WO2025163165A1

WO2025163165A1 - Therapeutic dosage form and therapeutic dosing regimen of dmt/harmine combination

Info

Publication number: WO2025163165A1
Application number: PCT/EP2025/052571
Authority: WO
Inventors: Daniel CLAUSSEN; Dario DORNBIERER; Davor Kosanic; Milan SCHEIDEGGER; Robin VON ROTZ; Michael KOMETER; John SMALLRIDGE
Original assignee: Reconnect Labs Ag
Current assignee: Reconnect Labs Ag
Priority date: 2024-01-31
Filing date: 2025-01-31
Publication date: 2025-08-07
Anticipated expiration: 2026-07-31

Abstract

The present invention relates to a pharmaceutical composition comprising (a) harmine or a pharmaceutically acceptable salt thereof; and (b) N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, wherein the w/w ratio of harmine to N,N-dimethyltryptamine is from 1.2 to 1.4, as well as to a kit of parts comprising (a) harmine or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier; and (b) N,N- dimethyltryptamine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein the w/w ratio of harmine to N,N-dimethyltryptamine is from 1.2 to 1.4. The pharmaceutical compositions of the present invention and the kits of parts of the present invention are particularly useful in treating and or preventing psychiatric, psychosomatic or somatic disorders.

Description

Therapeutic dosage form and therapeutic dosing regimen of DMT/harmine combination

Field of the invention

The present invention relates to a pharmaceutical composition comprising (a) harmine or a pharmaceutically acceptable salt thereof; and (b) /V,A/-dimethyltryptamine or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, wherein the w/w ratio of harmine to /V,A/-dimethyltryptamine is from 1.2 to 1.4, as well as to a kit of parts comprising (a) harmine or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier; and (b) N,N- dimethyltryptamine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein the w/w ratio of harmine to N, /V-dimethyltryptami ne is from 1 .2 to 1 .4. The pharmaceutical compositions of the present invention and the kits of parts of the present invention are particularly useful in treating and or preventing psychiatric, psychosomatic or somatic disorders.

Background of the invention

Affective spectrum disorders are widespread in society and are significant contributors to the current economic burden in health care, reaching double-digit billion CHF amounts in Switzerland and orders of magnitude more worldwide. Along the affective spectrum the most prevalent mood disorders include depression (major depressive disorder, dysthymia, double depression, seasonal affective disorder, burnout, postpartum depression, premenstrual dysphoric disorder) and bipolar disorders (characterized by periods of depression and hypomania/mania). Despite high prevalence, most of the available therapies show suboptimal efficacy and are currently prescribed in a lengthy trial and error approach for weeks or months to see clinical benefit. Still fewer than 50% of all patients with depression show full remission with optimized standard treatment, including trials on numerous medications. Thus, there is an urgent need for novel mental health therapies with more rapid and sustainable therapeutic effects.

Recently, a novel class of rapid-acting antidepressant psychotropic compounds such as ketamine, psilocybin, and LSD was discovered to alleviate symptoms of anxiety and depression. Repeated administration of ketamine was shown to sustain antidepressant effects, but puts patients at risk due to its addictive potential. Moreover, there are major shortcomings of using compounds such as LSD for clinical purposes due to its long duration of action (10-12 hours). Additionally, both LSD and psilocybin show rapid tolerance at serotonergic receptors (Nichols 2016), which makes them less suited for repeated dosing regimens.

In contrast, the traditional indigenous plant concoction commonly made from Banisteriopsis caapi and Psychotria viridis or Diplopterys cabrerana, called ayahuasca, known as psychedelic agent, is increasingly recognized due to its beneficial effects on physical and mental health, making it a promising candidate for therapeutic use (Dominguez-Clave et al. 2016, Ayahuasca: Pharmacology, neuroscience and therapeutic potential. Brain research bulletin). Herein, psychedelic agent refers to an agent that can cause an altered state of consciousness in a subject that uses it. Altered state of consciousness refers to any condition different from a normal waking state, and may include, but is not limited to, experiencing cognitive or perceptual alterations (e.g. hallucinations), intense emotions, or day-dreaming. Ayahuasca has been suggested to exhibit positive effects in patients with psychological, somatic, and psychosomatic illnesses and has been used for centuries in natural medicine in Latin American regions (Frecska, E., Bokor, P. & Winkelman, M., 2016. The Therapeutic Potentials of Ayahuasca: Possible Effects against Various Diseases of Civilization. Frontiers in pharmacology, 7(e42421), pp.35-17). In small pilot studies, ayahuasca shows rapid and more sustained antidepressant properties in depressed patients (Osorio, F. de L. et al., 2015. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report., 37(1), pp.13-20; Palhano-Fontes, F. et al., 2018. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychological medicine, 7, pp.1-9; Santos, Dos, R.G. et al., 2016. Antidepressive and anxiolytic effects of ayahuasca: a systematic literature review of animal and human studies., 38(1), pp.65-72), compared to the transient antidepressant effects of ketamine, where a considerable number of patients relapse within 7 days of treatment (Sanacora, G. et al., 2016. Balancing the Promise and Risks of Ketamine Treatment for Mood Disorders). While the mechanism of such action is not known, the potentially therapeutic effect of ayahuasca is hypothesized to rely on its ability of resetting neuronal circuits underlying maladaptive neurobehavioral states.

Ayahuasca concoction comprises a mixture of A/,A/-dimethyltryptamine (DMT) and beta-carbolines (e.g. harmine, harmaline, tetrahydroharmine, among others.). Ayahuasca is a) non-toxic, b) has a low addictive abuse potential, c) does not produce tolerance, and d) shows an antidepressant potential (Dominguez- Clave et al. 2016; Barbosa, P.C.R. et al., 2012. Health status of ayahuasca users. S. D. Brandt & T. Passie, eds. Drug Testing and Analysis, 4(7-8), pp.601-609). In order for DMT to become bioavailable, peroral formulations usually contain plant-based sources of DMT (e.g. from Psychotria viridis) combined with P-carbolines (e.g. from Banisteriopsis caapi) that act as selective reversible monoamine oxidase A (MAO-A) inhibitors to prevent degradation of DMT in the body (Callaway, J.C. et al., 1996. Quantitation of N,N-dimethyltryptamine and harmala alkaloids in human plasma after oral dosing with ayahuasca. Journal of analytical toxicology, 20(6), pp.492-497). DMT is a structural analogue of serotonin and is widely found in nature, including plants, mammalian organisms, human brains and body fluids (Barker, S.A., 2018. N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function. Frontiers in neuroscience, 12, pp.139-17).

Although ayahuasca ingestion is considered safe (Barbosa et al. 2012), it brings along a number of undesired side effects (e.g. nausea, vomiting, diarrhea, hallucinations), compromising its clinical utility. Most of its side effects can be attributed to suboptimal pharmacokineticZ-dynamic properties due to the random admixture of plant material (with unknown or adverse toxicity), and variability in alkaloid content - precluding its use as a standardized prescription medicine in the clinical context. Moreover, upon peroral administration of ayahuasca, DMT is readily absorbed into the bloodstream and causes rapid changes in the consumer’s perception, with potentially distressing side effects (Riba, J. et al., 2003. Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics. The Journal of pharmacology and experimental therapeutics, 306(1), pp.73-83).

An alternative to ayahuasca that solves the problems of side effects outlined above is pharmahuasca, also known as synthetic ayahuasca. According to the disclosure of the document DE102016014603A1 , the term pharmahuasca or synthetic ayahuasca relates to combinations, compositions, mixtures and preparations comprising at least two members of the group of the active ingredients naturally occurring in and isolatable from Banisteriopsis caapi, Psychotria viridis and/or Diplopterys cabrerana, consisting of harmine, harmaline, d-tetrahydroharmine, N,N-dimethyltryptamine (DMT), mono-N-methyltryptamine, 5- methoxy-N,N-dimethyltryptamine, 5-hydroxy-N,N-dimethyltryptamine, 2-methyl-1,2,3,4-tetrahydro-|3- carboline, harmol, harmalol, tetrahydroharmol, as well as their natural and unnatural stereoisomers and racemates, available in solid, liquid or semi-solid form, characterized in that at least one of the active ingredients is selected from the group of P-carbolines consisting of harmine, harminole and tetrahydrohamine and its stereoisomers and racemate, and at least one of the active substances is selected from the group containing terminal N-substituted tryptamines consisting of N,N- dimethyltryptamine (DMT), mono-N-methyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 5-hydroxy- N,N-dimethyltryptamine. The active ingredients can be contained independently, in whole or in part - individually and in admixture, together and in several dosage forms, in the form of bases or their natural and synthetic salts, where applicable, or as /V-oxides, bound to ion exchangers or another matrix, can be present as complexes and inclusion compounds, can be synthesized and / or can be obtained from any natural plant material by extraction and - the sum of the concentrations of the active ingredients is at least

O.0001 %. It was hypothesized thatperoral pharmahuasca would be more tolerable compared to traditional ayahuasca, due to the elimination of plant admixtures with unknown toxicity, which are known to cause undesired side effects (e.g. vomiting, nausea, diarrhea). According to Wikipedia (https://en.wikipedia.org/wiki/Pharmahuasca), 50 mg DMT and 100 mg harmaline is usually the recommended dosage per person for pharmahuasca. However, combinations of 50 mg harmaline, 50 mg harmine, and 50 mg DMT have been tested with success. The constituents are put into separate gelatin capsules. The capsule with harmaline/harmine is swallowed first and the capsule containing the DMT is taken 15 to 20 minutes later.

To date, the limiting factor for pharmaceutical applications of pharmahuasca is inability to obtain highly bioavailable formulations of N,N-di methyltryptamine and harmine that would be suitable for administration to the patient in need thereof. Among others, the poor and highly heterogenous gastro-intestinal absorption of harmine is caused by its poor solubility in water and its ability to readily crystallize to completely insoluble and thus unabsorbable needles under various gastro-intestinal conditions (e.g. sudden increase in pH, when harmine transits from the acidic stomach into more basic environments (duodenum, ileum, etc.). It was found, that circumventing the gastrointestinal route - e.g. by delivering harmine via the buccal/sublingual route - can dramatically improve overall pharmacokinetic performance. As it is known to the person skilled in the art, in order manufacture sublingual, buccal or oromucosal dosage forms (e.g. orodispersible tablet/films, sublingual drops/spray) the compound has to show a high solubility, in order to load sufficient amount of the compound in to one dose unit (sprays/drops: max. 1 ml/dose; ODT: max. 0.5 ml/dose).

To date, the limiting factor of administering standardized formulations of DMT and harmine in clinical research or therapeutic settings is the lack of understanding which dose ratios yield the most optimal results in terms of pharmacokinetic performance, as well as treatment duration, efficacy, and safety/tolerability. In particular, traditional botanical ayahuasca is known for its unpredictable effects in terms of PK-PD variability and adverse effects profile (see also Bouso et al. 2022; doi: 10.1371/journal.pgph.0000438). Thus, better standardization and dose optimization of combined harmine/DMT formulations are key for improving the benefit-risk ratio for clinical applications. Thus, to date, another limiting factor for pharmaceutical applications of pharmahuasca is inability to obtain highly bioavailable formulations of harmine/DMT that would be suitable for administration to the patient in need thereof.

Document WO 2021/259962 discloses certain compositions and kits comprising harmine and DMT for the treatment of psychiatric disorders.

Document DE 10 2016 014603 teaches certain pharmaceutical compositions comprising harmine and a salt of DMT.

Aicher (Aicher Helena et al., ..Frontiers in Psychiatry, vol. 14, January 8 2024) teaches potential therapeutic effects of an ayahuasca-inspired N.N-DMT and harmine formulation and discloses certain controlled trial in healthy subjects.

Summary of the invention

There is a need for highly bioavailable formulations of harmine/DMT that would be suitable for administration to the patient in need thereof. Such formulations are provided by the present invention, as described in the embodiments described herein and as characterized by the appended claims.

Accordingly, the present invention provides compositions and combinations wherein the w/w ratio of harmine to N, /\/-di methyltryptami ne is from 1 .2 to 1 .4. It has been demonstrated that such a dosing allows for minimizing the inter-subject variability of PK parameters upon administration of the composition/combination. It has been further shown that high efficacy and positive subjective effects can be achieved when dosing the composition/combination of DMT/harmine according to the invention, at the same time avoiding high dose load of active ingredient (i.e., high cumulative drug load). Surprisingly, the dosing regime of the invention allows for maximizing the efficacy while minimizing the adverse side effects and optimizing the treatment duration. This finding is indeed counter-intuitive, as at increased drug load the skilled person would normally expect increased occurrence of side effects.

Furthermore, the dosing of harmine and N,N-di methyltryptamine according to the present invention has been found to allow for minimizing inter-subject variability in the clinic, thus allowing for more predictable clinical outcomes, as demonstrated in Figure 7. The invention, which is as in the hereto appended claims, will be summarized in the following embodiments.

In a first embodiment, the present invention relates to a pharmaceutical composition comprising (a) harmine or a pharmaceutically acceptable salt thereof; and (b) /V,A/-dimethyltryptamine or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, wherein the w/w ratio of harmine to N,N-di methyltryptamine is from 1 .2 to 1 .4.

In a second embodiment, the present invention relates to a kit of parts comprising (a) harmine or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier; and (b) N,N- dimethyltryptamine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein the w/w ratio of harmine to N,N-di methyltryptamine is from 1 .2 to 1 .4.

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

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

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

In a sixth embodiment, the present invention relates to a method for treating a psychiatric, psychosomatic or somatic disorder, the method comprising the step of administering the pharmaceutical composition of the present invention or the kit of parts of the present invention to an individual in need thereof. It is to be assumed that a therapeutically active amount is to be administered.

Brief description of figures

The invention will be further illustrated using the following figures. It is to be understood that the appended figures serve merely illustrative purposes and are not meant to limit the scope of the invention in any way. Fig. 1 presents pharmacokinetics analysis. In each analysis either the dose of DMT or harmine is varied while the other is fixed in order to directly compare the effects of escalating each formulation component independently. It has been demonstrated that the inter-subject variability of PK parameters (area under the curve and maximum plasma level) is lowest at a dose of DMT of 90 mg and at a dose of harmine of 120 mg (both normalized with respect to free base content). It has further been demonstrated that modulation of the harmine dose is a better predictor of DMT plasma level than modulation of the DMT dose.

Fig. 2 presents efficacy of different formulations tested. It has been demonstrated that at a dose of DMT of 90 mg and at a dose of harmine of 120 mg (both normalized with respect to free base content) high efficacy and positive subjective effects can be achieved, at the same time avoiding high dose of active ingredient (i.e. , high cumulative drug load).

Fig. 3 shows the study of subjective drug effect intensity and efficacy. The maximum subjective drug intensity (‘Max Intensity’) rating, during the period of acute drug effects, and the respective number of subjects (‘Count’) reporting each rating value is shown. The data are split by subjects whose Efficacy Index values were above or below 60% to demonstrate the non-obvious relationship between subjective drug intensity and efficacy with increasing total dose load. As demonstrated herein, increasing the total dose load can increase maximum reported drug effect intensity. However, when the doses are increased beyond a dose of DMT of 90 mg and at a dose of harmine of 120 mg (both normalized with respect to free base content), the efficacy starts to decrease.

Fig. 4 shows the comparison of subjective drug effect duration for different tested doses, studying subjective drug intensity vs time (part 1). The line shading indicates the total dose load to highlight the total dose-response relationship. It has been demonstrated that a dose of DMT of 90 mg and at a dose of harmine of 120 mg (both normalized with respect to free base content), as provided in the present invention, is comparably efficacious to a much higher cumulative drug load regime with a total dose of DMT of 90 mg and at a dose of harmine of 180 mg (both normalized with respect to free base content), with a reduced duration of subjective drug effects. Part 2 of the figure represents the same data, normalized with respect to their starting intensity.

Fig. 5 presents a Table summarizing the side effects for different tested dosages. For a dose of DMT of

90 mg and at a dose of harmine of 120 mg (both normalized with respect to free base content), as provided in the present invention, the fewest post-acute adverse events were reported, which is surprising as the skilled person would expect the adverse events to increase with the total cumulative drug load.

Fig. 6 presents the design of clinical study. Escalating sublingual doses of 0-120 mg DMT and 0-180 mg harmine (both normalized with respect to free base content) were administered in a single-blind manner to 16 healthy participants randomized to two sequences (n=8) with 6 treatment sessions at least 1 week apart. The total dose per session was administered in 3 dosing steps every 20 minutes. This study design allows for a systematic assessment of different dose ratios of combined harmine/DMT on pharmacokinetic/pharmacodynamic parameters, safety/tolerability, and surrogate efficacy outcomes.

Fig. 7 presents values of the coefficient of variation (%CV) for the data presented in Figure 1 to compare inter-subject variability in pharmacokinetic parameters (AUG and Cmax) across different total API doses. For each total dose, the DMT(mg):harmine(mg) dose combinations are indicated above the bars, which clearly demonstrate the lowest inter-subject variability that is obtained for harmine/DMT ratio of 1.33, as specifically demonstrated for a dosage of 90 mg of harmine of 120 mg of DMT.

Detailed description of the invention

As previously mentioned, in one embodiment, the present invention relates to a pharmaceutical composition comprising (a) harmine or a pharmaceutically acceptable salt thereof; and (b) N,N- dimethyltryptamine or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In the composition of the present invention, the w/w ratio of harmine to N,N-di methyltryptamine is from 1.2 to 1.4.

Accordingly, it is required that in the composition of the present invention the w/w ratio of harmine to N,N- dimethyltryptamine is from 1.2 to 1.4. It is apparent to the skilled person that while (a) may be harmine, it may also be a pharmaceutically acceptable salt thereof, whereas the weight of harmine in said w/w ratio relates exclusively to the weight of harmine free base, and not its salt. Thus, should (a) be a pharmaceutically acceptable salt of harmine, the weight of the salt has to be recalculated to account for the weight of a pure harmine free base corresponding to the weight of said salt, for the purposes of defining the w/w ratio in the definition of the composition of the present invention. Similarly, it is further apparent that while (b) may be N,N-di methyltryptamine, it may also be a pharmaceutically acceptable salt thereof, whereas the weight of N, /V-di methyltryptami ne in said w/w ratio relates exclusively to the weight of N, /V-dimethyltryptamine free base, and not its salt. Thus, should (b) be a pharmaceutically acceptable salt of N, /V-di methyltryptami ne, the weight of the salt has to be recalculated to account for the weight of a pure A/,A/-dimethyltryptamine free base corresponding to the weight of said salt, for the purposes of defining the w/w ratio in the definition of the composition of the present invention.

Again, it is apparent to the skilled person that while (a) may comprise harmine, harmine may also be replaced by a pharmaceutically acceptable salt thereof, whereas the weight of harmine in said w/w ratio relates exclusively to the weight of harmine free base, and not its salt. Thus, should (a) comprise a pharmaceutically acceptable salt of harmine, the weight of the salt has to be recalculated to account for the weight of a pure harmine free base corresponding to the weight of said salt, for the purposes of defining the w/w ratio in the definition of the kits of parts of the present invention. Similarly, it is further apparent that while (b) may include N, M-dimethyltryptamine, it may also be replaced with pharmaceutically acceptable salt thereof, whereas the weight of N, /V-dimethyltryptami ne in said w/w ratio relates exclusively to the weight of /V,/V-dimethyltryptamine free base, and not its salt. Thus, should (b) comprise a pharmaceutically acceptable salt of N, M-dimethyltryptamine, the weight of the salt has to be recalculated to account for the weight of a pure N, /\/-di methyltryptamine free base corresponding to the weight of said salt, for the purposes of defining the w/w ratio in the definition of the kits of parts of the present invention.

In the pharmaceutical composition of the present invention, as well as in the kit of parts of the present invention, the w/w ratio of harmine to N,N-di methyltryptami ne is from 1 .2 to 1 .4. Accordingly, the w/w ratio of harmine to N, /V-dimethyltryptami ne in the composition or in the kit of parts of the present invention may be 1.20, 1.21 , 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31 , 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1 .38, 1 .39, or 1 .40. Preferably, the w/w ratio of harmine to N, M-dimethyltryptamine in the composition of the invention or in the kit of parts of the invention is from 1 .30 to 1 .35. Thus, in this preferred embodiment, the w/w ratio of harmine to N,N-di methyltryptamine may be 1.30, 1.31 , 1.32, 1.33, 1.34 or 1.35. More preferably, the w/w ratio of harmine to N, M-dimethyltryptami ne is form 1 .32 to 1 .34. Even more preferably, the w/w ratio of harmine to N,N-di methyltryptamine is about 1.33. Still more preferably, the w/w ratio of harmine to N,N-di methyltryptamine is 1.33.

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.

Pharmaceutically acceptable salt of the compounds discussed herein (in particular of harmine or DMT), 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, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N- dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. 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- phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Preferred pharmaceutically acceptable salts of harmine 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 harmine is a hydrochloride salt. As understood herein, harmine is a compound of the formula:

The compound as shown in the formula hereinabove may also be referred to as harmine free base, or harmine FB. Harmine (7-methoxy-1-methyl-9H-pyrido[3, 4-b]-indole), also known as banisterine or as telepathine, is an alkaloid that occurs in a number of different plants, including harmel (Peganum harmala) or Banisteriopsis caapi. It belongs to a group of beta-carbolines. Harmine reversibly inhibits monoamine oxidase A (MAO-A), but it does not inhibit the monoamine oxidase B (MAO-B).

In the compositions, the pharmaceutical compositions, the kits of parts and the methods of the present invention harmine is primarily used as a selective reversible inhibitor of MAO-A. Other nervous system effects include increased Brain-derived neurotrophic factor (BDNF) protein levels as well as analgesic and antinociceptive effects. Ayahuasca constituents were further shown to stimulate neuronal cell proliferation and to prevent neuronal damage and improve cell viability. Besides those neuroprotective effects, harmine and other beta-carbolines might be able to raise dopamine levels in the CNS and thus be effective to alleviate the symptoms of parkinsonism. Other pharmacological activities of harmine include anti-inflammatory, antidiabetic, and antitumor activities. Specifically, antimicrobial (antiprotozoal, antibacterial, insecticidal, and antifungal) activity has been documented for P. harmala-derived betacarbolines. Various other studies have shown antineoplastic, antiproliferative, antioxidant, as well as immune-modulatory (anti-inflammatory) effects for harmala alkaloids. In addition, cardiovascular effects were reported such as vasorelaxant, antihypertensive, and negative inotropic effects, as well as anti- angiogenic inhibitory and anti-platelet aggregation effects (Moloudizargari M, Mikaili P, Aghajanshakeri S, Asghari MH, Shayegh J. Pharmacological and therapeutic effects of Peganum harmala and its main alkaloids. Pharmacogn Rev. 2013 Jul;7(14):199-212. doi: 10.4103/0973-7847.120524. PMID: 24347928; PMCID: PMC3841998; Zhang, L., Li, D. & Yu, S. Pharmacological effects of harmine and its derivatives: a review. Arch. Pharm. Res. 43, 1259-1275 (2020). https://doi.org/10.1007/s12272-020-01283-6).

Several structural analogues of harmine include harmaline, tetrohydroharmine, harmol, harmalol, tetrahydroharmol, 2-methyl-1 ,2,3,4-tetra-hydro-0-carboline. It is noted that the analogues of harmine listed herein are all MAO-A inhibitors. Therefore, it is further envisaged that harmaline, tetrohydroharmine, harmol, haramolol, tetrahydroh armol, 2-methyl-1,2,3,4.tetra-hydro-|3-carboline may also be used in the compositions, the pharmaceutical compositions, the kits of parts and/or the methods of the present invention, replacing harmine. It is accordingly expected that harmaline, tetrohydroharmine, harmol, haramolol, tetrahydroharmol, 2-methyl-1,2,3,4.tetra-hydro-0-carboline would also benefit from the approaches described herein to increase solubility and/or bioavailability of their formulations.

Preferably, the harmine or a pharmaceutically acceptable salt thereof is a harmine free base.

As referred to herein, N,N-di methyltryptamine (or DMT) is a compound of formula:

Accordingly, DMT (/V,/ -dimethyltryptamine) is a psychedelic substance that is a structural analogue of serotonin and melatonin. DMT is also a structural and functional analogue of other psychedelic substances, including bufotenin (5-hydroxy-A/,/\/-dimethyltryptamine), psilocybin (phosphate ester of 4- hydroxy-A/,/V-dimethyltryptamine) and psilocin (4-hydroxy-/V,A/-dimethyltryptamine). Further known analogues of DMT include mono-N-methyltryptamine. The analogues of DMT listed herein also show activity as psychedelic agents. Furthermore, the analogues of DMT listed herein are all mono-amines, and as such are potential substrates of MAO-A monoamine oxidase.

As referred to herein, a pharmaceutically acceptable salt of DMT is as defined hereinabove. Particularly preferred pharmaceutically acceptable salt of DMT is DMT hemifumarate or DMT hemisuccinate. Still more preferably, the pharmaceutically acceptable salt of DMT is DMT hemisuccinate.

Accordingly, the present invention relates to a salt of DMT, wherein said salt is DMT hemifumarate or DMT hemisuccinate. It is particularly preferred that the salt of DMT is DMT hemisuccinate.

As understood herein, whenever a reference to DMT or a pharmaceutically acceptable salt thereof is made, it is also to be understood as a narrower reference to DMT hemifumarate or DMT hemisuccinate, or more preferably DMT hemisuccinate. As understood herein and as apparent to the skilled person, in DMT hemisuccinate salt, two molecules of DMT per each molecule of succinate are present. In other words, stoichiometry of DMT to succinate (i.e., molar ratio of DMT to succinate) is 2:1. Similarly, as understood herein and as apparent to the skilled person, in DMY hemifumarate salt two molecules of DMT per each molecule of fumarate are present. In other words, stoichiometry of DMT to fumarate (i.e., molar ratio of DMT to fumarate) is 2:1 .

The hemisuccinate salt of DMT is particularly advantageous for use in pharmaceutical applications due to good aqueous solubility of said salt.

Compounds referred to herein or pharmaceutically acceptable salts thereof may exist as hydrates, or solvates thereof. Accordingly, solvates, hydrates as well as anhydrous forms of the salt are also encompassed by the invention. The solvent included in the solvates is not particularly limited and can be any pharmaceutically acceptable solvent. Examples include water and Ci-4 alcohols (such as methanol or ethanol).

Preferably, in the composition of the present invention or in the kit of parts of the present invention, (a) comprises an uronic acid.

As it is to be understood herein, in the case of the composition, it is to be understood that the composition as a whole, i.e., the composition comprising (a) and (b), as defined herein, further comprises uronic acid. However, the skilled person understands that the expression that (a) comprises an uronic acid may also be interpreted as the pharmaceutically acceptable salt of harmine, as recited in (a), is a salt of uronic acid.

As it is further to be understood herein, when considering the kit of parts of the present invention, and stating that (a) comprises uronic acid, it may be meant that either the part (a) of the kit of parts of the present invention comprises, as a further pharmaceutically acceptable carrier, an uronic acid, or that in the part (a) of the kit of parts of the present invention the pharmaceutically acceptable salt is a salt of uronic acid.

The term uronic acid is known to the skilled person. Preferably, uronic acid (which also may be referred to as alduronic acid) is herein understood as a sugar acid comprising both carbonyl group (i.e. a -CHO group or a -CO- group, preferably when present in its linear form) and a carboxylic acid functional group (i.e., -C00H group). One exemplary uronic acid is glucuronic acid, obtainable from glucose upon the oxidation of its terminal hydroxyl group. Glucuronic acid can be presented using the following Fischer projection:

As it is apparent to the skilled person, such a sugar may further have a cyclic form, for example:

Uronic acids derived from hexoses (i.e., monosaccharides characterized by the presence of six carbon atoms) may be referred to as hexuronic acids. Uronic acids derived from pentoses (i.e., monosaccharides characterized by the presence of five carbon atoms) may be referred to as penturonic acids. Monosaccharide is preferably as defined hereinbelow.

Accordingly and preferably, in the composition of the present invention, the uronic acid is a penturonic acid or a hexuronic acid. More preferably, in the composition of the present invention, the uronic acid is a hexuronic acid. Even more preferably, in the composition of the present invention, the uronic acid is glucuronic acid or galacturonic acid. Still more preferably, the uronic acid is glucuronic acid.

Within the present invention, it is preferred that if the composition of the present invention, or the part of the kit of parts of the present invention, comprises harmine and an uronic acid, the composition or the part of the kit of parts comprises a salt of harmine and uronic acid. The uronic is as defined hereinabove.

Preferably, the uronic acid comprised in (a) is glucuronic acid or galacturonic acid. More preferably, the uronic acid comprised in (a) is glucuronic acid. According to the present invention, in the pharmaceutical composition comprising (a) and (b), (a) and (b) will be mixed together or packaged together, being suitable for being administered together. 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. Herein, if (a) and (b) are comprised within one composition, they are typically formulated for the same route of administration.

If administration of the kit of parts of the present invention is discussed, meant is administration of the parts of the kit of parts of the present invention.

In the present invention, the kit of parts refers to a combination of individual components (a) and (b) which are kept physically separate but adjacent. The skilled person will understand that the components (parts) of the kit may be combined before administration, that the components (parts) may be administered simultaneously, or that the components (parts) of the kit may be administered sequentially. In the case of sequential administration, the components (parts) of the kit are typically to be administered preferably within a time range of between 15 minutes and 120 minutes in order to achieve the effects of the present invention. The components of the kit of parts can be formulated for different routes of administration. 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), transdermal route of administration, inhalation route of administration and transdermal route of administration. It should be noted that herein, oral route of administration may refer to peroral route of administration, buccal route of administration and/or sublingual route of administration. Herein, components (a) and (b) may be formulated for administration through any of these routes of administration. It will be understood that (a) and (b) can be formulated for administration using the same route of administration, it will be further understood that (a) and (b) can be formulated for administration using different routes of administration. As apparent to the skilled person, the dosage may 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. Particularly advantageous are dosages according to the present invention, as described herein and as recited in the appended claims.

The parts of the kit of parts or 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, within the present invention, harmine (or its pharmaceutically acceptable salt) and/or DMT (or its pharmaceutically acceptable salt)are to be administered sublingually or buccally, more preferably harmine (or its pharmaceutically acceptable salt) and/or DMT (or its pharmaceutically acceptable salt) are to be administered sublingually. Further preferably, when reference is made to harmine (or its pharmaceutically acceptable salt) and/or DMT (or its pharmaceutically acceptable salt), harmine (or its pharmaceutically acceptable salt) and DMT (or its pharmaceutically acceptable salt) is preferably meant.

The parts of the kit of parts of the invention or 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 parts of the kit or the pharmaceutical composition of the invention are 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 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 or with the parts of the inventive kit of parts, 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 or with the parts of the inventive kit of parts, 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 parts (a) and (b) of the kit of parts of the present invention or 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.

According to the present invention, the compositions and parts of the kits of parts of the present invention may be formulated by using carrier particles. The carrier particles are not to be particularly limited and any carrier particles known to the skilled person can be used within the invention.

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, <10s, preferably <10s) 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.

It is to be understood that the compositions and parts of the kits of parts of the present invention may be that is formulated as carrier particles may be formulated as orodispersible tablet. Accordingly, said carrier particles loaded with said composition or said part(s) of the kits of parts of the present invention may be compacted together to form a tablet. Depending on the disintegration properties of the tablet, said tablet may be orodispersible. The skilled person is capable of formulating and/or administering said orodispersible particle.

Preferably, 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.

It was surprisingly found that 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.

In some embodiments, the template material described herein comprises a salt. In some embodiments, the template material described herein comprises an organic salt. In some embodiments, the template material described herein is a carbonate salt or comprises a carbonate salt to a substantial degree. In some embodiments, the template material described herein comprises 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. In some embodiments, the energy is applied in form of a rise in temperature, and/or alteration of pressure. In some embodiments, the physical step of “transforming” induces an endothermic chemical reaction in the template material. The chemical step of “transforming” comprises providing a chemical reactant to the template material. In some embodiments, the reactant provided in the chemical step of “transforming” reacts with the template material but not or not substantially with the carrier material. In some embodiments, the chemical reactant provided in the chemical step of “transforming” is 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. In some embodiments, the carrier particles mask the unpleasant taste of a loaded agent, because the loaded agent is continuously released at the site of absorption. 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. In some embodiments, the carrier particle can be loaded with less effort and/or has a particularly high loading capacity.

In some embodiments, the carrier particle has 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. In some embodiments, 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.

In certain embodiments, 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.

In certain embodiments, 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.

In certain embodiments, combining a carrier material with a template material comprises adding the template material described herein and the carrier material described herein to a combining liquid. In some embodiments, the combining liquid described herein is 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 combining liquid described herein is water. In some embodiments, the combining liquid described herein is 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.

In certain embodiments, combining a carrier material with a template material comprises 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.

In certain embodiments, combining a precursor of the carrier material forms the carrier material in a chemical reaction with the surface of the template material. In some embodiments, the soluble precursor of the carrier material described herein is phosphoric acid.

The conversion grade is relevant in embodiments 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.

In certain embodiments, a soluble precursor of the carrier material is 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. In some embodiments, the soluble precursor of the carrier material described herein is 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.

In certain embodiments, the carrier material is added in a super-saturated solution to the template material and distributed on the template material by the initiation of chemical precipitation.

In certain embodiments, combining a carrier material with a template material comprises chemical precipitation and crystallization of the carrier material on the template material.

In certain embodiments, combining a carrier material with a template material comprises chemical layering and crystallization of the carrier material on the template material.

In certain embodiments, combining a carrier material with a template material 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.

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 affects 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.

In certain embodiments, transforming the template material comprises 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.

In certain embodiments, transforming the template material comprises 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 antisintering 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, in certain embodiments, the maximal suitable temperature for the transformation of the template material described herein is set about 100°C, about 200°C, about 400°C, about 500°C, or about 600°C below the melting temperature of the carrier material.

In certain embodiments, transforming the template material comprises 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.

In certain embodiments, transforming the template material comprises 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.

In some embodiments, the pressure is reduced during the heating for transforming the template material to a temperature in a certain range, e.g., from 840 °C to 1200 °C.

In some embodiments, the pressure is increased during the heating for transforming the template material to a temperature in a certain range, e.g., from 840 °C to 1200 °C.

In some embodiments, the heating for transforming the template material induces an endothermic chemical reaction.

In some embodiments, an inert substance (e.g., noble gas) is 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. In some embodiments, 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.

In certain embodiments, the step of transforming the template material comprises 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.

In some embodiments, the calcination as described herein induces decomposition of template material comprising a carbonate (e.g., carbonate salts such as calcium carbonate) to carbon dioxide.

In some embodiments, the calcination as described herein induces decomposition of template material comprising a metallic carbonate to a metallic oxide, preferably to a basic oxide.

In some embodiments, the calcination as described herein induces the decomposition of hydrated template material by the removal of water. In some embodiments, the calcination as described herein induces the decomposition of volatile matter in the template material.

Accordingly, the calcination 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.

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.

In some embodiments, the subsequent addition of water as described herein reacts with a metallic oxide.

Accordingly, the transformation step method comprises the addition of water enables the production of carrier particles with secondary internal structures that are beneficial to enhance one or more desired drug delivery properties.

In certain embodiments, 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 (III) oxide. In some embodiments, the subsequent addition of water as described herein 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 supports the secondary structure formation and facilitates subsequent template material removal.

In certain embodiments, removing the template material comprises 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.

In some embodiments, removing the template material comprises dissolution of the transformed template material with water or an aqueous solution. In some embodiments, the pH of the aqueous solution is 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.

In some embodiments, removing the template material comprises 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 comprises dissolution of the transformed template material supports the formation of the secondary internal structures.

In certain embodiments, the template material comprises a metal carbonate. In certain embodiments, the template material comprises at least one metal carbonate selected from the group of IJ2CO3, LiHCOs, Na₂CO₃, NaHCOs, Na₃H(CO₃)2, MgCO₃, Mg(HCO₃)₂, AI₂(CO₃)₃, K₂CO₃, KHCO₃, CaC0₃, Ca(HCO₃)₂, MnC0₃, FeCO₃,NiCO₃, Cu₂CO₃, CuCO₃, ZnCO₃, Rb₂CO₃, PdCO₃, Ag₂CO₃, Cs₂CO₃, CSHCO₃, BaCO₃, and (BiO)₂CO₃.

In certain embodiments, the template material comprises 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.

In certain embodiments, the template material comprises more than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% metal carbonate.

In certain embodiments, 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 l_i₂CO₃, LiHCOs, Na₂CO₃, NaHCOs, Na₃H(CO₃)₂, MgCO₃, Mg(HCO₃)₂, AI₂(CO₃)₃, K₂CO₃, KHCO₃, CaCO₃, Ca(HCO₃)₂, MnCO₃, FeCO₃,NiCO₃, Cu₂CO₃, CuCO₃, ZnCO₃, Rb₂CO₃, PdCO₃, Ag₂CO₃, Cs₂CO₃, CsHCOs, BaCO₃, and (BiO)₂CO₃.

In certain embodiments, the template material comprises more than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% magnesium carbonate.

In certain embodiments, the template material comprises calcium carbonate.

In certain embodiments, the template material comprises more than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% calcium carbonate.

In some embodiments, the calcium carbonate as described herein comprises anhydrous calcium carbonate, complexes comprising calcium carbonate and/or hydrated calcium carbonate such as CaCO₃-H₂O and/or calcium carbonate hexahydrate.

In some embodiments, the calcium carbonate as described herein is 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 HsPC ) on the surface of the template material and can be transformed as described herein.

In certain embodiments, the carrier material comprises at least one salt and/or complex selected from the group of calcium phosphate and magnesium phosphate.

In certain embodiments, the carrier material comprises at least one salt and/or complex of magnesium phosphate.

In certain embodiments the carrier material 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.

Accordingly, 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, the carrier particles as encompassed by the present invention 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 and parts of the kits of parts 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 chloride.

Preferably, the content of the hydroxyapatite in said particle (not loaded with the composition or part(s) of the kits of parts 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.

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, 6.5pm or 14pm; a powder with a particle size range of about: 1 to 100 pm, 100pm to 300pm or 300pm to 600pm) or nanoparticles.

In certain embodiments, the template material comprises particles that have a diameter of 1 to 300 pm. In certain embodiments, the template material 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.

The particle size of the template material influences the diameter of the carrier particle. In certain embodiments, the particles of the template material have about the same median diameter as the median diameter of the carrier particles. In embodiments 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 embodiments 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.

The person skilled in the art can predict the carrier material from the template material, carrier material, and the techniques used for combining the template material with the carrier material as described herein. In certain embodiments, the carrier particles have a diameter of 1 to 300 pm.

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.

Accordingly, the method for the production of the carrier particles as described herein wherein the carrier particles have a diameter in a certain range can be particularly useful for further processing (e.g., flowability) and/or application (e.g., diffusion surface) of the carrier particle produced according to said method.

In certain embodiments, the carrier particles have a surface area between 15m2/g to 400 m2/g or 30m2/g to 400m2/g.

In certain embodiments, the carrier particles have a surface area between about 15m2/g to 400 m2/g about 30m2/g to 400m2/g, about 50m2/g to 350m2/g, about 70m2/g to 320m2/g, about 90m2/g to 300m2/g or about 100m2/g to 280m2/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).

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).

In certain embodiments the carrier particle is 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.

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 15m2/g to 400 m2/g, preferably 30m2/g to 400m2/g.

In certain embodiments, the secondary internal structure comprises pores having a diameter size in the range of > 0.2 m and < 1 .5 pm.

In certain embodiments 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.

In certain embodiments 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.

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, the maximal pore size depends on the size particles of the template material.

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 is particularly useful for the subsequent drug loading and drug release of the carrier particles produced as described herein.

In certain embodiments, the total volume of the secondary internal structures in the obtained carrier particles with secondary internal structures is 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.

In certain embodiments, the total volume of the secondary internal structures described herein is the median internal volume of the carrier particles obtained as described herein.

In certain embodiments, 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.

In certain embodiments, 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.

In certain embodiments of the carrier particle as described herein and obtainable as described hereinabove, the carrier particle has 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 certain embodiments of the carrier particle as described herein, 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.

In some embodiments, an agent that is loaded on the carrier particle is 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 the present invention, the agent to be loaded in the carrier particle is the composition or the part(s) of the kits of parts of the present invention.

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.

In some embodiments, the loading solvent described herein comprises 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. In some embodiments, 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. In some embodiments, the loading solvent described herein comprises at least one surface-active agent such as a tenside. In some embodiments, the addition of the loading solvent occurs under increased pressure, to support the loading solvent by entering into the inside of the carrier particle. In some embodiments, loading on and into the carrier particle as described herein comprises the addition of an antisolvent that reduces the solubility of the agent to be loaded in the loading solvent. In some embodiments, the antisolvent is 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.

In some embodiments, the loading solvent is 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. It has been surprisingly found by the present inventors that the formulations of the compositions and parts of the kits of parts of the present invention formulated using carrier particles show improved bioavailability and/or reduced bitter taste, thereby leading to increased compliance with the patients.

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

Thus, preferably, the present invention relates to an embodiment, wherein the compositions and parts of the kits of parts of the present invention may be 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 or the part(s) of the kits of parts 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.

It has been surprisingly found by the present inventors that formulations of harmine according to the present invention, in particular harmine glucuronate, when formulated by using carrier particles with hollow internal structures (carrier particles with secondary internal structures) do not lead to bitter taste upon administration into oral cavity. Accordingly, by formulating the compositions, the salts, the pharmaceutical compositions of the present invention or the parts of kits of parts of the present invention, masking of the bitter taste of harmine or its salt is achieved. In turn, the skilled person will appreciate that this may lead to improved compliance.

Accordingly, the invention further relates to a method for masking the bitterness of a compound, wherein the compound is harmine or a pharmaceutically acceptable salt thereof, or DMT or a pharmaceutically acceptable salt thereof, the method comprising loading a compound having a bitter taste onto a carrier particle wherein a) the carrier particle comprises a loading cavity and wherein the carrier particle comprises a basic salt; and b) wherein the bitterness of the compound is masked by the carrier particle during oral mucosal absorption.

The inventors found that a carrier particle comprising a basic salt and a loading cavity can be used to mask taste, such as bitterness, of a compound, the compound being DMT, harmine or their salts, and that this masking effect goes beyond the masking properties of the geometric form of the carrier particle for certain compounds. Without being bound by theory, the basic salt may turn a part of the loaded compound to a tasteless form (e.g., the freebase or non-salt form of the loaded compound), which may then embody a film or barrier to shield the compound from being perceived as having a certain taste, e.g. by shielding the compound from the tastebuds. As such, the combination of chemical and structural shielding can mask tastes surprisingly well while also providing improved drug delivery properties. This method can be applied to any taste, preferably to a quantifiable taste such as bitterness.

This method may be used to improve compliance of a subject to a therapy (e.g. a therapy with a bad taste) or to improve oral mucosal absorption by improving tolerability of the compound in the mouth.

Accordingly, the invention further relates to a pharmaceutical composition comprising carrier particles, comprising a) a carrier particle comprising a loading cavity and comprising of a basic salt; and b) a compound having a bitter taste, wherein the compound is harmine or a pharmaceutically acceptable salt thereof, or DMT or a pharmaceutically acceptable salt thereof, wherein the bitterness of the compound is masked by the carrier particle during oral mucosal absorption. It is to be understood that the compound having a bitter taste, as described herein, may have a bitter taste in its salt form but no bitter taste or a reduced bitter taste in its non-salt form. The particle therefore enables the processing of the salt form instead of the non-salt form can for example facilitate loading of particles and/or tablet production.

The basic salt is not necessarily the primary constituent of the carrier particle. The basic salt can also only be present in small amounts (e.g. below the detection limit of certain measurement methods) for example residues from production, as long as it is sufficient to react with the loading agent in a sufficient amount to mask the taste. In certain embodiments, the basic salt is calcium hydroxide and/or magnesium hydroxide.

In certain embodiments, the invention relates to the method of the invention or the pharmaceutical composition comprising carrier particles of the invention, wherein the basic salt is calcium hydroxide.

In certain embodiments, the invention relates to the method of the invention or the pharmaceutical composition comprising carrier particles of the invention, wherein the carrier particle comprises a porous hydroxyapatite shell, at least one hollow cavity and calcium hydroxide.

In certain embodiments, the invention relates to the method of the invention or the pharmaceutical composition comprising carrier particles of the invention, wherein the carrier particle comprises a porous hydroxyapatite shell, at least one hollow cavity and calcium hydroxide, wherein 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.

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).

In certain embodiments, the invention relates to the method of the invention or the pharmaceutical composition comprising carrier particles of the invention, wherein the carrier particle 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.

In certain embodiments, the invention relates to a method for the production of carrier particles with secondary internal structures comprising 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.

It is to be understood that the carrier particles used in a method for masking the bitterness of a compound of the invention or in the pharmaceutical composition comprising carrier particles of the invention are as described hereinabove, and can be obtained as described hereinabove.

Preferably, the pharmaceutical composition comprising carrier particles 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.

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 parts of the kit of parts 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 oral, parenteral or topical administration. Typically and preferably the parts of the kit of parts of the invention is administered in the form of a tablet, capsule, sachets, powder, granule, pellet, orodispersible tablet, mucoadhesive film, lyophilizate, oral or parenteral solution, suspension, suppository, ointment, cream, lotion, gel, paste and/or may contain liposomes, micelles and/or microspheres.

The parts of the kit of parts or 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 citrus-, licorice-, mint-, grape-, black currant- or eucalyptus-based flavorants known to those well-skilled in the art.

Within the scope of the present invention encompassed are also embodiments wherein the taste masking is achieved by incorporation into taste-masking particles, e.g. carrier particles as described herein.

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, or the parts of the inventive kit of parts, 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 or to the parts of the kit of parts of the present invention. In order to increase stability, the pharmaceutical composition or the parts of the kit of parts 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 or in the parts of the kit of parts in order to facilitate uniform distribution of the inventive composition or the parts of the inventive kit of parts.

Topical formulations include or are preferably ointments, creams, lotions, gels, gums, solutions, pastes or may contain liposomes, micelles or microspheres.

In a further embodiment, the present invention relates to the pharmaceutical composition of the present invention or the kit of parts of the present invention for use as a medicament. The medicament comprising the pharmaceutical composition of the present invention or the kit of parts 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 post-traumatic stress disorder, treatment of adjustment disorders, treatment of attachment disorders; and/or treatment of attention deficit disorders, such as attention-deficit hyperactivity disorder (ADHD), autism and autismspectrum disorders, and/or impulse control disorder; preferably 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 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; h) as an agent for pharmacological induction of meditative states; i) treatment of tendency to aggressive behavior of the patient against himself and against other persons; and/or treatment of behavioral disorders 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); k) stimulation of oxytocin release; l) as agent for increasing the concentration of neurotransmitters in the central nervous system; as agent for increasing the concentration of serotonin in the central nervous system; and/or as agent for increasing the concentration of dopamine in the central nervous system; m) as neuroprotective and neuroregenerative agent; treatment of movement disorders such as Parkinson’s disease and essential tremor; sleep and autonomic nervous system disorders; Alzheimer’s disease 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; 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 s) treatment of pain, psychosomatic pain, intestinal pain, perimenstrual pain, migraine and other types of headaches, neuropathic pain, phantom pain, musculoskeletal pain, rheumatic pain, and arthritis

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 pharmaceutical composition of the present invention or the kit of parts 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 pharmaceutical composition of the present invention, the kit of parts 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, 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 pharmaceutical composition of the present invention, or the kit of parts of the present invention. It is to be understood that the pharmaceutical composition of the present invention, or the kit of parts 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 neurodegenerative disorder. Preferably, said psychiatric disorder is selected from depression, stress-related affective disorder, major depressive disorder, dysthymia, treatment-resistant depression, burnout, anxiety, post-traumatic stress disorder, addiction, eating disorder, and obsessive- compulsive disorder. Preferably, said neurodegenerative disorder is selected from Parkinson’s disease, essential tremor, stroke, multiple sclerosis and other demyelinating diseases, neuroinflammation, autonomic dysfunction, neuropathic or phantom pain, migraine and other types of headaches, neuronal damage due to excessive substance abuse, 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, the psychiatric disorder is selected from adjustment disorders. Preferably, said psychiatric disorder is adjustment disorder. In one embodiment, the psychiatric disorder is addiction, in particular substance addiction, such as cocaine addiction.

Preferably, it is to be understood that said composition comprising harmine, or said salt of harmine is to be administered simultaneously, separately or sequentially with DMT or its pharmaceutically acceptable salt, as discussed hereinabove.

Within the scope of the present invention, harmine, as comprised in the pharmaceutical composition of the present invention or kit of parts of the present invention, and DMT, as comprised within the pharmaceutical composition of the present invention or the kit of parts 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 harmine is between 5 mg and 200 mg (in case a salt or solvate of harmine is administered, the amount is to be recalculated to account for the mg content of harmine in said salt) and/or the total dose of DMT is between 5 mg and 100 mg (in case a salt or solvate is used, the amount is to be recalculated to account for the mg content of DMT in said salt).

The bolus dose, as referred to herein, may also be referred to as the daily dose.

Preferably, the daily dose of N,N-di methyltryptamine is between 80 and 100 mg. Accordingly, the daily dose of / ,/V-dimethyltryptamine may be 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100 mg. More preferably the daily dose of N,N-di methyltryptamine is between 85 and 95 mg. Even more preferably, the daily dose of N, M-dimethyltryptamine is about 90 mg. Still more preferably, the daily dose of N, /V-dimethyltryptami ne is 90 mg. It is to be understood that in a salt or solvate of DMT is administered, the amount is to be recalculated to account for the mg content of DMT in said salt or solvate.

Preferably, the daily dose of harmine is between 110 and 130 mg. Accordingly, the daily dose of harmine may be 110, 111, 112, 113, 114,115, 116, 117, 118, 119, 120, 121 , 122, 123, 124, 125, 126, 127, 128, 129 or 130 mg. More preferably, the daily dose of harmine is between 115 and 125 mg. Even more preferably, the daily dose of harmine is about 120 mg. Still more preferably, the daily dose of harmine is 120 mg. It is to be understood that in a salt or solvate of harmine is administered, the amount is to be recalculated to account for the mg content of harmine in said salt or solvate. Further within the scope of the present invention, harmine, as comprised in the pharmaceutical composition ofthe present invention or kit of parts of the present invention, and DMT, as comprised within the pharmaceutical composition of the present invention or the kit of parts of the present invention can be administered to a subject incrementally. It is preferred that each increment of harmine is between 5 mg and 80 mg, and/or each increment of DMT is between 5 mg and 50 mg. It is to be understood that harmine and DMT may be administered together, separately, or sequentially. Furthermore, it is preferred that the total daily dose of harmine and the total daily dose DMT of is as disclosed hereinabove for the daily/bolus dose of harmine and DMT, respectively.

As disclosed in the foregoing, in the composition of the present invention, as well as in the kit of parts of the present invention, the dose of A/,/\/-dimethyltryptamine is between 80 and 100 mg, preferably between 85 and 95 mg, more preferably, about 90 mg, even more preferably 90 mg, and the w/w ratio of harmine to N, /V-dimethyltryptami ne is from 1 .2 to 1 .4. Accordingly, the dose of N, M-dimethyltryptami ne is between 80 and 100 mg, preferably between 85 and 95 mg, more preferably, about 90 mg, even more preferably 90 mg, and the w/w ratio of harmine to N,N-di methyltryptamine in the composition or in the kit of parts of the present invention may be 1.20, 1.21 , 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31 , 1.32, 1 .33, 1 .34, 1 .35, 1 .36, 1 .37, 1 .38, 1 .39, or 1 .40. Preferably, the dose of A/,/V-dimethyltryptami ne is between 80 and 100 mg, preferably between 85 and 95 mg, more preferably, about 90 mg, even more preferably 90 mg, and the w/w ratio of harmine to /V,A/-dimethyltryptamine in the composition of the invention or in the kit of parts of the invention is from 1 .30 to 1 .35. Thus, in this preferred embodiment, the dose of N,N- dimethyltryptamine is between 80 and 100 mg, preferably between 85 and 95 mg, more preferably, about 90 mg, even more preferably 90 mg, and the w/w ratio of harmine to N,N-di methyltryptamine may be 1 .30, 1.31 , 1.32, 1.33, 1.34 or 1.35. More preferably, the dose of N,N-di methyltryptamine is between 80 and 100 mg, preferably between 85 and 95 mg, more preferably, about 90 mg, even more preferably 90 mg and the w/w ratio of harmine to N,N-di methyltryptamine is form 1.32 to 1.34. Even more preferably, the dose of /V,A/-dimethyltryptamine is between 80 and 100 mg, preferably between 85 and 95 mg, more preferably, about 90 mg, even more preferably 90 mg and the w/w ratio of harmine to N,N- dimethyltryptamine is about 1 .33. Still more preferably, the dose of N, /V-dimethyltryptamine is between 80 and 100 mg, preferably between 85 and 95 mg, more preferably, about 90 mg, even more preferably 90 mg and the w/w ratio of harmine to N, /V-dimethyltryptamine is 1 .33. The dose of N, /V-dimethyltryptamine is understood as amount of N, /V-dimethyltryptamine comprised in the composition or in the kit of parts, preferably as a daily dose or a bolus dose of N, /V-di methyltryptami ne.

As mentioned previously, the pharmaceutical composition of the present invention or the kit of parts of the present invention may be formulated as a disintegrating tablet. The tablet may be prepared by using carrier particles, including explicitly any preferred embodiment of the carrier particles provided herein.

In the disintegrating tablet of the present invention, the dose of A/,A/-dimethyltryptamine is preferably between 80 and 100 mg. Accordingly, the dose of N, M-dimethyltryptamine in the disintegrating tablet of the present invention may be 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100 mg. More preferably the dose of N,N-di methyltryptamine in the disintegrating tablet of the present invention is between 85 and 95 mg. Even more preferably, the dose of N,N-di methyltryptamine in the disintegrating tablet of the present invention is about 90 mg. Still more preferably, the dose of N,N- dimethyltryptamine in the disintegrating tablet of the present invention is 90 mg. It is to be understood that in a salt or solvate of DMT is administered, the amount is to be recalculated to account for the mg content of DMT in said salt or solvate. As it is further to be understood herein, the dose of M,A/-di methyl tryptamine in the disintegrating tablet of the present invention may correspond to a single bolus dose of N,N- dimethyltryptamine, or to the daily dose of said N, M-dimethyltryptamine. Alternatively, said daily dose may be comprised in a single tablet, or may be divided into a number of tablets, for example with incremental administration in mind. It is then preferred that an orodispersible tablet for each increment of DMT comprises a dose of between 5 mg and 50 mg, provided that the total daily dose is as described herein.

Preferably, the dose of harmine in the disintegrating tablet of the present invention is between 110 and 130 mg. Accordingly, the dose of harmine in the disintegrating tablet of the present invention may be 110, 111 , 112, 113, 114,115, 116, 117, 118, 119, 120, 121 , 122, 123, 124, 125, 126, 127, 128, 129 or 130 mg. More preferably, the dose of harmine in the disintegrating tablet of the present invention is between 115 and 125 mg. Even more preferably, the dose of harmine in the disintegrating tablet of the present invention is about 120 mg. Still more preferably, the dose of harmine in the disintegrating tablet of the present invention is 120 mg. It is to be understood that in a salt or solvate of harmine is administered, the amount is to be recalculated to account for the mg content of harmine in said salt or solvate. As it is further to be understood herein, the dose of harmine in the disintegrating tablet of the present invention may correspond to a single bolus dose of harmine, or to the daily dose of said harmine. Alternatively, said daily dose may be comprised in a single tablet, or may be divided into a number of tablets, for example with incremental administration in mind. It is then preferred that an orodispersible tablet for each increment of harmine comprises a dose of between 5 mg and 50 mg, provided that the total daily dose is as described herein.

In one embodiment, the orodispersible tablet of the present invention comprises both N,N- dimethyltryptamine and harmine, formulated together in a single tablet, as described hereinabove. However, in one embodiment, the present invention provides separate tablets comprising N,N- dimethyltryptamine, or its pharmaceutically acceptable salt, formulated as described herein, and separate tablets comprising harmine or its pharmaceutically acceptable salt, as described herein.

Particularly preferred embodiments of the present invention are described in the following numbered items.

1 . A pharmaceutical composition comprising

(a) harmine or a pharmaceutically acceptable salt thereof; and

(b) N, /V-di methyltryptami ne or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, wherein the w/w ratio of harmine to /V, /V-di methyltryptamine is from 1 .2 to 1 .4.

2. A kit of parts comprising

(a) harmine or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier; and

(b) /V,/V-dimethyltryptamine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein the w/w ratio of harmine to / , /V-di methyltryptamine is from 1 .2 to 1 .4.

3. The pharmaceutical composition of item 1 or the kit of parts of item 2, wherein the w/w ratio of harmine to /V, /V-di methyltryptamine is from 1 .30 to 1 .35.

4. The pharmaceutical composition of item 1 or 3, or the kit of parts of item 2 or 3, wherein the w/w ratio of harmine to /V,/V-dimethyltryptamine is about 1.33, preferably wherein the w/w ratio of harmine to /V, /V-di methyltryptamine is 1.33.

5. The pharmaceutical composition of any one of items 1 , 3 or 4 or the kit of parts of any one of items 2 to 4, wherein (a) further comprises uronic acid.

6. The pharmaceutical composition of item 5 or the kit of parts of item 5, wherein the uronic acid is glucuronic acid or galacturonic acid, preferably glucuronic acid. 7. The pharmaceutical composition of any one of items 1 or 3 to 6 or the kit of parts of any one of items 2 to 6, wherein (b) comprises hemisuccinate salt of N,N-di methyltryptamine.

8. The pharmaceutical composition of any one of items 1 or 3 to 7 or the kit of parts of any one of items 2 to 7, wherein said pharmaceutical composition or the part(s) of said kit of parts is/are formulated by using carrier particles with secondary internal structures.

9. The pharmaceutical composition of item 8 or the kit of parts of item 8, wherein said carrier particles comprise hydroxyapatite.

10. The pharmaceutical composition of any one of items 1 or 3 to 9, or the kit of parts of any one of items 2 to 9, wherein said pharmaceutical composition or the parts of said kit of parts is/are formulated as orally disintegrating tablet.

11. The pharmaceutical composition of item 10 or the kit of parts of item 10, wherein the orally disintegrating tablet comprising (b) comprises between 80 and 100 mg N,N-di methyltryptamine, preferably wherein the orally disintegrating tablet comprising (b) comprises about 90 mg N,N- dimethyltryptamine.

12. The pharmaceutical composition of item 10 or 11 or the kit of parts of item 10 or 11 , wherein the orally disintegrating tablet comprising (a) comprises between 115 and 125 mg harmine, preferably wherein the orally disintegrating tablet comprising (a) comprises about 120 mg harmine.

13. The pharmaceutical composition of any one of items 1 or 3 to 12, or the kit of parts of any one of items 2 to 12, for use as a medicament.

14. The pharmaceutical composition of any one of items 1 or 3 to 12, or the kit of parts of any one of items 2 to 12, for use in the treatment and/or prevention of a psychiatric, psychosomatic or somatic disorder, preferably for use in the treatment and/or prevention of a psychiatric disorder.

15. The pharmaceutical composition for use of item 14, or the kit of parts for use of item 14, for use in the treatmentof a psychiatric disorder, wherein the psychiatric disorder is selected from depression, stress-related affective disorder, major depressive disorder, dysthymia, treatment-resistant depression, burnout, anxiety, post-traumatic stress disorder, addiction, eating disorder, and obsessive-compulsive disorder.

16. The pharmaceutical composition for use of item 14 or 15, or the kit of parts for use of item 14 or 15, wherein said composition or the parts of said kit of parts is/are to be administered sublingually.

17. The pharmaceutical composition for use of any one of items 14 to 16, or the kit of parts for use of any one of items 14 to 16, wherein the daily dose of N,N-di methyltryptamine is between 80 and 100 mg, preferably about 90 mg.

18. The pharmaceutical composition for use of any one of items 14 to 17, or the kit of parts for use of any one of items 14 to 17, wherein the daily dose of harmine is between 115 and 125 mg, preferably about 120 mg.

The invention will be illustrated in the following examples, which however are not to be construed as limiting.

Examples

Manufacturing of TIP-based ODT containing different ratios of Harmine Glucuronate and DMT Hemisuccinate

Harmine Glucuronate Loading on TIP (25% HRM-GLC) Procedure

A: Manufacturing of Harmine Glucuronate Solution (HRM-GIc-SOL)

B: Loading of Harmine Glucuronate on TIP DMT Hemisuccinate Loading on TIP Procedure

A: Manufacturing of DMT-Monosodiumsuccinate-Solution B: Loading of DMT-Monosodiumsuccinate-Solution on TIP

Loading of TIP (template inverted particle / Cas[(OH)(PO4)3])

DMTS loading [20%], neutralized with 1 eq. NaOH Preparation DMT succinate solution (neutralized):

202.4 mg DMT succinate was placed in a beaker. 0.4 mL water and 0.2 mL ethanol were added. The mixture was heated slightly (40 °C) and stirred until a clear solution was obtained. NaOH (1 N solution) was added very slowly (to prevent precipitation of DMT) and stirred until a clear solution was formed. The pH was about 7. The entire solution was drawn up into a 2 ml syringe.

Loading TIP particles:

808.4 mg TIP was weighed out and placed in a crystallizing dish (the smaller the better - this ensures that the solution falls onto the powder and not onto the walls or bottom of the vessel). The crystallizing dish was now heated to 40 °C on a hot plate. Now, about 0.25 ml of DMTS solution was slowly spread directly onto the powder. Using a spatula, the liquid was distributed homogeneously over the entire powder by stirring and reducing any lumps. If the powder already appeared very moist, the powder was dried briefly (40 °C + convection). The dripping/intermediate drying procedure was repeated until the entire volume was added. The dripping could be faster in the beginning and was slowed down towards the end (when most of the particles are already loaded) to prevent over-wetting of the powder (and thus the risk of external crystallization). The final product was dried in several steps. The XRPD analysis has revealed the presence of DMT hemisuccinate in the TIP particles.

Manufacturing ODT tablets:

The amount of 1) harmine glucuronate loaded TIP, DMT Hemisuccinate loaded TIP, 3) unloaded TIP, 4) Ac-Di-Sol, 5) menthol, 6) sucralose and 7) peppermint flavor as given in the table below are blended using a turbula powder mixer (1 Omin). Then, each tablet (15mm) is manually compressed using a table top tablet press.

Single-blind, randomized, two-arm, dose-response study of DMT and harmine in healthy subjects

Participants and Study Design: 16 healthy female and male subjects (25-45 y) with no current or previous history of neurological or psychiatric disorder and no first-degree relatives with history of Axis-I psychiatric disorder were recruited by medical screening. In this single-blind pilot study, acute subjective effects and blood samples following the administration of escalating doses of DMT and harmine as a sublingual single preparation were measured. Additionally, on the fourth test day participants received either DMT or harmine only as a sublingual preparation according to their arm allocation. Study participants completed a telephone and medical screening before enrolment to the study. The study was approved by the Cantonal Ethics Committee of the Canton of Zurich (Basec-Nr. 2022-00973) and Swiss Federal Office of Public Health (BAG-Nr. (AB)-8/5-BetmG - 2022 / 018086). All participants provided written informed consent according to the declaration of Helsinki and were monetary compensated for the completion of the study.

Study setting: The study was conducted during the daytime in a furnished group treatment room to provide a comfortable living room atmosphere with dimmable lights and sound systems. Throughout all study days, a standardized playlist containing non-stimulating background music was played to provide a feeling of comfort and relaxation, with silence periods in between. Up to 4 participants were co-administered with the substance on a study day with experimenters present in the room all the time for supervision. Pharmacological intervention: A standardized and quality-controlled sublingual formulation containing N,N-Dimethyltryptamine hemisuccinate and harmine glucuronate was prepared according to well- established pharmaceutical procedures described hereinabove and summarized below. The sublingual formulation was manufactured by blending the drugs with the GRAS (Generally Recognized As Safe) excipient calcium phosphate to form a homogenous powder blend. Moreover, sucralose (sweetener) and orange, menthol or peppermint flavor (aroma) was added for taste masking. The final formulation was compacted into fast disintegrating tablets made using TIP particles by powder blending 1) harmine glucuronate loaded TIP particles with 2) N,N-DMT Hemisuccinate loaded TIP particles to yield a final strength per dose of 0-60 mg harmine (corresp. to the freebase) and 0-40 mg DMT (corresp. to the freebase), administered at 3 dosing intervals every 20 minutes.

In more detail, harmine glucuronate loaded TIP particles was manufactured as follows: Harmine glucuronate was dissolved in dH2O to yield a concentration of 25% (m/v). The specific amount of TIP particles was calculated to yield a loading coefficient of the particles of 25%. Then, the aqueous solution was slowly dropped onto the powder (in a Petri dish) and constantly stirred to yield a homogeneous paste. The paste was then air-dried at room temperature overnight.

Similarly, the N,N-DMT Hemisuccinate loaded TIP particles were manufactured as follows: N,N-DMT Hemisuccinate was dissolved in EtOH (>99%) to yield a 10% solution. The ethanolic solution was added to the correct amount of TIP particles and EtOH was slowly evaporated in the rotary evaporator for 2h, at 40°C, at 100 mbar, with 0.8 bar N2 flux.

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 sublingual formulation was administered with varying fixed bolus doses of DMT and harmine with two fixed increments of DMT and harmine in 20 minute intervals, resulting in 3 administrations over 40 minutes. Specifically, different dosing conditions with varying DMT:harmine ratios in the dose range between 0- 120 mg DMT and 0-180 mg harmine were tested. The dose ratios of harmine to DMT ranged from 0 to 2 (w/w) and were administered in a single-blind, within-subject, sequential ascending order with two different sequences in two arms. Participants were randomized to one of the sequences in a 1 :1 ratio. On the 4th study day, participants received DMT or harmine only, depending on the arm they were allocated to. For details see Figure 6. The intensity of subjective effects (psychometrics of acute effects) was monitored at baseline, 0, 20, 40, 60, 85, 120, 150, 180, 240, 300 and 540 min after administration. A series of well-established computer- based psychometric tools including visual analogue scales (VAS) for various drug effects and side effects, the Altered States of Consciousness Rating Scale (5D/11 D-ASC), acute subjective drug effects (VAS), and drug-induced adverse effects (AES), were included. Other well-established questionnaires were used as secondary endpoints, such as the Mystical Experience Questionnaire (MEQ), Challenging Experiences Questionnaire (CEQ), Emotional breakthrough inventory (EBI), Psy-Flex Questionnaire (Psy-Flex), Persisting Effects Questionnaire (PEQ), MINDSENS composite index (MS), Gratitude Questionnaire (GQ- 6), Affective Neuroscience Personality Scale (ANPS), Watts Connectedness Questionnaire (WCS), Sussex-Oxford Compassion Scale (SOCS), Visual Self-Transcendence Scale (VST), Psychological Insight Scale (PIS-6), WHO-5 Well-Being Index (WHO-5), Perceived Stress Scale (PSS), Griffiths Significance Ratings (GSR), Brief Symptom Checklist (BSCL), User Experience Questionnaire (USX), Sleep Quality Scale - Short (SQS-S), Metaphysical Beliefs Questionnaire (MBQ), Highly Sensitive Person Questionnaire (HSPQ), Attachment Style Questionnaire -Short (ASQ-S), Attribution of Consciousness Questionnaire (AOCQ).

The participants were screened for (serious) adverse effects throughout the experiment by the study physician, including questionnaire-based assessments (visual analogue scale: 1-10) at baseline, 0, 20, 40, 60, 85, 120, 150, 180, 240, 300 and 540 min after drug administration. The following side-effect items were assessed: bodily symptoms / discomfort (breathing difficulties, heart racing, chest pain, stomach pain, unpleasant body sensations / muscle pain, headache, nausea, vomiting, fainting, psychological symptoms / discomfort (unspecific discomfort, anxiety, panic, delusions, agitation, dissociation, reduction of vigilance). Vital signs (systolic/diastolic blood pressure, heart rate, blood oxygenation level) were monitored throughout the study at baseline, 20, 40, 60, 85, 120, 180, 240, 300, 540, 1440 (= 24h) min after drug administration. ECG was measured at baseline, 85, 150, 300, 540, and 1440 min after administration. Body temperature was measured at baseline, 85, 180, 300, 540, and 1440 min after administration. The same protocol was used for all study days. Participants were released at the end of the study day but will come back the following day for their assessments 24 hours after first substance administration.

On all study days, blood samples were taken from the left antecubital vein on 15 timepoints i.e. at baseline, and O, 20, 40, 60, 70, 85, 100, 120, 150, 180, 240, 300, 420, 540, 1440 min after administration for analysis of DMT and harmine concentrations in plasma. The venous catheter was connected to Heidelberger plastic tube extensions, to collect blood samples without disturbing the subjects during their psychedelic experience. The intravenous line was kept patent with a slow drip (10 ml/h) of heparinized saline (1000 III heparin in 0.9 g NaCI/dL; HEPARIN Bichsel; Bichsel AG, 3800 Unterseen, Switzerland). Blood samples were immediately centrifuged for 10 minutes at 2000 RCF and plasma samples were kept frozen at -80 °C until assay.

DMT was purchased from Lipomed (Arlesheim, Switzerland), NMT and 3-IAA were purchased from Sigma-Aldrich (St. Louis, USA), and harmine, harmol, DMT-N-oxide, harmine-d3 and DMT-d6 were purchased from Toronto Research Chemicals (Toronto, Canada). All other used chemicals were of highest grade available. For the sample preparation 200 pl of plasma were spiked with 50 pl internal standard (IS) mixture (40 ng/ml DMT-d6 and harmine-d3) 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. Calibrator and QC samples containing 3-IAA were prepared separately, replacing plasma by water. The calibration ranges were 0.5-500 ng/ml for DMT and DMT-N-oxide, 2.5-120 ng/ml for harmine, 1-80 ng/ml for harmol, 0.015-10 ng/ml for NMT and 35- 3000 ng/ml for 3-IAA. 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 Kinetex C18 column 50 x 2.1 mm, 2.6 pm (Phenomenex, Aschaffenburg, Germany), the flow rate was set to 0.5 ml/min with the following gradient: starting conditions 98% eluent A, decreasing to 70% within 4 min, followed by a quick decrease to 5% within 1 min, holding for 0.5 min and returning to starting conditions for 1 .5 min, resulting in a total runtime of 7 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 ions: DMT m/z 189— >115, DMT-N-oxide m/z 205— >117, harmine m/z 213— ► 169, harmol m/z 199^131 , NMT m/z 175^144 and 3-IAA m/z 176^103.

PK profiles were quantified from 16 subjects that received various doses of 0-180 mg of harmine glucuronate together with various doses of 0-120 mg DMT formulated in TIP as part of the previously described study. As explained above, the ODTs were administered sublingually in 3 fixed dosing intervals every 20 minutes on empty stomach (last meal > 10 hours; last drink > 90 mins) under the supervision of an experimenter. On all study days, blood samples were taken from the left antecubital vein on 15 timepoints i.e. at baseline, and 0, 20, 40, 60, 70, 85, 100, 120, 150, 180, 240, 300, 420, 540, 1440 min after administration for analysis of DMT and harmine concentrations in plasma. The venous catheter was connected to Heidelberger plastic tube extensions, to collect blood samples without disturbing the subjects during their psychedelic experience. The intravenous line was kept patent with a slow drip (10 ml/h) of heparinized saline (1000 III heparin in 0.9 g NaCI/dL; HEPARIN Bichsel; Bichsel AG, 3800 Unterseen, Switzerland). Blood samples were immediately centrifuged for 10 minutes at 2000 RCF and plasma samples were kept frozen at -80 °C until assay. The quantification of DMT and harmine in blood plasma was performed according to the methods described in the previous paragraph.

Analysis approach: Data presented in Fig. 1 are pharmacokinetic parameters extracted from the blood plasma concentration data. ‘Cmax’ was calculated here as the maximum recorded blood plasma concentration for the specified drug (i.e., DMT or harmine) for each subject across all samples recorded during a study day. The area under the curve (‘AUG’) was calculated here using the trapezoid method as a numerical approximation of the integral of the drug concentration-time curve - i.e., the drug exposure over time. To demonstrate the modulation of DMT blood plasma concentrations over time by harmine, Cmax and AUG values were plotted separately for subjects either administered escalating doses of DMT with a fixed dose of harmine (120mg) across study days or administered escalating doses of harmine with a fixed dose of DMT (90mg) across study days.

The ‘Efficacy Index’ data presented in Fig. 2 is the unweighted average of four endpoints or endpoint dimensions: The total score from the Emotional Breakthrough Index (EBI), the total score from the Psychological Insight Scale (PIS-6), and the Oceanic Boundlessness and the Insightfulness dimensions from the Altered States of Consciousness Rating Scale (5D/11 D-ASC). This combination of endpoints and dimensions was selected to capture what is contemporarily understood to be the most therapeutically relevant elements of a pharmaceutically mediated altered state of consciousness. Fig.2 was designed to demonstrate how this measure of efficacy changes with increasing cumulative dose load, and to more accurately reflect the evidence for an optimal balance between these two features, i.e., 90 mg DMT and 120 mg harmine compared to higher or lower cumulative dose load regimes. This highlights the balance between ensuring high efficacy and the lowest possible cumulative dose load. It is also important to consider this balance with respect to subjects’ reported tolerability and agreeableness for a given cumulative dose load, and therefore Fig. 2 also presents data for ‘Positive Mood Rating’. This metric is a dimension of the Mystical Experiences Questionnaire (MEQ), which is itself an instrument understood to be potentially predictive of positive therapeutic outcomes. To demonstrate the optimal level of subjective acute effects for achieving high efficacy, it was necessary to visualize the relationship between the maximum subjective drug effect intensity ('Max Intensity'), efficacy, and how these are modulated by cumulative dose load. By plotting the distribution of Max Intensity for each dose regime, it would be clear that higher intensity ratings would become more frequent across subjects. However, only by contrasting low efficacy (<60% Efficacy Index) and high efficacy (>= 60% Efficacy Index) can it be clearly demonstrated that high cumulative dose load and the accompanying higher intensity ratings do not guarantee higher efficacy. In fact, Fig. 3 demonstrates that the 90mg DMT and 120mg harmine dose regime can more often achieve significant intensity ratings which also correspond to high efficacy outcomes. However, higher cumulative dose load regimes continue to increase the frequency of high intensity ratings, although the majority are low efficacy outcomes. This demonstrates that there is an optimal dose range which can achieve significant subjective effects with optimal therapeutic efficacy outcomes, while further increasing cumulative dose load leads to higher intensity of subjective effects with comparably lower therapeutic efficacy.

It is demonstrated in Fig. 4 that dose regimes differ in the duration of subjective drug effects. As part of the optimisation process, it is also relevant to consider the influence of cumulative dose load on the duration of subjective drug effects. As demonstrated in Fig. 2, the higher cumulative dose load regimes tend to achieve the highest efficacy outcomes. However, Fig. 4 highlights the finding that acute subjective effect duration is generally increased also. Importantly, the 90mg DMT and 120mg harmine dose regime is able to achieve comparable efficacy to the 90mg DMT and 180mg harmine dose regime while inducing a significantly shorter effect duration. This surprising finding is also a key element of the optimisation process for dose regime identification. From the perspective of developing cost-effective and scalable psychedelic assisted therapy applications, achieving sufficiently high efficacy with a reduced subjective effect duration is highly desirable. Implemented in this way, ensuring that the acute effects within a therapeutic session persist for a sufficient duration, while not being longer than necessary in duration to reach targeted efficacy, is valuable to developing this method at scale. It has been further found that starting intensity value of ~7.3 seen for the harmine/DMT ratio of 2 and the starting intensity value of ~6.0 seen for the harmine/DMT ratio of 1.33, as presented in Figure 4 (part 1), are surprisingly similar, as the skilled person would rather expect this starting intensity value to be significantly higher for the ratio of harmine to DMT of 2. Importantly, as it further can be seen from part 2 of Figure 4, presenting the same data as part 1 , but normalized with respect to maximum intensity, the ratio of harmine to DMT of 2 clearly produces higher intensity over time compared to the ratio harmine/DMT of 1.33, despite normalization with respect to intensity. Accordingly, this data further support the fact that the effect of achieving reduced subjective effect duration while maintaining high intensity is achieved for the ratio of harmine/DMT of 1 .33, compared to the ratio of harmine/DMT of 2.

It is demonstrated in Fig. 5 how dose regimes differ in their frequency and severity of adverse events. In the days following a dose administration day, subjects were invited to report any health-related events and to rate these events regarding their severity and likelihood of being related to their participation in previous study days. The table in Fig. 5 was populated by aligning the adverse events reports from subjects with the corresponding previous drug dose regime. Adverse events were excluded from this table where subjects reported the drug-relatedness of their adverse event as either ‘not related’ or ‘unlikely related’; this measure is vital in ensuring that only relevant adverse events are used to compare dose regimes. It is a notable surprise to demonstrate a ratio of 1.33 is associated with the fewest number of adverse events, as regimes of a lower cumulative dose load were expected to achieve the fewest adverse events. This finding indicates that a ratio of 1.33 has the best tolerability profile of the ratios reported.

In conclusion, an optimized dosing regimen involving a novel pharmaceutical composition comprising a combination of sublingual DMT and harmine in TIP (carrier particles) is provided. It has been found that a harmine/DMT w/w ratio of 1.33 enhances the pharmacokinetic parameters and therapeutic efficacy while optimizing treatment duration and adverse effects. Surprisingly, this optimized ratio allows for high efficacy with a lower total dose load of the active ingredients. This invention addresses some of the limitations of administering traditional botanical ayahuasca or oral pharmahuasca in a clinical or therapeutic setting, offering a novel approach with improved pharmacokinetic performance and precise standardized dosing to maximize efficacy and improve safety/tolerability.

Figure 7 further discusses the values of Coefficient of Variation (CV%) which is indicative of inter-subject variability in the studies conducted at different dose conditions. The lower value of CV% indicates lower, and hence more favorable, inter-subject variability. CV% values were calculated from pharmacokinetic parameters derived from blood plasma concentration data. Cmax was determined as the maximum observed plasma concentration, while AUG was computed using a 'linearup-logdown' method combining linear and logarithmic trapezoidal rules for ascending and descending portions of the concentration-time curve, respectively. Total API dose is calculated as the sum of DMT and harmine dose values in mg. For each dose condition, CV% was computed separately for both parameters to quantify inter-subject variability. The analysis specifically compared CV% values across different dose combinations of DMT and harmine to identify combinations yielding the highest consistency between individuals. This analytical approach revealed the unexpected finding that there exists a narrow window of total API dose where variability is lowest, corresponding to a harmine/DMT ratio of 1.2-1.4, with the 90mg DMT and 120mg harmine dose regime achieving the lowest CV% values for both Cmax and AUG. This finding indicates that, of the ratios reported, a harmine/DMT ratio of 1 .33 achieves the most reliable pharmacokinetic profile across individuals.

Claims

1 . A pharmaceutical composition comprising

(a) harmine or a pharmaceutically acceptable salt thereof; and

(b) N, /V-di methyltryptami ne or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, wherein the w/w ratio of harmine to /V,A/-dimethyltryptamine is from 1.2 to 1.4, wherein said w/w ratio of harmine to N, /V-dimethyltryptami ne is calculated with respect to harmine free base and N,N- dimethyltryptamine free base.

2. A kit of parts comprising

(b) N, /V-dimethyltryptamine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein the w/w ratio of harmine to /V,/V-dimethyltryptamine is from 1.2 to 1.4, wherein said w/w ratio of harmine to N, /V-dimethyltryptami ne is calculated with respect to harmine free base and N,N- dimethyltryptamine free base.

3. The kit of parts of claim 2, wherein (a) and (b) are to be administered simultaneously, separately or sequentially.

4. The pharmaceutical composition of claim 1 or the kit of parts of claim 2 or 3, wherein the w/w ratio of harmine to /V, /V-di methyltryptami ne is from 1 .30 to 1 .35.

5. The pharmaceutical composition of claim 1 or 4, or the kit of parts of any one of claims 2 to 4, wherein the w/w ratio of harmine to /V, A/-di methyltryptami ne is about 1 .33.

6. The pharmaceutical composition of claim 1 or 4, or the kit of parts of any one of claims 2 to 4, wherein the w/w ratio of harmine to /V, A/-di methyltryptami ne is 1 .33.

7. The pharmaceutical composition of any one of claims 1, or 4 to 6 or the kit of parts of any one of claims 2 to 6, wherein (a) further comprises uronic acid

8. The pharmaceutical composition of any one of claims 1, or 4 to 6 or the kit of parts of any one of claims 2 to 6, wherein (a) further comprises glucuronic acid or galacturonic acid.

9. he pharmaceutical composition of any one of claims 1 , or 4 to 6 or the kit of parts of any one of claims 2 to 6, wherein (a) further comprises glucuronic acid.

10. The pharmaceutical composition of any one of claims 1 or 4 to 9 or the kit of parts of any one of claims 2 to 9, wherein (b) comprises hemisuccinate salt of N,N-di methyltryptamine.

11 . The pharmaceutical composition of any one of claims 1 or 4 to 10 or the kit of parts of any one of claims 2 to 10, wherein said pharmaceutical composition or the part(s) of said kit of parts is/are formulated by using carrier particles with secondary internal structures.

12. The pharmaceutical composition of claim 11 or the kit of parts of claim 11 wherein the carrier particles with secondary internal structures are carrier particles with hollow internal structures.

13. The pharmaceutical composition of claim 11 or 12 or the kit of parts of claim 11 or 12, wherein said carrier particles comprise hydroxyapatite.

14. The pharmaceutical composition of any one of claims 11 to 13 or the kit of parts of any one of claims 11 to 13, wherein the carrier particle comprises a porous hydroxyapatite shell, at least one hollow cavity and calcium hydroxide.

15. The pharmaceutical composition of any one of claims 11 to 13 or the kit of parts of any one of claims 11 to 13, wherein the carrier particle comprises at least one hollow cavity.

16. The pharmaceutical composition of any one of claims 1 or 4 to 15, or the kit of parts of any one of claims 2 to 15, wherein said pharmaceutical composition or the parts of said kit of parts is/are formulated as orally disintegrating tablet.

17. The pharmaceutical composition of claim 16 or the kit of parts of claim 16, wherein the orally disintegrating tablet comprising (b) comprises between 80 and 100 mg /V,A/-dimethyltryptamine.

18. The pharmaceutical composition of claim 16 or the kit of parts of claim 16, wherein the orally disintegrating tablet comprising (b) comprises about 90 mg N,N-di methyltryptamine.

19. The pharmaceutical composition of claim 16 or the kit of parts of claim 16, wherein the orally disintegrating tablet comprising (a) comprises between 115 and 125 mg harmine.

20. The pharmaceutical composition of claim 16 or the kit of parts of claim 16, wherein the orally disintegrating tablet comprising (a) comprises about 120 mg harmine.

21. The pharmaceutical composition of any one of claims 1 or 4 to 20, formulated as orally disintegrating tablet, wherein the orally disintegrating tablet comprises 90 mg N,N- dimethytryptamine and 120 mg harmine, wherein the pharmaceutical composition is formulated by using carrier particles with secondary internal structures.

22. The kit of parts of any one of claims 2 to 20, wherein the parts of the kit of parts are formulated as orally disintegrating tablets, wherein the orally disintegrating tablet comprising (b) comprises 90 mg /V,A/-dimethytryptamine, the orally disintegrating tablet comprising (a) comprises 120 mg harmine, and wherein the parts of the kit of parts are formulated by using carrier particles with secondary internal structures.

23. The pharmaceutical composition of any one of claims 1 or 4 to 21 , or the kit of parts of any one of claims 2 to 20 or 22, for use as a medicament.

24. The pharmaceutical composition of any one of claims 1 or 4 to 21 , or the kit of parts of any one of claims 2 to 20 or 22, for use in the treatment and/or prevention of a psychiatric, psychosomatic or somatic disorder.

25. The pharmaceutical composition for use of claim 24 or the kit of parts for use of claim 24, for use in the treatment and/or prevention of a psychiatric disorder.

26. The pharmaceutical composition for use of claim 25, or the kit of parts for use of claim 25, wherein the psychiatric disorder is selected from depression, stress-related affective disorder, major depressive disorder, dysthymia, treatment-resistant depression, burnout, anxiety, post-traumatic stress disorder, addiction, eating disorder, and obsessive-compulsive disorder.

27. The pharmaceutical composition for use of any one of claims 24 to 26, or the kit of parts for use of any one of claims 24 to 26, wherein said composition or the parts of said kit of parts is/are to be administered sublingually.

28. The pharmaceutical composition for use of any one of claims 24 to 27, or the kit of parts for use of any one of claims 24 to 27, wherein the daily dose of N,N-di methyltryptamine is between 80 and 100 mg, preferably about 90 mg, more preferably 90 mg, and/or wherein the daily dose of harmine is between 115 and 125 mg, preferably about 120 mg, more preferably 120 mg.

29. Use of the pharmaceutical composition of any one of claims 1 or 4 to 21 or of the kit of parts of any one of claims 2 to 20 or 22 in the manufacture of a medicament for use in the treatment and/or prevention of a psychiatric, psychosomatic or somatic disorder.

30. The use of claim 29, wherein the treatment and/or prevention of a psychiatric, psychosomatic or somatic disorder is a treatment or prevention of a psychiatric disorder.

31. The use of claim 30, wherein the psychiatric disorder is selected from depression, stress-related affective disorder, major depressive disorder, dysthymia, treatment-resistant depression, burnout, anxiety, post-traumatic stress disorder, addiction, eating disorder, and obsessive-compulsive disorder.

32. The use of any one of claims 29 to 31 , wherein said composition or the parts of said kit of parts is/are to be administered sublingually.

33. The use of any one of claims 29 to 32, wherein the daily dose of /V,/V-dimethyltryptamine is between 80 and 100 mg, preferably about 90 mg, more preferably 90 mg, and/or wherein the daily dose of harmine is between 115 and 125 mg, preferably about 120 mg, more preferably 120 mg.

34. A method for treating a psychiatric, psychosomatic or somatic disorder, the method comprising the step of administering a therapeutically active amount of the pharmaceutical composition of claim 1 to an individual in need thereof.

35. The method of claim 34, wherein the psychiatric, psychosomatic or somatic disorder is a psychiatric disorder.

36. The method of claim 35, wherein the psychiatric disorder is selected from depression, stress- related affective disorder, major depressive disorder, dysthymia, treatment-resistant depression, burnout, anxiety, post-traumatic stress disorder, addiction, eating disorder, and obsessive- compulsive disorder.

37. The method of claim 34, wherein said composition is administered sublingually.

38. The method of claim 34, wherein the daily dose of N,N-di methyltryptamine is between 80 and 100 mg, preferably about 90 mg, more preferably 90 mg, and/or wherein the daily dose of harmine is between 115 and 125 mg, preferably about 120 mg, more preferably 120 mg.

39. A method for treating a psychiatric, psychosomatic or somatic disorder, the method comprising the step of administering a therapeutically active amount of or the parts of the kit of parts of claim 2 to an individual in need thereof.

40. The method of claim 39, wherein the psychiatric, psychosomatic or somatic disorder is a psychiatric disorder.

41. The method of claim 40, wherein the psychiatric disorder is selected from depression, stress- related affective disorder, major depressive disorder, dysthymia, treatment-resistant depression, burnout, anxiety, post-traumatic stress disorder, addiction, eating disorder, and obsessive- compulsive disorder.

42. The method of claim 39, wherein said parts of the kit of parts are administered sublingually.

43. The method of claim 39, wherein the daily dose of N,N-di methyltryptamine is between 80 and 100 mg, preferably about 90 mg, more preferably 90 mg, and/or wherein the daily dose of harmine is between 115 and 125 mg, preferably about 120 mg, more preferably 120 mg.