind, a set of assessment instruments were combined to form the ‘Efficacy Index’. This is calculated by combining the total score for the following metrics: The main experiential drug effect of a “Blissful State” (a dimension from the ‘11 dimensional altered states of consciousness scale’; 11 D-ASC), and the percentage change from pre-intake to post-intake for the Cognitive Flexibility questionnaire, Psychological Flexibility questionnaire, and the Well-being Index (WHO-5 questionnaire). For the Well-being Index the baseline was defined as prior to drug intake on the first study day. This ‘Efficacy Index’ is based on the notion, that in the treatment of anxiety and related mental health disorders, psychedelic drugs are used to enhance psychological and cognitive flexibility. Psychedelics facilitate openness to experiences and cognitive defusion, helping patients detach from rigid, anxious thought patterns, and reducing worries about past and future events. This increased mental flexibility is positively related to psychological wellbeing according to the therapeutic principles of Acceptance and Commitment Therapy (ACT).

Further explored was the average value of each dimension from the 11 -dimensional altered state of consciousness scale (11 D-ASC) across study participants. This serves to visualize the subjective effects of this formulation more comprehensively, allowing us to contrast the experiential profile or ‘fingerprint’ of these effects against existing or future formulations. The findings indicate a pronounced increase in 'blissfulness', 'insightfulness', and 'spiritual experiences' with higher doses, while mitigating many of the hallucinogenic effects typically associated with this class of compounds. Most notably, less favorable subjective experiences such as ‘Anxiety’, ‘Disembodiment’, or ‘Impaired Cognition and Control’ were not significantly elevated (Fig. 14).

In summary, presented is an optimized dosing regimen involving a novel pharmaceutical composition of sublingual 5-MeO-DMT in TIP. This formulation improves the benefit-risk profile for administering 5-MeO- DMT to clinical populations by optimizing the pharmacokinetic parameters. Specifically, it moderates the rapid absorption kinetics typically observed with injected, intranasal, or inhaled 5-MeO-DMT, which can lead to intense and potentially distressing perturbations in consciousness. By extending the pharmacokinetic exposure profile, this formulation not only diminishes the overall intensity of acute psychedelic effects but also prolongs and enhances the duration of positive effects on mood and mindfulness-type physical and mental relaxation without signs of sedation or reductions in mental clarity. Consequently, sublingual 5-MeO-DMT in TIP exhibits an optimized safety and tolerability profile suitable for clinical use, as it significantly reduces perceptual/sensory alterations in consciousness and avoids inducing anxiety, fearful reactions, ego dissolution, or other challenging experiences, as well as motor, bodily, or cognitive impairments within therapeutic dose ranges. This is unique and surprising for dose ranges that might otherwise elicit strong psychedelic effects, potentially leading to challenging experiences and safety concerns in vulnerable patients. Indeed, real-world evidence from observational studies suggests that similar doses of inhaled 5-MeO-DMT could result in challenging experiences, particularly in psychedelic-naive participants (Ermakova et al. 2021 ; Uthaug et al. 2020; Metzner 2013). Strong psychedelic doses of 5-MeO-DMT require careful psychological and medical pre-screening, intense monitoring during sessions, and dedicated therapeutic aftercare, which restricts patient access and the scalability of 5-MeO-DMT in clinical practice. Specifically, patients experiencing anxiety, distress, irritability, worry, negative rumination, and psychophysiological tension could benefit from a formulation which lacks strong hallucinogenic properties. The present invention offers a gentle and gradual onset of effects, an attenuated psychedelic and challenging experience profile, while still maintaining therapeutic effects, as demonstrated by surrogate efficacy markers such as rapid induction of mindful relaxation, positive mood enhancement, and increased psychological/cognitive flexibility and well-being.

In conclusion, this invention addresses some of the limitations of administering 5-MeO-DMT via the inhaled, injected, or intranasal administration route in a clinical or therapeutic setting, offering a novel approach with optimized pharmacokinetic profiles and scalable dosing approach to maximize efficacy and improve safety/tolerability for patients with anxiety disorders and other mental health conditions.

Claims

2. The composition of claim 1 , wherein 5-methoxy-N,N-dimethyltrypatmine or a pharmaceutically acceptable salt thereof is 5-methoxy-N,N-dimethyltrypatmine tartrate.

3. The composition of claim 1 , wherein 5-methoxy-N,N-dimethyltrypatmine or a pharmaceutically acceptable salt thereof is 5-methoxy-N,N-dimethyltrypatmine in its free-base form.

4. The composition of claim 1 or 2, wherein the templated carrier particles are templated inverted particles.

5. The composition of claim 4, wherein the templated inverted particles are characterized by secondary internal structure.

6. The composition of claim 4 or 5, wherein the templated inverted particles are characterized by a hollow internal structure.

7. The composition of any one of claims 4 to 6, wherein the templated inverted particles comprise at least one hollow cavity.

8. The composition of claim any one of claims 4 to 7, wherein the templated carrier particles comprise calcium phosphate and/or magnesium phosphate.

9. The composition of any one of claims 4 to 8, wherein the templated carrier particle comprises a porous hydroxyapatite shell, at least one hollow cavity and calcium hydroxide.

10. The composition of any one of claims 1 to 9, wherein the templated carrier particles are loaded with 5-methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof in a ratio of 15%w/w.

11. The composition of any one of claims 1 to 10, further comprising at least one pharmaceutically acceptable carrier.

12. The composition of any one of claims 1 to 11 , wherein the composition is adapted for sublingual delivery.

13. The composition of any one of claims 1 to 11 , wherein the composition is formulated as ODT, sublingual film or buccal spray.

14. A tablet comprising the composition of any one of claims 1 to 11 .

15. The tablet of claim 14, wherein the tablet is a sublingual tablet.

16. The tablet of claim 15, wherein the tablet is a table with a dose of 5-methoxy-N,N- dimethyltryptamine or a pharmaceutically acceptable salt thereof corresponding to 5 to 40 mg of 5- methoxy-N,N-dimethyltryptamine.

17. The composition of any one of claims 1 to 13, for use as a medicament.

18. The composition of any one of claims 1 to 13, for use in the treatment of a psychiatric, psychosomatic or somatic disorder.

19. The composition for use of claim 18, wherein the psychiatric, psychosomatic or somatic disorder is selected from depression, depressive episode, major depressive disorder, dysthymia, double depression, seasonal affective disorder, treatment-resistant depression, depressive episodes in bipolar disorder, postpartum depression, premenstrual dysphoric disorder, stress-related affective disorders, e.g. burnout or depression in patients with chronic somatic disorders, panic attacks, panic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder; obsessive- compulsive disorder; body dysmorphic disorder, body schema disorders, body integrity dysphoria, body integrity identity disorder; post-traumatic stress disorder, attachment disorders; attention deficit disorders, such as attention-deficit hyperactivity disorder (ADHD), autism and autismspectrum disorders, impulse control disorder, substance addiction, drug dependence, sexual dysfunction, sleep disorders associated with acute or chronic stress, agitation, depression, excessive worry and rumination, hyperarousal and anxiety, Parkinson’s disease, essential tremor; Alzheimer’s disease, frontotemporal dementia, Parkinson’s dementia, Lewy body dementia, multiple system atrophy, obesity; eating disorders including anorexia, bulimia, and binge eating disorder, inflammation, autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, type 1 diabetes mellitus, Guillain- Barre syndrome, psoriasis, Crohn’s disease, Behcet’s disease, infectious diseases, preferably caused by fungi infection, helminth infection, or bacterial infection; ulcers, asthma, and bronchitis.

20. The composition for use of claim 18 or 19, wherein the dose of 5-methoxy-N,N-dimethyltryptamine is between 5 and 100 mg.

21. The composition for use of claim 20, wherein the 5-methoxy-N,N-dimethyltryptamine is administered as a single bolus dose, wherein the total dose is between 5mg and 60 mg.

22. The composition for use of claim 21 , wherein a bolus dose of between 10 and 30 mg is administered.

23. The composition for use of claim 21 , wherein a bolus dose of between 40 and 60 mg is administered.

24. The composition for use of any one of claims 21 to 23, wherein the bolus dose is to be administered daily.

25. The composition for use of claim 20, wherein the 5-methoxy-N,N-dimethyltryptamine is administered at increments, wherein the interval between he increments is between 2 and 20 minutes, and wherein each increment is at a dose of between 5 mg and 20 mg, wherein the total dose of 5-methoxy-N,N-dimethyltryptamine is between 20 and 100 mg.

26. The composition for use of any one of claims 17 to 25, wherein the composition is to be administered on a daily basis.