High Solubility Formulation of Halmin

Abstract

The present invention relates to a composition comprising harmine and (i) uronic acid or (ii) carboxylic acid and monosaccharide, a salt of harmine and uronic acid, a kit of parts comprising (a) the composition or salt of the present invention and a pharmaceutically acceptable carrier and (b) DMT or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and a pharmaceutical composition comprising the composition or salt of the present invention and a pharmaceutically acceptable carrier. The composition, salt, kit of parts, and pharmaceutical composition of the present invention are particularly useful in the treatment of mental disorders, psychosomatic disorders, or physical disorders.

Description

Technical Field

[0001] The present invention relates to a composition comprising harmine and (i) uronic acid or (ii) carboxylic acid and monosaccharide, a salt of harmine and uronic acid, a kit of parts comprising (a) the composition or salt of the present invention and a pharmaceutically acceptable carrier and (b) DMT or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and a pharmaceutical composition comprising the composition or salt of the present invention and a pharmaceutically acceptable carrier. The composition, salt, kit of parts, and pharmaceutical composition of the present invention are particularly useful in the treatment of mental disorders, psychosomatic disorders, or physical disorders.

Background Art

[0002] Affective spectrum disorders are widespread in society and are a major factor in the current economic burden in healthcare, reaching into the tens of billions of Swiss francs in Switzerland and dwarfing amounts globally. Along with the affective spectrum, the most common mood disorders include depression (major depressive disorder, dysthymia, bipolar depression, seasonal affective disorder, burnout syndrome, postpartum depression, premenstrual dysphoric disorder) and bipolar disorder (characterized by periods of depression and hypomania / mania). Despite the high prevalence, most available treatments show suboptimal effectiveness and are currently prescribed through a long-term trial-and-error approach over weeks or months to confirm clinical benefit. Less than 50% of all patients with depression show complete remission with optimized standard treatment, including numerous drug therapy trials. Therefore, there is an urgent need for new mental health therapies with more rapid and sustained therapeutic effects.

[0003] In recent years, new classes of fast-acting antidepressant-like compounds such as ketamine, psilocybin, and LSD have been discovered for alleviating the symptoms of anxiety and depression. Repeated administration of ketamine has been shown to sustain the antidepressant effect, but it poses a risk to patients due to the potential for addiction. Furthermore, compounds such as LSD have a long duration of action (10-12 hours), which is a major problem for clinical use. Additionally, both LSD and psilocybin exhibit rapid tolerance at serotoninergic receptors (Nichols 2016), making them less suitable for repeated dosing regimens.

[0004] In contrast, traditional indigenous plant preparations commonly made from Banisteriopsis caapi, Psychotria viridis or Diplopterys cabrerana, known as ayahuasca and as a hallucinogenic drug, are increasingly recognized as having beneficial effects on physical and mental health and are promising candidates for therapeutic use (Dominguez-Clave et al. 2016). Here, a hallucinogenic drug refers to an agent that can cause an altered state of consciousness in the subject using it. An altered state of consciousness refers to any state different from the normal waking state and includes, but is not limited to, experiencing alterations in cognition or perception (e.g., hallucinations), emotions, or daydreaming. Ayahuasca has been suggested to show favorable effects in patients with psychological, physical, and psychosomatic illnesses and has been used as a natural therapy in the Latin American region for centuries (Frecska et al. 2016). In small-scale pilot studies, ayahuasca has shown rapid and more sustained antidepressant properties in depressed patients compared to the transient antidepressant effect of ketamine (Sanacora et al. 2016) in which a significant number of patients relapse within 7 days after treatment (Osorio et al. 2015; Palhano-Fontes et al. 2018; Santos et al. 2016). Although the mechanism of such action is not known, a hypothesis has been proposed that the potential therapeutic effect of ayahuasca is due to its ability to reset the neural circuits underlying maladaptive neurobehavioral states.

[0005] The ayahuasca preparation contains a mixture of N,N-dimethyltryptamine (DMT) and β-carbolines (e.g., harmine, harmaline, tetrahydroharmine in particular). Ayahuasca is a) non-toxic, b) has a low potential for abuse, c) does not produce tolerance, and d) shows promise as an antidepressant (Dominguez-Clave et al. 2016; Barbosa et al. 2012). To make DMT biologically available, oral formulations usually contain a plant-based source of DMT (e.g., from Psychotria viridis) in combination with a β-carboline (e.g., from Banisteriopsis caapi) that acts as a selective reversible monoamine oxidase A (MAO-A) inhibitor to prevent the breakdown of DMT in the body (Callaway et al. 1996). DMT is a structural analog of serotonin and is widely found in nature, including in plants, mammalian organisms, and the human brain and body fluids (Barker 2018).

[0006] Although ayahuasca ingestion is considered safe (Barbosa et al. 2012), its clinical utility is compromised because it causes many undesirable side effects (e.g., nausea, vomiting, diarrhea, hallucinations). Most of these side effects may be due to suboptimal pharmacokinetic / pharmacodynamic properties resulting from the random mixing of plant materials (with unknown or harmful toxicities) and variations in alkaloid content, so it cannot be used as a standardized prescription drug in a clinical setting. Furthermore, when ayahuasca is administered orally, DMT is readily absorbed into the bloodstream, which can cause rapid changes in the consumer's perception and painful side effects (Riba et al. 2003).

[0007] An alternative to ayahuasca that solves the above-mentioned side effect problem is pharmahuasca, also known as synthetic ayahuasca. According to the disclosure of German Patent Application Publication No. 102016014603 A1 (Patent Document 1), the term pharmahuasca or synthetic ayahuasca consists 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-β-carboline, harmol, harmalol, tetrahydroharmol, and their natural and unnatural stereoisomers and racemates, and is available in solid, liquid, or semi-solid form, with at least one of the active ingredients selected from the group of β-carbolines consisting of harmine, harminol, and tetrahydroharmine, and their stereoisomers and racemates, and at least one of the active substances 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, related to a combination, composition, mixture, and preparation containing at least two members of the group of active ingredients that are naturally present in and isolable from Banisteriopsis caapi, Psychotria viridis, and / or Diplopterys cabrerana. The active ingredients can be independently, wholly or partially, - individually and in mixtures, together and in several dosage forms, contained in the form of a base bound to an ion exchanger or another matrix or its natural and synthetic salts (where applicable) or as an N-oxide, can exist as complexes and inclusion compounds, can be synthesized and / or obtained from any natural plant material by extraction - and the total concentration of the active ingredients is at least 0.0001%. Since plant mixtures with unknown toxicity that are known to cause undesirable side effects (e.g., vomiting, nausea, diarrhea) are excluded, the hypothesis has been put forward that oral pharmahuasca is more tolerable than traditional ayahuasca.According to Wikipedia (https: / / en.wikipedia.org / wiki / Pharmahuasca), the recommended dosage of pharmahuasca per person is usually 50 mg of DMT and 100 mg of harmaline. However, a combination of 50 mg of harmaline, 50 mg of harmine, and 50 mg of DMT has been tested and proven successful. The components are placed in separate gelatin capsules. First, swallow the capsule containing harmaline / harmine, and then take the capsule containing DMT 15 - 20 minutes later.

[0008] To date, the limiting factor in the pharmaceutical application of pharmahuasca is the inability to obtain a formulation or salt of harmine with high bioavailability suitable for administration to patients who need it. In particular, the poor and highly non-uniform gastrointestinal absorption of harmine is due to its low solubility in water and its tendency to easily crystallize and become completely insoluble, and thus non-absorbable and needle-shaped, under various gastrointestinal conditions (e.g., the sharp increase in pH when harmine migrates from the acidic stomach to a more basic environment (duodenum, ileum, etc.)). It has been found that the overall pharmacokinetic performance can be dramatically improved by avoiding the gastrointestinal route, for example, by delivering harmine via the buccal / sublingual route. As is known to those skilled in the art, for the manufacture of sublingual, buccal, or oral mucosal dosage forms (e.g., orally disintegrating tablets / films, sublingual drops / sprays), the compound must exhibit high solubility in order to carry a sufficient amount of the compound in a single dosage unit (spray / drop: maximum 1 mL / dose; ODT: maximum 0.5 mL / dose). The same applies to the pharmaceutical application of harmine alone, which has been limited by the limited solubility of harmine and its salts until now.

[0009] Thus, to date, the limiting factor in the pharmaceutical application of pharmahuasca is the inability to obtain a formulation or salt of harmine with high bioavailability suitable for administration to patients who need it.

[0010] International Publication No. 2021 / 259962 (Patent Document 2) discloses specific compositions and kits containing harmine and DMT for treating mental disorders.

[0011] U.S. Patent Application Publication No. 2021 / 401786 (Patent Document 3) discloses a specific composition for treating burns, which contains carboxylic acids (such as palmitic acid, stearic acid, oleic acid), harmine, fructose, and glucose. The literature Marx Sebastien et al ("Design and synthesis of a new soluble natural [beta]-carboline derivative for preclinical study by intravenous injection", International Journal of Molecular Sciences, DOI 10.3390 / ijms20061491) (Non-Patent Document 1) discloses harmine derivatives developed for the purpose of obtaining improved solubility and good biological activity.

Prior Art Documents

Patent Documents

[0012]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Documents

[0013]

Non-Patent Document 1

Summary of the Invention

[0014] The technical problem to be solved by the present invention was to provide a formulation of harmine characterized by improved solubility. This technical problem to be solved is solved by the embodiments disclosed herein and characterized in the claims.

[0015] The inventors have surprisingly found that a composition comprising harmine (or a pharmaceutically acceptable salt thereof) and (i) uronic acid or (ii) carboxylic acid and monosaccharide has significantly improved solubility (see, for example, Tables 12 and 14) compared to prior art harmine formulations containing free harmine base or harmine hydrochloride. The composition shows better bioavailability and less variability between subjects compared to prior art compositions.

[0016] The present invention is summarized in the following embodiments.

[0017] In a first embodiment, the present invention relates to a composition comprising harmine or a pharmaceutically acceptable salt thereof and (i) uronic acid or (ii) carboxylic acid and monosaccharide.

[0018] In a second embodiment, the present invention relates to a salt of harmine and uronic acid.

[0019] In the third embodiment, the present invention relates to a kit of parts comprising (a) the composition of the present invention or a salt of the present invention and a pharmaceutically acceptable carrier, and (b) DMT or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0020] In the fourth embodiment, the present invention relates to a pharmaceutical composition comprising (a) the composition of the present invention or a salt of the present invention and a pharmaceutically acceptable carrier.

[0021] In the fifth embodiment, the present invention relates to a pharmaceutical composition comprising (a) the composition of the present invention or a salt of the present invention and (b) DMT or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0022] In the sixth embodiment, the present invention relates to the composition of the present invention, the salt of the present invention, the kit of parts of the present invention, or the pharmaceutical composition of the present invention for use as a medicament.

[0023] In the seventh embodiment, the present invention relates to the composition of the present invention, the salt of the present invention, the kit of parts of the present invention, or the pharmaceutical composition of the present invention for use in the treatment and / or prevention of mental disorders, psychosomatic disorders, or physical disorders.

[0024] In the eighth embodiment, the present invention relates to DMT hemisuccinate.

[0025] In the ninth embodiment, the present invention is 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, and the method comprises loading the bitterness-bearing compound onto carrier particles, a) the carrier particles contain loading cavities and the carrier particles contain a basic salt, and b) the bitterness of the compound is masked by the carrier particles during oral mucosal absorption.

[0026] In the tenth embodiment, the present invention relates to a pharmaceutical composition comprising carrier particles, comprising: a) carrier particles comprising a loading cavity and a basic salt; and b) a compound having bitterness, wherein the compound is harmine or a pharmaceutically acceptable salt thereof, or DMT or a pharmaceutically acceptable salt thereof, and the bitterness of the compound is masked by the carrier particles during oral mucosal absorption.

Brief Description of Drawings

[0027]

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Mode for Carrying Out the Invention

[0028] The present invention will be described in detail below. It is understood that all of the features listed below can be combined as long as there is no express contrary indication.

[0029] In one embodiment, the present invention relates to a composition comprising harmine or a pharmaceutically acceptable salt thereof, and (i) uronic acid or (ii) carboxylic acid and monosaccharide.

[0030] Harmine has the formula:

[0031]

Chemical formula

[0032] and is the compound of.

[0033] The compound represented by the above formula may also be called harmine free base or harmine FB. Harmine (7-methoxy-1-methyl-9H-pyrido[3,4-b]-indole) is also known as banisterine or telepathine, and is an alkaloid present in many different plants including Peganum harmala or Banisteriopsis caapi. It belongs to the group of β-carbolines. Harmine reversibly inhibits monoamine oxidase A (MAO-A), but does not inhibit monoamine oxidase B (MAO-B).

[0034] In the compositions, pharmaceutical compositions, kits of parts, and methods of the present invention, harmine is mainly used as a selective reversible inhibitor of MAO-A. Other nervous system effects include an increase in the level of brain-derived neurotrophic factor (BDNF) protein in addition to analgesic and anti-nociceptive effects. The components of ayahuasca have further been shown to stimulate the proliferation of nerve cells, prevent nerve damage, and improve cell survival. In addition to these neuroprotective effects, harmine and other β-carbolines can increase dopamine levels in the CNS and may thus be effective in alleviating the symptoms of parkinsonism. Other pharmacological activities of harmine include anti-inflammatory activity, anti-diabetic activity, and anti-tumor activity. Specifically, anti-microbial (anti-protozoal, antibacterial, insecticidal, and anti-fungal) activity has been reported for β-carbolines derived from P. harmala. Various other studies have shown anti-malignant tumor, anti-proliferative, anti-oxidant, and immunomodulatory (anti-inflammatory) effects of harmala alkaloids. Furthermore, in addition to anti-angiogenic inhibition and anti-platelet aggregation effects, cardiovascular effects such as vasorelaxant effects, antihypertensive effects, and negative inotropic effects have been reported (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).

[0035] Some of the structural analogs of harmine include harmaline, tetrahydroharmine, harmol, harmalol, tetrahydroharmol, and 2-methyl-1,2,3,4-tetrahydro-β-carboline. It should be noted that all of the harmine analogs listed herein are MAO-A inhibitors. Thus, it is further contemplated that harmaline, tetrahydroharmine, harmol, harmalol, tetrahydroharmol, and 2-methyl-1,2,3,4-tetrahydro-β-carboline may be used in the compositions, pharmaceutical compositions, kits of parts, and / or methods of the present invention. Thus, harmaline, tetrahydroharmine, harmol, harmalol, tetrahydroharmol, and 2-methyl-1,2,3,4-tetrahydro-β-carboline are also expected to benefit from the approaches described herein to increase the solubility and / or bioavailability of their formulations.

[0036] Pharmaceutically acceptable salts of the compounds discussed herein (particularly harmine or DMT) can be formed, for example, by protonation with an inorganic or organic acid of an atom having an easily protonatable lone pair such as an amino group or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts include, for example, alkali metal salts such as sodium salts or potassium salts; alkaline earth metal salts such as calcium salts 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; aralkylamine 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, etc.Exemplary acid addition salts include, for example, mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate (e.g., sulfate or bisulfate, etc.), nitrate, phosphate (e.g., phosphate, hydrogen phosphate, or dihydrogen phosphate, etc.), carbonate, bicarbonate, perchlorate, borate, or thiocyanate, etc.; 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), camphorsulfonate, or pivalate, etc.; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate, etc.; glycerophosphate; and acidic amino acid salts such as aspartate or glutamate, etc. Preferred pharmaceutically acceptable salts of harmine include hydrochloride, hydrobromide, mesylate, sulfate, tartrate, fumarate, acetate, citrate, and phosphate. A particularly preferred pharmaceutically acceptable salt of harmine is hydrochloride.

[0037] Preferably, harmine or its pharmaceutically acceptable salt is the harmine free base. Thus, preferably, the present invention relates to a composition comprising harmine and (i) uronic acid or (ii) a carboxylic acid and a monosaccharide.

[0038] The compounds or their pharmaceutically acceptable salts referred to herein may exist as their hydrates or solvates. Accordingly, solvates, hydrates, and anhydrous forms of the salts are also encompassed by the present invention. The solvent contained in the solvate is not particularly limited and may be any pharmaceutically acceptable solvent. Examples include water and C , ,

[0037] ,

[0038] , , 1~4 , Examples include alcohol (such as methanol or ethanol).

[0039] However, in one embodiment of the present invention, it is understood that the composition may contain a pharmaceutically acceptable salt of harmine, such as harmine hydrochloride.

[0040] The composition of the present invention may (i) contain uronic acid. Preferably, uronic acid (which may also be called alduronic acid) is understood herein as a sugar acid containing both a carbonyl group (i.e., -CHO group or -CO- group, preferably when present in a linear form) and a carboxylic acid functional group (i.e., -COOH group). One exemplary uronic acid is glucuronic acid, which can be obtained from glucose when the terminal hydroxyl group of glucose is oxidized. Glucuronic acid can be represented using the following Fischer projection:

[0041]

Chemical formula

[0042] As will be apparent to those skilled in the art, such sugars may further exist in a cyclic form, for example,

[0043]

Chemical formula

[0044] and may have.

[0045] Uronic acids derived from hexoses (i.e., monosaccharides characterized by the presence of 6 carbon atoms) may sometimes be called hexuronic acids. Uronic acids derived from pentoses (i.e., monosaccharides characterized by the presence of 5 carbon atoms) may sometimes be called penturonic acids. Monosaccharides are preferably as defined below in this specification.

[0046] Therefore, preferably, in the composition of the present invention, the uronic acid is penturonic acid or hexuronic acid. More preferably, in the composition of the present invention, the uronic acid is hexuronic acid. Even more preferably, in the composition of the present invention, the uronic acid is glucuronic acid or galacturonic acid. Even more preferably, the uronic acid is glucuronic acid.

[0047] Furthermore, a composition of the present invention in which the uronic acid is substituted with aldonic acid or aldaluronic acid is disclosed.

[0048] Furthermore, embodiments in which the above uronic acid exists as the above pharmaceutically acceptable salt are also included in the present invention. However, preferably, the uronic acid exists as a free acid.

[0049] Preferably, the composition of the present invention (i) contains uronic acid.

[0050] Preferably, the composition of the present invention contains harmine and uronic acid, and preferably, the composition contains a salt of harmine and uronic acid. Uron is as defined above.

[0051] The composition of the present invention may (ii) contain a carboxylic acid and a monosaccharide. Preferably, the carboxylic acid and the monosaccharide are preferably present in a molar ratio of 0.5 to 2.0, more preferably in a molar ratio of about 1:1.

[0052] The carboxylic acid is preferably of the formula R-COOH (wherein R is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, and C 3~6 cycloalkyl, and the alkyl, the alkenyl, the alkynyl, and the cycloalkyl are each optionally Hal, -OH, -CN, -O-(C 1~6 alkyl), -SH, -S(C 1~6 alkyl), -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl)(C 1~6 alkyl), -CO(C 1~6(alkyl), -COOH, -COO(C 1~6 (alkyl), -CONH2, -CONH(C 1~6 (alkyl), and -CON(C 1~6 (alkyl)(C 1~6 (alkyl) selected from, preferably selected from -OH, -CN, -SH, -NH2, -COOH, and -CONH2, more preferably selected from -OH, -NH2, -COOH, and -CONH2, and even more preferably substituted with one or more arbitrary substituents selected from -OH and -COOH). One or less arbitrary substituents are -CO(C 1~6 (alkyl), -COOH, -COO(C 1~6 (alkyl), -CONH2, -CONH(C 1~6 (alkyl), and -CON(C 1~6 (alkyl)(C 1~6 (alkyl) is even more preferably selected from.

[0053] As used herein, the term "alkyl" refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group that may be straight-chain or branched. Thus, an "alkyl" group does not contain any carbon-carbon double bonds or any carbon-carbon triple bonds. "C 1~5 (alkyl)" means an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless otherwise defined, the term "alkyl" preferably refers to C 1~4 (alkyl), more preferably methyl or ethyl, and even more preferably methyl.

[0054] As used herein, the term "alkenyl" refers to a monovalent unsaturated acyclic hydrocarbon group that may be straight-chain or branched and contains one or more (e.g., one or two) carbon-carbon double bonds but does not contain any carbon-carbon triple bonds. The term "C 2~5"Alkenyl" means an alkenyl group having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1,3-dien-yl or buta-1,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless otherwise defined, the term "alkenyl" preferably refers to C 2~4 alkenyl.

[0055] As used herein, the term "alkynyl" may be straight-chain or branched, and refers to a monovalent unsaturated acyclic hydrocarbon group containing one or more (e.g., one or two) carbon-carbon triple bonds and optionally one or more (e.g., one or two) carbon-carbon double bonds. The term "C 2~5 alkynyl" means an alkynyl group having 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl. Unless otherwise defined, the term "alkynyl" preferably refers to C 2~4 alkynyl.

[0056] As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon ring group including, in addition to monocyclic rings, bridged rings, spiro rings, and / or fused ring systems (e.g., which may be composed of two or three rings; e.g., a fused ring system composed of two or three fused rings). "Cycloalkyl" may refer to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless otherwise defined, "cycloalkyl" preferably refers to C 3~11 cycloalkyl, more preferably C 3~7 cycloalkyl. Particularly preferred "cycloalkyl" is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropyl or cyclohexyl).

[0057] As used herein, the term "Hal" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I).

[0058] Preferably, R is selected from C 1~6 alkyl and C 2~6 alkenyl, and the alkyl or the alkenyl is each optionally Hal, -OH, -CN, -O-(C 1~6 alkyl), -SH, -S(C 1~6 alkyl), -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl)(C 1~6 alkyl), -CO(C 1~6 alkyl), -COOH, -COO(C 1~6 alkyl), -CONH2, -CONH(C 1~6 alkyl), and -CON(C 1~6 alkyl)(C 1~6 alkyl), preferably selected from -OH, -CN, -SH, -NH2, -COOH, and -CONH2, more preferably selected from -OH, -NH2, -COOH, and -CONH2, still more preferably selected from -OH and -COOH, and may be substituted with one or more optional substituents. It is more preferable that one or less optional substituents are selected from -CO(C 1~6 alkyl), -COOH, -COO(C 1~6 alkyl), -CONH2, -CONH(C 1~6 alkyl), and -CON(C 1~6 alkyl)(C 1~6 alkyl).

[0059] Preferably, the carboxylic acid is selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, glycolic acid, lactic acid, citric acid, 2-hydroxypropionic acid, 3-hydroxypropionic acid, 3-hydroxybutyric acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, tartaric acid, malic acid, maleic acid, fumaric acid, and glutaton acid.

[0060] More preferably, the carboxylic acid is selected from acetic acid, propionic acid, butyric acid, lactic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, malic acid, maleic acid, and fumaric acid.

[0061] Even more preferably, the carboxylic acid is selected from acetic acid, propionic acid, lactic acid, and malic acid.

[0062] Even more preferably, the carboxylic acid is malic acid or acetic acid.

[0063] In one embodiment, the carboxylic acid is an amino acid, and thus, the formula R-COOH (wherein R is substituted with -NH2 at the carbon atom adjacent to the COOH group of the R-COOH and may further be optionally substituted with one arbitrary substituent selected from -OH, -NH2, -COOH, and -CONH2) is a C 1~6 alkyl. Preferably, the carboxylic acid is an L-natural amino acid as known to those skilled in the art.

[0064] Therefore, when the carboxylic acid is an amino acid, the carboxylic acid is preferably selected from glutamic acid and aspartic acid.

[0065] Furthermore, embodiments in which the carboxylic acid mentioned above exists as a pharmaceutically acceptable salt are also included in the present invention. However, preferably, the carboxylic acid exists as a free acid.

[0066] A monosaccharide is preferably defined as a simple sugar having a linear and unbranched carbon skeleton with one carbonyl functional group and one hydroxyl functional group on each of the remaining carbon atoms. In the case of a specific carbon atom, the hydroxy group may not be present. Therefore, a monosaccharide has the formula H-(CHX) n -(C=O)-(CHX) m -H, (wherein, n + m + 1 is preferably selected from 3, 4, 5, 6, and 7, each X is independently H or -OH, provided that at least two examples of X are OH, and two or less examples of X are H, preferably one or less examples of X are H, more preferably each X is -OH) is a compound of

[0067] Preferably, the monosaccharide is a hexose or a pentose. The hexose is a monosaccharide as defined herein with n + m + 1 = 6 and preferably each example of X being -OH. The pentose is a monosaccharide as defined herein with n + m + 1 = 5 and preferably each example of X being -OH).

[0068] More preferably, the monosaccharide is a hexose.

[0069] Even more preferably, the monosaccharide is glucose or fructose.

[0070] Therefore, preferably, in the composition of the present invention, the carboxylic acid is malic acid or acetic acid, and / or the monosaccharide is glucose or fructose.

[0071] In one embodiment of the present invention, the composition of the present invention comprises (ii) a carboxylic acid and a monosaccharide. Preferably, the carboxylic acid and the monosaccharide are present in a molar ratio of preferably 0.5 to 2.0, more preferably in a molar ratio of about 1:1.

[0072] Preferably, in the composition of the present invention, the halmine and the uronic acid of (i) or the halmine and the carboxylic acid of (ii) are present in a molar ratio of 0.5 to 2.0, preferably in a molar ratio of about 1:1. Therefore, when the composition of the present invention contains halmine and (i) uronic acid, the halmine and the uronic acid are present in a molar ratio of 0.5 to 2.0, preferably in a molar ratio of about 1:1. Further, therefore, when the composition of the present invention contains halmine and (ii) carboxylic acid and monosaccharide, the halmine and the carboxylic acid of (ii) are present in a molar ratio of 0.5 to 2.0, preferably in a molar ratio of about 1:1.

[0073] Preferably, the composition of the present invention is an amorphous composition. Thus, as referred to herein, an amorphous composition is a composition having no detectable crystal structure. The inventors have inferred that due to the inability of the components of the composition, such as harmine and uronic acid or harmine and carboxylic acid and monosaccharide, to form a detectable crystal structure, the solubility of the composition and accordingly the solubility of harmine are significantly improved compared to the compositions of the prior art.

[0074] The composition of the present invention may include a natural deep eutectic solvent or a co-amorphous system as defined above. The use of natural deep eutectic solvents to improve the bioavailability of therapeutic compounds (Molecules, 2016 Nov 14;21(11):1531.doi:10.3390 / molecules21111531) and co-amorphous systems with improved solubility (Crystal Growth & Design 2021 21 (6),3280-3289,DOI:10.1021 / acs.cgd.1c00015) have been recently reported.

[0075] In one embodiment, the present invention relates to salts of harmine and uronic acid. It is understood that the salts of harmine and uronic acid preferably feature a 1:1 stoichiometry. Preferred salts of harmine and uronic acid are harmine glucuronate and harmine galacturonate.

[0076] In a further embodiment, the present invention relates to a pharmaceutical composition comprising (a) the composition of the present invention or a salt of the present invention and (b) a pharmaceutically acceptable carrier. Here, a composition or salt containing harmine is referred to.

[0077] In a further embodiment, the present invention relates to a pharmaceutical composition comprising (a) the composition of the present invention or a salt of the present invention (comprising harmine) and (b) DMT or a pharmaceutically acceptable salt thereof and (c) a pharmaceutically acceptable carrier.

[0078] As referred to herein, DMT has the formula:

[0079] [Chemical]

[0080] is a compound of.

[0081] Thus, DMT (N,N-dimethyltryptamine) is a hallucinogenic substance that is a structural analog of serotonin and melatonin. DMT is also a structural and functional analog of other hallucinogenic substances including bufotenin (5-hydroxy-N,N-dimethyltryptamine), psilocybin (the phosphate ester of 4-hydroxy-N,N-dimethyltryptamine), and psilocin (4-hydroxy-N,N-dimethyltryptamine). Further known analogs of DMT include mono-N-methyltryptamine. The analogs of DMT listed herein also exhibit activity as hallucinogens. Furthermore, all of the analogs of DMT listed herein are monoamines and are thus potential substrates for MAO-A monoamine oxidase. Accordingly, it is further contemplated that psilocybin, psilocin, and mono-N-methyltryptamine may be used in the compositions, pharmaceutical compositions, kits of parts, and / or methods of the present invention in place of DMT. In particular, it is contemplated that psilocin or psilocybin may be used in the compositions, pharmaceutical compositions, kits of parts, and / or methods of the present invention in place of DMT. One of ordinary skill in the art would think that such pharmaceutical compositions, compositions, or kits of parts containing psilocin or psilocybin in place of DMT can be used to treat diseases treatable with the pharmaceutical compositions, compositions, or kits of parts of the present invention.

[0082] As referred to herein, the pharmaceutically acceptable salts of DMT are as defined above. Particularly preferred pharmaceutically acceptable salts of DMT are DMT hemifumarate or DMT hemisuccinate. Even more preferably, the pharmaceutically acceptable salt of DMT is DMT hemisuccinate.

[0083] Accordingly, the present invention relates to a salt of DMT, which is a DMT hemifumarate or a DMT hemisuccinate. It is particularly preferred that the salt of DMT is a DMT hemisuccinate. The inventors obtained an amount of DMT hemisuccinate sufficient for physicochemical property evaluation. The inventors further showed that crystallization of a specific crystal form of DMT hemisuccinate can occur in carrier particles, preferably template-inverted particles.

[0084] As understood herein, when referring to DMT or a pharmaceutically acceptable salt thereof, it is always understood as a narrow reference to DMT hemifumarate or DMT hemisuccinate, or more preferably DMT hemisuccinate. As understood herein and as will be apparent to those skilled in the art, in DMT hemisuccinate, there are two molecules of DMT per molecule of succinic acid. In other words, the stoichiometry of DMT with respect to succinic acid (the molar ratio of DMT to succinic acid) is 2:1. Similarly, as understood herein and as will be apparent to those skilled in the art, in DMT hemifumarate, there are two molecules of DMT per molecule of fumaric acid. In other words, the stoichiometry of DMT with respect to fumaric acid (the molar ratio of DMT to fumaric acid) is 2:1.

[0085] The present invention further provides DMT hemisuccinate in crystal form A and crystal form B. These crystal forms are as characterized below.

[0086] The polymorph of DMT hemisuccinate called crystalline form A is characterized by an X-ray powder diffraction pattern (Cu-Kα1) that includes a peak at approximately 16.14 ± 0.2°. Preferably, the X-ray powder diffraction pattern (Cu-Kα1) further includes one or more peaks selected from 13.50 ± 0.2°, 17.84 ± 0.2°, 19.67 ± 0.2°, 21.81 ± 0.2°, 23.19 ± 0.2°, and 25.36 ± 0.2°. More preferably, the X-ray powder diffraction pattern preferably includes at least 3, at least 4, at least 5, or all of the listed peaks. Further, the X-ray diffraction pattern (Cu-Kα1) further includes one or more peaks selected from 11.66 ± 0.2°, 12.31 ± 0.2°, 18.77 ± 0.2°, 19.38 ± 0.2°, 20.25 ± 0.2°, 21.81 ± 0.2°, 22.45 ± 0.2°, 23.57 ± 0.2°, 24.38 ± 0.2°, 25,79 ± 0.2°, 28.02 ± 0.2°, 29.79 ± 0.2°, and 30.82 ± 0.2°. Even more preferably, the X-ray powder diffraction pattern preferably includes at least 3, at least 4, at least 5, or all of the listed peaks. Additional peaks are as provided in the experimental section.

[0087] The polymorph of DMT hemisuccinate, called crystalline form B, is characterized by an X-ray powder diffraction pattern (Cu-Kα1) that includes a peak at approximately 15.57 ± 0.2°. Preferably, the X-ray powder diffraction pattern (Cu-Kα1) further includes one or more peaks selected from 10.09 ± 0.2°, 16.52 ± 0.2°, 16.82 ± 0.2°, 17.06 ± 0.2°, 19.34 ± 0.2°, 19.93 ± 0.2°, 21.13 ± 0.2°, 22.91 ± 0.2°, and 23.45 ± 0.2°. More preferably, the X-ray powder diffraction pattern preferably includes at least 3, at least 4, at least 5, or all of the listed peaks. Further, the X-ray diffraction pattern (Cu-Kα1) further includes one or more peaks selected from 21.38 ± 0.2°, 22.07 ± 0.2°, 23.81 ± 0.2°, 24.14 ± 0.2°, 28.60 ± 0.2°, and 28.74 ± 0.2°. Even more preferably, the X-ray powder diffraction pattern preferably includes at least 3, at least 4, at least 5, or all of the listed peaks. Additional peaks are as provided in the experimental section.

[0088] It is understood that all diffraction angles provided when discussing the X-ray powder diffraction pattern are given as 2θ.

[0089] The hemisuccinate salts of DMT, particularly its crystalline forms A and B, are particularly advantageous for use in drug applications because of the good water solubility of the salts. These crystalline forms can be obtained as described in the Examples chapter.

[0090] According to the present invention, in a pharmaceutical composition comprising (a) and (b), (a) and (b) are mixed together or packaged together, and thus are suitable for being administered together. It is known to those skilled in the art that the small molecule drug can be administered through oral administration route, parenteral administration route (including intravenous administration route, intramuscular administration route, and subcutaneous administration route), nasal (or intranasal) administration route, intraocular administration route, transmucosal administration route (buccal administration route, sublingual administration route, vaginal administration route, and rectal administration route), inhalation administration route, and transdermal administration route. Here, when (a) and (b) are included in one composition, they are usually formulated for the same administration route.

[0091] In a further embodiment, the present invention relates to a kit of parts comprising (a) the composition of the present invention or a salt of the present invention and a pharmaceutically acceptable carrier, and (b) DMT or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0092] In the present invention, a kit of parts refers to a combination of individual components (a) and (b) that are physically separated but held adjacent to each other. One skilled in the art will understand that the components (parts) of the kit may be combined before administration, the components (parts) may be administered simultaneously, or the components (parts) of the kit may be administered sequentially. In the case of sequential administration, the components (parts) of the kit are usually preferably administered within a time range of 15 minutes to 120 minutes in order to achieve the effects of the present invention. The components of the kit of parts can also be formulated for different administration routes. It is known to those skilled in the art that small molecule drugs can be administered through oral administration routes, parenteral administration routes (including intravenous administration routes, intramuscular administration routes, and subcutaneous administration routes), nasal (or intranasal) administration routes, intraocular administration routes, transmucosal administration routes (buccal administration routes, sublingual administration routes, vaginal administration routes, and rectal administration routes), transdermal administration routes, inhalation administration routes, and percutaneous administration routes. It should be noted that in this specification, the enteral administration route may refer to the oral administration route, the buccal administration route, and / or the sublingual administration route. Here, components (a) and (b) can be formulated for administration through any of these administration routes. It is understood that (a) and (b) can be formulated for administration using the same administration route, and it is further understood that (a) and (b) can be formulated for administration using different administration routes.

[0093] The dosage depends on the administration route, the severity of the disease, the age and weight of the subject, and other factors that a attending physician usually considers when determining the individual regimen and dosage level for a particular patient or subject. The parts or pharmaceutical compositions of the kit of parts of the present invention can be administered via any route including parenteral administration, intramuscular administration, subcutaneous administration, topical administration, transdermal administration, intranasal administration, intravenous administration, sublingual administration, or rectal administration.

[0094] Preferably, in the present invention, harmine and / or DMT are administered sublingually or buccally, and more preferably, harmine and / or DMT are administered sublingually. Even more preferably, when referring to harmine and / or DMT, it preferably means harmine and DMT.

[0095] The parts of the kit of parts of the present invention or the pharmaceutical composition of the present invention can be prepared by mixing suitably selected, pharmaceutically acceptable excipients, vehicles, adjuvants, additives, surfactants, drying agents, or diluents known to those skilled in the art, and can be suitably adapted for oral administration, transmucosal administration, parenteral administration, or topical administration. Typically and preferably, the kit of parts or pharmaceutical composition of the present invention is administered in the form of tablets, orally disintegrating tablets, mucoadhesive films, lyophilized agents, capsules, sachets, powders, granules, pellets, oral or parenteral liquids, suspensions, suppositories, ointments, creams, lotions, gels, pastes, and / or may contain liposomes, micelles, and / or microspheres.

[0096] The term "pharmaceutically acceptable" indicates that a compound or composition, typically and preferably a salt or carrier, when typically and preferably used in a formulation, or when typically and preferably used to treat an animal, preferably a human, must be chemically and toxicologically compatible with other component(s), typically and preferably components of the composition of the present invention or parts of the kit of parts of the present invention. Preferably, the term "pharmaceutically acceptable" indicates that a compound or composition, typically and preferably a salt or carrier, when typically and preferably used in a formulation, or when typically and preferably used to treat an animal, preferably a human, must be chemically and toxicologically compatible with other component(s), typically and preferably components of the composition of the present invention or parts of the kit of parts of the present invention. It should be noted that pharmaceutical compositions can be formulated by techniques known to those skilled in the art, for example, the techniques disclosed in "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, 22 nd edition.

[0097] The pharmaceutically acceptable carriers of parts (a) and (b) of the kit of parts of the present invention or of the pharmaceutical composition of the present invention are, but are not limited to, 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, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter. The pharmaceutically acceptable carriers of the present invention can be solid, semi-solid, or liquid.

[0098] According to the present invention, the compositions, salts, and parts of the kits of parts of the present invention can be formed by using carrier particles. The carrier particles are not particularly limited, and any carrier particles known to those skilled in the art can be used within the present invention.

[0099] As used herein, the term "carrier particle" refers to a substance that is non-toxic or substantially non-toxic to a subject and can be used to improve the desired drug delivery characteristics of a solid pharmaceutical composition. Carrier particles described herein have no or substantially no therapeutic effect upon administration to a subject unless they carry a therapeutic agent. In some embodiments, carrier particles described herein are pharmacologically inert unless they carry a therapeutic agent. In some embodiments, carrier particles described herein do not dissolve or substantially do not dissolve in water. Desired drug delivery characteristics of the solid pharmaceutical compositions described herein include, but are not limited to, efficacy, safety, pharmacokinetic properties (e.g., bioavailability), physical stability, chemical stability, drug loading capacity, and / or disintegration time. In some embodiments, the desired drug delivery characteristics of the solid pharmaceutical composition are physical stability, drug loading capacity, and disintegration time. In some embodiments, the desired drug delivery characteristics of the solid pharmaceutical composition are that the drug loading capacity of the solid pharmaceutical composition is high (e.g., v / v≧50%, ≧55%, ≧60%, ≧65%, ≧70%, ≧75%, ≧80%, preferably ≧60%, more preferably 60% - 85% drug loading capacity), the disintegration time of the solid pharmaceutical composition is short (e.g., ≦15s, ≦14s, ≦13s, ≦12s, ≦11s, ≦10s, preferably ≦10s), and / or physical stability (e.g., for an 11 mm tablet, ≧200N, ≧210N, ≧220N, ≧230N, ≧240N, or ≧250N, or for a 6 mm tablet, ≧40N, ≧50N, ≧60N, preferably a tablet hardness of ≧50N for a 6 mm tablet). Carrier particles as described herein can have any shape, and preferably, carrier particles described herein have a shape similar to spherical, spheroidal, and / or bead-like. Removal of the template material can result in at least one pore in a generally uniform structure otherwise. Carrier particles can preferably form a hollow structure in a dry environment. Thus, carrier particles described herein do not disintegrate or substantially do not disintegrate upon drying.

[0100] It is understood that the compositions, salts, and parts of the kits of parts of the present invention may be formulated as carrier particles or as orally disintegrating tablets. Accordingly, the carrier particles carrying the composition, the salt, or the parts of the kit of parts (s) of the present invention can be compressed together to form tablets. Depending on the disintegration properties of the tablets, the tablets may be orally dispersible. Those skilled in the art can formulate and / or administer the orally dispersible particles.

[0101] Preferably, as referred to herein, the carrier particles are templated carrier particles, preferably templated inverted particles, sometimes referred to as TIP particles. Techniques for the manufacture and use of TIP particles are described in detail in International Patent Application No. PCT / EP2022 / 051799, which is hereby incorporated by reference in its entirety.

[0102] The templated inverted particles may also be referred to as carrier particles having a secondary internal structure. As described in International Patent Application No. PCT / EP2022 / 051799, the method for generating carrier particles having a secondary internal structure includes: a) combining a carrier material with a template material, wherein the carrier material forms a primary structure around the template material; b) deforming the template material; c) removing the deformed template material; and d) obtaining carrier particles having a secondary internal structure.

[0103] Surprisingly, it has been found that when generated using the deformed template material as described herein, the carrier particles exhibit the desired drug delivery properties.

[0104] Accordingly, when referring to the above carrier particles, it always preferably means particles that can be obtained according to the method for generating carrier particles having the above secondary internal structure.

[0105] As used herein, the term "primary structure" refers to a layer of carrier material that includes a template material. In some embodiments, the primary structure includes additional structural elements (e.g., petals) that increase the surface area of the carrier particles.

[0106] As used herein, the term "secondary internal structure" means a hollow internal structure in which nucleation sites are concentrated on the inner surface of the hollow internal structure. Thus, the secondary internal structure enables crystallization within the carrier particles.

[0107] As used herein, the term "carrier material" refers to the material or mixture that constitutes the raw material of the carrier particles described herein. In some embodiments, the carrier material described herein is an inorganic salt or contains an inorganic salt to a substantial extent. In some embodiments, the carrier material described herein is insoluble or poorly soluble in water. In some embodiments, the carrier material dissolves 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 non-polymeric or contains a non-polymer to a substantial extent.

[0108] As used herein, the term "template material" refers to a solid material that includes particles suitable for functioning as a template to enable the formation of the primary structure of carrier particles. The particles in the template material preferably have a spherical, spheroid, and / or bead-like shape. In some embodiments, the template materials described herein are non-polymeric or contain non-polymeric to a substantial extent. In some embodiments, the template materials described herein have a uniform or substantially uniform particle size distribution. In some embodiments, the template materials described herein have a distribution width (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. Thus, the template material is any material that is deformable and has sufficient stability to hold the carrier material. In order to avoid dissolution of the template material during the step of combining the carrier material with the template material, a poorly soluble template material should be used in the combination liquid. In some embodiments, the template materials described herein are poorly soluble in at least one organic solvent selected from the group consisting of dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicone oil, γ-butyrolactone, and tetrahydrofuran. In some embodiments, the template materials described herein are poorly soluble in water. In some embodiments, the template materials described herein are poorly soluble in an aqueous solution containing a solubility modifier (e.g., brine).In some embodiments, the term "poorly soluble" as described herein refers to a solubility at 25 °C of about <100 mg / L, <80 mg / L, <60 mg / L, <40 mg / L, <20 mg / L, <10 mg / L, <9 mg / L, <8 mg / L, <7 mg / L, <6 mg / L, <5 mg / L, <4 mg / L, <3 mg / L, <2 mg / L, <1 mg / L, <0.9 mg / L, <0.8 mg / L, <0.7 mg / L, <0.6 mg / L, <0.5 mg / L, <0.4 mg / L, <0.3 mg / L, <0.2 mg / L, <100 μg / L, <90 μg / L, <80 μg / L, <70 μg / L, <60 μg / L, <50 μg / L, <40 μg / L, <30 μg / L, <25 μg / L, or <20 μg / L.

[0109] 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 or comprises a carbonate to a substantial extent. In some embodiments, the template material described herein comprises a basic oxide.

[0110] As used herein, the term "transform" refers to changing the properties of a template material by at least one physical process and at least one chemical process that together enable removal of the template material. The physical process of "transforming" includes applying energy to the material. In some embodiments, the energy is applied in the form of a temperature increase and / or a pressure change. In some embodiments, the physical process of "transforming" induces an endothermic chemical reaction in the template material. The chemical process of "transforming" includes supplying a chemical reactant to the template material. In some embodiments, the reactant supplied in the chemical process of "transforming" reacts with the template material but does not react or substantially react with the carrier material. In some embodiments, the chemical reactant supplied in the chemical process of "transforming" is supplied in liquid form, dissolved form, and / or gaseous form.

[0111] Accordingly, the carrier particles described herein are carrier particles having a secondary internal structure. In some embodiments, without being bound by theory, these secondary internal structures enable high drug loading because the carrier particles can carry drugs not only on the surface of the carrier particles but also inside the secondary internal structure. The loaded agent or drug can exit the carrier by diffusing through the porous carrier wall. In some embodiments, the carrier particles have a certain stability at the target site (e.g., on the mucosa of a patient). Thus, these carrier particles can remain at the target site (e.g., by adhering to the mucosa), enabling specific drug delivery. In some embodiments, because the loaded agent is continuously released at the absorption site, the carrier particles mask the unpleasant taste of the loaded agent. The release rate of the loaded agent can be controlled by the shape of the template material and / or a diffusion rate regulator such as a disintegrant. Accordingly, the diffusion of the unpleasant taste to the perceived location (e.g., the tongue) is reduced.

[0112] The secondary internal structure described herein enables efficient drug loading into the carrier particles. Further, the secondary internal structure is accessible, for example, through pores for carrying a solvent. In some embodiments, the carrier particles can be loaded with less effort and / or have a particularly high loading capacity.

[0113] In some embodiments, the carrier particles have a particularly large surface area that is beneficial for interparticle forces. These interparticle forces act between the carrier particles in the absence of water and enhance the mechanical stability of the carrier particle mass. This improvement in mechanical stability reduces the need for additional stabilizing materials in the use of carrier particles in solid pharmaceutical compositions, such as pharmaceutical compositions in the form of tablets. In some embodiments, the interparticle forces acting between the carrier particles can be attenuated by water, and as a result, the disintegration time of solid pharmaceutical compositions containing the carrier particles described herein, such as pharmaceutical compositions in the form of tablets, can be shortened.

[0114] In certain embodiments, the carrier material is an inorganic material or consists mainly of an inorganic material.

[0115] The term "consisting essentially of" when used in the context of materials in this specification 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.

[0116] In certain embodiments, the carrier material and the template material are inorganic salts or consist essentially of inorganic salts.

[0117] The carrier particles described herein have a secondary internal structure that is beneficial for enhancing one or more desired drug delivery properties.

[0118] In the process of generating the particles, preferably, the template material is suspended in a liquid before combining the carrier material with the template material.

[0119] The template material can be suspended in a combination liquid (e.g., water) while stirring in a reaction vessel. The set stirring speed ensures stable turbulent mixing that prevents aggregation of the particles, thereby enabling individual treatment of the particles.

[0120] In certain embodiments, combining the carrier material with the template material includes adding the template material described herein and the carrier material described herein to a combination liquid. In some embodiments, the combination liquid described herein is at least one organic solvent selected from the group consisting of dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicone oil, γ-butyrolactone, and tetrahydrofuran. In some embodiments, the combination liquid described herein is water. In some embodiments, the combination liquid described herein is an aqueous solution containing a solubility modifier (e.g., saline).

[0121] In order to avoid dissolution of the template material during the step of combining the carrier material with the template material, an appropriate ratio of the amount of the template material to the amount of the combined liquid should be used. This appropriate ratio depends on the solubility of the template material in the combined liquid. In some embodiments, the amounts of the template material and the combined liquid are selected such that the template material dissolves in the combined liquid by 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 0.008% (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 0.006% (w / w), less than about 0.0055% (w / w), or less than about 0.005% (w / w).

[0122] In certain embodiments, combining the carrier material with the template material includes chemical precipitation, lamination, and / or crystallization of the carrier material onto the template material. The term "chemical precipitation" as used herein refers to the process of converting a chemical substance from a solution to a solid by converting the substance to an insoluble form.

[0123] In certain embodiments, the carrier material is formed in a chemical reaction with the surface of the template material by combining precursors of the carrier material. In some embodiments, the soluble precursor of the carrier material described herein is phosphoric acid.

[0124] The conversion grade is related to embodiments in which precursors of the carrier material are combined to form the carrier material in a chemical reaction with the surface of the template material. If the conversion grade is too low, perforated particles or particles with broken shells may occur, while if the conversion is too high, the size of the internal cavity may become small, and many external crystals such as dicalcium phosphate are generated, which further changes into hydroxyapatite slabs. In some embodiments, the conversion grade described herein is from about 30% to about 60%, from about 35% to about 55%, or from about 40% to about 50%.

[0125] The temperature during the chemical precipitation described herein can potentially have a substantial impact on the material. For example, dicalcium phosphate, as it is, is a form with lower thermodynamic stability than hydroxyapatite. Therefore, if the temperature is too low and the addition of orthophosphoric acid to calcium carbonate is too early or not controlled, the precipitation is induced, more dicalcium phosphate is generated, and as a result, separated crystals that are more difficult to process are produced. In some embodiments, the temperature during the chemical precipitation is about 60 °C or higher, preferably from about 60 °C to about 100 °C, more preferably from about 70 °C to about 95 °C, and even more preferably from about 80 °C to about 95 °C.

[0126] In certain embodiments, the soluble precursor of the carrier material is added to the template material in solution and distributed onto the template material by the addition of a reactant that converts the soluble precursor of the carrier material into an insoluble carrier material. In some embodiments, the soluble precursor of the carrier material described herein is sodium phosphate or calcium chloride (e.g., Despotovie, R., et al., 1975, Calc. Tis Res. 18, 13 - 26).

[0127] The term "lamination", as used herein, refers to the technique of adding at least one layer of the carrier onto the template material.

[0128] Any deposition technique known in the art can 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 (as described, e.g., in Decher, G. H. J. D., et al., 1992, Thin solid films, 210, 831-835), hydrogen bonding (as described, e.g., in Such, G. K. et al., 2010, Chemical Society Reviews, 40(1), 19-29), hydrophobic interactions (as described, e.g., in Serizawa, T., Kamimura, S., et al., 2002, Langmuir, 18(22), 8381-8385), and / or covalent bonding (as described, e.g., in Zhang, Y., et al., 2003, Macromolecules, 36(11), 4238-4240), electroplating and electrodeposition (as described, e.g., in Chandran, R., Panda, S. K. & Mallik, A. A short review on the advancements in electroplating of CuInGaSe2 thin films. Mater Renew Sustain Energy 7, 6(2018)) are utilized to prepare at least one layer on the template material, particularly to prepare a multilayer film on the template material.

[0129] As used herein, the term "crystallization" refers to the process of conversion of a chemical substance from a supersaturated solution.

[0130] In certain embodiments, the carrier material is added to the template material in a supersaturated solution and is deposited on the template material by initiation of chemical precipitation.

[0131] In certain embodiments, combining the carrier material with the template material includes chemical precipitation and crystallization of the carrier material onto the template material.

[0132] In certain embodiments, combining the carrier material with the template material includes chemical lamination and crystallization of the carrier material onto the template material.

[0133] In certain embodiments, combining the carrier material with the template material includes chemical precipitation and lamination of the carrier material onto the template material.

[0134] The chemical precipitation process can be carried out by feeding a solution of the precursor of the template material onto the carrier material or into a liquid containing the carrier material. During this process, the carrier material can start to grow (e.g., in the form of a crystalline lamellar structure) on the surface of the template material, thereby forming a stratum layer. In certain embodiments, the template materials described herein are converted into carrier materials. In certain embodiments, at least about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% of the template materials described herein are converted into carrier materials.

[0135] By chemical precipitation, lamination, and / or crystallization, the carrier material can be finely and / or uniformly distributed on the template material. This fine and / or uniform distribution affects the formation of the secondary internal structure.

[0136] Thus, the carrier particles produced as described herein exhibit particularly fine and / or uniform secondary internal structures by using chemical precipitation, lamination, and / or crystallization of the carrier material onto the template material.

[0137] In certain embodiments, deforming the template material includes heating to a temperature of 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.

[0138] In certain embodiments, deforming the template material includes heating to a temperature of 840 °C to 1200 °C.

[0139] The conditions can be optimized to avoid interparticle condensation during the heating process that could lead to issues with redispersibility. In some embodiments, it is not necessary to further add an agent to avoid interparticle condensation, while in other embodiments, an agent to avoid interparticle condensation (e.g., an anti-sintering agent) is added during and / or prior to the heating process described herein. Such anti-sintering agents are described, for example, in Okada, M., et al., 2014, Journal of nanoparticle research, 16(7), 1-9.

[0140] The deformation of the template material described herein can be carried out at any suitable temperature or any suitable temperature range. To enable the deformation of the template material described herein, the minimum suitable temperature for deformation is set at a specific temperature, for example, about 210 °C (e.g., when using silver carbonate and gold carbonate as the template material), about 840 °C (e.g., when using calcium carbonate as the template material), about 900 °C, about 1000 °C, or about 1200 °C (e.g., when using potassium carbonate and / or sodium carbonate as the template material). One skilled in the art can determine the appropriate minimum suitable temperature from the decomposition temperature of the template material. Increasing the temperature can shorten the deformation time, but if the carrier material melts, it can have an undesirable effect on the carrier particles, such as incomplete formation of carrier particles or a decrease in the hardness of the carrier particles. To avoid melting of the carrier material, the maximum suitable temperature for the deformation of the template material described herein is set below the melting temperature of the carrier material. Distortion and / or loss of the desired structure for increasing the surface area of the carrier particles (e.g., petals on the surface of the carrier particles) can already occur at a temperature below the melting temperature of the carrier material. Thus, in certain embodiments, the maximum suitable temperature for the deformation of the template material described herein is set about 100 °C, about 200 °C, about 400 °C, about 500 °C, or about 600 °C lower than the melting temperature of the carrier material.

[0141] In certain embodiments, deforming the template material comprises heating the template material from around its decomposition temperature to around the melting temperature of the carrier material, preferably to a temperature about 400 °C lower than the melting temperature of the carrier material from around the decomposition temperature of the template material, more preferably to a temperature about 500 °C lower than the melting temperature of the carrier material from around the decomposition temperature of the template material.

[0142] In certain embodiments, deforming the template material comprises heating to a temperature of 840 °C to 1600 °C, preferably 840 °C to 1200 °C, more preferably around 1100 °C.

[0143] The duration of heating for deforming the template material described herein depends on various factors such as the template material, the carrier material, the temperature range, the particle size, and / or the desired surface area of the carrier particles.

[0144] The duration of heating for deforming the template material described herein may be, for example, about 1 hour. In certain embodiments, the duration of heating for deforming the template material described herein is from about 5 minutes to about 24 hours, from about 10 minutes to about 12 hours, 20 minutes to about 4 hours.

[0145] The heating (e.g., heating to a specific range of temperatures, e.g., 840 °C to 1200 °C or 600 °C to 900 °C) for deforming the template material described herein can be achieved by any heating pattern such as a linear increase in temperature or with one or more preheating steps. The preheating step described herein may include holding the temperature at a specific temperature level for a certain time before heating the template material to a specific range of temperatures, e.g., 840 °C to 1200 °C or 600 °C to 900 °C. By preheating, undesirable volatile components such as solvents can be removed, for example.

[0146] In some embodiments, the pressure is reduced during heating to a specific range of temperatures, e.g., 840 °C to 1200 °C, for deforming the template material.

[0147] In some embodiments, the pressure is increased during heating to a specific range of temperatures for deforming the template material, such as 840 °C to 1200 °C.

[0148] In some embodiments, the heating for deforming the template material induces an endothermic chemical reaction.

[0149] In some embodiments, an inert substance (e.g., a noble gas) is supplied to avoid side reactions during heating of the template material to a specific range of temperatures, such as 840 °C to 1200 °C, for deforming the template material.

[0150] In some embodiments, the heating for deforming the template material induces evaporation of the volatile fraction of the template material.

[0151] Heating to a specific range of temperatures, such as 840 °C to 1200 °C, can initiate deformation of the template material, but does not change or changes the carrier material to the same extent. This enables the deformed template material to be removed based on the changed properties. Lower temperatures (e.g., about 600 °C to about 839 °C or about 600 °C to about 900 °C) can be used to better maintain the petal structure, thereby increasing the hardness of the resulting tablets.

[0152] When the temperature is higher than the recommended range, the fine petal structure of the particles melts and decreases, and the flexibility of the petals decreases, so the hardness of the tablets produced using such overheated material is greatly reduced. Pharmaceutical compacts made using overheated material exhibit capping and lamination and cannot be used equally well in pharmaceutical formulations.

[0153] Thus, the heating step for deforming the template material enables the production of carrier particles having a secondary internal structure beneficial for enhancing one or more desired drug delivery characteristics.

[0154] In certain embodiments, the step of deforming the template material includes calcination.

[0155] As used herein, the term "calcination" refers to heating a solid or a mixture containing a solid to a high temperature (e.g., a temperature of 840 °C to 1200 °C or 600 °C to 900 °C) while supplying air or oxygen to the solid or mixture.

[0156] In some embodiments, the calcination described herein induces the decomposition of a template material containing carbonate (e.g., carbonate such as calcium carbonate) into carbon dioxide.

[0157] In some embodiments, the calcination described herein induces the decomposition of a template material containing metal carbonate into metal oxide, preferably basic oxide.

[0158] In some embodiments, the calcination described herein induces the decomposition of a hydrated template material by removing moisture.

[0159] In some embodiments, the calcination described herein induces the decomposition of volatile substances in the template material.

[0160] Thus, the calcination step for deforming the template material enables the generation of carrier particles having a secondary internal structure beneficial for enhancing one or more desired drug delivery characteristics.

[0161] In certain embodiments, deforming the template material includes subsequent addition of water.

[0162] The subsequent addition of water deforms the template material in a chemical reaction, but does not change or substantially change the carrier material. Thereby, based on the changed properties, the deformed template material can be removed.

[0163] In some embodiments, the water added later as described herein reacts with the metal oxide.

[0164] Thus, the deformation process method involving the addition of water enables the generation of carrier particles having a secondary internal structure beneficial for enhancing one or more desired drug delivery characteristics.

[0165] In certain embodiments, the addition of water enables an exothermic reaction.

[0166] As used herein, the term "exothermic reaction" refers to a reaction in which the overall standard enthalpy change is negative.

[0167] Subsequent addition of water as described herein deforms the template material in an exothermic chemical reaction without changing or substantially changing the carrier material. Thereby, based on the changed properties, the deformed template material can be removed.

[0168] The basic oxides described herein are non-toxic or substantially non-toxic at the dosages used as described herein. In some embodiments, the water added later as described herein reacts with the basic oxide. In some embodiments, the water added later as described herein reacts with at least one basic oxide selected from the group consisting 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 water added later as described herein reacts with magnesium oxide and / or calcium oxide.

[0169] The exothermic reaction 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 3.34 g / cm 3 with water results in calcium hydroxide with a density of 2.21 g / cm 3 .

[0170] Therefore, the addition of water through the exothermic reaction aids in the formation of the secondary structure and facilitates the subsequent removal of the template material.

[0171] In certain embodiments, removing the template material includes dissolving the deformed template material to form a secondary internal structure.

[0172] The deformed template material can be removed by dissolving it in a solvent in which the deformed template material dissolves but the carrier material does not, thereby forming a secondary internal structure.

[0173] In some embodiments, removing the template material includes dissolving the deformed template material in water or an aqueous solution. In some embodiments, the pH of the aqueous solution is changed prior to dissolving the deformed template material to increase the solubility of the deformed template material in the aqueous solution or decrease the solubility of the carrier material.

[0174] In some embodiments, removing the template material includes dissolving the deformed template in an organic solvent.

[0175] Removing the template material by dissolution is particularly gentle on the carrier material. Thus, this gentle removal aids in maintaining the primary carrier material structure and enables the formation of a secondary internal structure that is particularly beneficial for crystallization during the drug loading process.

[0176] Therefore, removing the template material includes dissolving the deformed template material to aid in the formation of a secondary internal structure.

[0177] In certain embodiments, the template material includes metal carbonates.

[0178] In certain embodiments, the template material is Li2CO3, LiHCO3, Na2CO 3、 NaHCO3, Na3H(CO3) 2、 MgCO 3、Mg(HCO3)2, Al2(CO3)3, K2CO3, KHCO3, CaCO3, Ca(HCO3)2, MnCO3, FeCO3, NiCO3, Cu2CO3, CuCO3, ZnCO3, Rb2CO3, PdCO3, Ag2CO 3、 It contains at least one metal carbonate selected from the group consisting of Cs2CO3, CsHCO3, BaCO3, and (BiO)2CO3.

[0179] In certain embodiments, the template material contains at least one metal selected from the group consisting of Fe, Mg, Al, Mn, V, Ti, Cu, Ga, Ge, Ag, Au, Sm, U, Zn, Pt, and Sn. In certain embodiments, the template material contains at least one non-metal selected from the group consisting of Si, S, Sb, I, and C.

[0180] In certain embodiments, the template material contains more than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% metal carbonate.

[0181] In certain embodiments, the template material contains more than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% Li2CO3, LiHCO3, Na2CO 3、 NaHCO3, Na3H(CO3) 2、 MgCO 3、 Mg(HCO3)2, Al2(CO3)3, K2CO3, KHCO3, CaCO3, Ca(HCO3)2, MnCO3, FeCO3, NiCO3, Cu2CO3, CuCO3, ZnCO3, Rb2CO3, PdCO3, Ag2CO3, Cs2CO3, CsHCO3, BaCO3, and (BiO)2CO3.

[0182] In certain embodiments, the template material contains more than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% magnesium carbonate.

[0183] In certain embodiments, the template material contains calcium carbonate.

[0184] In certain embodiments, the template material comprises calcium carbonate in an amount greater than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99%.

[0185] In some embodiments, the calcium carbonate described herein includes anhydrous calcium carbonate, complexes containing calcium carbonate, and / or hydrated calcium carbonate such as CaCO3·H2O, and / or calcium carbonate hexahydrate.

[0186] In some embodiments, the calcium carbonate described herein is anhydrous calcium carbonate.

[0187] The metal carbonates described herein can be used as a basis for generating a carrier material (e.g., an insoluble metal phosphate resulting from the reaction of a metal carbonate and H3PO4) having distinct properties on the surface of the template material and can be deformed as described herein.

[0188] In certain embodiments, the carrier material comprises at least one salt and / or complex selected from the group consisting of calcium phosphate and magnesium phosphate.

[0189] In certain embodiments, the carrier material comprises at least one salt and / or complex of magnesium phosphate.

[0190] In certain embodiments, the carrier material comprises at least one salt and / or complex of calcium phosphate.

[0191] Calcium phosphate and magnesium phosphate have particularly low solubility in water and exhibit moderate heat resistance. Furthermore, calcium phosphate and magnesium phosphate are generally pharmacologically inert and non-toxic. Thus, calcium phosphate and magnesium phosphate are robust, non-toxic, and enable the deformation of the template materials described herein without decomposition.

[0192] Therefore, the generation of the carrier particles described in this specification is particularly efficient when the carrier material contains at least one salt and / or complex selected from the group consisting of calcium phosphate and magnesium phosphate.

[0193] Preferably, the carrier particles included in the present invention contain calcium phosphate and / or magnesium phosphate. More preferably, the carrier particles included in the present invention contain calcium phosphate.

[0194] Preferably, the calcium phosphate is present in the form of hydroxyapatite. As referred to herein, hydroxyapatite is a substance represented by the formula Ca5(OH)(PO4)3.

[0195] Therefore, preferably, the carrier particles included in the present invention contain hydroxyapatite. More preferably, the carrier particles included in the present invention further contain calcium hydroxide.

[0196] Therefore, preferably, the present invention relates to an embodiment in which the compositions, salts, and parts of the kits of parts of the present invention can be formulated by using carrier particles having a secondary internal structure, the carrier particles containing hydroxyapatite and optionally containing calcium chloride.

[0197] Preferably, it is understood herein that the term "carrier particles having a secondary internal structure" may also be referred to as "carrier particles having a hollow internal structure".

[0198] Preferably, the content of hydroxyapatite in the particles (not carrying the compositions, salts, or parts (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, and even more preferably about 100% w / w.

[0199] The template material can have various structures, for example, powders (e.g., powders having a D50 of about 1.9 μm, 2.3 μm, 3.2 μm, 4.5 μm, 5.5 μm, 6.5 μm, or 14 μm; powders having a particle size range of about 1 - 100 μm, 100 μm - 300 μm, or 300 μm - 600 μm) or nanoparticles.

[0200] In certain embodiments, the template material comprises particles having a diameter of 1 - 300 μm. In certain embodiments, the template material consists of about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 99% of particles having a diameter of 1 - 300 μm. In certain embodiments, the template material comprises particles having a median particle size of about 1 - 300 μm, about 1 - 250 μm, about 1 - 200 μm, about 1 - 150 μm, about 1 - 100 μm, about 1 - 90 μm, about 1 - 80 μm, about 1 - 70 μm, about 1 - 60 μm, about 1 - 50 μm, about 1 - 40 μm, about 1 - 30 μm, or about 1 - 20 μm.

[0201] The particle size of the template material affects the diameter of the carrier particles. In certain embodiments, the particles of the template material have a median particle size that is substantially the same as the median particle size of the carrier particles. In embodiments where the template material and the carrier material are combined by lamination and / or crystallization as described herein, the carrier particles have a median particle size that is the same or larger compared to the template material.

[0202] In embodiments where the template material and the carrier material are combined by chemical precipitation as described herein, the carrier particles have a median particle size that is the same or smaller compared to the template material.

[0203] One skilled in the art can predict the carrier material from the template material, the carrier material, and the techniques used for the combination of the template material and the carrier material described herein.

[0204] In certain embodiments, the carrier particles have a diameter of 1 - 300 μm.

[0205] Particles of a specific size can be obtained by methods known in the art, including grinding, 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; U.S. Patent No. 5376347A). Measurement of particle size and shape can be performed 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).

[0206] In some applications, particularly small carrier particle sizes are desirable. In certain embodiments, the carrier particles have a diameter of about 1 to 20 μm, about 1 to 15 μm, about 1 to 10 μm, or about 1 to 5 μm for use in pulmonary and / or intranasal administration. In some applications, particularly small carrier particle sizes are desirable to increase the diffusion surface and promote the release of the agent being carried.

[0207] In some applications, larger carrier particle sizes are desirable to enhance the fluidity of the carrier particles and make further processing easier. In certain embodiments, the carrier particles have a diameter of about 5 to 300 μm, about 10 to 250 μm, about 15 to 200 μm, or about 20 to 150 μm.

[0208] Accordingly, the method for producing the carrier particles described herein, wherein the carrier particles have a specific range of diameters, can be particularly useful for further processing (e.g., fluidity) and / or application (e.g., diffusion surface) of the carrier particles produced according to the method.

[0209] In certain embodiments, the carrier particles have a surface area of 15 m2 / g to 400 m2 / g or 30 m2 / g to 400 m2 / g.

[0210] In certain embodiments, the carrier particles have a surface area of about 15 m2 / g to 400 m2 / g, about 30 m2 / g to 400 m2 / g, about 50 m2 / g to 350 m2 / g, about 70 m2 / g to 320 m2 / g, about 90 m2 / g to 300 m2 / g, or about 100 m2 / g to 280 m2 / g as measured by five-point BET (Brunnauer-Emmet-Teller) surface area analysis using nitrogen as the gas.

[0211] Alternatively, the surface area of the carrier particles can be measured by any method known in the art (see, for example, 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).

[0212] The surface area of the carrier particles can be varied, for example, by changes in the surface structure due to the particle size of the carrier material, the carrier material, and / or the parameters described herein (e.g., heat, duration of heating).

[0213] In certain embodiments, the carrier particles are used as an adsorbent.

[0214] The larger the specific surface area of the carrier particles described herein, the stronger the van der Waals interaction when the particles are brought into contact. This effect results in a higher tensile strength of the final dosage form. These van der Waals interactions are attenuated by the addition of water and can assist in the disintegration of the particle mass.

[0215] Therefore, the method for producing the carrier particles described herein enables mechanical stability and disintegration ability when the carrier particles have a surface area of 15 m2 / g to 400 m2 / g, preferably 30 m2 / g to 400 m2 / g.

[0216] In certain embodiments, the secondary internal structure includes pores having a diameter size in the range of ≧0.2 μm and ≦1.5 μm.

[0217] In certain embodiments, the secondary internal structure includes pores having a diameter size of ≧ about 0.2 μm, ≧ about 0.3 μm, ≧ about 0.4 μm, ≧ about 0.5 μm, ≧ about 0.6 μm, ≧ about 0.7 μm, ≧ about 0.8 μm, ≧ about 0.9 μm, ≧ about 1 μm, ≧ about 1.1 μm, ≧ about 1.2 μm, ≧ about 1.3 μm, or ≧ about 1.5 μm.

[0218] In certain embodiments, the secondary internal structure includes pores having a diameter size in the range of about ≧0.2 μm to ≦1.5 μm, about ≧0.3 μm to ≦1.5 μm, about ≧0.4 μm to ≦1.5 μm, about ≧0.5 μm to ≦1.5 μm, about ≧0.6 μm to ≦1.5 μm, about ≧0.7 μm to ≦1.5 μm, about ≧0.8 μm to ≦1.5 μm, about ≧0.9 μm to ≦1.5 μm, about ≧1 μm to ≦1.5 μm, about ≧1.1 μm to ≦1.5 μm, about ≧1.2 μm to ≦1.5 μm, or about ≧1.3 μm to ≦1.5 μm.

[0219] The pore diameter of the carrier particles can be measured by any method known in the art (see, for example, Markl, D. et al., 2018, International Journal of Pharmaceutics, 538(1-2), 188-214).

[0220] The porous structure that can be formed by the method for producing carrier particles described herein allows for pores of particularly large sizes. This large pore size facilitates drug loading onto the carrier particles and accelerates drug release from the carrier particles.

[0221] When the pore size diameter exceeds 90% of the particle size of the template material, the carrier particles become unstable. Thus, the maximum pore size depends on the particle size of the template material.

[0222] In certain embodiments, the secondary internal structure comprises pores having a diameter size of about ≦270 μm, about ≦225 μm, about ≦180 μm, about ≦135 μm, about ≦90 μm, about ≦81 μm, about ≦72 μm, about ≦63 μm, about ≦54 μm, about ≦45 μm, about ≦36 μm, about ≦27 μm, or about ≦18 μm. Thus, the method for generating carrier particles described herein, wherein the secondary internal structure comprises pores having a specific diameter size, is particularly useful for subsequent drug loading and drug release of the carrier particles generated as described herein.

[0223] In certain embodiments, the total volume of the secondary internal structure in the carrier particles having the obtained secondary internal structure is in the range of ≧10% to ≦90% of the particle volume when determined by SEM-FIB and SEM image analysis of cross-sectional images of the resin-embedded particles. Another analytical method for measuring the volume ratio of the internal structure and the particles includes the calculation of porosity as the ratio of the tapped bulk of the carrier material to the true crystal density of the carrier material.

[0224] The total volume of the secondary internal structure refers to the internal volume inside the particles generated by the removal of the template material. In certain embodiments, the total volume of the secondary internal structure described herein is the average internal volume of the carrier particles obtained as described herein.

[0225] In certain embodiments, the total volume of the secondary internal structure described herein is the central internal volume of the carrier particles obtained as described herein.

[0226] In certain embodiments, the total volume of the secondary internal structure in the carrier particles having the obtained secondary internal structure is greater 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.

[0227] In certain embodiments, the total volume of the secondary internal structure in the carrier particles having the obtained secondary internal structure is greater 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.

[0228] In certain embodiments, the total volume of the secondary internal structure in the carrier particles having the obtained secondary internal structure is about ≥10% to ≤90%, about ≥15% to ≤90%, about ≥20% to ≤90%, about ≥25% to ≤90%, about ≥30% to ≤90%, about ≥35% to ≤90%, about ≥40% to ≤90%, about ≥45% to ≤90%, about ≥50% to ≤90%, about ≥55% to ≤90%, about ≥60% to ≤90%, about ≥65% to ≤90%, about ≥70% to ≤90%, about ≥10% to ≤80%, about ≥15% to ≤80%, about ≥20% to ≤80%, about ≥25% to ≤80%, about ≥30% to ≤80%, about ≥35% to ≤80%, about ≥40% to ≤80%, about ≥45% to ≤80%, about ≥50% to ≤80%, about ≥55% to ≤80%, about ≥60% to ≤80%, about ≥65% to ≤80%, about ≥70% to ≤80%, about ≥10% to ≤70%, about ≥15% to ≤70%, about ≥20% to ≤70%, about ≥25% to ≤70%, about ≥30% to ≤70%, about ≥35% to ≤70%, about ≥40% to ≤70%, about ≥45% to ≤70%, about ≥50% to ≤70%, about ≥55% to ≤70%, about ≥60% to ≤70%, about ≥65% to ≤70%, about ≥10% to ≤60%, about ≥15% to ≤60%, about ≥20% to ≤60%, about ≥25% to ≤60%, about ≥30% to ≤60%, about ≥35% to ≤60%, about ≥40% to ≤60%, about ≥45% to ≤60%, about ≥50% to ≤60%, about ≥55% to ≤60%, about ≥10% to ≤50%, about ≥15% to ≤50%, about ≥20% to ≤50%, about ≥25% to ≤50%, about ≥30% to ≤50%, about ≥35% to ≤50%, about ≥40% to ≤50%, or about ≥45% to ≤50% of the particle volume.

[0229] In certain embodiments of the carrier particles described herein and obtainable as described above, the carrier particles have a loading capacity of ≥72% v / v, ≥70% v / v, ≥68% v / v, ≥66% v / v, ≥64% v / v, ≥62% v / v, or ≥60% v / v.

[0230] In certain embodiments of the carrier particles described herein, the carrier particles have a loading capacity of ≥60% v / v.

[0231] As used herein, the term "loading capacity" refers to the volume of carrier particles that can be used for loading an agent, compared to the total volume of the carrier particles. Thus, carrier particles having a loading capacity of 60% v / v can load an agent that is 60% of the volume of the carrier particles. The volume of the carrier particles is calculated from the diameter of the carrier particles. Thus, in this calculation, the volume of the internal structure is part of the volume of the carrier particles.

[0232] In some embodiments, the agent carried on the carrier particles is composed of a carrier solvent, and the carrier solvent is removed to complete the loading.

[0233] Dissolve the agent to be loaded in the carrier solvent and contact it with the carrier particles to ensure that the loaded particles are completely and thoroughly wetted. The carrier solvent can be removed by any solvent removal method known to those skilled in the art. In some embodiments, the carrier solvent is removed by a method selected from the group consisting of evaporation, vacuum-assisted evaporation, air drying, vacuum freeze-drying, freeze-drying at atmospheric pressure, spray drying, spray drying in a fluid bed apparatus, microwave-assisted drying, electrospray-assisted drying, dielectric drying, fluid bed-assisted drug loading, and solvent adsorption method.

[0234] In the present invention, the agent carried on the carrier particles is a part (s) of the composition, salt, or kit of parts of the present invention.

[0235] In some embodiments, the solvent adsorption method includes high-shear granulation.

[0236] The selection of a suitable carrier solvent depends on the toxicity of the solvent, the vapor pressure of the solvent, the properties of the agent to be loaded (e.g., the pH stability and / or solubility of the agent to be loaded), and / or the properties of the carrier material.

[0237] In some embodiments, the carrier solvent described herein comprises at least one organic solvent, preferably at least one organic solvent selected from the group consisting of dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicone oil, γ-butyrolactone, and tetrahydrofuran. In some embodiments, the carrier solvent described herein is water.

[0238] Since some loading solvents such as water have a high surface tension, additional measures may be required to assist the penetration of the carrier particles described herein into the pores (plural) of the carrier particles, despite the exceptionally large pore diameter. In some embodiments, the carrier solvent described herein comprises at least one surfactant such as a tenside. In some embodiments, the carrier solvent is added under high pressure to assist the carrier solvent by allowing the carrier solvent to penetrate into the interior of the carrier particles.

[0239] In some embodiments, the loading onto and into the carrier particles described herein comprises the addition of an antisolvent that reduces the solubility of the agent to be loaded in the carrier solvent. In some embodiments, the antisolvent is at least one antisolvent selected from the group consisting 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, silicone oil, γ-butyrolactone, and tetrahydrofuran.

[0240] In some embodiments, the carrier solvent is removed, for example, by evaporation due to an increase in temperature and / or a decrease in pressure. The maximum temperature for removing the carrier solvent depends on the thermal stability of the agent to be loaded.

[0241] The carrier particles having the secondary internal structure described herein can be compressed to obtain compressed carrier particles.

[0242] As used herein, the term "compressed carrier material" refers to a mass of more than one carrier particle in which an adhesive force acts between the carrier particles.

[0243] As used herein, the term "compression" refers to applying pressure to more than one particle (e.g., carrier particles) to form a compressed carrier material, and the carrier particles remain at least partially adhered to each other even after the pressure is released. Techniques for compression are known to those skilled in the art (see, e.g., Odeku, O.A. et al., 2007, Pharmaceutical Reviews, 5(2)). Examples of compression techniques include, but are not limited to, tableting, roller compression, slugging, briquetting, and / or centrifugation.

[0244] The compressed carrier materials described herein are particularly stable and can be used to obtain particularly stable pharmaceutical compositions. During compression, the large surface area of the carrier particles described herein forms strong interparticle van der Waals adhesive forces that enable mechanical stability. When administered, water penetrates between the particles (e.g., by capillary forces), and the van der Waals adhesive forces weaken as a function of distance, causing the compressed carrier material to disintegrate.

[0245] Accordingly, the compressed carrier materials described herein exhibit certain mechanical stability and / or a rapid disintegration time.

[0246] The inventors have surprisingly found that the formulations of the compositions, salts, and parts of the kits of parts of the invention formulated using carrier particles exhibit improved bioavailability and / or reduced bitterness, thereby leading to increased patient compliance.

[0247] Accordingly, preferably, the carrier particles described in the present invention are compressed.

[0248] Accordingly, preferably, the present invention relates to an embodiment in which the composition, salt, and parts of the kit of parts of the present invention can be formulated by using carrier particles having a secondary internal structure (which may also be referred to as a hollow internal structure), the carrier particles are compressed, the carrier particles contain hydroxyapatite, and optionally contain calcium chloride. Preferably, the content of hydroxyapatite in the particles (not carrying the composition, salt, or parts (s) of the kit 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.

[0249] The inventors have surprisingly found that when the formulation of harmine according to the present invention, particularly harmine glucuronate, is formulated by using carrier particles having a hollow internal structure (carrier particles having a secondary internal structure), it does not cause bitterness when administered orally. Accordingly, by formulating the composition, salt, pharmaceutical composition, or parts of the kit of parts of the present invention, the bitterness of harmine or its salt is masked (see Part 8 of the examples). As a result, those skilled in the art will understand that compliance can be improved.

[0250] Accordingly, the present 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, and the method comprises loading the compound having bitterness onto carrier particles, a) the carrier particles contain a loading cavity and the carrier particles contain a basic salt, and b) the bitterness of the compound is masked by the carrier particles during oral mucosal absorption.

[0251] The inventors have found that carrier particles containing a basic salt and a supported cavity can be used to mask the taste of a compound (the compound is DMT, harmine, or a salt thereof), such as bitterness, and this masking effect exceeds the masking properties of the geometric form of the carrier particles for a specific compound. Without being bound by theory, the basic salt can convert a part of the supported compound into a tasteless form (e.g., the free base or non-salt form of the supported compound), and then, for example, by shielding the compound from taste buds, a film or barrier can be embodied that shields the compound so that it is not perceived as having a specific taste. Thus, by combining chemical shielding and structural shielding, improved drug delivery properties are provided while at the same time surprisingly well masking the taste. This method can be applied to any taste, preferably to quantifiable tastes such as bitterness.

[0252] Using this method, compliance with the treatment of a subject (e.g., a treatment with an unpleasant taste) can be improved, or the oral mucosal absorption can be improved by improving the tolerance of the compound in the oral cavity.

[0253] Accordingly, the present invention further relates to a pharmaceutical composition comprising carrier particles, comprising: a) carrier particles comprising a supported cavity and a basic salt; and b) a compound having bitterness, wherein the compound is harmine or a pharmaceutically acceptable salt thereof or DMT or a pharmaceutically acceptable salt thereof, and the bitterness of the compound is masked by the carrier particles during oral mucosal absorption. It is understood that the compounds having bitterness described herein have bitterness in their salt form, but may not have bitterness or may have reduced bitterness in their non-salt form. Thus, the particles can enable processing in the salt form instead of the non-salt form, for example, facilitating the loading of the particles and / or the production of tablets.

[0254] The basic salt is not necessarily the main component of the carrier particles. The basic salt may be present in only a small amount (e.g., less than the detection limit of a specific measurement method), such as a residue during production, as long as it is sufficient to react with the carrier agent in an amount sufficient to mask the taste. In certain embodiments, the basic salt is calcium hydroxide and / or magnesium hydroxide.

[0255] In certain embodiments, the present invention relates to a method of the present invention or a pharmaceutical composition comprising the carrier particles of the present invention, wherein the basic salt is calcium hydroxide.

[0256] In certain embodiments, the present invention relates to a method of the present invention or a pharmaceutical composition comprising the carrier particles of the present invention, wherein the carrier particles comprise a porous hydroxyapatite shell, at least one hollow cavity, and calcium hydroxide.

[0257] In certain embodiments, the present invention relates to a method of the present invention or a pharmaceutical composition comprising the carrier particles of the present invention, wherein the carrier particles comprise a porous hydroxyapatite shell, at least one hollow cavity, and calcium hydroxide, and the calcium hydroxide is present in an amount less than that of the hydroxyapatite, preferably 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 less than the amount of hydroxyapatite.

[0258] In certain embodiments, the present invention relates to a method of the present invention or a pharmaceutical composition comprising the carrier particles of the present invention, wherein the carrier particles can be obtained or are obtained by: a) combining a carrier material with a template material, wherein the carrier material forms a primary structure around the template material; b) deforming the template material; c) removing the deformed template material; and d) obtaining carrier particles having a secondary internal structure.

[0259] In certain embodiments, the present invention relates to a method for producing carrier particles having a secondary internal structure, comprising: a) combining a carrier material with a template material, wherein the carrier material forms a primary structure around the template material; b) deforming the template material; c) removing the deformed template material; and d) obtaining carrier particles having a secondary internal structure.

[0260] It is understood that the method for masking the bitterness of the compounds of the present invention or the carrier particles used in the pharmaceutical composition odor containing the carrier particles of the present invention is as described above and can be obtained as described above.

[0261] Preferably, the pharmaceutical composition containing the carrier particles of the present invention is a solid pharmaceutical composition, preferably a solid pharmaceutical composition for oral, sublingual, buccal, nasal, bronchial, rectal, urethral, and / or vaginal administration, more preferably a solid pharmaceutical composition for oral, sublingual, or buccal administration.

[0262] Tablets, capsules, or sachets for oral administration are usually supplied in dosage units and can contain conventional excipients such as binders, fillers, diluents, tableting agents, lubricants, detergents, disintegrants, colorants, flavors, and wetting agents. Tablets may be coated according 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 starches, polyvinylpyrrolidone, 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 by conventional mixing, filling, or tableting methods. The mixing operation may be repeated to disperse the active agent in a composition containing a large amount of filler. These operations are conventional.

[0263] The parts of the kit of parts of the present invention are suitably selected and known to those skilled in the art, and can be prepared by mixing pharmaceutically acceptable excipients, vehicles, adjuvants, additives, surfactants, desiccants, or diluents, and can be suitably adapted for oral administration, parenteral administration, or topical administration. Typically and preferably, the parts of the kit of parts of the present invention are in the form of tablets, capsules, subpacks, powders, granules, pellets, orally disintegrating tablets, mucoadhesive films, lyophilized agents, oral or parenteral solutions, suspensions, suppositories, ointments, creams, lotions, gels, pastes, and / or may contain liposomes, micelles, and / or microspheres.

[0264] The parts of the kit of parts of the present invention or the pharmaceutical composition as a liquid composition for oral administration can be provided, for example, in the form of an aqueous solution, emulsion, syrup, or elixir, or in the form of a dry product reconstituted with water or a suitable liquid carrier at the time of use. The liquid composition may contain suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible oils; emulsifying agents such as lecithin, sorbitan monooleate, or acacia; non-aqueous carriers (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol, or ethyl alcohol; preservatives such as methyl or propyl p-hydroxybenzoate, or sorbic acid; penetration enhancers such as dimethyl sulfoxide (DMSO); pH buffer systems such as phosphate buffer, carbonate buffer, citrate buffer, citrate-phosphate buffer, and other pharmaceutically acceptable buffer systems; solubilizing agents such as β-cyclodextrin, and conventional additives such as conventional flavors or coloring agents as required. Oral formulations may also include or be formulated as conventional formulations such as tablets or granules.

[0265] The oral formulation may optionally further contain a taste masking component in order to optimize the taste perception of the oral formulation. Examples of such taste masking components may be citrus, licorice, mint, grape, blackcurrant, or eucalyptus fragrances known to those skilled in the art.

[0266] Embodiments in which taste masking is achieved by incorporating taste masking particles, such as the carrier particles described herein, are also included within the scope of the present invention.

[0267] Examples of dosage forms for nasal administration include solutions, suspensions, or emulsions of the active compound in a liquid carrier in the form of nasal drops. Suitable liquid carriers include water, propylene glycol, and other pharmaceutically acceptable alcohols. When administered in the form of drops, preferably, the formulation may be placed in a container equipped with a conventional dropper / closure device, such as a pipette, etc., which preferably delivers a substantially constant volume of the composition / drops. The dosage form may be sterilized if necessary. The dosage form may optionally contain adjuvants such as preservatives, stabilizers, emulsifying or suspending agents, wetting agents, salts for changing the osmotic pressure, or buffers. Examples of buffer systems include phosphate buffer, carbonate buffer, citrate buffer, citrate-phosphate buffer, and other pharmaceutically acceptable buffer systems. The nasal formulation may optionally further contain an odor masking component in order to optimize the odor.

[0268] For parenteral administration, a liquid dosage unit containing the composition of the present invention and a sterile carrier or parts of the kit of parts of the present invention and a sterile carrier can be prepared. Parenteral solutions are usually prepared by dissolving the compound in a carrier, filtering, autoclaving for sterilization, and then filling and sealing in suitable vials or ampoules.

[0269] Adjuvants such as local anesthetics, preservatives, and buffers may be added to the pharmaceutical composition or parts of the kit of parts of the present invention. To enhance stability, after filling the vial, the pharmaceutical composition or parts of the kit of parts may be frozen and water may be removed under vacuum. Advantageously, a surfactant or a humectant may be included in the pharmaceutical composition or parts of the kit of parts to facilitate uniform distribution of the composition of the present invention or parts of the kit of parts of the present invention.

[0270] Examples of topical preparations include, or are preferred, ointments, creams, lotions, gels, gums, solutions, pastes, or may contain liposomes, micelles, or microspheres.

[0271] In a further embodiment, the present invention relates to the composition of the present invention, the salt of the present invention, the kit of parts of the present invention, or the pharmaceutical composition of the present invention for use as a medicament.

[0272] A medicament comprising the composition of the present invention, the salt of the present invention, the kit of parts of the present invention, or the pharmaceutical composition of the present invention can be used in the treatment of many diseases and disorders. The diseases and disorders are preferably selected from the following: a) Treatment of depression, depressive episodes, major depressive disorder, mood swings, bipolar depression, seasonal affective disorder, treatment-resistant depression, depressive episodes in bipolar disorder, postpartum depression, premenstrual dysphoric disorder, and / or stress-related mood disorders, such as burnout syndrome or depression in patients with chronic physical diseases; b) Treatment of anxiety disorders such as panic attacks, panic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder, etc.; treatment of obsessive-compulsive disorder, treatment of post-traumatic stress disorder, treatment of attachment disorder; and / or treatment of attention deficit disorders such as attention deficit hyperactivity disorder (ADHD), autism, and autism spectrum disorder, 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, etc.); treatment of substance intoxication, drug dependence, tolerance, dependence on or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, caffeine, stimulants, research chemicals, hallucinogens, inhalants, nicotine, opioids, GHB, dissociatives (including ketamine, fencyclidine), sedatives, hypnotics, or anti-anxiety agents; treatment of smoking addiction; and / or as a smoking cessation aid, d) As an adjunct to psychotherapy and / or psychoanalysis; e) As an aid in the diagnosis of dysfunctions and / or mental and physical diseases; f) Treatment of sexual dysfunction; g) Treatment of neuroses; and / or as an agent to induce deep relaxation; h) As an agent to pharmacologically induce a meditative state; i) Treatment of the tendency of a patient's aggressive behavior towards himself / herself and others; and / or treatment of behavioral disorders and socially harmful behaviors; j) Treatment of alexithymia; and / or improvement of mentalization and social skills (e.g., attachment / developmental disorders, autism spectrum disorder); k) Stimulation of oxytocin release; l) As an agent to increase the concentration of neurotransmitters in the central nervous system; as an agent to increase the concentration of serotonin in the central nervous system; and / or as an agent to increase the concentration of dopamine in the central nervous system; m) As a neuroprotective and neuroregenerative agent; treatment of movement disorders such as Parkinson's disease and essential tremor; sleep disorders and autonomic nervous system disorders; treatment of Alzheimer's disease and other types of dementia; as an agent to support stroke rehabilitation through angiogenesis and reduction of infarct volume and neuronal death; treatment of nerve damage caused by excessive substance abuse; as an anti-aging agent, a regenerative agent, for the prevention and treatment of aging symptoms; protection from free radical damage; and / or protection and improvement of damage caused by ionizing radiation; n) as an appetite regulator; as a weight loss agent; for the treatment and prevention of obesity; for the treatment of eating disorders including anorexia nervosa, bulimia nervosa, and binge eating disorder; for the activation of lipid metabolism and physiological fat burning; for the activation of carbohydrate metabolism; for the activation of physiological glycogen burning; for the treatment and prevention of diabetes; and / or for the treatment of insulin resistance; o) for the treatment of inflammation; for the treatment of chronic low-grade inflammation, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, and other demyelinating diseases, type 1 diabetes mellitus, Guillain-Barré syndrome, and / or for the treatment of autoimmune diseases including psoriasis; for the treatment of infectious diseases (preferably caused by fungal infections, helminth infections, or bacterial infections); for the treatment of ulcers, asthma, and bronchitis; and / or for the treatment of autoinflammatory diseases including Crohn's disease and / or Behçet's disease. p) for the stimulation of the immune response; q) as an anti-tumor agent and anti-metastatic agent; for the treatment and / or prevention of cancer, abnormal cell proliferation, and mutations r) for the treatment and / or prevention of cardiovascular diseases; for the treatment of abnormal blood pressure and abnormal heart rate s) for the treatment of pain, psychosomatic pain, intestinal pain, menstrual pain, migraine and other types of headache, neuropathic pain, phantom limb pain, musculoskeletal pain, rheumatic pain, and arthritis

[0273] It is understood that the above list of diseases is only given as specific examples and should not be construed as limiting the present invention. Among the above, one or more selected from a), b), and c) are preferred.

[0274] In a further embodiment, the present invention relates to a composition of the present invention, a salt of the present invention, a kit of parts of the present invention, or a pharmaceutical composition of the present invention for use in the treatment and / or prevention of mental disorders, psychosomatic disorders, or physical disorders.

[0275] Accordingly, the present invention further relates to the use of a composition of the present invention, a salt of the present invention, a kit of parts of the present invention, or a pharmaceutical composition of the present invention for the manufacture of a medicament for the treatment and / or prevention of mental disorders, psychosomatic disorders, or physical disorders.

[0276] Furthermore, accordingly, the present invention relates to a method for treating (and / or preventing) a mental disorder, psychosomatic disorder, or physical disorder, the method comprising administering to an individual in need thereof the composition of the present invention, a salt of the present invention, a kit of parts of the present invention, or a pharmaceutical composition of the present invention. It is understood that the composition of the present invention, a salt of the present invention, a kit of parts of the present invention, or a pharmaceutical composition of the present invention is administered in a therapeutically effective amount.

[0277] "Treatment" of a disorder or disease can result, for example, in halting the progression of the disorder or disease (e.g., the symptoms do not worsen) or delaying the progression of the disorder or disease (if the halt in progression is only transient). "Treatment" of a disorder or disease can also result in partial remission (e.g., improvement of symptoms) or complete remission (e.g., disappearance of symptoms) in a subject / patient suffering from the disorder or disease. Accordingly, "treatment" of a disorder or disease may refer to an improvement of the disorder or disease, which can thereby result, for example, in halting the progression of the disorder or disease or delaying the progression of the disorder or disease. Such partial or complete remission may recur after treatment. It is understood that a subject / patient may experience a wide range of responses to treatment (such as exemplary responses as described hereinabove). Treatment of a disorder or disease can include, in particular, radical treatment (preferably leading to complete remission of the disorder or disease and ultimately to a cure) and symptomatic treatment (including alleviation of symptoms).

[0278] The term "prevention" of a disorder or disease, as used herein, is well known in the art. For example, a patient / subject suspected of being predisposed to a disorder or disease can particularly benefit from the prevention of that disorder or disease. The subject / patient may have a susceptibility or predisposition to a disorder or disease, including but not limited to, a genetic predisposition. Such predispositions can be determined by standard methods or assays, for example, using genetic markers or phenotypic indicators. It is understood that the disorder or disease to be prevented according to the present invention has not been diagnosed or cannot be diagnosed in the patient / subject (e.g., the patient / subject shows no clinical or pathological symptoms). Thus, the term "prevention" includes using the compounds of the present invention before any clinical and / or pathological symptoms are diagnosed or determined, or before they can be diagnosed or determined by a treating physician.

[0279] Preferably, within the scope of the present invention, the mental disorder, psychosomatic disorder, or physical disorder is a mental disorder or neurodegenerative disorder. Preferably, the mental disorder is selected from depression, stress-related mood disorder, major depressive disorder, mood swings, treatment-resistant depression, burnout syndrome, anxiety disorder, post-traumatic stress disorder, addiction, eating disorder, and obsessive-compulsive disorder. Preferably, the neurodegenerative disorder is selected from Parkinson's disease, essential tremor, stroke, multiple sclerosis and other demyelinating diseases, neuroinflammation, autonomic dysfunction, neuropathic pain or phantom limb pain, migraine and other types of headache, nerve damage due to excessive substance abuse, Alzheimer's disease and other types of dementia. Preferably, multiple sclerosis and other demyelinating diseases relate to multiple sclerosis. Preferably, Alzheimer's disease and other types of dementia are related to Alzheimer's disease.

[0280] Preferably, the composition containing harmine or a salt of harmine is understood to be administered simultaneously, separately, or sequentially with DMT or a pharmaceutically acceptable salt thereof, as described above herein.

[0281] Preferably, within the scope of the present invention, the ratio of the dose of harmine to the dose of DMT is 0.5 to 2.0. More preferably, the ratio is 0.75 to 1.5. Even more preferably, the ratio is about 1.0.

[0282] Within the scope of the present invention, harmine and DMT contained in the composition of the present invention, the salt of the present invention, the pharmaceutical composition of the present invention, or the kit of parts of the present invention (optionally contained in 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 the single bolus dose, the total dose of harmine is 5 mg to 200 mg (when a salt or solvate of harmine is administered, the amount is recalculated considering the mg content of harmine in the salt) and / or the total dose of DMT is 5 mg to 100 mg (when a salt or solvate is used, the amount is recalculated considering the mg content of DMT in the salt).

[0283] Furthermore, within the scope of the present invention, harmine and DMT contained in the composition of the present invention, the salt of the present invention, the pharmaceutical composition of the present invention, or the kit of parts of the present invention (optionally contained in the pharmaceutical composition of the present invention or the kit of parts of the present invention) can be administered to a subject incrementally. Each increment of harmine is preferably 5 mg to 80 mg and / or each increment of DMT is preferably 5 mg to 50 mg. It is understood that harmine and DMT may be administered together, separately, or sequentially. Furthermore, it is preferable that the total dose of harmine is 100 mg to 300 mg and / or the total dose of DMT is 50 mg to 150 mg. It is even more preferable that the interval between increments is 5 to 60 minutes, preferably 15 to 60 minutes.

[0284] It is further disclosed herein that in addition to combination with DMT, harmine can also be used as an individual agent in the treatment of many diseases and / or disorders.

[0285] Accordingly, the compositions containing harmine of the present invention, pharmaceutical compositions containing harmine of the present invention or pharmaceutically acceptable salts thereof can be used to treat or prevent many diseases and disorders. Preferably, the diseases and disorders are selected from Parkinson's disease, Alzheimer's disease and other types of dementia, stroke, multiple sclerosis, neurodegeneration / inflammation, nerve damage caused by excessive substance abuse, autonomic dysfunction, pain syndromes, cardiovascular disorders, cancer, infectious diseases (preferably caused by fungal infections, helminth infections, or bacterial infections), diabetes, autoimmune diseases, asthma, bronchitis, and arthritis.

[0286] As used herein, the term "about", when used in the context of a numerical value, preferably refers to ±10% of that value, more preferably ±5% of that value, even more preferably ±1% of that value, and even more preferably the value itself.

[0287] The present invention will be described in the following examples, which should not be construed as limiting.

Examples

[0288] Tests on the physicochemical properties of various HRM solid-state forms and their suitability for developing sublingual / oral mucosal dosage forms.

[0289] In Part 1 of this section, the physicochemical properties of several salts, polymorphs, and compositions of harmine were investigated. The main objective was to identify solid state forms or compositions of harmine with high solubility in water (>20% (w / v)), which is a physicochemical prerequisite for delivering a high drug load (>50 mg) via the oral mucosa administration route. The reason is that oral mucosa dosage forms such as sublingual / buccal sprays, drops, films, or meltable tablets all require compounds with high solubility to ensure an acceptable size (e.g., drops / sprays: ≤0.2 mL / dose; meltable tablets: ≤0.5 mL / dose; preferably ≤0.1 mL / dose), and thus ensure the acceptability of the pharmaceutical product. Similarly, for a scalable process and high loading efficiency, the loading of carrier particles, such as TIP particles, requires high solubility of the compound in water, EtOH, or DMSO.

[0290] In Part 2 of this section, several pharmaceutical formulations of harmine were developed. Thereby, the oral mucosa absorption, pharmacokinetics, and acceptability of the formulations were evaluated. The objective of this study was to identify a sublingual formulation that tastes good (neither bitter nor unpleasant), exhibits high bioavailability, has low first-pass metabolism, and low variability among subjects.

[0291] In Part 3, an overview of a planned study aimed at further investigating the in vivo properties (PKPD) of the most promising candidates identified in Part 2 will be provided.

[0292] Part 1: Physicochemical screening (solid state) of various harmine salts, polymorphs, and compositions. To identify new solid state forms of harmine, the following experiments were conducted: 1) Polymorph screening of harmine HCl 2) Screening of harmine salts 3) Screening of compositions containing harmine and various acids

[0293] Polymorph screening of harmine HCl - Overview: The active ingredient, harmine-HCl, was investigated for polymorphs and pseudopolymorphs by thermal analysis (DSC, TGA), spectroscopy (IR, Raman, NMR), powder X-ray diffraction (XRPD), and crystallization experiments from various solvents. Solubility experiments were also conducted. To protect the DSC sensor from the HCl evolved gas, the provided harmine-HCl was measured using a so-called "Chip-DSC". According to CAS (Chemical Abstract Service), the melting point (decomposition) is 272 - 275 °C, but Chip-DSC shows a direct decomposition (20 K / min) starting from about 260 °C without a distinct melting peak. Thermogravimetric measurements at 10 K / min before decomposition showed a two-step mass loss that was not very significant. The mass decreased by 4.2% up to 200 °C, by 12.5% from 200 °C to 300 °C, and further by 60% after 300 °C.

[0294] Harmine-HCl is converted to the scNF1 form after storage at rest (RT / 100% RH for 7 days). The scNF1 form also occurred during the process of cooling crystallization in water / acetone (70 / 30), water / dioxane (70 / 30), water / THF (70 / 30), and water / acetonitrile (70 / 30). Furthermore, the scNF1 form was produced by gas diffusion crystallization in water / 1,4-dioxane, water / 2-propanol, and water / acetonitrile. In long-term slurries, the generation of scNF1 was successful using acetone / water (80 / 20) and acetonitrile / water (90 / 10). Using the solvents acetone and acetonitrile, rapid precipitation of the scNF1 form by the anti-solvent water is achieved. The scNF1 form can also be crystallized by evaporating the solvent water.

[0295] When measured using TGA after storage at rest (RT / 100% RH, 7 days), the scNF1 form was harmine-HCl dihydrate. After 5 weeks under ambient conditions, traces of harmine-HCl were identified next to the dihydrate form in the powder diffractogram. A more detailed characterization of the scNF1 form was not requested by the client.

[0296] A total of 162 experiments were conducted in the polymorph screening. Except for the dihydrate, no new solid forms of harmine-HCl were obtained.

[0297] Screening of Harmine Salts - Overview The drug substance harmine was investigated for salt screening of various salts by crystallization experiments and grinding experiments from various solvents. Solubility experiments were also conducted before starting the salt screening. During the screening process, 14 new solid phases were detected by using XRPD. The new solid state entities are listed in Table 1 below:

[0298] Table 1: New Solid State Forms of Harmine

[0299]

Table 1-1

[0300]

Table 1-2

[0301] Experimental Setup The acids used in the salt screening are summarized in Table 2 below:

[0302] Table 2: Acids Used in Salt Screening

[0303]

Table 2

[0304] The various solvents used in the salt screening are summarized in Table 3 below. Figure 14 shows a schematic diagram regarding the solvent selection.

[0305] Table 3: Information on Solvents Used

[0306]

Table 3-1

[0307]

Table 3-2

[0308] The summary of the experiments conducted with the API and the salt former in a 1:1 molar ratio is shown in Table 4 below:

[0309] Table 4: Summary of the experiments conducted with the API and the salt former in a 1:1 molar ratio

[0310]

Table 4

[0311] Experimental procedure for each harmine Salt with scNF1-succinic acid - exemplified by ethHAR001EVA013: Weigh 35.6 mg of the active ingredient and 19.8 mg of the salt former into a 4 mL vial. Add 4 mL of methanol at 45 °C, seal the container, and stir on a magnetic stirring plate for 10 minutes. Keep the syringe, cannula, and 0.2 μm ReZist® syringe filter attachment in a drying cabinet preheated to 47 °C. Quickly and completely draw up the solution with a syringe, filter it through a 0.2 μm ReZist® filter, and place it in a new 4 mL vial at 45 °C for the evaporation experiment. After the evaporation experiment, seal the sample. The following Table 5 shows further experiments to obtain harmine succinate:

[0312] Table 5. Experiments to obtain harmine succinate

[0313]

Table 5

[0314] Salt with scNF2-L(+)-tartaric acid - ethHAR001GRI002: Weigh 40 mg of the API and 28.3 mg of L(+)-tartaric acid as the salt-forming agent into a grinding jar containing 10 ceramic balls (3 balls of 5 mm and 7 balls of 2 mm). Add 2 drops of water / methanol and seal the container. Insert the grinding jar into a Fritsch Micromill Pulverisette 7 and grind the sample for 30 minutes. Select the following conditions for grinding: · 10 ceramic balls (3 balls of 5 mm and 7 balls of 2 mm) · Temperature: Ventilated chamber environment - room temperature · Grinding time: 30 minutes

[0315] Prepare the solid residue in a 4 mL PTFE vial.

[0316] Salt with scNF3-L-ascorbic acid - ethHAR001GRI003: Weigh 40 mg of the API and 33.2 mg of L-ascorbic acid as the salt-forming agent into a grinding jar containing 10 ceramic balls (3 balls of 5 mm and 7 balls of 2 mm). Add 2 drops of water / methanol and seal the container. Insert the grinding jar into a Fritsch Micromill Pulverisette 7 and grind the sample for 30 minutes. Select the following conditions for grinding: · 10 ceramic balls (3 balls of 5 mm and 7 balls of 2 mm) · Temperature: Ventilated chamber environment - room temperature · Grinding time: 30 minutes

[0317] Prepare the solid residue in a 4 mL PTFE vial.

[0318] Salt with scNF4-L(-)-malic acid - Example - ethHAR001EVA016: Weigh 40 mg of the active ingredient and 25.3 mg of the salt-forming agent, L-ascorbic acid, into a 4 mL vial. Add 4 mL of pyridine at 25 °C, seal the container, and stir on a magnetic stirring plate for 10 minutes. Store the syringe, cannula, and 0.2 μm ReZist® syringe filter attachment in a dry cabinet preheated to 25 °C. Quickly and completely aspirate the solution with the syringe, filter it through a 0.2 μm ReZist® filter, and transfer it to a new 4 mL vial at 25 °C for the evaporation experiment. After the evaporation experiment, seal the sample. The following Table 6 shows further experiments for obtaining harmine malate:

[0319] Table 6. Experiments for Obtaining Harmine Malate

[0320]

Table 6

[0321] Salt with scNF5-citric acid - Exemplification - ethHAR001EVA017: Weigh 35.6 mg of the active ingredient and 32.2 mg of the salt-forming agent, citric acid, into a 4 mL vial. Add 4 mL of methanol at 45 °C, seal the container, and stir on a magnetic stirring plate for 10 minutes. Store the syringe, cannula, and 0.2 μm ReZist® syringe filter attachment in a dry cabinet preheated to 47 °C. Quickly and completely aspirate the solution with the syringe, filter it through a 0.2 μm ReZist® filter, and transfer it to a new 4 mL vial at 45 °C for the evaporation experiment. After the evaporation experiment, seal the sample. The following Table 7 shows further experiments for obtaining harmine citrate:

[0322] Table 7. Experiments for Obtaining Harmine Citrate

[0323]

Table 7

[0324] Salt with scNF6-L(+)-tartaric acid - ethHAR001EVA014: Weigh 35.6 mg of the active ingredient and 25.1 mg of L(+)-tartaric acid, the salt-forming agent, into a 4 mL vial. Add 4 mL of methanol at 45 °C, seal the container, and stir on a magnetic stirring plate for 10 minutes. Keep the syringe, cannula, and 0.2 μm ReZist® syringe filter attachment in a drying cabinet preheated to 47 °C. Quickly and completely aspirate the solution with a syringe, filter it through a 0.2 μm ReZist® filter, and transfer it to a new 4 mL vial at 45 °C for the evaporation experiment. After the evaporation experiment, seal the sample.

[0325] Salt with cNF7 and scNF4-L(-)-malic acid - ethHAR001EVA016: Weigh 35.6 mg of the active ingredient and 22.5 mg of L(-)-malic acid, the salt-forming agent, into a 4 mL vial. Add 4 mL of methanol at 45 °C, seal the container, and stir on a magnetic stirring plate for 10 minutes. Keep the syringe, cannula, and 0.2 μm ReZist® syringe filter attachment in a drying cabinet preheated to 47 °C. Quickly and completely aspirate the solution with a syringe, filter it through a 0.2 μm ReZist® filter, and transfer it to a new 4 mL vial at 45 °C for the evaporation experiment. After the evaporation experiment, seal the sample.

[0326] Salt with scNF8-methanesulfonic acid - ethHAR001EXP113: Weigh 40 mg of the active ingredient into a 4 mL vial. Add 1 mL of water at 25 °C, seal the container, and stir on a magnetic stirring plate for 10 minutes. Quickly add methanesulfonic acid (12 μL) to the solution. Seal the vial appropriately by additional application of a screw cap and parafilm. Place the vial on a magnetic stirrer using the following parameters: · Stirring speed: 1000 rpm · Temperature: Draft environment - RT · Stirring time: 5 days

[0327] To confirm that the suspension is homogeneous, check the suspension daily. After 5 days, filter the slurry through a 13 mm Hirsch funnel fitted with Whatman® filter paper No. 540. Dry the solid residue in air (for about 1 hour), then place it in a new clean 4 mL vial equipped with a PTFE seal.

[0328] Salt with scNF9 - sulfuric acid - ethHAR001EXP114: Weigh 40 mg of the active ingredient into a 4 mL vial. Add 1 mL of water at 25 °C, seal the container, and stir on a magnetic stirring plate for 10 minutes. Rapidly add sulfuric acid (10.3 μL) to the solution. Keep a syringe, cannula, and 0.2 μm ReZist® syringe filter attachment in a drying cabinet preheated to 25 °C. Quickly and completely aspirate the solution with a syringe, filter it through a 0.2 μm ReZist® filter, and place it in a new 4 mL vial at 25 °C for the evaporation experiment. After the evaporation experiment, seal the sample.

[0329] Salt with scNF10 - L - tartaric acid - ethHAR001GRI014: Weigh 40 mg of the API and 28.3 mg of L - tartaric acid, the salt - forming agent, into a grinding jar containing 10 ceramic balls (3 balls of 5 mm and 7 balls of 2 mm). Seal the container. Insert the grinding jar into a Fritsch Micromill Pulverisette 7 and grind the sample for 30 minutes. Select the following conditions for grinding: · 10 ceramic balls (3 balls of 5 mm and 7 balls of 2 mm) · Temperature: Ventilated chamber environment - room temperature · Grinding time: 30 minutes

[0330] Prepare the solid residue in a 4 mL PTFE vial.

[0331] Salt with scNF11 - L - ascorbic acid - ethHAR001GRI015: Weigh 40 mg of the API and L-ascorbic acid, which is 28.3 mg of the salt-forming agent, into a grinding jar containing 10 ceramic balls (3 balls of 5 mm and 7 balls of 2 mm). Seal the container. Insert the grinding jar into a Fritsch Micromill Pulverisette 7 and grind the sample for 30 minutes. Select the following conditions for grinding: · 10 ceramic balls (3 balls of 5 mm and 7 balls of 2 mm) · Temperature: Ventilated chamber environment - room temperature · Grinding time: 30 minutes

[0332] Prepare the solid residue in a 4 mL vial made of PTFE.

[0333] Salt with scNF12-phosphoric acid - ethHAR001EXP115: Weigh 40 mg of the active ingredient into a 4 mL vial. Add 1 mL of water at 25 °C, seal the container, and stir on a magnetic stirrer plate for 10 minutes. Quickly add phosphoric acid (9.8 μL) to the solution. Seal the vial properly by additional application of a screw cap and parafilm. Place the vial on a magnetic stirrer using the following parameters: · Stirring speed: 1000 rpm · Temperature: Draft environment - RT · Stirring time: 5 days

[0334] Check the suspension daily to confirm its homogeneity. After 5 days, filter the slurry through a 13 mm Hirsch funnel fitted with Whatman (registered trademark) filter paper No. 540. Dry the solid residue in air (for about 1 hour), and then place it in a new clean 4 mL vial equipped with a PTFE seal.

[0335] Salt with scNF13-L-tartaric acid - ethHAR001EVA019: Weigh 40 mg of the active ingredient and 28.3 mg of the salt-forming agent, L-tartaric acid, into a 4 mL vial. Add 4 mL of pyridine at 25 °C, seal the container, and stir on a magnetic stirrer plate for 10 minutes. Store the syringe, cannula, and 0.2 μm ReZist® syringe filter attachment in a dry cabinet preheated to 25 °C. Quickly and completely aspirate the solution with the syringe, filter it through a 0.2 μm ReZist® filter, and transfer it to a new 4 mL vial at 25 °C for the evaporation experiment. After the evaporation experiment, seal the sample.

[0336] Salt with scNF14-L-ascorbic acid - ethHAR001EVA020: Weigh 40 mg of the active ingredient and 33.2 mg of the salt-forming agent, L-ascorbic acid, into a 4 mL vial. Add 4 mL of pyridine at 25 °C, seal the container, and stir on a magnetic stirrer plate for 10 minutes. Store the syringe, cannula, and 0.2 μm ReZist® syringe filter attachment in a dry cabinet preheated to 25 °C. Quickly and completely aspirate the solution with the syringe, filter it through a 0.2 μm ReZist® filter, and transfer it to a new 4 mL vial at 25 °C for the evaporation experiment. After the evaporation experiment, seal the sample.

[0337] Characterization of the new salt form Qualitative solubility (temperature dependence) Set up 4 glass jacketed beakers of 250 mL, connect them with silicone hoses, and connect them to a Julabo F25 HE thermostat so that the temperature can be set. Each beaker has a Pt100 sensor for monitoring the temperature, a stopper with a hole sealed with a play fabric, and a vial holder with space for 4 4 mL vials for quadruple solubility measurements. Place the beakers on a powerful magnetic stirrer plate so that the temperature is distributed as homogeneously as possible in the liquid medium. Use water as the medium. Connect the Pt100 sensor and Julabo to a measuring computer that can control the Julabo and read the temperature of the Pt100 sensor.

[0338] To measure the solubility by weight in mass percent, a Sartorius LE26P microbalance with an accuracy of ±0.01 mg is used.

[0339] Into a 4 mL vial, 1 - 2 mL of each solvent is placed and a magnetic stirrer is attached. Then, the solid to be measured is added until supersaturated. The prepared vial is sealed, placed in a vial holder, and equilibrated in the apparatus at the test temperature for 48 hours. After 24 hours, equilibrium should be reached between the solid and liquid phases. The liquid phase is removed and transferred to a second vial through a Whatman 20 μm PTFE pre - syringe filter. The instruments used, such as the pre - syringe filter, syringe, and cannula, are first cooled or heated to the measurement temperature. First, the second vial is emptied, then the weight of the solution is measured, and finally it is evaporated again to ensure a constant mass. Then, the solubility can be calculated in mass percent from this data.

[0340] X - ray diffraction During the salt screening, 14 new solid entities were found. The X - ray diffraction patterns including that of harmine are shown in Figures 15 - 29.

[0341] Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) The thermal behaviors (DSC and TGA) of the provided sample (ethHAR001) and all the prepared salts scNF01 - scNF12 are shown in Figures 35 - 47. The results of the thermal tests are summarized in Table 8 below.

[0342] Table 8. Summary of DSC and TGA results

[0343]

Table 8 - 1

[0344]

Table 8 - 2

[0345] Thermal behavior of various salts To investigate the thermal behavior of various salts, TGA / DSC measurements were carried out (see Table 8 above). It can be observed that all salts show a mass change up to 160 °C. In contrast, in order to investigate the "nature" of the mass loss, so-called preparative DSC measurements were carried out. Therefore, further DSC measurements were performed at various temperatures, and subsequently powder X-ray diffraction measurements were performed after sample cooling. The results and the defined temperatures are summarized in Table 10.

[0346] Table 10. Results of preparative DSC experiments

[0347]

Table 10

[0348] Spectroscopy Since all the salts prepared showed insufficient thermal properties, the focus was placed on phosphates. All other experiments were aborted. To investigate whether the salts prepared were hydrogen phosphates or dihydrogen phosphates, several spectra of the prepared phosphate (ethHAR001EXP115-scNF12), potassium hydrogen phosphate, and potassium dihydrogen phosphate were collected and compared with each other. The results are shown in Figure 61.

[0349] The figure shows that experiment ethHAR001EXP115 forms a halo-like curve at 500 - 1250 cm-1 corresponding to the behavior of the spectrum of potassium hydrogen phosphate salt. Therefore, it can be concluded that the salt prepared is also a hydrogen phosphate and not a dihydrogen phosphate. In the salt formed, not all the important signals of dihydrogen phosphate are detected.

[0350] Property evaluation The property evaluation of the newly discovered solid phase was carried out by the following methods: XRPD, polarized light microscopy (PLM), DSC, TGA, IR, and 1 1H-NMR.

[0351] If previous test results by XRPD method and DSC / TGA combined method have already shown that the new form cannot be used in subsequent galenic processes, the complete characterization of the new entity was aborted within the framework of the dynamic screening process.

[0352] Table 11 below provides an overview of the characterization methods utilized for the new solid phase.

[0353] Table 11: Overview of the characterization methods for the new halmine solid state

[0354]

Table 11

[0355] Further analysis Micrographs of various halmine salts are shown in Figures 30 - 34. IR spectra of various halmine salts are shown in Figures 48 - 54.

[0356] Salt screening - Conclusion A total of 14 new solid state entities were obtained from the active ingredient halmine (solid - chemistry: ethHAR001) using 8 different salt - forming agents. The screening results indicate that halmine salts can be obtained from salt - forming experiments using both strong and weak acids. However, upon further investigation of the weak acid salts, it became clear that these new halmine salts exhibit numerous thermal phenomena in the low - temperature range, indicating the release of water molecules or solvent molecules of the formed hydrates or solvates. Furthermore, the complex thermograms indicate that decomposition reactions of the salt - forming agents occur (see Table 5). Therefore, the use of weak acids was discontinued in the screening, and instead strong acids such as methanesulfonic acid, sulfuric acid, and phosphoric acid were used as salt - forming agents. The three obtained strong acid salts were also subjected to thermal analysis.

[0357] Of the total three salts formed from strong acids, only the harmine-phosphate shows a promising DSC thermogram with one endothermic signal at 254.8 °C that can be assigned to the melting of the salt. The detected mass loss starts only at 240 °C (see Figure 36), and further solubility tests were performed on the phosphate of harmine. However, compared to the harmine-HCl salt, they do not show any improvement in solubility characteristics. Therefore, the inventors conducted a screening of various harmine compositions described in the following section to further investigate strategies for improving solubility.

[0358] Screening of Compositions Containing Harmine and Various Acids In the above-mentioned screening experiments of polymorphs and salts, no solid-state form of harmine with improved stability was obtained compared to standard harmine HCl. Therefore, the inventors prepared harmine of various compositions and conducted additional screening to examine their solubility in water.

[0359] For this purpose, aqueous solutions containing harmine and acids such as D-glucuronic acid, D-galacturonic acid, D-gluconic acid, tartaric acid, succinic acid, citric acid, mucic acid, ascorbic acid, acetic acid, aspartic acid, and glutamic acid were formed and tested for solubility. For this purpose, in a first experiment, 1 g of the free base of harmine was added to 5 g of dH2O to a final concentration of 20% (w / w). Then, the above acids were individually added to the solution in different molar ratios (e.g., 1:1 or 2:1) to examine whether the acid could solubilize the free base of harmine by protonation or complex formation.

[0360] Summary of Results Tartaric acid, succinic acid, citric acid, mucic acid, glutamic acid, and ascorbic acid were unable to solubilize harmine. All of these acids formed a paste of the same color as harmine. On the other hand, D-glucuronic acid, D-galacturonic acid, and D-gluconic acid showed a solubility of more than 15%. The high solubility is due to the sugar acid, and it is considered that a strong interaction occurs between harmine and the acid, forming a charge transfer complex. Glucuronic acid showed the highest solubility.

[0361] The compositions of the tested formulations and their solubilities are summarized in Table 12 below:

[0362] Table 12: Tested Compositions and Their Solubilities

[0363]

Table 12-1

[0364]

Table 12-2

[0365] Furthermore, Table 13 below shows the solubilities of various compositions of harmine and uronic acid, with the composition of harmine and glucuronic acid showing the highest solubility:

[0366] Table 13: Additional Tested Compositions and Their Solubilities

[0367]

Table 13-1

[0368]

Table 13-2

[0369] The mixtures and salts were further tested as follows.

[0370] A composition containing harmine and glucuronic acid in a 1:1 molar ratio was dissolved in water up to 25% (by combining 250 mg of harmine FB, 234 mg of glucuronic acid, and 1.0 g of water). A yellow transparent solution without particles was obtained, indicating that harmine (or its formed salt) was completely dissolved. The results of the dissolution are shown in Figure 6.

[0371] A composition containing harmine and galacturonic acid in a 1:1 molar ratio was dissolved in water up to 21% (by combining 212 mg of harmine free base, 212 mg of galacturonic acid, and 1.0 g of water). The solution thus obtained was transparent, indicating complete dissolution (Figure 8).

[0372] By combining 250 mg of harmine FB, 114 mg of glucuronic acid, 132 mg of galacturonic acid, 60 mg of acetic acid, and 1.0 g of water, a composition containing harmine, glucuronic acid, and galacturonic acid in a 1:1:1 molar ratio was dissolved in water up to 25%. A yellow transparent solution without particles, indicating complete dissolution, was obtained (Figure 8).

[0373] By combining 212 mg of harmine FB, 180 mg of glucose, 90 mg of acetic acid, and 1.0 g of water, a composition containing harmine, glucose, and acetic acid in a 1:1:1.5 molar ratio was dissolved in water up to 21%. As shown in Figure 9, this composition is soluble in water.

[0374] By combining 212 mg of harmine FB, 90 mg of fructose, 67 mg of malic acid, and 1.0 g of water, a composition containing harmine, fructose, and malic acid in a 1:0.5:0.5 molar ratio was dissolved in water up to 21%. A transparent solution was obtained (Figure 10).

[0375] Conclusion - Screening of Compositions Containing Harmine and Various Acids Therefore, the inventors have surprisingly identified novel compositions and / or salts of harmine with high solubility in water.

[0376] Therefore, it has been shown that a specific composition containing harmine as described in claim 1 exhibits improved solubility compared to harmine free base or harmine hydrochloride. In the most promising compositions containing harmine and glucuronic acid, very high solubility was obtained. For this reason, harmine glucuronate was formed and characterized as described in the "Characteristic Evaluation" of the previous salt screening section. The formation of harmine glucuronate and the analysis of its characteristics are described below:

[0377] Formation of harmine glucuronate Weigh equimolar amounts of harmine and glucuronic acid and place both substances in a beaker equipped with a magnetic stirrer. Add deionized water (diH2O) while stirring until a clear solution is formed. Typically, a harmine concentration of >20% can be easily achieved. That is, 1 g of harmine (+ equimolar amount of glucuronic acid) dissolves easily in 5 mL of water (i.e., final volume 5 mL). For example, about 3 mL of diH2O can be added while stirring until the solid dissolves. Then, use a syringe to inject diH2O until the final volume reaches 5 mL. Then stir this solution again until a homogeneous solution is obtained. Evaporate the clear solution with a RotaVap until a completely dry precipitate is obtained.

[0378] Solubility test The solubility of harmine phosphate is considerably lower than that of the hydrochloride. At least, in view of the data in water. On the other hand, the weight solubility of harmine glucuronate is about 8 times that of harmine hydrochloride at 25°C. Thus, harmine glucuronate exhibits extremely improved solubility compared to the two harmine salts. This property could be further enhanced by the amorphous structure of the precipitate. The solubility is summarized in Table 14 below and Figures 59 and 60:

[0379] Table 14: Comparison of the solubility of harmine phosphate, harmine HCl, and harmine glucuronate in H2O and EtOH at 25°C and 37°C

[0380] [Table 14]

[0381] NMR Analysis of Harmine Glucuronate The NMR analysis of harmine glucuronate indicates that the molar ratio of harmine and glucuronic acid is maintained. Furthermore, a new powder diffractogram is detected after recrystallization, which may indicate the formation of a salt or co-crystal. Here, since the ΔpKs value of both compounds is 4.27, the possibility of salt formation is high. To confirm this result, a powder diffractogram of purer glucuronic acid must be recorded for comparison. The NMR of harmine glucuronate is shown in Figures 56 and 57.

[0382] PXRD Analysis of Harmine Glucuronate The PXRD of harmine glucuronate shows a completely amorphous structure of harmine glucuronate (Figures 55 + 58), which can also explain the high solubility. The electron micrograph of harmine glucuronate supports the hypothesis of a completely amorphous structure (Figure 11).

[0383] Part 2: Development of an Oral Mucosal Formulation of Harmine with Improved Bioavailability, Less First-Pass Metabolism, and Improved Palatability Purpose of the study. In this study, the aim was to identify a sublingual harmine formulation with excellent 1) pharmaceutical properties (e.g., physical / chemical stability, scalability of the manufacturing process), 2) pharmacokinetic properties (high bioavailability, low variability of plasma levels between / within subjects), and 3) patient compliance (e.g., palatability (e.g., bitterness, etc.), ease of handling). The formulations are summarized in Table 15 below and will be described in the following sections.

[0384] Table 15. Overview of the Developed Harmine Sublingual Formulations F1 - F7

[0385]

Table 15

[0386] Formulation 1: The harmine free base was ground and sieved (0.1 mm). A 100 mg dose was placed between the gum and lip of a volunteer to investigate the mucosal absorption of the compound. Even after more than 1 hour had elapsed, most of the compound was still present in the cheek, indicating that the ability of harmine to pass through the mucosa is very low. Therefore, this approach was not investigated further.

[0387] Formulation 2: The harmine hemifumarate was ground and sieved (0.1 mm). 125 mg (equivalent to 100 mg of harmine free base) was placed between the gum and lip of a volunteer to investigate the mucosal absorption of the compound. Even after more than 1 hour had elapsed, most of the compound was still present in the cheek, indicating that the ability of harmine to pass through the mucosa is very low. Therefore, this approach was not investigated further.

[0388] Formulation 3: Harmine HCl (4000 mg) and mannitol (bulking agent; 4000 mg) were dissolved in 20 mL of water at 50 °C. Then, this solution was quickly transferred to an aluminum mold (0.5 mL per cavity (equivalent to 100 mg)). In view of the low stability of the solution at low temperature (crystal formation of harmine HCl), the solution was shock frozen at -80 °C and then transferred to a freeze dryer pre-cooled to -80 °C to prevent thawing of the sample. Then, the sample was freeze-dried for 36 hours. Then, the melt tablets were given to 10 healthy volunteers to evaluate the plasma profile. Thereby, 200 mg (equivalent to 170 mg of harmine free base for 2 melt tablets) was placed between the gum and lip of a volunteer to investigate the mucosal absorption of the compound. In all volunteers, the melt tablets completely dissolved within 15 - 30 minutes. The PK profile is shown in Figure 13.

[0389] Formulation 4: A sublingual drop formulation containing harmine hemisuccinate and DMT hemisuccinate was formulated by sequentially dissolving both compounds in dH2O (first harmine, then DMT). The final formulation contained 750 mg of harmine glucuronate (equivalent to 375 mg of harmine FB) and 165 mg of DMT hemisuccinate (equivalent to 125 mg of free DMT base) in 2.5 mL of dH2O. The volume of the sublingual formulation (0.1 mL) was dispensed sublingually (using a 0.1 mL Eppendorf pipette), and then the sublingual dose was administered to 4 beagle dogs (2 males and 2 females) by keeping the mouth closed for at least 30 seconds to allow the formulation to be absorbed. A total of 5 administrations were given at 20-minute intervals (t0, t20 min, t40 min, t60 min, t80 min) to achieve the total dose.

[0390] Formulation 5: Fast-disintegrating sublingual tablets were manufactured using TIP particles. Thus, harmine HCl was dissolved in EtOH (99.8%) to a concentration of 1% (m / v). The specific amount of TIP particles was calculated such that the loading coefficient of the particles was 25%. Then, the EtOH was slowly evaporated over 4 hours using a rotary evaporator. From the scanning electron microscope photographs, it was revealed that external crystallization of harmine HCl was significant and the loading of the particles had failed, so this batch was discarded without further evaluation (Figure 12). It was thought that the failure of loading was due to supersaturation of the ethanol solution and the formation of crystals of harmine HCl, so the experiment was repeated with a lower concentration (Formulation 6).

[0391] Formulation 6: A fast-disintegrating sublingual tablet was prepared using TIP particles. Thus, harmine HCl was dissolved in EtOH (99.8%) to a concentration of 0.1% (m / v). The specific amount of TIP particles was calculated such that the particle loading coefficient was 25%. Subsequently, the ethanol solution was added to the exact amount of TIP particles, and the EtOH was slowly evaporated over 4 h using a rotary evaporator. Scanning electron micrographs revealed no external crystallization of harmine hydrochloride, indicating successful particle loading (Figure 12). A sublingual dose was administered to one healthy volunteer by placing a powder equivalent to 20 mg of harmine free base sublingually. A total of five doses were administered at 20-min intervals (t0, t20 min, t40 min, t60 min, t80 min) to achieve a total dose of 100 mg.

[0392] Formulation 7: A fast-disintegrating sublingual tablet was prepared using TIP particles. Thus, harmine glucuronate could be dissolved in dH2O to a concentration of 25% (m / v). The specific amount of TIP particles was calculated such that the particle loading coefficient was 25%. Subsequently, this aqueous solution was slowly dropped onto the powder (in a Petri dish) and continuously stirred to obtain a uniform paste. The paste was then air-dried overnight at room temperature. Scanning electron micrographs revealed no external crystallization of harmine glucuronate, indicating successful particle loading (Figure 12). Formulation 7 was evaluated in a planned PKPD study (Part 4), which is described in detail below.

[0393] Palatability. The bitterness of each formulation (F1–7) was examined in five volunteers using a “numerical bitterness rating scale of 0–10” (0 = none, 1–3 = mild, 4–6 = moderate, 7–10 = severe).

[0394] Pharmacokinetics. The pharmacokinetic properties were investigated in humans and dogs. More specifically, F1 and F2 were tested in three healthy volunteers. Since neither formulation was absorbed from the mucosa (the majority of the administered dose still remained in the cheek even after more than 1 hour had elapsed), no further investigation was carried out on the PK profile. F3 was tested in ten healthy volunteers, F4 was tested in four beagle dogs (two males and two females), F6 was tested in one healthy volunteer, and F7 was tested in eight healthy volunteers (detailed in Part 4). F5 was not further tested in humans in view of the unsuccessful manufacturing process (incomplete loading of harmine HCl onto the TIP carrier system) and the inability to scale up the process to industrial scale.

[0395] Blood analysis for human PK trials: DMT was purchased from Cayman (Ann Arbor, USA), harmine and NMT (N-ω-methyltryptamine) were purchased from Sigma-Aldrich (St. Louis, USA), and DMT-d6 was purchased from Toronto Research Chemicals (Toronto, Canada). All other chemicals used were of the highest available grade. To prepare the samples, 200 μL of plasma, 50 μL of internal standard (IS) (20 ng / mL DMT-d6), and 50 μL of methanol (MeOH) were added to a tube. Proteins were precipitated by adding 400 μL of acetonitrile (ACN), the samples were shaken for 10 minutes, and centrifuged at 10,000 rpm for 5 minutes. A further 350 μL of the supernatant was transferred to an autosampler vial, evaporated to dryness under a gentle nitrogen stream, and reconstituted with 250 μL of eluent mixture (98:2, v / v). Calibrant and quality control (QC) samples were prepared as appropriate by replacing MeOH with the calibrant or QC solution. Samples were analyzed 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 phase consisted of a mixture of water (eluent A) and ACN (eluent B), both containing 0.1% formic acid (v / v). A Kinetex C18 column (100×2.1 mm, 1.7 μm) (Phenomenex, Aschaffenburg, Germany) was used, and the flow rate was set at 0.5 mL / min with the following gradient: starting conditions 98% eluent A for 0.8 minutes, decreasing to 60% within 6.7 minutes, then rapidly decreasing to 8% within 0.1 minutes. These conditions were held for 0.9 minutes and switched to the starting conditions for re-equilibration for 0.5 minutes. The mass spectrometer was operated in positive electrospray ionization mode with multiple reaction monitoring events scheduled. The following transitions from precursor ions to product ions were selected: DMT, m / z 189.1→58.2, DMT-D3, m / z, 195.1→64.1, harmine, m / z 213.0→169.2, NMT, m / z 175.1→144.0.The calibration standard substance concentration ranges were 0.5 ng / mL to 60 ng / mL for DMT, 3 ng / mL to 360 ng / mL for harmine, and 0.5 ng / mL to 60 ng / mL for NMT. Therefore, the lower limit of sensitivity was 0.5 mg / mL for DMT, 3 ng / mL for harmine, and 0.5 ng / mL for NMT.

[0396] Blood analysis for human PK trials: Plasma samples were analyzed using the established RGA2 LC-MS / MS assay. Harmine, DMT, harmol, and DMT N-oxide were weighed and dissolved in acetonitrile / dimethyl sulfoxide (50 / 50, v / v). Stock solutions of harmine and DMT N-oxide were prepared in amber glass, and stock solutions of DMT and harmol were prepared in non-light-shielded glass. Calibration standard substances and QC stock solutions were diluted with acetonitrile to obtain a 200 μg / mL solution, and further diluted with dog plasma (K2EDTA) to obtain solutions with matrix concentrations of 1.00 to 5000 ng / mL. Nifedipine was used as the internal standard for harmine, DMT, harmol, and DMT N-oxide. This was dissolved in dimethyl sulfoxide, further diluted with acetonitrile, and added at a solution concentration of 0.02 μg / mL. Dilutions of calibration standard substances and QC were prepared in plastic, and the internal standard solution was prepared in amber glass.

[0397] Extraction of plasma samples Control dog plasma (K2EDTA), standard substances, QC, or test samples (50 μL) were dispensed into the bottom of a 96-well round-bottom plate. Proteins were precipitated by adding 150 μL of internal standard substance to calibration standard substances, QC, single blanks, and test samples (150 μL of acetonitrile to double blanks). The plate was vortexed and centrifuged at 2400 × g for 5 minutes at a temperature set to maintain 4°C. Using a Tomtec robot, 150 μL of deionized water / formic acid (100 / 0.2, v / v) was dispensed into a clean 96-well round-bottom plate, followed by 75 μL of the supernatant. The plate was then vortexed briefly and centrifuged at 2400 × g for 5 minutes at a temperature set to maintain 4°C before analysis.

[0398] Result Loading of harmine or its salt onto TIP particles: Figure 12 shows SEM images of the failure to load harmine HCl (A; 1% in EtOH) onto TIP and the successful loading of harmine HCl (B; 0.1% in EtOH) and harmine glucuronate (C; 25% in H2O). As shown, TIP particles can load harmine HCl, but only when using very low substance concentrations (0.1%) in organic solvents such as EtOH. Loading at higher concentrations (1%) causes external crystallization. Furthermore, when using H2O as the solvent, it induces rapid precipitation of HRM HCl as the free base when exposed to the basic residues within the TIP particles. Therefore, in view of the immiscibility of H2O as a solvent and the low solubility of HRM HCl in EtOH, a loading solution with a concentration of 0.1% in EtOH had to be used. However, this is 1) not practical for large-scale handling (e.g., 1 Kg of HRM HCl has to be dissolved in 1000 L of EtOH, which is impractical, expensive, and also causes additional risks of using flammable / explosive solvents), and 2) the final loading results are very poor in view of the very low concentration of HRM HCl in the loading solution. Regarding the latter point, it could be shown that the loading process of TIP particles is most efficient when adding a highly concentrated drug substance solution (in either EtOH, H2O, or DMSO) to the particles.

[0399] Exceptional results were obtained when loading harmine glucuronate onto TIP particles. This is mainly due to the high solubility of harmine glucuronate in H2O (about 45% at room temperature) and its ability to form a stable solution even when exposed to the basic residues of TIP particles. This property of HRM GLU is thought to be due to its highly amorphous structure, resulting in less crystallization compared to HRM HCl (which easily crystallizes as the free base especially when exposed to the basic residues within TIP particles).

[0400] Thus, handling harmin glucuronate on a large scale is very practical (for example, up to 1 Kg of HRM GLU can be dissolved in 1 L of water), and it can be very efficiently supported on TIP particles.

[0401] Palatability. Five volunteers scored the bitterness of formulations F1 - F7 on a numerical rating scale of 0 - 10 (0 = none, 1 - 3 = mild, 4 - 6 = moderate, 7 - 10 = severe). As shown in Table 16, F3 and F4 were scored as having severe bitterness, while all other formulations had no perceived bitterness or were mild.

[0402] Table 16. Bitterness scores of F1 - F7 on a numerical rating scale of 0 - 10 (0 = none, 1 - 3 = mild, 4 - 6 = moderate, 7 - 10 = severe) by five volunteers. Mean values, standard deviation (SD), and severity range are shown.

[0403]

Table 16

[0404] Pharmacokinetic properties. Figure 12 shows the plasma profiles of harmine and its hepatic metabolite harmol after administration of A) HRM HCL (reference state) as an oral capsule, B) F3, C) F4, and D) F6 to 10 healthy volunteers. As shown in Panels A and B, the bioavailability of harmine increases by delivery via the sublingual route, most likely because sublingual absorption is more efficient than gastrointestinal absorption and first-pass metabolism is reduced. The reduction in first-pass metabolism after sublingual administration compared to oral administration is even clearer when comparing the ratio of harmine to its hepatic metabolite harmol, which is a direct indicator of first-pass metabolism. After oral administration of HRM HCl (A), the ratio of harmine to harmol is approximately 2:1 (80 ng / mL:30 ng / mL). After sublingual administration of F3 (B), the ratio of harmine to harmol increases to approximately 4:1 (100 ng / mL:25 ng / mL), indicating avoidance of first-pass metabolism via the sublingual route. This effect is even more pronounced when using the sublingual drops of HRM GLU (F4) instead of the sublingual ODT of HRM HCl (F3). In this case (F4), the ratio of harmine to harmol is approximately 50:1 (250 ng / mL:5 ng / mL), which may be due to the highly efficient mucosal absorption of HRM GLU (although not wishing to be bound by theory). Due to the high solubility of HRM GLU, a high concentration gradient may occur between the formulation and the mucosal tissue, increasing the absorption of HRM GLU through the mucosa. Furthermore, its amorphous structure may also improve the ability to pass through the membrane. Similarly, the TIP particles loaded with HRM HCl (F6) had a reduced first-pass metabolism compared to the oral or sublingual HRM HCl (F3) formulations, resulting in a ratio of harmine to harmol of approximately 7:1 (70 ng / mL:10 ng / mL). The difference in the ratio of harmine to harmol after administration of F4 and F6 may be due to the fact that in Experiment C, a much higher dose of harmine was administered (8 vs. 1.3 mg / kg BW), which may have saturated the harmine-degrading enzyme system and caused an unbalanced increase in the level of harmine compared to its metabolite harmol.

[0405] In addition to the ratio of harmine to harmol as an indicator of first-pass metabolism, the Cmax value also indicates the ratio of the drug absorbed into the blood system. Again, sublingual administration leads to an improvement in bioavailability (due to better absorption and reduced first-pass metabolism), such that the average Cmax value is approximately 80 ng / mL for oral administration (A) of HRM HCl at about 3.5 mg / kg, whereas it is substantially higher, at about 100 ng / mL, for sublingual administration (B) of F3 at about 2.8 mg / kg BW. Similarly, when F4 at about 8 mg / kg BW was administered sublingually, despite being administered not as a bolus but in five equal increments at 20-minute intervals (t0, t20 min, t40 min, t60 min, t80 min), the average Cmax value was 250 ng / mL. Therefore, it is predicted that a higher Cmax value would result if the entire dose of F4 were administered as a bolus, further clearly indicating that the bioavailability of harmine is higher after sublingual administration compared to oral administration. Interestingly, when F6 at about 1.3 mg / kG BW was administered sublingually, despite being administered not as a bolus but in five equal increments at 20-minute intervals (t0, t20 min, t40 min, t60 min, t80 min), the Cmax was 70 ng / mL. Therefore, it is predicted that a higher Cmax value would result if the entire dose of F6 were administered as a bolus, further clearly indicating that the bioavailability of harmine is higher after sublingual administration compared to oral administration.

[0406] Conclusion: In summary, for sublingual delivery of harmine, bioavailability is higher and first-pass metabolism is reduced compared to oral administration. This was the case for formulations F3, F4, and F6. In any case, F3 and F4 were evaluated as extremely bitter, so the use of these formulations is substantially limited. Furthermore, severe bitterness (similarly for taste masking agents such as flavorings or sweaters) induces saliva production, increases swallowing, which likewise shortens the residence time of the compound within the oral mucosa cavity, increasing dose loss due to first-pass metabolism and PK variability. Therefore, F6 represents a preferred formulation that exhibits high bioavailability, low first-pass metabolism, very good palatability, and can be easily manufactured not only on a small scale but also on a large scale (e.g., using a high-shear mixer). Based on this data, in view of the high solubility and membrane permeability properties of harmine glucuronate compared to harmine HCl, F7 is considered to exhibit performance equal to or better than F6.

[0407] Part 4: Planned PKPD study using novel harmine formulations (open-label, within-subject dose-response study of DMT and harmine in healthy subjects) Participants and study design: Eight healthy female and male subjects (25 - 45 years old, BMI 18.5 - 30) without a current or past history of neurological or psychiatric disorders and no first-degree relative with a history of Axis-I psychiatric disorders will be recruited by medical screening. In this open-label pilot study, acute subjective effects and blood samples are measured after administration of various ratios and escalating doses of DMT and harmine as sublingual single preparations. Furthermore, on one study day, participants are given DMT only as a sublingual preparation. Since this is a dose-setting study, participants are given a preferred dose range and can discontinue / continue administration of further doses within specified limits to enhance safety and tolerability.

[0408] Pharmacological intervention: Prepare a standardized and quality-controlled sublingual pharmahuasca formulation containing N,N-dimethyltryptamine hemifumarate and harmine glucuronate according to the well-established pharmaceutical procedures described in Part 2 of this section (Formulation 7). Manufacture a fast-disintegrating sublingual tablet made using TIP particles by powder blending 1) TIP particles loaded with harmine glucuronate and 2) TIP particles loaded with N,N-DMT hemifumarate such that the final strength per dose is 20 mg of DMT (calculated value of the corresponding free base amount) and 20 mg of harmine (calculated value of the corresponding free base amount), or 5 mg of DMT (calculated value of the corresponding free base amount) and 5 mg of harmine (calculated value of the corresponding free base amount) for low-dose conditions.

[0409] More specifically, prepare TIP particles loaded with harmine glucuronate as follows: Dissolve harmine glucuronate in dH2O to a concentration of 25% (m / v). Calculate the specific amount of TIP particles such that the loading coefficient of the particles is 25%. Then, slowly drip this aqueous solution onto the powder (in a Petri dish) and continuously stir to obtain a uniform paste. Then, air-dry the paste at room temperature overnight.

[0410] Similarly, prepare TIP particles loaded with N,N-DMT hemifumarate as follows: Dissolve N,N-DMT hemifumarate in EtOH (>99%) to obtain a 10% solution. Add the ethanol solution to the exact amount of TIP particles and slowly evaporate the EtOH using a rotary evaporator for 2 hours at 40 °C, 100 mbar, with a N2 flow of 0.8 bar.

[0411] On the day of the test, the participants are administered the tablets sublingually under the supervision of the experimenter. The sublingual preparation administers DMT and harmine at 20-minute intervals with a maximum of three fixed increments while varying the fixed bolus doses of DMT and harmine. Specifically, four different dosing conditions are tested with the DMT:harmine ratio varying as 1:1, 1:0.5, 1:2, and 1:0 (DMT:harmine). Thus, the maximum dose of 100 mg of DMT is co-administered with 0 / 50 / 100 / 200 mg of harmine. The dose ratios of 1:1, 1:0.5, and 1:2 are administered in a randomized order, and the condition of DMT only is tested on the last day of the test (Day 4).

[0412] Study procedure: On all test days, blood samples are taken from the left median cubital vein of the participants at 12 time points, i.e., at baseline and 20, 40, 60, 80, 100, 120, 180, 240, 300, 360, and 420 minutes after administration, to analyze the concentrations of DMT and harmine in the plasma. The venous catheter is connected to a Heidelberger plastic tube extension to collect blood samples without disturbing the subjects during the hallucinatory experience. The venous line is kept in place while slowly dripping heparinized saline (1000 IU heparin in 0.9 g NaCl / dL; HEPARIN Bichsel; Bichsel AG, 3800 Unterseen, Switzerland) at 10 mL / h. The blood samples are immediately centrifuged at 2000 RCF for 10 minutes, and the plasma samples are stored frozen at -80 °C until assay.

[0413] During the baseline period and through the drug action periods at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, and 360 minutes after administration, the intensity of the subjective effects (psychometric measurement of acute effects) is monitored. A series of well-established computer-based psychometric tools are included, such as visual analog scales for various drug effects and side effects, the altered states of consciousness evaluation scale (5D / 11D-ASC), visual analog scale (VAS), and drug adverse effects (AES). As secondary assessment items, questionnaires for difficult experiences (CEQ), positive-negative affect schedule (PANAS), emotional breakthrough inventory (EBI), Psy-Flex questionnaire (Psy-Flex), nature relatedness scale (NR6), questionnaire for persisting effects (PEQ), MINDSENS composite index (MS), questionnaire for acceptance and action II (AAQ), gratitude questionnaire (GQ-6), affective neuroscience personality scale (ANPS), connectedness questionnaire (C-SOW), sex-oxford compassion scale (SOCS), visual self-transcendence scale (VST), psychological insight scale (PIS-6), questionnaire for psychological insight (PIQ), and other well-established questionnaires such as the symptom checklist (SCL-90-R) are used.

[0414] Participants are screened for (severe) side effects, including evaluations (visual analog scale: 1 - 10) based on questionnaires for physical and mental discomfort, dyspnea, palpitations, chest pain or abdominal pain, unpleasant body sensations / muscle pain, headache, nausea, vomiting, and fainting by the attending physician throughout the experimental period at baseline, 30 minutes, 60 minutes, 120 minutes, 240 minutes, and 480 minutes after drug administration. Vital signs (systolic / diastolic blood pressure, heart rate, body temperature, blood oxygen concentration) are monitored throughout the test period at baseline, 30 minutes, 60 minutes, 120 minutes, 240 minutes, and 360 minutes after drug administration. The same protocol is used on all test days.

[0415] References 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. 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. 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. Dominguez - Clave, E. et al., 2016. Ayahuasca: Pharmacology, neuroscience and therapeutic potential. Brain research bulletin. 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. Nichols, D. E., 2016. Psychedelics. Pharmacological Reviews, 68(2), pp. 264 - 355. 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. 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. Sanacora, G. et al., 2016. Balancing the Promise and Risks of Ketamine Treatment for Mood Disorders. 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.

[0416] Part 5: Preparation of the crystalline form of DMT hemisuccinate DMT hemisuccinate Form B: Preparation using MEK (methyl ethyl ketone) DMT (41.3 mg) was dissolved in MEK (800 μL), and then heated to 50 °C. Succinic acid (12.95 mg) dissolved in water (300 μL) was added to the DMT solution. Thereafter, the solution was cooled to room temperature and placed in the refrigerator for 12 hours, but no solid was formed. Then, the solution was transferred to a Schlenk vial. LSM was completely dried at 50 °C under vacuum. The residue was an off-white powder containing a little oily residue.

[0417] Preparation using 2-propanol DMT (44.3 mg) was dissolved in 2-propanol (1000 μL), and then heated to 50 °C. Succinic acid (13.90 mg) dissolved in water (300 μL) was added to the DMT solution. Thereafter, the solution was cooled to room temperature and placed in the refrigerator for 12 hours, but no solid was formed. Then, the solution was transferred to a Schlenk vial. LSM was completely dried at 50 °C under vacuum. The residue was a white powder and there was no oily residue.

[0418] 1 The identity of the compound was confirmed using 1H NMR measurement (see Figure 62). Spectra were acquired at room temperature in deuterated solvent (d6-DMSO) on a Bruker Advance DRX 400 spectrometer (400 MHz). Information regarding the chemical shift δ is given in ppm relative to the irradiation frequency. The signal of the deuterated solvent was used as an internal standard.

[0419] DMT hemisuccinate Form A: Variant example using MEK (methyl ethyl ketone) Approximately 2 g of DMT (0.5) was transferred to a 100 mL Schlenk flask and filled with water to approximately 20 mL. Approximately 0.5 M NaOH solution was added until pH 10 was reached and stabilized (at least 15 mL). Here, the free base precipitated and then became oily. The product was extracted with 80 mL of MTBE, and the solvent was completely removed using a rotary evaporator. The obtained oil was taken up in n-heptane (5 mL) and recrystallized. The crystals were filtered and dried. Yield 1.34 g DMT

[0420] DMT (1 g) was dissolved in MEK (25 mL), and then heated to 50 °C. Succinic acid (0.5 equimolar) dissolved in water (5 mL) was added to the DMT solution. 20 mL was distilled off, and the remaining solution was stored in the refrigerator for 3 hours. Since crystallization was not observed, the solvent evaporated almost completely within 10 days. The molasses-like residue crystallized within another 4 days. The product had a slight yellow color. The product was DMT hemisuccinate Form A and contained a trace amount of DMTS.

[0421] For powder X-ray diffraction (XRPD), the sample was placed in a standard glass capillary (φ = 0.7 mm). Measurements were carried out at room temperature while rotating the sample in transmission mode using a D8 Bruker Advance diffractometer (Cu-Kα1 = 1.54059 Å, Johansson primary beam monochromator, position-sensitive detector). Data were collected in the 2θ range of 2 - 40°. The tube voltage and current were 40 kV and 40 mA, respectively. Measurements were performed for both Form A and Form B. The peak tables are shown below.

[0422]

Table 17-1

[0423]

Table 17-2

[0424]

Table 17-3

[0425]

Table 17-4

[0426] Part 6: Production of TIP-based ODTs Containing Harmine Gluconate and DMT Hemisuccinate in Various Ratios

[0427]

Table 18

[0428] Procedure

Table 19

[0429]

Table 20

[0430]

Table 21

[0431] Procedure

Table 22

[0432]

Table 23

[0433] By XRPD measurement (performed as described in Part 5), it was revealed that DMT hemisuccinate was formed in the TIP particles, as discussed in the following specific examples.

[0434] Loading of TIP (template-inverted particles / Ca5[(OH)(PO4)3]) Loading of DMTS [20%], neutralized with 1 equivalent of NaOH Preparation of DMT succinate solution (neutralized): 202.4 mg of DMT succinate was placed in a beaker. 0.4 mL of water and 0.2 mL of ethanol were added. The mixture was heated slightly (40 °C) and stirred until a clear solution was obtained. NaOH (1N solution) was added very slowly (to prevent precipitation of DMT) and stirred until a clear solution was formed. The pH was approximately 7. The entire solution was drawn up into a 2 mL syringe.

[0435] Loading of TIP particles: 808.4 mg of TIP was weighed and placed in a crystallization dish (the smaller the better - this ensures that the solution falls on the powder rather than on the walls or bottom of the container). The crystallization dish was heated to 40 °C on a hot plate. Next, approximately 0.25 mL of DMTS solution was slowly spread directly onto the powder. Using a spatula, it was stirred to homogeneously distribute the liquid throughout the powder by reducing any lumps. If the powder appeared to be very wet beforehand, the powder was dried briefly (40 °C + convection). The dropwise / intermediate drying procedure was repeated until the total volume was added. To prevent overwetting of the powder (and thus the risk of external crystallization), it may be dripped quickly at first and slowed down towards the end (when most of the particles are already loaded). The final product was dried in several steps. XRPD analysis revealed the presence of DMT hemisuccinate in the TIP particles (see Figure 63).

[0436] Manufacture of ODT tablets: The amounts of 1) harmine gluconate-loaded TIP, 2) DMT hemisuccinate-loaded TIP, 3) unloaded TIP, 4) Ac-Di-Sol, 5) menthol, 6) sucralose, and 7) peppermint flavor shown in the following table were blended (for 10 minutes) using a Turbula powder mixer. Then, each tablet (15 mm) was manually compressed using a tableting press.

[0437]

Table 24

[0438] Part 7: Double-Blind, Randomized, Two-Arm Dose-Response Study of DMT and Harmine in Healthy Subjects (Open-Label, Within-Subject Dose-Response Study of DMT and Harmine in Healthy Subjects) Participants and Study Design: Twelve healthy female and male subjects (25 - 45 years old) without a current or past history of neurological or psychiatric disorders and without a first-degree relative with a history of Axis-I psychiatric disorders were recruited by medical screening. In this double-blind pilot study, acute subjective effects and blood samples were measured after administration of escalating doses of DMT and harmine as single sublingual preparations. Furthermore, on the 4th day of the trial, participants were administered either DMT or harmine only as a sublingual preparation according to group assignment. Study participants had completed a telephone and medical screening prior to study enrollment. This study was approved by the Canton Ethics Committee of Zurich (Basec-Nr. 2022-00973) and the Swiss Federal Office of Public Health (BAG-Nr. (AB)-8 / 5-BetmG-2022 / 018086). All participants provided written informed consent in accordance with the Declaration of Helsinki and received financial compensation for study completion.

[0439] Study Setting: This study was conducted during the day in a group therapy room with furniture to provide a comfortable living room atmosphere with dimmable lighting and an acoustic system. Throughout the entire study day, a standard playlist including non-stimulating BGM was played to provide comfort and a sense of relaxation, with periods of silence in between. On the study day, substances were co-administered to a maximum of 4 participants with the experimenter always present in the room for supervision.

[0440] 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 in Part 2 of this section (Formulation 7). The sublingual formulation was manufactured by blending the drug with calcium phosphate, a GRAS (Generally Recognized As Safe) excipient, to form a homogeneous powder blend. Additionally, sucralose (sweetener) and flavors of orange, menthol, or peppermint were added for taste masking. The final formulation was compressed into fast-disintegrating tablets using TIP particles by powder blending 1) TIP particles loaded with harmine glucuronate and 2) TIP particles loaded with N,N-DMT hemisuccinate such that the final strength per dose was 0 - 60 mg of harmine (corresponding to the free base) and 0 - 40 mg of DMT (corresponding to the free base), and administered at three dosing intervals every 20 minutes.

[0441] More specifically, TIP particles loaded with harmine glucuronate were manufactured as follows: Harmine glucuronate was dissolved in dH2O to a concentration of 25% (m / v). The specific amount of TIP particles was calculated such that the loading coefficient of the particles was 25%. This aqueous solution was then slowly dripped onto the powder (in a Petri dish) and continuously stirred to obtain a uniform paste. The paste was then air-dried at room temperature overnight.

[0442] Similarly, TIP particles loaded with N,N-DMT hemisuccinate were manufactured as follows: N,N-DMT hemisuccinate was dissolved in EtOH (>99%) to obtain a 10% solution. The ethanol solution was added to an exact amount of TIP particles, and the EtOH was slowly evaporated using a rotary evaporator for 2 hours at 40 °C, 100 mbar, with a N2 flow of 0.8 bar.

[0443] On the day of the test, under the supervision of the experimenter, the tablets were sublingually administered to the participants on an empty stomach (last meal > 10 hours, last beverage > 90 minutes). The sublingual preparation was administered in two fixed increments of DMT and harmine at 20-minute intervals while varying the fixed bolus doses of DMT and harmine, resulting in three administrations over 40 minutes. Specifically, seven different dosing conditions were tested with a varying DMT:harmine ratio within the dose range of 0 - 120 mg of DMT and 0 - 180 mg of harmine. The dose ratio of harmine to DMT ranged from 0 - 2 (w / w) and was administered to two groups in two different orders, in a single-blind, within-subject, sequential ascending order.

[0444] At baseline, 0, 20, 40, 60, 85, 120, 150, 180, 240, 300, 540, 1440 (= 24 hours) after administration, the strength of the subjective effects (psychometric measurement of acute effects) was monitored. A series of well-established computer-based psychometric tools were included, such as the Visual Analogue Scale (VAS) for various drug effects and side effects, the Altered States of Consciousness Rating Scale (5D / 11D-ASC), the Acute Subjective Drug Effect (VAS), and the Adverse Drug Effect (AES). As secondary evaluation items, other well-established questionnaires were used, such as the Mystical Experience Questionnaire (MEQ), the Challenging Experience Questionnaire (CEQ), the Emotional Breakthrough Inventory (EBI), the Psy-Flex Questionnaire (Psy-Flex), the Persisting Effects Questionnaire (PEQ), the MINDSENS Composite Index (MS), the Gratitude Questionnaire (GQ-6), the Affective Neuroscience Personality Scale (ANPS), the Watts Connectedness Scale (WCS), the Self-Compassion Scale - Sex - Oxford (SOCS), the Visual Self-Transcendence Scale (VST), the Psychological Insight Scale (PIS-6), the WHO-5 Well-being Index (WHO-5), the Perceived Stress Scale (PSS), the Griffiths Significance Rating (GSR), the Brief Symptom Checklist (BSCL), the User Experience Questionnaire (USX), the Sleep Quality Scale - Short (SQS-S), etc.

[0445] Participants were screened by the investigators throughout the experimental period for (severe) side effects including evaluation based on a questionnaire (visual analog scale: 1 - 10) at baseline, 0, 20, 40, 60, 85, 120, 150, 180, 240, and 360 minutes after drug administration. The following side effect items were evaluated: physical symptoms / discomforts (dyspnea, palpitations, chest pain, stomach pain, unpleasant body sensations / muscle pain, headache, nausea, vomiting, syncope), mental symptoms / discomforts (unspecified discomfort, anxiety disorder, panic, delusions, excitement, dissociation, reduced vigilance). Vital signs (systolic / diastolic blood pressure, heart rate, blood oxygen concentration) were monitored throughout the experimental period at baseline, 0, 20, 40, 60, 85, 120, 150, 180, 240, 300, 540, 1440 (= 24 hours) after drug administration. ECG was measured at baseline, 75, 150, 300, 540, and 1440 minutes after administration. Body temperature was measured at baseline, 75, 180, 300, 540, and 1440 minutes after administration. The same protocol was used on all test days. Participants were released on the last day of the test but returned for evaluation the next day, 24 hours after the first substance administration.

[0446] On all test days, blood samples were taken from the left median cubital vein at 15 time points, namely at baseline and at 0, 20, 40, 60, 70, 85, 100, 120, 150, 180, 240, 300, 420, 540, 1440 minutes after administration to analyze the concentrations of DMT and harmine in plasma. The venous catheter was connected to a Heidelberger plastic tube extension to take blood samples without disturbing the subjects during the hallucination experience. The venous line was kept in place while heparinized saline (1000 IU heparin in 0.9 g NaCl / dL; HEPARIN Bichsel; Bichsel AG, 3800 Unterseen, Switzerland) was slowly infused (10 mL / h). Blood samples were immediately centrifuged at 2000 RCF for 10 minutes and plasma samples were stored frozen at -80°C until assay.

[0447] 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 chemicals used were of the highest available grade. To prepare the samples, 50 μL of an internal standard (IS) mixture (40 ng / mL DMT-d6 and harmine-d3) and 50 μL of methanol (MeOH) were added to 200 μL of plasma. Proteins were precipitated by adding 400 μL of acetonitrile (ACN). The samples were shaken for 10 minutes and centrifuged at 10,000 rpm for 5 minutes. 350 μL of the supernatant was transferred to an autosampler vial, evaporated to dryness under a gentle nitrogen stream at room temperature, and reconstituted with 100 μL of an eluent mixture (98:2, v / v). External calibration substances and quality control (QC) samples were prepared as appropriate by replacing MeOH with the calibration substance or QC solution mixture. Calibration substances and QC samples containing 3-IAA were prepared separately by replacing plasma with 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 analyzed using 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 phase consisted of a mixture of water (eluent A) and ACN (eluent B), both containing 0.1% formic acid (v / v).A Kinetex C18 column 50×2.1 mm, 2.6 μm (Phenomenex, Aschaffenburg, Germany) was used, and the flow rate was set to 0.5 mL / min with the following gradient: starting condition 98% eluent A, decreasing to 70% within 4 minutes, then rapidly decreasing to 5% within 1 minute, holding for 0.5 minute, returning to the starting condition in 1.5 minutes, and the total run time was 7 minutes as a result. The mass spectrometer was operated in positive electrospray ionization mode with multiple reaction monitoring events scheduled. The following transitions from precursor ions to product ions were selected as quantitative 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.

[0448] As part of the aforementioned test (Part 7; actual PKPD test), the PK profiles were quantified from two representative subjects who took high-dose (180 mg) of halmint glucuronate together with a fixed dose of 90 mg of DMT formulated with TIP. As explained above, under the supervision of the experimenter, at fasting (last meal > 10 hours, last beverage > 90 minutes), the ODT was sublingually administered at three fixed dosing intervals every 20 minutes. On both test days, blood samples were collected from the left median cubital vein at 15 time points, namely, at baseline and at 0, 20, 40, 60, 70, 85, 100, 120, 150, 180, 240, 300, 420, 540, and 1440 minutes after dosing, in order to analyze the concentrations of DMT and halmint in plasma. The venous catheter was connected to a Heidelberger plastic tube extension to collect blood samples without disturbing the subjects during the hallucinatory experience. The venous line was left in place while slowly dripping heparinized saline (1000 IU heparin in 0.9 g NaCl / dL; HEPARIN Bichsel; Bichsel AG, 3800 Unterseen, Switzerland) at 10 mL / h. The blood samples were immediately centrifuged at 2000 RCF for 10 minutes, and the plasma samples were frozen and stored at -80 °C until assay. The quantification of halmint in plasma was performed according to the method described in the previous paragraph. The results are shown in Figure 64. This experiment demonstrates that the glucuronate of halmint formulated in this way is biologically available.

[0449] Part 8: Bitterness of Halmint Glucuronate Formulation In the rotary evaporation process, halmint HCL was loaded onto TIP particles at a drug loading rate of 30% using ethanol. After removing 90% of the initially used solvent, a small amount of water was added to the rotary evaporator and then dried. Water was added to initiate the ionization of halmint HCL and calcium hydroxide on the surface of the loaded TIP particles.

[0450] The taste of masked preparations was compared using a physical mixture of TIP and harmine HCl. The physical mixture had an aversive bitter taste due to harmine HCl. The TIP preparation was tasteless.

[0451] The capillary sorption process was used to load harmine glucuronate onto TIP particles with a drug loading rate of 25% using water.

[0452] The taste of masked preparations was compared using a physical mixture of TIP and harmine glucuronate. The physical mixture had an aversive bitter taste due to harmine glucuronate. The TIP preparation had significantly less bitterness.

[0453] The loaded TIP particles are shown in Figure 65.

[0454] The bitterness of six different harmine formulations was examined in five volunteers using a "numerical bitterness rating scale of 0 - 10" (0 = none, 1 - 3 = mild, 4 - 6 = moderate, 7 - 10 = severe). Thus, an amount of formulation corresponding to 20 mg of harmine free base was administered to the sublingual area of the volunteers. The manufacturing procedures of Formulations 1 - 6 are presented below. The summary of the tested formulations and the tasting results of the compounds are presented in the following table:

[0455]

Table 25

[0456] Manufacturing procedures of the tested formulations Formulation 1: Harmine free base was ground and sieved (0.1 mm). Formulation 2: Harmine hemifumarate was ground and sieved (0.1 mm). Formulation 3: Harmine HCl (4000 mg) and mannitol (bulking agent; 4000 mg) were dissolved in 20 mL of water at 50 °C. Subsequently, this solution was quickly transferred to an aluminum mold (0.5 mL per cavity (equivalent to 100 mg)). In view of the low stability of the solution at low temperatures (crystal formation of harmine HCl), the solution was shock-frozen at -80 °C and then transferred to a freeze dryer pre-cooled to -80 °C to prevent thawing of the sample. Formulation 4: A sublingual drop containing harmine glucuronate was prepared by dissolving the compound in dH2O. The final solution contained 750 mg of harmine glucuronate (equivalent to 375 mg of harmine FB) in 2.5 mL of dH2O. Formulation 7: Fast-disintegrating sublingual tablets were manufactured using TIP particles. Thus, harmine HCl was dissolved in EtOH (99.8%) to obtain a concentration of 0.1% (m / v). The specific amount of TIP particles was calculated such that the loading coefficient of the particles was 25%. Subsequently, the ethanol solution was added to the exact amount of TIP particles, and EtOH was slowly evaporated over 4 hours using a rotary evaporator. Formulation 6: Fast-disintegrating sublingual tablets were manufactured using TIP particles. Thus, harmine glucuronate was dissolved in dH2O to obtain a concentration of 25% (m / v). The specific amount of TIP particles was calculated such that the loading coefficient of the particles was 25%. Subsequently, this aqueous solution was slowly dropped onto the powder (in a Petri dish) and continuously stirred to obtain a uniform paste. Then, the paste was air-dried at room temperature overnight.

[0457] Further examples and / or embodiments are disclosed in the following numbered items.

[0458] 1. A composition comprising harmine or a pharmaceutically acceptable salt thereof (preferably harmine) and (i) uronic acid, or (ii) a carboxylic acid and a monosaccharide present preferably in a molar ratio of 0.5 to 2.0, more preferably in a molar ratio of about 1:1.

[0459] 2. The composition according to item 1, wherein the uronic acid of halmine and (i) or the carboxylic acid of halmine and (ii) are present in a molar ratio of 0.5 to 2.0, preferably a molar ratio of about 1:1.

[0460] 3. The composition according to item 1 or 2, comprising halmine and uronic acid, preferably comprising a salt of halmine and uronic acid.

[0461] 4. The composition according to any one of items 1 to 3, which is an amorphous composition or contains a natural deep eutectic solvent.

[0462] 5. A salt of halmine and uronic acid.

[0463] 6. The composition according to any one of items 1 to 4 or the salt according to item 5, wherein the uronic acid is glucuronic acid or galacturonic acid.

[0464] 7. The composition according to item 1 or 2, wherein the carboxylic acid is malic acid or acetic acid and / or the monosaccharide is glucose or fructose.

[0465] 8. (a) The composition according to any one of items 1 to 4, 6, or 7 or the salt according to item 5 or 6 and a pharmaceutically acceptable carrier, and (b) DMT or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and A kit of parts.

[0466] 9. (a) The composition according to any one of items 1 to 4, 6, or 7 and / or the salt according to item 5 or 6 and (b) DMT or a pharmaceutically acceptable salt thereof and A pharmaceutically acceptable carrier, and A pharmaceutical composition.

[0467] 10. (a) The composition according to any one of items 1 to 4, 6, or 7 and / or the salt according to item 5 or 6 and a pharmaceutically acceptable carrier, and A pharmaceutical composition comprising

[0468] 11. The composition according to any one of items 1 to 4, 6, or 7, the salt according to item 5 or 6, the kit of parts according to item 8, or the pharmaceutical composition according to item 9 or 10 for use as a medicament.

[0469] 12. The composition according to any one of items 1 to 4, 6, or 7, the salt according to item 5 or 6, the kit of parts according to item 8, or the pharmaceutical composition according to item 9 for use in the treatment and / or prevention of mental disorders, psychosomatic disorders, or physical disorders.

[0470] 13. The composition, salt, kit of parts, or pharmaceutical composition for use as described in item 12, wherein the mental disorder is selected from depression, stress-related mood disorder, major depressive disorder, mood swings, treatment-resistant depression, burnout syndrome, anxiety disorder, post-traumatic stress disorder, addiction, eating disorder, and obsessive-compulsive disorder.

[0471] 14. The composition or salt for use as described in item 12 or 13, wherein the composition or the salt is administered simultaneously with, separately from, or sequentially with DMT or a pharmaceutically acceptable salt thereof.

[0472] 15. The composition or salt for use as described in item 14, or the kit of parts or pharmaceutical composition for use as described in item 12 or 13, wherein the ratio of harmine to DMT is 0.5 to 2.0, preferably about 1.0.

[0473] 16. Harmine and DMT are administered incrementally, Preferably, each increment of harmine is 5 mg to 80 mg, and / or each increment of DMT is 5 mg to 50 mg, and / or the total dosage of harmine is 100 mg to 300 mg, and / or the total dosage of DMT is 50 mg to 150 mg, and / or the interval between increments is 5 minutes to 60 minutes, or Harmine and DMT are administered as a single bolus dose, Preferably, the total dosage of harmine is 5 mg to 200 mg and / or the total dosage of DMT is 5 mg to 100 mg A composition for use as described in item 14 or 15, a salt for use as described in item 14 or 15, a kit of parts for use as described in any one of items 12, 13, or 15, or a pharmaceutical composition for use as described in any one of items 12, 13, or 15.

[0474] 17. A composition for use as described in any one of items 14 to 16, in which harmine and / or DMT is administered sublingually, a salt for use as described in any one of items 14 to 16, a kit of parts for use as described in any one of items 12, 13, 15, or 16, or a pharmaceutical composition for use as described in any one of items 12, 13, 15, or 16.

[0475] 18. A composition as described in any one of items 1 to 4, 6, or 7, a salt as described in item 5 or 6, or a pharmaceutical composition as described in item 10 for use in the treatment and / or prevention of a disease or disorder selected from Parkinson's disease, Alzheimer's disease and other types of dementia, stroke, multiple sclerosis, neurodegeneration / inflammation, nerve damage due to excessive substance abuse, autonomic dysfunction, pain syndromes, cardiovascular disorders, cancer, infectious diseases (preferably caused by fungal infection, helminth infection, or bacterial infection), diabetes, autoimmune diseases, asthma, bronchitis, and arthritis.

Claims

1. Harmine or a pharmaceutically acceptable salt thereof, (i) Uronic acid, or (ii) Carboxylic acids and monosaccharides present in a molar ratio of 0.5 to 2.0, A composition containing the following:

2. The composition according to claim 1, wherein harmine and (i) uronic acid, or harmine and (ii) carboxylic acid are present in a molar ratio of 0.5 to 2.

0.

3. The composition according to claim 2, wherein harmine and (i) uronic acid, or harmine and (ii) carboxylic acid are present in a molar ratio of about 1:

1.

4. A composition according to any one of claims 1 to 3, comprising harmine or a pharmaceutically acceptable salt thereof, and uronic acid.

5. The composition according to claim 4, comprising harmine and a salt of uronic acid.

6. The compound according to any one of claims 1 to 3, wherein harmine or a pharmaceutically acceptable salt thereof is harmine.

7. The composition according to any one of claims 1 to 3, which is an amorphous composition or contains a natural deep eutectic solvent.

8. Harmine and uronic acid salts.

9. The composition according to any one of claims 1 to 3 or the salt according to claim 8, wherein the uronic acid is glucuronic acid or galacturonic acid.

10. The composition or salt according to claim 9, wherein the uronic acid is glucuronic acid.

11. The composition according to claim 1 or 2, comprising harmine or a pharmaceutically acceptable salt thereof, present in a molar ratio of 0.5 to 2.0, and (ii) carboxylic acids and monosaccharides.

12. The composition according to claim 11, wherein harmine or a pharmaceutically acceptable salt thereof, and (ii) carboxylic acids and monosaccharides are present in a molar ratio of about 1:

1.

13. The composition according to claim 1 or 2, wherein the carboxylic acid in (ii) is malic acid or acetic acid and / or the monosaccharide in (ii) is glucose or fructose.

14. (a) A composition according to any one of claims 1 to 3 or a salt according to claim 8 and a pharmaceutically acceptable carrier, (b) DMT or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, A kit of parts, including...

15. (a) The composition according to any one of claims 1 to 3 and / or the salt according to claim 8, (b) DMT or a pharmaceutically acceptable salt thereof, A pharmaceutically acceptable carrier, A pharmaceutical composition containing the following:

16. (a) The composition according to any one of claims 1 to 3 and / or the salt according to claim 8, A pharmaceutically acceptable carrier, A pharmaceutical composition containing the following:

17. The composition, the salt, the kit of parts (or parts), or the pharmaceutical composition is formulated using carrier particles having a secondary internal structure, preferably the carrier particles comprising hydroxyapatite, according to any one of claims 1 to 3, the salt according to claim 8, (X) (a) A composition according to any one of claims 1 to 3 or a salt according to claim 8 and a pharmaceutically acceptable carrier, (b) DMT or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, kit of parts, or (Y) (a) The composition according to any one of claims 1 to 3 and / or the salt according to claim 8, (b) DMT or a pharmaceutically acceptable salt thereof, A pharmaceutically acceptable carrier, A pharmaceutical composition containing the following:

18. A composition for use as a pharmaceutical, according to any one of claims 1 to 3, a composition comprising the salt according to claim 8, (X) (a) A composition according to any one of claims 1 to 3 or a salt according to claim 8 and a pharmaceutically acceptable carrier, (b) DMT or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, kit of parts, or (Y) (a) The composition according to any one of claims 1 to 3 and / or the salt according to claim 8, (b) DMT or a pharmaceutically acceptable salt thereof, A pharmaceutically acceptable carrier, A pharmaceutical composition containing the following:

19. A composition according to any one of claims 1 to 3, for use in the treatment and / or prevention of mental illness, psychosomatic illness, or physical illness, comprising the salt according to claim 8, (X) (a) A composition according to any one of claims 1 to 3 or a salt according to claim 8 and a pharmaceutically acceptable carrier, (b) DMT or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, kit of parts, or (Y) (a) The composition according to any one of claims 1 to 3 and / or the salt according to claim 8, (b) DMT or a pharmaceutically acceptable salt thereof, A pharmaceutically acceptable carrier, A pharmaceutical composition containing the following:

20. A composition comprising the composition for use or a salt of the composition for use, kit of parts for use, or pharmaceutical composition for use according to claim 19, wherein the mental disorder is selected from depression, stress-related affective disorder, major depressive disorder, dysthymia, treatment-resistant depression, burnout syndrome, anxiety disorder, post-traumatic stress disorder, addiction, eating disorder, and obsessive-compulsive disorder.

21. A composition, kit of parts for use, or pharmaceutical composition for use comprising the composition or salt for use according to claim 19, wherein the composition or salt is administered simultaneously, separately, or sequentially with DMT or a pharmaceutically acceptable salt thereof.

22. Preferably, the ratio of harmine to DMT is 0.5 to 2.0, preferably about 1.0, and comprising the composition for use or a salt according to claim 19, a kit of parts for use, or a pharmaceutical composition for use.

23. A composition, kit of parts, or pharmaceutical composition for use comprising the composition or salt for use according to claim 19, wherein harmine and / or DMT are administered sublingually.

24. Harmine and DMT were administered in gradually increasing doses. Preferably, each increment of harmine is 5 mg to 80 mg, and / or each increment of DMT is 5 mg to 50 mg, and / or the total dose of harmine is 100 mg to 300 mg, and / or the total dose of DMT is 50 mg to 150 mg, and / or the interval between increments is 5 minutes to 60 minutes. A composition for use or a composition comprising a salt according to claim 19, a kit of parts for use, or a pharmaceutical composition for use.

25. Harmine and DMT were administered as a single bolus dose. Preferably, the total dose of harmine is 5 mg to 200 mg and / or the total dose of DMT is 5 mg to 100 mg. A composition for use or a composition comprising a salt according to claim 19, a kit of parts for use, or a pharmaceutical composition for use.

26. DMT or a pharmaceutically acceptable salt thereof is DMT hemisuccinate. (X) (a) A composition according to any one of claims 1 to 3 or a salt according to claim 8 and a pharmaceutically acceptable carrier, (b) DMT or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, kit of parts, (Y) (a) The composition according to any one of claims 1 to 3 and / or the salt according to claim 8, (b) DMT or a pharmaceutically acceptable salt thereof, A pharmaceutically acceptable carrier, A pharmaceutical composition containing,

27. For use in the treatment and / or prevention of diseases or disorders selected from Parkinson's disease, Alzheimer's disease and other types of dementia, stroke, multiple sclerosis, neurodegeneration / inflammation, nerve damage due to excessive substance abuse, autonomic dysfunction, pain syndromes, cardiovascular disorders, cancer, infectious diseases (preferably caused by fungal, helminthic, or bacterial infections), diabetes, autoimmune diseases, asthma, bronchitis, and arthritis, the composition according to any one of claims 1 to 3, the composition comprising the salt according to claim 8, or (Z) (a) The composition according to any one of claims 1 to 3 and / or the salt according to claim 8, A pharmaceutically acceptable carrier, A pharmaceutical composition containing the following:

28. DMT hemisuccinate.

29. X-ray powder diffraction pattern containing a peak of approximately 16.14 ± 0.2° (2θ) (Cu-Kα １ The crystalline form A of the salt according to claim 28, characterized by the following:

30. The aforementioned X-ray powder diffraction pattern (Cu-Kα １ The crystal form according to claim 29, further comprising one or more peaks selected from 13.50±0.2°, 17.84±0.2°, 19.67±0.2°, 21.81±0.2°, 23.19±0.2° and 25.36±0.2° (2θ).

31. X-ray powder diffraction pattern (Cu-Kα) containing a peak of approximately 15.57 ± 0.2° (2θ) １ The crystalline form B of the salt according to claim 30, characterized by the following:

32. The aforementioned X-ray powder diffraction pattern (Cu-Kα １ The crystal form according to claim 31, further comprising one or more peaks selected from 10.09±0.2°, 16.52±0.2°, 16.82±0.2°, 17.06±0.2°, 19.34±0.2°, 19.93±0.2°, 21.13±0.2°, 22.91±0.2°, and 23.45±0.2° (2θ).

33. A method for masking the bitterness of a compound, The compound is harmine or a pharmaceutically acceptable salt thereof, or DMT or a pharmaceutically acceptable salt thereof, and the method includes supporting a bitter compound on carrier particles. a) The carrier particles include a supported cavity, and the carrier particles include a basic salt, b) A method in which the bitter taste of the compound is masked by the carrier particles during absorption into the oral mucosa.

34. A pharmaceutical composition containing carrier particles, a) A carrier particle containing a support cavity and containing a basic salt, b) A compound having a bitter taste, which is harmine or a pharmaceutically acceptable salt thereof, or DMT or a pharmaceutically acceptable salt thereof. Includes, A pharmaceutical composition in which the bitter taste of the compound is masked by the carrier particles during absorption into the oral mucosa.

35. A method for masking the bitterness of a pharmaceutical composition comprising the compound described in claim 33 or the carrier particles described in claim 34, wherein the carrier particles are a) A step of combining a carrier material with a template material, wherein the carrier material forms a primary structure around the template material, b) A step of deforming the template material, c) A step of removing the deformed template material, d) A step to obtain carrier particles having a secondary internal structure A method obtained by [meaning].

36. A method for masking the bitter taste of a pharmaceutical composition comprising the compound described in claim 33 or the carrier particles described in claim 34, The template material is an inorganic material or consists mainly of an inorganic material, and / or A method wherein the carrier material is an inorganic material or consists mainly of an inorganic material.

37. A method for masking the bitterness of a pharmaceutical composition comprising the compound described in claim 33 or the carrier particles described in claim 34, wherein the carrier material and the template material are inorganic salts or consist mainly of inorganic salts.

38. A method for masking the bitterness of a pharmaceutical composition comprising the compound described in claim 33 or the carrier particles described in claim 34, wherein the combination of the carrier material with a template material includes chemical precipitation, lamination, and / or crystallization of the carrier material on the template material. Removing the template material includes dissolving the deformed template material to form a secondary internal structure, and / or Deforming the template material involves heating it to a temperature of 600°C to 1200°C, preferably. a) Including heating to a temperature of 600°C to 900°C, b) The step of deforming the template material includes baking and / or c) A method wherein the step of deforming the template material includes the subsequent addition of water, and preferably the addition of water is an exothermic reaction.

39. A method for masking the bitterness of a pharmaceutical composition comprising the compound described in claim 33 or the carrier particles described in claim 34, wherein the template material comprises calcium carbonate and / or The carrier material comprises at least one salt and / or complex selected from the group consisting of calcium phosphate and magnesium phosphate, preferably, a) The carrier particles have a diameter of 1 to 300 μm, b) The carrier particles have a surface area of ​​15 m² / g to 400 m² / g, c) The secondary internal structure includes pores having diameter sizes in the range of ≥0.2 μm and ≤1.5 μm, and / or d) A method wherein the total volume of the secondary internal structure in the carrier particles having the obtained secondary internal structure is in the range of ≥10% to ≤90% of the particle volume.

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