New compositions and methods

Abstract

This disclosure provides novel transmucosal and subcutaneous pharmaceutical compositions and methods of preparation and use thereof, the pharmaceutical compositions comprising 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalo-8-yl)-but-1-one or 1-(4-fluoro-phenyl)-4-((6bR,10aS)-2,2-d2-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalo-8-yl)-but-1-one in the form of a free base, eutectic or salt.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201880018346.0, which was filed on March 23, 2018, and was entitled "New Composition and Method".

[0002] Cross-references to related applications

[0003] This application claims priority to U.S. Provisional Application No. 62 / 476,538, filed March 24, 2017, the contents of which are incorporated herein by reference in their entirety.

[0004] field

[0005] This disclosure relates to certain novel transmucosal and subcutaneous pharmaceutical formulations comprising substituted heterocyclic fused γ-carboline, the preparation of such formulations and methods of using them, for example, in the treatment of 5-HT-related diseases. 2A Diseases or disorders mediated by receptors, serotonin transporter (SERT), and / or dopamine D1 / D2 receptor signaling pathways. This invention includes methods for treating and / or preventing diseases and disorders, including but not limited to anxiety, psychosis, schizophrenia, sleep disorders, sexual dysfunction, migraine, headache-related disorders, social phobia, gastrointestinal disorders such as gastrointestinal motility disorders and obesity; depression (including major depressive disorder (MDD)) and mood disorders associated with psychosis or Parkinson's disease; psychosis such as schizophrenia associated with depression; bipolar disorder (e.g., bipolar depression); and other psychotic and neurological disorders, as well as combinations with other medications. background

[0006] 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaloline-8-yl)-but-1-one (sometimes called 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaloline-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone or ITI-007) has the following structure:

[0007]

[0008] The compound of formula I is a potent 5-HT 2A The receptor ligand (Ki = 0.5 nM) has an affinity for the dopamine (DA) D2 receptor (K). i =32nM) and serum plasma membrane transport protein (SERT)(K i=26 nM, with a strong affinity for 3H-mipramine binding displacement assay using recombinant human SERT, but with antipsychotics (e.g., H1 histamine, 5-HT). 2c The binding of the compound to muscarinic receptors (with negligible cognitive and metabolic side effects) is minimal. This compound is currently being used in clinical trials, for example, to treat schizophrenia, bipolar disorder, and dementia, including Alzheimer's disease. Compounds of Formula I and their analogues, therapeutic methods comprising such compounds, and methods for preparing such compounds are disclosed in, for example, U.S. Patents US 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; RE39,680; RE39,679; U.S. Patent Publications US 2004 / 209864, 2010 / 113781, 2011 / 071080, 2011 / 112105, 2013 / 0202692, 2015 / 0079172, 2017 / 0183350; and PCT Publications WO 2017 / 165843 and WO 2017 / 117514. The contents of these U.S. Patents, U.S. Patent Publications, and PCT Publications are incorporated herein by reference in their entirety.

[0009] Deuterated variants of ITI-007 are generally disclosed in US 2017 / 0183350 and WO 2017 / 165843. Deuterated compounds are designed to slow or inhibit metabolism in vivo by substituting hydrogen atoms of ITI-007 at molecular positions that serve as targets for metabolic activity with deuterated atoms. The natural metabolites of ITI-007 possess pharmacological activity but exhibit slightly different receptor selectivity characteristics. Therefore, these deuterated derivatives can thus provide altered pharmacokinetic profiles due to modified metabolic rates or pathways, and due to changes in the overall pharmacological characterization resulting from altered balance shifts between active parent species and active metabolites.

[0010] One such deuterated compound is 1-(4-fluoro-phenyl)-4-((6bR,10aS)-2,2-d2-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaloline-8-yl)-but-1-one, i.e., compounds of formula II:

[0011]

[0012] Another type of deuterated compound is 1-(4-fluoro-phenyl)-4-((6bR,10aS)-1,1,2,2-d4-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaloline-8-yl)-but-1-one, i.e., compounds of formula III:

[0013]

[0014] Compounds of Formulas I, II, and III each undergo significant first-pass metabolism in the liver. This high metabolic rate necessitates the administration of higher oral doses than other routes, leading to increased hepatic burden, higher manufacturing costs, formulation difficulties, and potentially greater patient-to-patient variability in dose response. Therefore, new routes of administration are needed to avoid first-pass metabolism, which would result in correspondingly lower dosing requirements.

[0015] It has been disclosed that transmucosal delivery of many drugs, such as sublingual, buccal, and intranasal delivery, as well as subcutaneous delivery, are effective alternatives to traditional dosage forms such as parenteral and oral administration. Parenteral (intravenous) administration is highly effective in avoiding first-pass metabolism, but its usefulness is limited because it requires administration by trained professionals (typically in a clinical setting). In contrast, transmucosal delivery systems can be used to formulate drugs that can be taken by patients without professional supervision, and can result in rapid drug absorption with minimal first-pass metabolism. Subcutaneous delivery similarly provides highly efficient drug absorption with minimal first-pass metabolism, while also offering the possibility of delayed or prolonged release (compared to IV administration).

[0016] The use of transmucosal drug delivery formulations is well-known, with sublingual nitroglycerin formulations dating back to 1847. These formulations involve the transfer of the active pharmaceutical ingredient across mucous membranes, including the oral, nasal, and vaginal mucous membranes. These mucosal surfaces are more permeable to drugs than the skin (keratinized epithelium) and have similar permeability to the gastrointestinal mucosa, but without the GI absorption of drugs that leads to immediate metabolism via the liver. Oral mucosal delivery systems include the buccal and sublingual systems.

[0017] Existing transmucosal delivery systems include rapidly disintegrating tablets and rice paper capsules, thin soluble films, aerosol sprays, soluble gels, and aqueous solutions. Examples of soluble film delivery systems include those disclosed in the following documents: Fuchs's U.S. Patent 4,136,145, Schmidt's U.S. Patent 4,849,246, Horstmann's U.S. Patent 5,629,003, Zerbe's U.S. Patent 5,948,430, Yang's U.S. Patent 9,108,340, Yang's U.S. Patent 8,906,277, Yang's U.S. Patent 8,900,498, Yang's U.S. Patent 8,900,497, Yang's U.S. Patent 8,652,378, Yang's U.S. Patent 8,603,514, Bryson's U.S. Patent 9,427,412, and Bryson's U.S. Patent 8,414,922. Other transmucosal delivery systems are disclosed in the following documents: Delbressine's US Patent 5,763,476 (solutions and solids for sublingual and buccal use), Amancha's US Patent 9,216,175 (sublingual spray), Kottayil's US Patent 8,835,459 (sublingual spray), and Chen's US Patent 6,552,024 (different mucosal delivery systems). However, some drugs, such as apomorphine, have been found to be tolerable and effective in some transmucosal delivery forms but intolerant and ineffective in others (see US Patent 9,427,412, which describes a lack of efficacy or tolerability for sublingual tablets and intranasal sprays, but not for sublingual films). Furthermore, each formulation must be coordinated with the specific active pharmaceutical ingredient to ensure reliable delivery. Therefore, despite the long history of transmucosal drug delivery, considerable effort is required to adapt any chosen transmucosal delivery technology to specific active pharmaceutical ingredients.

[0018] Subcutaneous injections are well-known in the field and are commonly used to administer insulin, morphine, methotrexate, and many other medications and vaccines. Subcutaneous injections are typically administered by clinicians and other healthcare professionals using conventional syringes with small needles, but many specialized devices exist for patients self-administering subcutaneous injections, such as pre-filled syringes, auto-injectors, and durable syringes. These devices include the HumatroPen (Eli Lilly, Indianapolis, Indiana, US) for insulin injections and the Otrexup auto-injector (AntaresPharma, Ewing, New Jersey, US) for methotrexate injections.

[0019] There is a need for improved drug delivery systems for the safe, effective, and reliable delivery of compounds of Formula I and / or Formula II. This disclosure provides novel transmucosal and subcutaneous formulations that deliver these compounds without the drawbacks of existing parenteral and oral delivery systems.

[0020] Brief

[0021] This disclosure relates to novel transmucosal and subcutaneous pharmaceutical formulations comprising 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyridino[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaloline-8-yl)-but-1-one and its deuterated variants in the form of a free base, eutectic, or salt. Transmucosal formulations include, but are not limited to, oral, nasal, and vaginal formulations in liquid, solid, and / or aerosol forms, including sublingual, buccal, intranasal, and intravaginal tablets, rice paper capsules, films, sprays, and gels.

[0022] Other applications of the invention will become apparent from the detailed description provided below. It should be understood that while the detailed description and specific embodiments illustrate preferred embodiments of the invention, they are intended for illustrative purposes only and are not intended to limit the scope of the invention. Invention Details

[0023] The following description of preferred embodiments is merely exemplary and is in no way intended to limit the scope of the invention, its application, or its uses.

[0024] When used in context, a range is used as a shorthand to describe each and every value that belongs to that range. Any value within the range may be chosen as an end value of the range. Furthermore, all references cited herein are incorporated herein by reference in their entirety. In the event of any conflict between the definition of this disclosure and the cited references, this disclosure shall prevail.

[0025] Unless otherwise specified, all percentages and amounts expressed herein and in other parts of this specification shall be understood as weight percentages. Specified amounts are based on the weight of the active ingredient in the form of a free base equivalent.

[0026] In a first embodiment, this disclosure provides a transmucosal pharmaceutical formulation (formulation 1) comprising 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyridino[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaloline-8-yl)-but-1-one (a compound of formula I) in the form of a free base, cocrystal, or salt. This disclosure also provides formulations as follows:

[0027] 1.1. Formulation 1, wherein the formulation comprises a compound of formula I in the form of a free base.

[0028] 1.2. Formulation 1, wherein the formulation comprises a compound of formula I, in the form of a salt, such as a pharmaceutically acceptable salt, optionally in the form of an amorphous solid or a crystalline salt; or in the form of a cocrystal, such as a nicotinamide or isonicotinamide cocrystal.

[0029] 1.3. Formulation 1.2, wherein the salt form is toluenesulfonate, oxalate, cycloamino acid salt, 4-aminosalicylate or hydrochloride, wherein the salt form is a crystalline salt.

[0030] 1.4. Any of the above-mentioned preparations, wherein the preparation comprises 0.01-100 mg of a compound of formula I (free base equivalent), for example 0.01-75 mg, 0.01-50 mg, 0.01-30 mg, 0.01-20 mg, 0.1-20 mg, 5-20 mg, 10-20 mg, 10-30 mg, 20-30 mg, 20-50 mg or 50-100 mg.

[0031] 1.5. Any of the above-mentioned preparations, wherein the preparation comprises 0.01-10 mg of a compound of formula I (free base equivalent).

[0032] 1.6. Any of the above-mentioned preparations, wherein the preparation comprises 0.05-8 mg of a compound of formula I (free base equivalent), for example 0.1-5 mg or 5-10 mg.

[0033] 1.7. Any of the above formulations further comprises one or more hydrophilic, water-soluble or water-swellable polymers.

[0034] 1.8. Formulation 1.7, wherein the polymer is selected from natural or modified fibrous polymers, polymers of ethylene oxide and / or propylene oxide, polymers containing acrylic monomers, natural or modified gums (e.g., xanthan gum), natural or modified starches (e.g., pregelatinized starch), or any mixture thereof.

[0035] 1.9. Any of the above formulations further comprises a hydrophobic polymer or a polymer that is poorly soluble in water, such as a silicone polymer or a polyalkylene polymer (e.g., polyethylene).

[0036] 1.10. Any of the above formulations further comprises one or more excipients selected from plasticizers, surfactants, desiccants, flavoring agents, sweeteners, binders, disintegrants, humectants (e.g., polyols), wetting agents, antioxidants, buffers (e.g., acids, bases and / or their salts), and thickeners (e.g., gelling agents).

[0037] 1.11. Formulation 1.10, wherein the one or more excipients are selected from any one of the following: alcohols (ethanol, glycerol, propylene glycol), gums (e.g., gum arabic, guar gum, agar, xanthan gum, tragacanth gum, tung oil gum, gelling sugar), polysaccharides and polysaccharide derivatives (e.g., starch, dextran, pectin, alginate, carrageenan, cellulose, cellulose derivatives (e.g., carboxymethyl cellulose, methyl cellulose, hydroxyalkyl cellulose (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose)), gelatin, including non-gelling and gelling types (e.g., mammalian gelatin such as bovine gelatin, poultry gelatin, fish gelatin, (e.g., a mixture of high molecular weight and low molecular weight gelatin), synthetic polymers (e.g., polyvinylpyrrolidone, polyethylene oxide and / or polypropylene oxide polymers and copolymers (e.g., beroxam, such as beroxam 188), polyacrylate polymers (e.g., carbomer), poly Amide polymers), sugars and sugar alcohols (e.g., dextran, lactose, galactose, glucose, ribose, sucrose, trehalose, mannitol, maltitol, lacritol, sorbitol, xylitol, erythritol, galactitol, inositol), polypeptides / proteins, amino acids, inorganic or organic acids (e.g., citric acid, lactic acid, malic acid, gluconic acid, benzoic acid, toluenesulfonic acid, phosphoric acid, sulfuric acid, hydrochloric acid, tartaric acid, oxalic acid, cyclohexane, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, formic acid) and their salts (e.g., sodium, potassium, calcium, magnesium, lithium, and ammonium salts of the acids listed above), inorganic or organic bases (e.g., alkali metal or alkaline earth metal carbonates, bicarbonates, hydroxides, and oxides), anionic surfactants (e.g., sodium lauryl sulfate, sodium polyoxyethylene alkyl sulfate, sodium dodecylbenzenesulfonate, sodium lauroyl sarcosinate, sodium stearate), and cationic surfactants (e.g., benzoyl ammonium, cetylpyridinium, cetrimonium). Halides, benzyl chloride), zwitterionic surfactants (e.g., cocoaminoalkyl betaine, such as cocoaminopropyl betaine), nonionic surfactants (e.g., fatty alcohol ethoxylates (e.g., polyethylene glycol polydodecyl ether), sorbitan esters (e.g., lauryl sorbitan, dehydrosorbitan monooleate, palm sorbitan, stearyl sorbitan, tristearate sorbitan), polyethoxylated sorbitan esters (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80), and antioxidants (e.g., ascorbic acid, sodium metabisulfite, BHT, BHA, TBHQ, propyl gallate, β-carotene, tocopherol, tocotrienol).

[0038] 1.12. Formulation 1.11, wherein any one or more of the excipients are present in an amount of 0.01-20% by weight of the formulation, for example 0.01-15% or 0.01-10% or 0.1-20% or 0.1-15% or 0.1-10% or 0.5-10% or 0.5-5% or 1-5% or 2.5-5% or 1-3% or 0.1-1%.

[0039] 1.13. Any of the above formulations, which do not contain added plasticizers, surfactants or humectants (e.g., polyols).

[0040] 1.14. Any of the above formulations, wherein the formulation comprises 0.01-99% water, for example 0.01-10% water, 0.01-5% water, 50-99% water, 75-99% water, or 25-75% water.

[0041] 1.15. Any of the above-mentioned preparations, wherein the preparation is an instant tablet or a rice paper capsule, such as a sublingual tablet or a rice paper capsule.

[0042] 1.16. Formulation 1 or any one of 1.1-1.14, wherein the formulation is an oral spray, such as a sublingual spray or a buccal spray.

[0043] 1.17. Formulation 1 or any one of 1.1-1.14, wherein the formulation is a fast-dissolving film, such as a sublingual film or a buccal film.

[0044] 1.18. Formulation 1.17, wherein the film is a single-layer or multi-layer film.

[0045] 1.19. Formulation 1.17 or 1.18, wherein the film has a uniform or substantially uniform thickness.

[0046] 1.20. Formulations 1.17, 1.18 or 1.19, wherein the compound of formula I is uniformly or substantially uniformly distributed in the film.

[0047] 1.21. Formulation 1 or any one of 1.1-1.14, wherein the formulation is an intranasal spray.

[0048] 1.22. Formulation 1 or any one of 1.1-1.14, wherein the formulation is an oral gel, such as an instant sublingual or buccal gel.

[0049] 1.23. Formulation 1 or any one of 1.1-1.14, wherein the formulation is an intravaginal formulation, such as an intravaginal fast-dissolving tablet, rice paper capsule or gel, or intravaginal spray or intravaginal fast-dissolving film.

[0050] 1.24. Any of the above formulations, wherein a compound of formula I is incorporated into the formulation as a microparticle (e.g., a particle having an average diameter of less than 50 μm, less than 30 μm, less than 10 μm, less than 5 μm, or less than 1 μm).

[0051] 1.25. Any of the above formulations, wherein a compound of formula I is incorporated into the formulation as nanoparticles (e.g., particles having an average diameter of less than 100 nm, less than 50 nm, or less than 10 nm).

[0052] 1.26. Any of the above formulations, wherein the formulation is absorbed (e.g., dissolved) by the mucous membrane within 30 seconds after application.

[0053] 1.27. Any of the above formulations, wherein the dosage of the compound of formula I is 1-20% of the daily dose for oral administration, for example 5-15% of the oral dose.

[0054] 1.28. Any of the above-mentioned formulations, wherein the formulation further comprises a compound of formula II or a compound of formula III or a combination thereof.

[0055] 1.29. Any of the above-mentioned preparations, wherein the preparation is formulated for administration once daily, twice daily, three times daily, four times daily, once every two days, or once every three days.

[0056] 1.30. Any of the above formulations, wherein the formulation comprises a compound of formula I, in the form of a toluenesulfonate, such as a monotoluenesulfonate or a ditoluenesulfonate, or a mixture thereof.

[0057] 1.31. Formulation 1.30, wherein the formulation further comprises toluenesulfonic acid, for example, wherein the formulation comprises a compound of formula I in the form of toluenesulfonate and toluenesulfonic acid in a ratio of 1:3 to 3:1 or 1:2 to 2:1 or 1:1.5 to 1.5:1 or about 1:1.

[0058] 1.32. Any of the above formulations, wherein the compound of formula I is rich in deuterium at one or more hydrogen atom positions, for example, wherein any one or more hydrogen atom positions contain substantially greater levels of deuterium than those naturally incorporated at that position of the structure (e.g., greater than 0.1% or greater than 0.5% or greater than 1% or greater than 5%).

[0059] 1.33. Formulation 1.32, wherein the compound of formula I has more than 50% deuterium doping (i.e., more than 50 atomic %D) at any one or more hydrogen atom positions in the structure, for example more than 60% or more than 70% or more than 80% or more than 90% or more than 95% or more than 96% or more than 97% or more than 98% or more than 99%.

[0060] 1.34. Formulation 1 or any one of 1.1-1.31, wherein all hydrogen atom positions of the compound of formula I are not rich in deuterium (i.e. each hydrogen atom position contains naturally abundant deuterium or less than 0.1% deuterium).

[0061] In a second embodiment, this disclosure provides a transmucosal pharmaceutical formulation (formulation 2) comprising 1-(4-fluoro-phenyl)-4-((6bR,10aS)-2,2-d2-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyridino[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaloline-8-yl)-but-1-one (a compound of formula II) in the form of a free base, cocrystal, or salt. This disclosure also provides formulations as follows:

[0062] 2.1. Formulation 2, wherein the formulation comprises a compound of formula II in the form of a free base.

[0063] 2.2. Formulation 2, wherein the formulation comprises a compound of formula II, which is in salt form, such as a pharmaceutically acceptable salt form, optionally in amorphous solid or crystalline salt form; or in co-crystal form, such as nicotinamide or isonicotinamide co-crystal form.

[0064] 2.3. Formulation 2.2, wherein the salt is in the form of toluenesulfonate, oxalate, cycloamino acid salt, 4-aminosalicylate or hydrochloride, optionally wherein the salt is in the form of a crystalline salt.

[0065] 2.4. Any of the above-mentioned preparations, wherein the preparation comprises 0.01-100 mg of a compound of formula II (free base equivalent), for example 0.01-75 mg, 0.01-50 mg, 0.01-30 mg, 0.01-20 mg, 0.1-20 mg, 5-20 mg, 10-20 mg, 10-30 mg, 20-30 mg, 20-50 mg or 50-100 mg.

[0066] 2.5. Any of the above preparations, wherein the preparation comprises 0.01-10 mg of a compound of formula II (free base equivalent).

[0067] 2.6. Any of the above-mentioned preparations, wherein the preparation comprises 0.05-8 mg of the compound of formula II (free base equivalent), for example 0.1-5 mg or 5-10 mg.

[0068] 2.7. Any of the above formulations further comprises one or more hydrophilic, water-soluble or water-swellable polymers.

[0069] 2.8. Formulation 2.7, wherein the polymer is selected from natural or modified fibrous polymers, polymers of ethylene oxide and / or propylene oxide, polymers containing acrylic acid monomers, natural or modified gums (e.g., xanthan gum), natural or modified starches (e.g., pregelatinized starch), or any mixture thereof.

[0070] 2.9. Any of the above formulations further comprises a hydrophobic polymer or a polymer that is poorly soluble in water, such as a silicone polymer or a polyalkylene polymer (e.g., polyethylene).

[0071] 2.10. Any of the above formulations further comprises one or more excipients selected from plasticizers, surfactants, desiccants, flavoring agents, sweeteners, binders, disintegrants, humectants (e.g., polyols), wetting agents, antioxidants, buffers (e.g., acids, bases and / or their salts), and thickeners (e.g., gelling agents).

[0072] 2.11. Formulation 2.10, wherein said one or more excipients are selected from any one of the following: alcohols (ethanol, glycerol, propylene glycol), gums (e.g., gum arabic, guar gum, agar, xanthan gum, tragacanth gum, tung oil gum, gelling sugar), polysaccharides and polysaccharide derivatives (e.g., starch, dextran, pectin, alginate, carrageenan, cellulose, cellulose derivatives (e.g., carboxymethyl cellulose, methyl cellulose, hydroxyalkyl cellulose (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose)), gelatin, including non-gelling and gelling types (e.g., mammalian gelatin such as bovine gelatin, poultry gelatin, fish gelatin (e.g., a mixture of high and low molecular weight gelatin), synthetic polymers (e.g., polyvinylpyrrolidone, polyethylene oxide and / or polypropylene oxide polymers and copolymers (e.g., beroxam, such as beroxam 188), polyacrylate polymers (e.g., carbomer), poly... Amide polymers), sugars and sugar alcohols (e.g., dextrose, lactose, galactose, glucose, ribose, sucrose, trehalose, mannitol, maltitol, lactoitol, sorbitol, xylitol, erythritol, galactitol, inositol), polypeptides / proteins, amino acids, inorganic or organic acids (e.g., citric acid, lactic acid, malic acid, gluconic acid, benzoic acid, toluenesulfonic acid, phosphoric acid, sulfuric acid, hydrochloric acid, tartaric acid, oxalic acid, cyclohexane, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, formic acid) and their salts (e.g., sodium, potassium, calcium, magnesium, lithium, ammonium salts of the acids listed above), inorganic or organic bases (e.g., alkali metal or alkaline earth metal carbonates, bicarbonates, hydroxides, oxides), anionic surfactants (e.g., sodium lauryl sulfate, sodium polyoxyethylene alkyl sulfate, sodium dodecylbenzenesulfonate, sodium lauroyl sarcosinate, sodium stearate), cationic surfactants (e.g., benzoyl ammonium, cetylpyridinium, cetrimonium) Halides, benzyl chloride), zwitterionic surfactants (e.g., cocoaminoalkyl betaine, e.g., cocoaminopropyl betaine), nonionic surfactants (e.g., fatty alcohol ethoxylates (e.g., polyethylene glycol polydodecyl ether), sorbitan esters (e.g., lauryl sorbitan, dehydrosorbitan monooleate, palm sorbitan, stearyl sorbitan, tristearate sorbitan), polyethoxylated sorbitan esters (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80), and antioxidants (e.g., ascorbic acid, sodium metabisulfite, BHT, BHA, TBHQ, propyl gallate, β-carotene, tocopherol, tocotrienol).

[0073] 2.12. Formulation 2.11, wherein any one or more of the excipients are present in an amount of 0.01-20% by weight of the formulation, for example 0.01-15% or 0.01-10% or 0.1-20% or 0.1-15% or 0.1-10% or 0.5-10% or 0.5-5% or 1-5% or 2.5-5% or 1-3% or 0.1-1%.

[0074] 2.13. Any of the above formulations, which do not contain added plasticizers, surfactants or humectants (e.g., polyols).

[0075] 2.14. Any of the above formulations, wherein the formulation comprises 0.01-99% water, for example 0.01-10% water, 0.01-5% water, 50-99% water, 75-99% water, or 25-75% water.

[0076] 2.15. Any of the above-mentioned preparations, wherein the preparation is an instant tablet or a rice paper capsule, such as a sublingual tablet or a rice paper capsule.

[0077] 2.16. Formulation 2 or any one of 2.1-2.14, wherein the formulation is an oral spray, such as a sublingual spray or a buccal spray.

[0078] 2.17. Formulation 2 or any one of 2.1-2.14, wherein the formulation is a fast-dissolving film, such as a sublingual film or a buccal film.

[0079] 2.18. Formulation 2.17, wherein the film is a single-layer or multi-layer film.

[0080] 2.19. Formulation 2.17 or 2.18, wherein the film has a uniform or substantially uniform thickness.

[0081] 2.20. Formulations 2.17, 2.18 or 2.19, wherein the compound of formula II is uniformly or substantially uniformly distributed in the film.

[0082] 2.21. Formulation 2 or any one of 2.1-2.14, wherein the formulation is an intranasal spray.

[0083] 2.22. Formulation 2 or any one of 2.1-2.14, wherein the formulation is an oral gel, such as an instant sublingual or buccal gel.

[0084] 2.23. Formulation 2 or any one of 2.1-2.14, wherein the formulation is an intravaginal formulation, such as an intravaginal fast-dissolving tablet, rice paper capsule or gel, or intravaginal spray or intravaginal fast-dissolving film.

[0085] 2.24. Any of the above formulations, wherein the compound of formula II is incorporated into the formulation as a microparticle (e.g., a particle having an average diameter of less than 50 μm, less than 30 μm, less than 10 μm, less than 5 μm, or less than 1 μm).

[0086] 2.25. Any of the above formulations, wherein the compound of formula II is incorporated into the formulation as nanoparticles (e.g., particles having an average diameter of less than 100 nm, less than 50 nm, or less than 10 nm).

[0087] 2.26. Any of the above formulations, wherein the formulation is absorbed (e.g., dissolved) by the mucous membrane within 30 seconds after application.

[0088] 2.27. Any of the above formulations, wherein the dosage of the compound of formula II is 1-20% of the daily dose for oral administration, for example 5-15% of the oral dose.

[0089] 2.28. Any of the above-mentioned formulations, wherein the formulation further comprises a compound of formula I or a compound of formula III or a combination thereof.

[0090] 2.29. Any of the above preparations, wherein the preparation is formulated for administration once daily, twice daily, three times daily, four times daily, once every two days, or once every three days.

[0091] 2.30. Any of the above-described formulations, wherein the formulation comprises a compound of formula II, in the form of a toluenesulfonate, such as a monotoluenesulfonate or a xylenesulfonate, or a mixture thereof.

[0092] 2.31. Formulation 2.30, wherein the formulation further comprises toluenesulfonic acid, for example, wherein the formulation comprises a compound of formula II in the form of toluenesulfonate and toluenesulfonic acid in a ratio of 1:3 to 3:1 or 1:2 to 2:1 or 1:1.5 to 1.5:1 or about 1:1.

[0093] In a third embodiment, this disclosure provides a subcutaneous pharmaceutical formulation (formulation 3) comprising 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyridino[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaloline-8-yl)-but-1-one (a compound of formula I) in the form of a free base, cocrystal, or salt. This disclosure also provides formulations as follows:

[0094] 3.1. Formulation 3, wherein the formulation comprises a compound of formula I in the form of a free base.

[0095] 3.2. Formulation 3, wherein the formulation comprises a compound of formula I, in the form of a salt, such as a pharmaceutically acceptable salt, optionally in the form of an amorphous solid or a crystalline salt; or in the form of a cocrystal, such as a nicotinamide or isonicotinamide cocrystal.

[0096] 3.3. Formulation 3.2, wherein the salt is in the form of toluenesulfonate, oxalate, cycloamino acid salt, 4-aminosalicylate or hydrochloride, optionally wherein the salt is in the form of a crystalline salt.

[0097] 3.4. Any of the above-mentioned preparations, wherein the preparation comprises 0.01-100 mg of a compound of formula I (free base equivalent), for example 0.01-75 mg, 0.01-50 mg, 0.01-30 mg, 0.01-20 mg, 0.1-20 mg, 5-20 mg, 10-20 mg, 10-30 mg, 20-30 mg, 20-50 mg or 50-100 mg.

[0098] 3.5. Any of the above preparations, wherein the preparation comprises 0.01-10 mg of a compound of formula I (free base equivalent).

[0099] 3.6. Any of the above-mentioned preparations, wherein the preparation comprises 0.05-8 mg of a compound of formula I (free base equivalent), for example 0.1-5 mg or 5-10 mg.

[0100] 3.7. Any of the above formulations further comprises one or more of the following: water, water-soluble polymers (e.g., modified cellulose, polyvinylpyrrolidone, polyethylene glycol), water-miscible alcohols (e.g., ethanol, glycerol, and propylene glycol), fillers (e.g., sugars, sugar alcohols, and amino acids), inorganic salts (e.g., sodium chloride, calcium chloride, potassium chloride), buffers (e.g., carbonates and bicarbonates, citrates, phosphates, Tris salts), preservatives, antioxidants, chelating agents, and mixtures thereof.

[0101] 3.8. Any of the above formulations, wherein the formulation comprises 0.01-99% water, for example 0.01-10% water, 0.01-5% water, 50-99% water, 75-99% water, or 25-75% water.

[0102] 3.9. In any of the above formulations, the major amount (e.g., greater than 75%, greater than 85%, or greater than 90%) of the compound of formula I is immediately absorbed (e.g., within less than 1 minute or less than 5 minutes).

[0103] 3.10. In any of the above formulations, the major amount of the compound of formula I (e.g., greater than 25%, greater than 50%, or greater than 75%) is not immediately absorbed (e.g., within greater than 5 minutes, greater than 10 minutes, greater than 30 minutes, greater than 1 hour, or greater than 5 hours).

[0104] 3.11. Any of the above-mentioned formulations, wherein the formulation is packaged in a pre-filled syringe, a pre-filled auto-injector, a sealed vial, or a similar container.

[0105] 3.12. Any of the above formulations, wherein the formulation is used as a dry solid package, such as a lyophilized solid, for reconstitution in a pharmaceutically acceptable solvent (e.g., sterile water for injection) upon use.

[0106] 3.13. Any of the above formulations, wherein the dosage of the compound of formula I is 1-20% of the daily dose for oral administration, for example 5-15% of the oral dose.

[0107] 3.14. Any of the above-mentioned formulations, wherein the formulation further comprises a compound of formula II or a compound of formula III or a combination thereof.

[0108] 3.15. Any of the above preparations, wherein the preparation is formulated for application once daily or once every two days or once every three days or once weekly or once every two weeks or once every three weeks or once monthly or once every two months or once every three months or once every six months.

[0109] 3.16. Any of the above formulations, wherein the formulation comprises a compound of formula I, in the form of a toluenesulfonate, such as a monotoluenesulfonate or a xylenesulfonate or a mixture thereof.

[0110] 3.17. Formulation 3.16, wherein the formulation further comprises toluenesulfonic acid, for example wherein the formulation comprises a compound of formula I in the form of toluenesulfonate and toluenesulfonic acid in a ratio of 1:3 to 3:1 or 1:2 to 2:1 or 1:1.5 to 1.5:1 or about 1:1.

[0111] 3.18. Any of the above formulations, wherein the compound of formula I is rich in deuterium at one or more hydrogen atom positions, for example, wherein any one or more hydrogen atom positions contain substantially greater levels of deuterium than those naturally incorporated at that position of the structure (e.g., greater than 0.1% or greater than 0.5% or greater than 1% or greater than 5%).

[0112] 3.19. Formulation 3.18, wherein the compound of formula I has more than 50% deuterium doping (i.e., more than 50 atomic %D) at any one or more hydrogen atom positions in the structure, for example more than 60% or more than 70% or more than 80% or more than 90% or more than 95% or more than 96% or more than 97% or more than 98% or more than 99%.

[0113] 3.20. Formulation 3 or any one of 3.1-3.17, wherein all hydrogen atom positions of the compound of formula I are not rich in deuterium (i.e., each hydrogen atom position contains naturally abundant deuterium or less than 0.1% deuterium).

[0114] In a fourth embodiment, this disclosure provides a subcutaneous pharmaceutical formulation (formulation 4) comprising 1-(4-fluoro-phenyl)-4-((6bR,10aS)-2,2-d2-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyridino[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaloline-8-yl)-but-1-one (a compound of formula II) in the form of a free base, eutectic, or salt. This disclosure also provides formulations as follows:

[0115] 4.1. Formulation 4, wherein the formulation comprises a compound of formula II in the form of a free base.

[0116] 4.2. Formulation 4, wherein the formulation comprises a compound of formula II, in the form of a salt, such as a pharmaceutically acceptable salt, optionally in the form of an amorphous solid or a crystalline salt; or in the form of a cocrystal, such as a nicotinamide or isonicotinamide cocrystal.

[0117] 4.3. Formulation 4.2, wherein the salt is in the form of toluenesulfonate, oxalate, cycloamino acid salt, 4-aminosalicylate or hydrochloride, optionally wherein the salt is in the form of a crystalline salt.

[0118] 4.4. Any of the above-mentioned preparations, wherein the preparation comprises 0.01-100 mg of a compound of formula II (free base equivalent), for example 0.01-75 mg, 0.01-50 mg, 0.01-30 mg, 0.01-20 mg, 0.1-20 mg, 5-20 mg, 10-20 mg, 10-30 mg, 20-30 mg, 20-50 mg or 50-100 mg.

[0119] 4.5. Any of the above preparations, wherein the preparation comprises 0.01-10 mg of the compound of formula II (free base equivalent).

[0120] 4.6. Any of the above-mentioned preparations, wherein the preparation comprises 0.05-8 mg of the compound of formula II (free base equivalent), for example 0.1-5 mg or 5-10 mg.

[0121] 4.7. Any of the above formulations further comprises one or more of the following: water, water-soluble polymers (e.g., modified cellulose, polyvinylpyrrolidone, polyethylene glycol), water-miscible alcohols (e.g., ethanol, glycerol, and propylene glycol), fillers (e.g., sugars, sugar alcohols, and amino acids), inorganic salts (e.g., sodium chloride, calcium chloride, potassium chloride), buffers (e.g., carbonates and bicarbonates, citrates, phosphates, Tris salts), preservatives, antioxidants, chelating agents, and mixtures thereof.

[0122] 4.8. Any of the above formulations, wherein the formulation comprises 0.01-99% water, for example 0.01-10% water, 0.01-5% water, 50-99% water, 75-99% water, or 25-75% water.

[0123] 4.9. Any of the above formulations wherein a major amount (e.g., greater than 75%, greater than 85%, or greater than 90%) of the compound of formula II is immediately absorbed (e.g., within less than 1 minute or less than 5 minutes).

[0124] 4.10. Any of the above formulations wherein a significant amount (e.g., greater than 25%, greater than 50%, or greater than 75%) of the compound of formula II is not immediately absorbed (e.g., within greater than 5 minutes, greater than 10 minutes, greater than 30 minutes, greater than 1 hour, or greater than 5 hours).

[0125] 4.11. Any of the above-mentioned formulations, wherein the formulation is packaged for use in a pre-filled syringe, a pre-filled auto-injector, or a sealed vial or similar container.

[0126] 4.12. Any of the above formulations, wherein the formulation is packaged as a dry solid, such as a lyophilized solid, for reconstitution in a pharmaceutically acceptable solvent (e.g., sterile water for injection) upon use.

[0127] 4.13. In any of the above formulations, the dosage of the compound of formula II is 1-20% of the daily dose for oral administration, for example 5-15% of the oral dose.

[0128] 4.14. Any of the above-described formulations, wherein the formulation further comprises a compound of formula I or a compound of formula III, or a combination thereof.

[0129] 4.15. Any of the above preparations, wherein the preparation is formulated for application once daily or once every two days or once every three days or once weekly or once every two weeks or once every three weeks or once monthly or once every two months or once every three months or once every six months.

[0130] 4.16. Any of the above formulations, wherein the formulation comprises a compound of formula II, which is in the form of a toluenesulfonate, such as a monotoluenesulfonate or a ditoluenesulfonate or a mixture thereof.

[0131] 4.17. Formulation 4.16, wherein the formulation further comprises toluenesulfonic acid, for example, wherein the formulation comprises a compound of formula II in the form of toluenesulfonate and toluenesulfonic acid in a ratio of 1:3 to 3:1 or 1:2 to 2:1 or 1:1.5 to 1.5:1 or about 1:1.

[0132] In a fifth embodiment, this disclosure provides a transmucosal pharmaceutical formulation (formulation 5) comprising 1-(4-fluoro-phenyl)-4-((6bR,10aS)-1,1,2,2-d4-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyridino[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaloline-8-yl)-but-1-one (a compound of formula III) in the form of a free base, cocrystal, or salt. This disclosure also provides formulations in which:

[0133] 5.1. Formulation 5, wherein the formulation comprises a compound of formula III in the form of a free base.

[0134] 5.2. Formulation 5, wherein the formulation comprises a compound of formula III, in the form of a salt, such as a pharmaceutically acceptable salt, optionally in the form of an amorphous solid or a crystalline salt; or in the form of a cocrystal, such as a nicotinamide or isonicotinamide cocrystal.

[0135] 5.3. Formulation 5.2, wherein the salt is in the form of toluenesulfonate, oxalate, cycloamino acid salt, 4-aminosalicylate or hydrochloride, optionally wherein the salt is in the form of a crystalline salt.

[0136] 5.4. Any of the above-mentioned preparations, wherein the preparation comprises 0.01-100 mg of a compound of formula III (free base equivalent), for example 0.01-75 mg, 0.01-50 mg, 0.01-30 mg, 0.01-20 mg, 0.1-20 mg, 5-20 mg, 10-20 mg, 10-30 mg, 20-30 mg, 20-50 mg or 50-100 mg.

[0137] 5.5. Any of the above preparations, wherein the preparation comprises 0.01-10 mg of a compound of formula III (free base equivalent).

[0138] 5.6. Any of the above-mentioned formulations, wherein the formulation comprises 0.05-8 mg of a compound of formula III (free base equivalent), for example 0.1-5 mg or 5-10 mg.

[0139] 5.7. Any of the above formulations further comprises one or more hydrophilic, water-soluble or water-swellable polymers.

[0140] 5.8. Formulation 51.7, wherein the polymer is selected from natural or modified fibrous polymers, polymers of ethylene oxide and / or propylene oxide, polymers containing acrylic acid monomers, natural or modified gums (e.g., xanthan gum), natural or modified starches (e.g., pregelatinized starch), or any mixture thereof.

[0141] 5.9. Any of the above formulations further comprises a hydrophobic polymer or a polymer that is poorly soluble in water, such as a silicone polymer or a polyalkylene polymer (e.g., polyethylene).

[0142] 5.10. Any of the above formulations further comprises one or more excipients selected from plasticizers, surfactants, desiccants, flavoring agents, sweeteners, binders, disintegrants, humectants (e.g., polyols), wetting agents, antioxidants, buffers (e.g., acids, bases and / or their salts), and thickeners (e.g., gelling agents).

[0143] 5.11. Formulation 5.10, wherein said one or more excipients are selected from any one of the following: alcohols (ethanol, glycerol, propylene glycol), gums (e.g., gum arabic, guar gum, agar, xanthan gum, tragacanth gum, tung oil gum, gelling sugar), polysaccharides and polysaccharide derivatives (e.g., starch, dextran, pectin, alginate, carrageenan, cellulose, cellulose derivatives (e.g., carboxymethyl cellulose, methyl cellulose, hydroxyalkyl cellulose (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose)), gelatin, including non-gelling and gelling types (e.g., mammalian gelatin such as bovine gelatin, poultry gelatin, fish gelatin (e.g., a mixture of high and low molecular weight gelatin), synthetic polymers (e.g., polyvinylpyrrolidone, polyethylene oxide and polypropylene oxide polymers and copolymers (e.g., beroxam, such as beroxam 188), polyacrylate polymers (e.g., carbomer), polyamides, etc.). Amine polymers), sugars and sugar alcohols (e.g., dextran, lactose, galactose, glucose, ribose, sucrose, trehalose, mannitol, maltitol, lactoitol, sorbitol, xylitol, erythritol, galactitol, inositol), polypeptides / proteins, amino acids, inorganic or organic acids (e.g., citric acid, lactic acid, malic acid, gluconic acid, benzoic acid, toluenesulfonic acid, phosphoric acid, sulfuric acid, hydrochloric acid, tartaric acid, oxalic acid, cyclohexane, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, formic acid) and their salts (e.g., sodium, potassium, calcium, magnesium, lithium, and ammonium salts of the acids listed above), inorganic or organic bases (e.g., alkali metal or alkaline earth metal carbonates, bicarbonates, hydroxides, and oxides), anionic surfactants (e.g., sodium lauryl sulfate, sodium polyoxyethylene alkyl sulfate, sodium dodecylbenzenesulfonate, sodium lauroyl sarcosinate, sodium stearate), cationic surfactants (e.g., benzoyl ammonium, cetylpyridinium, cetrimonium) Halides, benzyl chloride), zwitterionic surfactants (e.g., cocoaminoalkyl betaine, e.g., cocoaminopropyl betaine), nonionic surfactants (e.g., fatty alcohol ethoxylates (e.g., polyethylene glycol polydodecyl ether), sorbitan esters (e.g., lauryl sorbitan, dehydrosorbitan monooleate, palm sorbitan, stearyl sorbitan, tristearate sorbitan), polyethoxylated sorbitan esters (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80), and antioxidants (e.g., ascorbic acid, sodium metabisulfite, BHT, BHA, TBHQ, propyl gallate, β-carotene, tocopherol, tocotrienol).

[0144] 5.12. Formulation 5.11, wherein any one or more of the excipients are present in an amount of 0.01-20% by weight of the formulation, for example 0.01-15% or 0.01-10% or 0.1-20% or 0.1-15% or 0.1-10% or 0.5-10% or 0.5-5% or 1-5% or 2.5-5% or 1-3% or 0.1-1%.

[0145] 5.13. Any of the above formulations shall not contain added plasticizers, surfactants or humectants (e.g., polyols).

[0146] 5.14. Any of the above formulations, wherein the formulation comprises 0.01-99% water, for example 0.01-10% water, 0.01-5% water, 50-99% water, 75-99% water, or 25-75% water.

[0147] 5.15. Any of the above-mentioned preparations, wherein the preparation is an instant tablet or a rice paper capsule, such as a sublingual tablet or a rice paper capsule.

[0148] 5.16. Formulation 5 or any one of 5.1-5.14, wherein the formulation is an oral spray, such as a sublingual spray or a buccal spray.

[0149] 5.17. Formulation 5 or any of 5.1-5.14, wherein the formulation is a fast-dissolving film, such as a sublingual film or a buccal film.

[0150] 5.18. Formulation 5.17, wherein the film is a single-layer or multi-layer film.

[0151] 5.19. Formulation 5.17 or 5.18, wherein the film has a uniform or substantially uniform thickness.

[0152] 5.20. Formulations 5.17, 5.18 or 5.19, wherein the compound of formula III is uniformly or substantially uniformly distributed in the film.

[0153] 5.21. Formulation 5 or any one of 5.1-5.14, wherein the formulation is an intranasal spray.

[0154] 5.22. Formulation 5 or any one of 5.1-5.14, wherein the formulation is an oral gel, such as an instant sublingual or buccal gel.

[0155] 5.23. Formulation 5 or any one of 5.1-5.14, wherein the formulation is an intravaginal formulation, such as an intravaginal fast-dissolving tablet, rice paper capsule or gel, or intravaginal spray or intravaginal fast-dissolving film.

[0156] 5.24. Any of the above formulations, wherein a compound of formula III is incorporated into the formulation as a particulate (e.g., a particle having an average diameter of less than 50 μm, less than 30 μm, less than 10 μm, less than 5 μm, or less than 1 μm).

[0157] 5.25. Any of the above formulations, wherein the compound of formula III is incorporated into the formulation as nanoparticles (e.g., particles having an average diameter of less than 100 nm, less than 50 nm, or less than 10 nm).

[0158] 5.26. Any of the above formulations, wherein the formulation is absorbed (e.g., dissolved) by the mucous membrane within 30 seconds after application.

[0159] 5.27. Any of the above formulations, wherein the dosage of the compound of formula III is 1-20% of the daily dose for oral administration, for example 5-15% of the oral dose.

[0160] 5.28. Any of the above-mentioned formulations, wherein the formulation further comprises a compound of formula II or a compound of formula I or a combination thereof.

[0161] 5.29. Any of the above preparations, wherein the preparation is formulated for administration once daily, twice daily, three times daily, four times daily, once every two days, or once every three days.

[0162] 5.30. Any of the above formulations, wherein the formulation comprises a compound of formula III, in the form of a toluenesulfonate, such as a monotoluenesulfonate or a ditoluenesulfonate, or a mixture thereof.

[0163] 5.31. Formulation 5.30, wherein the formulation further comprises toluenesulfonic acid, for example, wherein the formulation comprises a compound of formula III in the form of toluenesulfonate and toluenesulfonic acid in a ratio of 1:3 to 3:1 or 1:2 to 2:1 or 1:1.5 to 1.5:1 or about 1:1.

[0164] In a sixth embodiment, this disclosure provides a subcutaneous pharmaceutical formulation (formulation 6) comprising 1-(4-fluoro-phenyl)-4-((6bR,10aS)-1,1,2,2-d4-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyridino[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaloline-8-yl)-but-1-one (a compound of formula III) in the form of a free base, eutectic, or salt. This disclosure also provides formulations as follows:

[0165] 6.1. Formulation 6, wherein the formulation comprises a compound of formula III in the form of a free base.

[0166] 6.2. Formulation 6, wherein the formulation comprises a compound of formula III, in the form of a salt, such as a pharmaceutically acceptable salt, optionally in the form of an amorphous solid or a crystalline salt; or in the form of a cocrystal, such as a nicotinamide or isonicotinamide cocrystal.

[0167] 6.3. Formulation 6.2, wherein the salt is in the form of toluenesulfonate, oxalate, cycloamino acid salt, 4-aminosalicylate or hydrochloride, optionally wherein the salt is in the form of a crystalline salt.

[0168] 6.4. Any of the above-mentioned preparations, wherein the preparation comprises 0.01-100 mg of a compound of formula III (free base equivalent), for example 0.01-75 mg, 0.01-50 mg, 0.01-30 mg, 0.01-20 mg, 0.1-20 mg, 5-20 mg, 10-20 mg, 10-30 mg, 20-30 mg, 20-50 mg or 50-100 mg.

[0169] 6.5. Any of the above formulations, wherein the formulation comprises 0.01-10 mg of the compound of formula III (free base equivalent).

[0170] 6.6. Any of the above-mentioned preparations, wherein the preparation comprises 0.05-8 mg of a compound of formula III (free base equivalent), for example 0.1-5 mg or 5-10 mg.

[0171] 6.7. Any of the above formulations further comprises one or more of the following: water, water-soluble polymers (e.g., modified cellulose, polyvinylpyrrolidone, polyethylene glycol), water-miscible alcohols (e.g., ethanol, glycerol, and propylene glycol), fillers (e.g., sugars, sugar alcohols, and amino acids), inorganic salts (e.g., sodium chloride, calcium chloride, potassium chloride), buffers (e.g., carbonates and bicarbonates, citrates, phosphates, Tris salts), preservatives, antioxidants, chelating agents, and mixtures thereof.

[0172] 6.8. Any of the above formulations, wherein the formulation comprises 0.01-99% water, for example 0.01-10% water, 0.01-5% water, 50-99% water, 75-99% water, or 25-75% water.

[0173] 6.9. Any of the above formulations wherein a major amount (e.g., greater than 75%, greater than 85%, or greater than 90%) of the compound of formula III is immediately absorbed (e.g., within less than 1 minute or less than 5 minutes).

[0174] 6.10. Any of the above formulations wherein a significant amount (e.g., greater than 25%, greater than 50%, or greater than 75%) of the compound of formula III is not immediately absorbed (e.g., within greater than 5 minutes, greater than 10 minutes, greater than 30 minutes, greater than 1 hour, or greater than 5 hours).

[0175] 6.11. Any of the above-described formulations, wherein the formulation is packaged for use in a pre-filled syringe, a pre-filled auto-injector, or a sealed vial or similar container.

[0176] 6.12. Any of the above formulations, wherein the formulation is packaged as a dry solid, such as a lyophilized solid, for reconstitution in a pharmaceutically acceptable solvent (e.g., sterile water for injection) upon use.

[0177] 6.13. In any of the above formulations, the dosage of the compound of formula III is 1-20% of the daily dose for oral administration, for example 5-15% of the oral dose.

[0178] 6.14. Any of the above-described formulations, wherein the formulation further comprises a compound of formula II or a compound of formula I, or a combination thereof.

[0179] 6.15. Any of the above preparations, wherein the preparation is formulated for application once daily or once every two days or once every three days or once weekly or once every two weeks or once every three weeks or once monthly or once every two months or once every three months or once every six months.

[0180] 6.16. Any of the above formulations, wherein the formulation comprises a compound of formula III, in the form of a toluenesulfonate, such as a monotoluenesulfonate or a ditoluenesulfonate, or a mixture thereof.

[0181] 6.17. Formulation 4.16, wherein the formulation further comprises toluenesulfonic acid, for example, wherein the formulation comprises a compound of formula III in the form of toluenesulfonate and toluenesulfonic acid in a ratio of 1:3 to 3:1 or 1:2 to 2:1 or 1:1.5 to 1.5:1 or about 1:1.

[0182] As used in this article, "deuteration" refers to the use of deuterium atoms ( 2 H) replaces hydrogen (protium) in the chemical structure. 1 (H) atoms. When deuterium is abundant at a position, it is assumed that the hydrogen atom position of the structure is replaced by deuterium. The natural abundance of deuterium is about 0.02%, so when the frequency of deuterium incorporation at a position exceeds 0.02%, the compound is "enriched" with deuterium at that specific position. Therefore, in any embodiment of the deuterated compound provided herein, any one or more hydrogen atoms can be enriched with deuterium at levels greater than 0.1% or greater than 0.5% or greater than 1% or greater than 5%, for example, greater than 50% or greater than 60% or greater than 70% or greater than 80% or greater than 90% or greater than 95% or greater than 96% or greater than 97% or greater than 98% or greater than 99%.

[0183] In all aspects and embodiments of the present disclosure comprising compounds of Formula I, wherein the compounds of Formula I are optionally deuterated at one or more hydrogen atom positions.

[0184] In all aspects and embodiments of the present disclosure that include compounds of Formula II, the compounds of Formula II are enriched only at the specified location (2, 2-d2).

[0185] In all aspects and embodiments of the present disclosure that include compounds of Formula III, the compounds of Formula III are enriched only at all designated locations (1, 1, 2, 2-d4).

[0186] In a second aspect, this disclosure provides a method (method 1) for producing a transmucosal formulation of formulation 1, formulation 2, or formulation 5, comprising the following steps:

[0187] (a) Optionally, in a suitable solvent or solvent mixture, combine a compound of formula I in its free or pharmaceutically acceptable salt form and / or a compound of formula II in its free or pharmaceutically acceptable salt form and / or a compound of formula III in its free or pharmaceutically acceptable salt form with a suitable pharmaceutically acceptable excipient; and

[0188] (b)(1) Remove the solvent to obtain a dry film; or (2) Remove the solvent to obtain a dry powder suitable for compression into tablets or rice paper capsules; or (3) Remove the solvent or a portion thereof to obtain a solution suitable for application by an aerosol spray device.

[0189] In a third aspect, this disclosure provides a method (method 2) for producing a subcutaneous formulation of formulation 3, formulation 4, or formulation 6, comprising any one of the following steps:

[0190] (a) Combining a compound of formula I in its free or pharmaceutically acceptable salt form and / or a compound of formula II in its free or pharmaceutically acceptable salt form and / or a compound of formula III in its free or pharmaceutically acceptable salt form with a suitable pharmaceutically acceptable excipient in a suitable injectable solvent or solvent mixture, and then packaging the resulting solution for use (e.g., in a pre-filled syringe or sealed vial or similar container or pre-filled auto-injector); or

[0191] (b) Combining a compound of formula I in free or pharmaceutically acceptable salt form and / or a compound of formula II in free or pharmaceutically acceptable salt form and / or a compound of formula III in free or pharmaceutically acceptable salt form in a suitable solvent or solvent mixture, optionally with a suitable pharmaceutically acceptable excipient, and then removing the solvent to obtain a dry solid (e.g., a lyophilized solid) for packaging.

[0192] The pharmaceutical formulations disclosed herein, such as formulations 1, 2, 3, 4, 5, and 6 below, may include any suitable pharmaceutically acceptable excipients, including but not limited to: diluents, such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, xylitol, sugars, etc.; binders, such as gum arabic, guar gum, tragacanth gum, gelatin, polyvinylpyrrolidone, such as polyvinylpyrrolidone (PVP). K-30, K-90), poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA), hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose acetate, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), etc.; disintegrants, such as starch, sodium glycolate starch, pregelatinized starch, cross-linked polyvinyl chloride, sodium carboxymethyl cellulose, etc.; lubricants, such as stearic acid, magnesium stearate, zinc stearate, etc.; flow aids, such as colloidal silica, etc.; solubilizing or wetting enhancers, such as anionic, cationic, or neutral surfactants; maltodextrin, complex forming agents, such as various grades of cyclodextrin and resins; release rate control agents, such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylate, waxes, etc.; and film-forming agents, plasticizers, colorants, flavoring agents, sweeteners, thickeners, preservatives, antioxidants, buffers, fillers, etc.

[0193] In some embodiments, the formulation may further comprise one or more antioxidants, such as tocopherol, butylated hydroxybenzene (BHT), propyl gallate (OPG), or ascorbic acid. The inclusion of antioxidants can further improve the chemical stability of the formulation by preventing oxidative chemical degradation of the active ingredient.

[0194] On the other hand, this disclosure provides formulation 1, formulation 2, formulation 3, formulation 4, formulation 5, or formulation 6 for the treatment of 5-HT-related diseases. 2A Diseases or abnormalities mediated by receptors, serotonin transporter (SERT) and / or dopamine D1 / D2 receptor signaling pathways, such as those selected from obesity, anorexia, bulimia, depression (including major depressive disorder (MDD)), anxiety, psychosis, schizophrenia, obsessive-compulsive disorder, sexual dysfunction, migraine, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, headache-related disorders, social phobia, dementia (including Alzheimer's disease and Parkinson's dementia), gastrointestinal disorders such as gastrointestinal motility disorders and obesity, or bipolar disorder (e.g., bipolar depression).

[0195] In another embodiment, the present invention provides for the prevention or treatment of 5-HT-related diseases. 2AA method (Method 1) for treating diseases or abnormalities mediated by receptor, serotonin transporter (SERT), and / or dopamine D1 / D2 receptor signaling pathways, comprising administering, to a patient in need, a therapeutically effective amount of a compound of Formula I and / or a compound of Formula II and / or a compound of Formula III via a transmucosal or subcutaneous route. Further embodiments of Method 1 include:

[0196] 1.1 Method 1, wherein the compound of Formula I and / or the compound of Formula II and / or the compound of Formula III are administered via a transmucosal route (e.g., via intraoral, intranasal, buccal, or sublingual absorption).

[0197] 1.2 Method 1.1, wherein the compound of Formula I and / or the compound of Formula II and / or the compound of Formula III are applied in the form of a composition selected from any one of the following formulation 1, formulation 2, or formulation 4.

[0198] 1.3 Method 1.1 or 1.2, wherein the compound of Formula I and / or the compound of Formula II and / or the compound of Formula III is administered sublingually, for example by sublingual film, sublingual spray, sublingual tablet or rice paper capsule (e.g., instant tablet or rice paper capsule) or sublingual solution (e.g., aqueous solution).

[0199] 1.4 Method 1.1 or 1.2, wherein a compound of formula I and / or a compound of formula II and / or a compound of formula III is applied to the cheek, for example by a cheek film, cheek spray, cheek sublingual tablet or rice paper capsule (e.g., an instant tablet or rice paper capsule).

[0200] 1.5 Method 1.1 or 1.2, wherein the compound of Formula I and / or the compound of Formula II and / or the compound of Formula III is administered orally, for example by an intraoral spray (e.g., an aerosol spray).

[0201] 1.6 Method 1.1 or 1.2, wherein the compound of Formula I and / or the compound of Formula II and / or the compound of Formula III is administered intranasally, for example by an intranasal spray (e.g., an aerosol spray).

[0202] 1.7 Method 1, wherein a compound of Formula I and / or a compound of Formula II and / or a compound of Formula III (e.g., a subcutaneous injection) is administered subcutaneously.

[0203] 1.8 Method 1.7, wherein the compound of Formula I and / or the compound of Formula II and / or the compound of Formula III are applied in the form of a composition selected from any one of the following formulations 3, 4, or 6.

[0204] 1.9 Method 1.7 or 1.8, wherein a compound of Formula I and / or a compound of Formula II and / or a compound of Formula III is administered by means of a pre-loaded syringe, autoinjector or puncture-resistant injector.

[0205] 1.10 Methods 1.7, 1.8 or 1.9, wherein a compound of Formula I and / or a compound of Formula II and / or a compound of Formula III is administered by a patient (e.g., self-administration).

[0206] 1.11 Method 1 or any of the following 1.1, wherein the disease or condition is selected from obesity, anorexia, bulimia, depression (including major depressive disorder (MDD)), anxiety, psychosis, schizophrenia, obsessive-compulsive disorder, sexual dysfunction, migraine, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, headache-related condition, social phobia, dementia (including Alzheimer's disease and Parkinson's dementia), gastrointestinal disorders such as gastrointestinal motility disorders and obesity, or bipolar disorder (e.g., bipolar depression).

[0207] 1.12 Method 1 or any of the following 1.1, wherein the disease or condition to be treated requires rapid intervention, such as acute anxiety, acute impulsivity or acute psychosis.

[0208] 1.13 Method 1 or any of the following 1.1, wherein the dose administered via a transmucosal (e.g., sublingual, buccal, intranasal, or intraoral) or subcutaneous route is 1-20% of the dose administered orally for the same condition, for example 5-15% of the oral dose.

[0209] A compound of Formula I or a compound of Formula II and / or a compound of Formula III, used in any of the following methods 1 or 1.1.

[0210] The pharmaceutical composition is selected from any one of the following formulations: formulation 1, formulation 2, formulation 3, formulation 4, formulation 5, or formulation 6, and is used in method 1 or any one of method 1.1.

[0211] The use of a compound of Formula I, or a compound of Formula II, or a compound of Formula III in the preparation of a medicament for transmucosal or subcutaneous administration, for example, any one of the following formulations 1, 2, 3, 4, 5, or 6, in method 1 or any one of method 1.1.

[0212] Methods for synthesizing compounds of Formula I and Formula II are known in the art and include those disclosed in the following documents: WO PCT / US08 / 03340 (WO 2008 / 112280); US Application Serial No. US 10 / 786,935; US Patent Nos. US6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; US RE39680 and USRE39679 and WO 2015 / 154025, the contents of which are incorporated herein by reference in their entirety. Salts of the compounds of the present invention can also be prepared as described in U.S. Patent Nos. US6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; USRE39680; USRE39679; and WO 2009 / 114181, the contents of which are incorporated herein by reference in their entirety.

[0213] The separation or purification of diastereomers of the compounds of the present invention can be carried out by conventional methods known in the art, such as column purification, preparative thin-layer chromatography, preparative HPLC, crystallization, grinding, simulated moving bed, etc.

[0214] Pharmaceutically acceptable salts of compounds of formulas I, II, and III can be synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Typically, these salts are prepared by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid in water, in an organic solvent, or in a mixture of both; typically, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Further details on the preparation of these salts, such as toluenesulfonates in amorphous or crystalline forms, can be found in PCT / US08 / 03340 and / or U.S. Provisional Application No. US 61 / 036,069.

[0215] Transmucosal dosage forms are known to those skilled in the art, and general methods for preparing these dosage forms have been described. Examples of soluble film delivery systems include those disclosed in the following documents: Fuchs' U.S. Patent US4,136,145, Schmidt's U.S. Patent US4,849,246, Horstmann's U.S. Patent US5,629,003, Zerbe's U.S. Patent US5,948,430, Yang's U.S. Patent US9,108,340, Yang's U.S. Patent US8,906,277, Yang's U.S. Patent US8,900,498, Yang's U.S. Patent US8,900,497, Yang's U.S. Patent US8,652,378, Yang's U.S. Patent US8,603,514, Bryson's U.S. Patent US9,427,412, and Bryson's U.S. Patent US8,414,922. Further preparations of transmucosal systems are disclosed in Delbressine's U.S. Patent 5,763,476 (Sublingual and buccal solutions and solids), Amancha's U.S. Patent 9,216,175 (Sublingual sprays), Kottayil's U.S. Patent 8,835,459 (Sublingual sprays), and Chen's U.S. Patent 6,552,024 (Various mucosal delivery systems). The contents of each of these references are incorporated herein by reference in their entirety. Example

[0216] Example 1A: Pharmacokinetic Comparison between Subcutaneous (SC) and Sublingual (SL) Administration in Dogs

[0217] In a non-crossover sequential study in dogs, the in vivo absorption and distribution of compounds of formula I and formula II in the form of tosylate were compared between subcutaneous and sublingual administration.

[0218] SC Administration: Six male beagle dogs aged 2 to 5 years were randomly divided into two groups of three. Dogs in Group 1 were administered the compound of Formula I at a dose of 1 mg / kg (free base equivalent) in 0.5% methylcellulose / distilled water solvent. Dogs in Group 2 were administered the compound of Formula II at a dose of 1 mg / kg (free base equivalent) in 0.5% methylcellulose / distilled water solvent. Administration was performed subcutaneously in the intrascapular region using a 22 or 23 gauge needle. Whole blood samples were collected via cephalic vein before and at time points 5, 15, and 30 minutes, 1, 2, 4, 6, 8, and 24 hours after the dose. After a minimum 7-day clearance period, the dogs were transferred to the sublingual region for the study.

[0219] SL Administration: Dogs in Group 1 were administered Compound I at a dose of 1 mg / kg (free base equivalent) in 0.5% methylcellulose / distilled water solvent. Dogs in Group 2 were administered Compound II at a dose of 1 mg / kg (free base equivalent) in 0.5% methylcellulose / distilled water solvent. Animals were anesthetized prior to administration of the doses with propofol (6 mg / kg), and anesthesia was maintained for 30 minutes with 3-4.5% isoflurane. Administration was sublingual, and the doses were administered 30 minutes later, then wiped off with nonwoven gauze. Whole blood samples were collected from the cephalic vein of the dogs before and at time points 5, 15, and 30 minutes, and 1, 2, 4, 6, 8, 24, 36, and 48 hours after the dose.

[0220] All blood samples were processed into plasma and drug concentrations were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS / MS). The area under the curve (AUC) of the parent and metabolites based on plasma versus time data was calculated using Prism 5.04 software (GraphPad Software, Inc.).

[0221] The results are summarized in Table 1A below (AUC for 0-24 hours):

[0222] Formula 1A

[0223]

[0224] The results showed that both SC and SL administration led to high plasma concentrations and high plasma AUCs. SL administration also resulted in significantly higher maximum plasma concentrations (Cmax) compared to SC administration for both compounds. For the compound of formula II, SL administration also led to significantly higher total AUCs, while the AUCs of the compound of formula I showed comparable results between SC and SL administration. The time to reach maximum plasma concentrations was also the same for both compounds with SC and SL administration.

[0225] Example 1B: Comparison of pharmacokinetics between subcutaneous and sublingual administration in dogs using metabolite analysis

[0226] The second study was conducted essentially as described in Example 1A, except that the parent (administered) compound and major known metabolites were analyzed from plasma samples. Following administration of either Formula I or Formula II, the main circulating metabolites were found to be the parent compound and N-demethylated metabolites. The results are summarized in Table 1B below (showing AUC over 0–24 hours):

[0227] Table 1B

[0228]

[0229] These results further demonstrate that both SC and SL administration resulted in high plasma concentrations and high plasma AUCs of the administered compounds. SL administration also resulted in higher maximum plasma concentrations (Cmax) of the drug compared to SC administration of both compounds. Furthermore, the results showed that both SC and SL administration led to very low rates of metabolite formation, indicating that these pathways effectively bypass the main sites of metabolic degradation (hepatic metabolism) for these compounds. Following SL administration, the AUC of the parent compound of Formula I circulating in plasma was approximately 22 times higher than that of its metabolite, compared to 27 times higher with SC administration. Conversely, when administered orally, the AUCs of the compound of Formula I and its demethylated metabolite circulating in plasma were found to be approximately 1:1 or less. Similarly, results for the compound of Formula II were shown (approximately 12 parent / metabolite ratio for SL and approximately 16 parent / metabolite ratio for SC).

[0230] Example 2: Pharmacokinetics of oral administration in dogs

[0231] Contrary to the subcutaneous and sublingual pharmacokinetics presented in Example 1, this example demonstrates that oral administration results in a significantly reduced systemic exposure of the drug due to the high degree of first-pass metabolism in the liver. This is true even when using doses 2.5 to 15 times higher than those used in the SC and SL studies.

[0232] As part of a larger long-term toxicology study, 20 male and female beagle dogs were administered either the control or the tosylate form of compound I at doses of 2.5, 5, 10, or 15 mg / kg. For the control group, dogs were given empty capsules. For the compound I, dogs were given normal-release oral capsules. Blood samples were obtained at 0.25 h, 0.5 h, 1 h, 4 h, 8 h, and 24 h. Blood samples were processed into plasma, and the concentration of the compound I was analyzed by high-performance liquid chromatography-mass spectrometry. Cmax, Tmax, and area under the curve (AUC, 0–24 h) were calculated using Phoenix WinNonlin software. The results are shown in Table 2 below.

[0233] Table 2

[0234] Administration: 2.5 mg / kg 5mg / kg 10mg / kg 15mg / kg AUC (ng-hr / mL) 40.05 52.45 142.5 248 Cmax (ng / mL) 5.51 7.72 29.0 44.5 Tmax(hr) 0.469 0.875 0.813 1.63

[0235] Compounds of Formula I exhibit dose-dependent oral absorption, and even at the highest oral dose, the plasma concentrations achieved are significantly lower than those obtained with sublingual and subcutaneous administration as shown in Example 1. Sublingual and subcutaneous administration of only 1.0 mg / kg of a compound of Formula I resulted in a 24-hour AUC that was 18 times higher than that of an oral administration of 2.5 mg / kg. Sublingual and subcutaneous administration even provided a 24-hour AUC of approximately three times that of an oral administration of 15 mg / kg at 1.0 mg / kg.

[0236] These results together clearly demonstrate the substantial loss of exposure caused by first-pass metabolism in the liver, and the unexpectedly high degree of improvement in exposure achieved using transmucosal drug delivery systems.

[0237] Example 3: Pharmacokinetics of SC and IV administration in monkeys

[0238] Studies were also conducted in monkeys to determine the plasma concentrations of the compound of Formula I and its major metabolites after administration of SL and SC at 0.5 mg / kg. Six cynomolgus monkeys were divided into two groups for IV and SC administration of the compound of Formula I. Animals were administered the compound in a fasted state. Blood samples were collected before and at 5 min, 15 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 36 h, and 48 h after the dose. All blood samples were processed into plasma and then analyzed by liquid chromatography-tandem mass spectrometry. The concentrations of the compound of Formula I and its five major known metabolites in the samples were tested. PK parameters were calculated using PK Solutions 2.0 software (Summit Research Services, Colorado, US).

[0239] The results showed that the bioavailability (based on a comparison of IV and SC pharmacokinetics) for compounds of Formula I or SC administration was approximately 74%. Most of the tested metabolites were found to be present below the limit of quantitation. Only the demethylated metabolite and the amide metabolite (oxidation of the methylene group adjacent to the N-methyl group to a carbonyl group) were found to be present at significant concentrations. The concentrations of both metabolites were found to be lower after SC administration than after IV administration. The results are shown in Table 3 below:

[0240] Table 3

[0241]

[0242] The results showed that SC administration in monkeys resulted in substantially lower levels of major metabolite formation compared to IV administration.

Claims

1. The use of a compound of formula I in the form of a free base or salt, or a compound of formula II in the form of a free base or salt, for the preparation of a medicament for the treatment or prevention of a disease or ailment, wherein the compound of formula I is 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaloline-8-yl)-but-1-one, and the compound of formula II is 1-(4-fluoro-phenyl)-4-((6bR,10aS)-2,2-d2-3-methyl-2,3,6b,9,10,10a-hexahydro-1H ,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-but-1-one, wherein the drug is an oral transmucosal drug preparation, wherein the preparation is a fast-dissolving tablet or rice paper capsule, a fast-dissolving film or an oral gel, wherein the disease or condition is selected from obesity, anorexia, bulimia, depression, major depressive disorder (MDD), anxiety, psychosis, schizophrenia, obsessive-compulsive disorder, sexual dysfunction, migraine, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, headache-related conditions, social phobia, dementia, Alzheimer's disease and Parkinson's dementia or bipolar disorder.

2. The use according to claim 1, wherein the disease or condition is selected from depression, major depressive disorder (MDD), anxiety, psychosis, schizophrenia, obsessive-compulsive disorder, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, dementia, Alzheimer's disease and Parkinson's dementia or bipolar disorder.

3. The use according to claim 1, wherein the disease or condition to be treated is selected from major depressive disorder (MDD), schizophrenia, or bipolar disorder.

4. The use according to claim 1, wherein the disease or condition is selected from depression, major depressive disorder (MDD), anxiety, psychosis, schizophrenia, and bipolar disorder.

5. The use according to claim 1, wherein the disease or condition to be treated is acute anxiety, acute impulsivity, or acute psychosis.

6. The use according to any one of claims 1-5, wherein the formulation is an instant tablet or a rice paper capsule.

7. The use according to any one of claims 1-5, wherein the formulation comprises a compound of formula I or a compound of formula II in the form of a free base.

8. The use according to any one of claims 1-5, wherein the formulation comprises a compound of formula I or a compound of formula II in a pharmaceutically acceptable salt form.

9. The use according to claim 8, wherein the salt is in the form of a toluenesulfonate.

10. The use according to any one of claims 1-5, further comprising one or more hydrophilic, water-soluble or water-swellable polymers.

11. The use according to claim 10, wherein the polymer is selected from natural or modified fibrous polymers, polymers of ethylene oxide and / or propylene oxide, polymers containing acrylic monomers, natural or modified gums, natural or modified starches, or any mixture thereof.

12. The use according to any one of claims 1-5 further comprises one or more excipients selected from plasticizers, surfactants, desiccants, flavoring agents, binders, disintegrants, humectants, wetting agents, antioxidants, buffers and thickeners.

13. Use according to any one of claims 1-5, wherein the formulation is a sublingual tablet or a rice paper capsule.

14. The use according to any one of claims 1-5, wherein the formulation comprises one or more gum polymers selected from gum arabic, guar gum, agar, xanthan gum, tragacanth gum, sylvestris gum, and gelling sugar.

15. The use according to any one of claims 1-5, wherein the formulation comprises one or more polymers selected from gelatin.

16. The use according to claim 15, wherein the gelatin is selected from bovine gelatin, poultry gelatin, and fish gelatin.

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