Novel compositions and methods.

NOVEL COMPOSITIONS AND METHODS

Cross reference to related requests

This application claims the priority of United States provisional patent application no. 62/476,538, filed on March 24, 2017, the contents of which are incorporated herein by reference in their entirety.

field of invention

This disclosure relates to certain novel transmucosal and subcutaneous pharmaceutical formulations comprising gamma-carbolines fused with substituted heterocycle, the preparation of such formulations and methods of use thereof, for example, in the treatment of diseases or abnormal conditions involving or mediated by the 5-HT2A receptor, serotonin transporter (SERT) and/or dopamine DI/D2 receptor signaling pathways. The invention includes methods of treatment and/or prophylaxis of diseases and disorders including, but not limited to, anxiety, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with head pain, social phobias, gastrointestinal disorders, such as gastrointestinal tract motility dysfunction and obesity; depression (including major depressive disorder (MDD)) and mood disorders associated with psychosis or Parkinson's disease; psychoses such as schizophrenia associated with depression; bipolar disorder (e.g., bipolar depression) and other psychiatric and neurological conditions, as well as combinations with other agents.

Background of the invention

-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1 H,7Hpyrid[3',4':4 ,5]pyrrolo[1,2,3-de]quinoxalin-8-íl)-butan-1-one (sometimes referred to as 4-((6bR,10aS)-3methyl-2,3, 6b,9,10,10a-hexahydro-1 H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-¡l)-1 -(4 -fluorophenyl)-1 butanone, or as ITI-007), has the following structure:

<img file="MX2022010797A_D0001.tif" />

The compound of formula I is a potent ligand of the 5-HT receptor₂A (K¡=0.5 nM) with strong affinity for dopamine (DA) D2 receptors (K¡=32 nM) and the serotonin transporter (SERT) (K¡=26 nM, measured using 3H-imipram binding displacement na to human recombinant SERT), but negligible binding to receptors associated with cognitive and metabolic side effects of antipsychotic drugs (e.g., H1 histaminergic, 5-HT2C, and muscarinic receptors). This compound is currently in clinical trials, that is, for the treatment of schizophrenia, bipolar disorder and dementia including Alzheimer's disease. The compound of formula I and analogs thereof, salts thereof and methods of treatment comprising such compounds and methods of making such compounds have been described, for example, in US Patents 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; RE39,680; RE39,679; United States Patent Publications 2004/209864, 2010/113781,2011/071080, 2011/112105, 2013/0202692, 2015/0079172, 2017/0183350; and PCT publication WO 2017/165843 and WO 2017/117514. The contents of each of these United States Patents, United States Patent Publications and PCT Publications are incorporated herein by reference in their entirety.

Deuterated variants of ITI-007 are generally described in US 2017/0183350 and WO 2017/165843. Deuterated compounds are designed to slow or inhibit metabolism in vivo by deuterium atoms substituted for hydrogen atoms of ITI-007 at molecular positions which are the target of metabolic activity. The natural metabolites of ITI-007 are pharmacologically active, but with somewhat different receptor selectivity profiles. These deuterated derivatives may therefore provide modified pharmacokinetic profiles due to altered rates or pathways of metabolism, as well as modified overall pharmacological profile due to the shift in equilibrium between active precursor species and active metabolite species.

One such deuterated compound is 1-(4-fluoro-phenyl)-4-((6bR,10aS)-2,2-Ó2-3-methyl2,3,6b,9,10,1 Oa-hexahydro-1 H 7H-pyrrolo[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one, the compound of formula II:

<img file="MX2022010797A_D0002.tif" />

Another such deuterated compound is 1-(4-fluoro-phenyl)-4-((6bR,10aS)-1,1,2,2-Ó4-3-methyl2,3,6b,9,10,10a-hexah ¡dro-1 H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-íl)-butan-1-one, the compound of formula III:

<img file="MX2022010797A_D0003.tif" />

Formula III

The compounds of formulas I, II and formula III each undergo significant first-pass metabolism in the liver. The high rate of metabolism requires administration of higher oral doses of drug than would otherwise be necessary, resulting in increased burden on the liver, increased manufacturing costs, difficulties in formulation, and potentially greater patient-to-patient variability in dose response. Therefore, there is a need for new routes of administration that avoid first-pass metabolism and which result in correspondingly lower dosage requirements.

It has been described that for a variety of drugs, transmucosal deliveries such as sublingual delivery, buccal delivery and intranasal delivery and subcutaneous delivery, are effective alternatives to traditional dosage forms, such as parenteral and oral dosing. Parenteral (intravenous) dosing is very effective in avoiding first-pass metabolism, but is limited in its usefulness because it requires administration by trained professionals, usually in a clinical setting. In contrast, transmucosal delivery systems can be used to form drugs which 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 providing the potential for delayed or extended release (compared to IV administration).

The use of transmucosal drug delivery formulations is well known, with sublingual formulations of nitroglycerin dating back to 1847. These formulations involve the transfer of active drug agent across mucosal membranes, including the oral mucosa, nasal mucosa, and the vaginal mucosa. These mucosal surfaces are much more permeable to drugs than the skin (keratinized epithelium) and have similar permeability to the gastrointestinal mucosa, but without the problem that Gl absorption of drugs results in immediate passage to the liver for metabolism. Oral mucosal delivery systems include buccal and sublingual systems.

Existing transmucosal delivery systems include rapidly disintegrating wafers and tablets, dissolvable films, aerosol sprays, dissolvable gels, as well as aqueous solutions. Examples of dissolvable film delivery systems include those described in US Patent 4,136,145 to Fuchs, US Patent 4,849,246 to Schmidt, US Patent 5,629,003 to Horstmann, US Patent 5,948,430 to Zerbe, US Patent 9,108,340 to Yang, US Patent 8,906,277 to Yang, US Pat. Yang US Patent 8,900,498, Yang US Patent 8,900,497, Yang US Patent 8,652,378, U.S. Patent 8,603,514 to Yang, U.S. Patent 9,427,412 to Bryson, and U.S. Patent 8,414,922 to Bryson. Other transmucosal systems are described in US Pat. ). However, such drugs, such as apomorphine, are found to be tolerated and effective in some forms of transmucosal delivery, but not in others (see US Patent 9,427,412 which describes the lack of efficacy or tolerability for sublingual tablets and intranasal sprays, but not for sublingual films). Additionally, individual formulations must be fine-tuned for particular active pharmaceutical ingredients to ensure delivery reliability. Thus, although the field of transmucosal drug delivery has a long history, considerable effort is required to adapt any selected transmucosal delivery technology to a particular active pharmaceutical ingredient.

Subcutaneous injection is also well known in the art and is popularly used for the administration of insulin, morphine, methotrexate and many other drugs and vaccines. Subcutaneous injection is frequently performed by doctors and other clinicians in person using traditional syringes with small-gauge needles, but there are also many specialty devices for patient self-administration of subcutaneous injection, such as prefilled syringes, autoinjectors, and portable injectors. Such devices include the HumatroPen for insulin injection (Eli Lilly, Indianapolis, Indiana, USA) and the autoinjector for methotrexate injection (Antares Pharma, Ewing, New Jersey, USA).

There is a need for improved pharmaceutical delivery systems for the safe, effective and reliable delivery of the compounds of formula I and/or the compound of formula II. The present disclosure provides novel transmucosal and subcutaneous formulations for the delivery of these compounds without the disadvantages of existing parenteral and oral delivery systems.

Brief description of the invention

The present disclosure is directed to novel transmucosal and subcutaneous pharmaceutical formulations comprising 1 -(4-fluoro-phenyl)-4-((6bR, 10aS)-3-methyl-2,3,6b,9,10,1 Oa- hexahydro-1 H,7Hpyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1 -one, as well as deuterated variants thereof, in forms free base, cocrystal 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, wafers, films, sprays and gels.

Additional areas of applicability of the present invention will become evident from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.

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Detailed description of the invention

The following description of the preferred embodiment(s) is merely exemplary in nature and is not intended in any way to limit the invention, its application or uses.

As used throughout the description, ranges are used as shorthand to describe each and every value that is within the range. Any value within the range can be selected as the end of the range. Furthermore, all references cited herein are incorporated herein by reference in their entirety. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure will control.

Unless otherwise specified, all percentages and quantities expressed herein and elsewhere in the specification should be understood to refer to percentages by weight. The quantities given are based on the active weight of the material in equivalent free base form.

In the first embodiment, the present disclosure provides a transmucosal pharmaceutical formulation (formulation 1) comprising 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9, 10,10ahexahídro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]qu¡noxalin-8-yl)-butan-1-one (compound of formula I), in the form of a free base, cocrystal or salt. The present disclosure further provides the following formulations:

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

1.2. Formulation 1, wherein the formulation comprises the compound of formula I in salt form, for example, in pharmaceutically acceptable salt form, optionally in solid or crystal amorphous salt form; or in cocrystal form, for example, in the form of a nicotinamide or isonicotinamide cocrystal.

1.3. Formulation 1.2, wherein the salt form is a tosylate, oxalate, cyclamate, 4-aminosalicylate, or hydrochloride salt form, optionally, wherein said salt form is a crystalline salt form.

1.4. Any preceding form, wherein the formulation comprises 0.01 to 100 mg of the compound of formula I (free base equivalent), for example, 0.01 to 75 mg, 0.01 to 50 mg, 0.01 to 30 mg, 0.01 to 20 mg, 0.1 to 20 mg, 5 to 20 mg, 10 to 20 mg, 10 to 30 mg, 20 to 30 mg, 20 to 50 mg or 50 to 100 mg.

1.5. Any preceding formulation, wherein the formulation comprises 0.01 to 10 mg of the compound of formula I (free base equivalent).

1.6. Any preceding formulation, wherein the formulation comprises 0.05 to 8 mg of the compound of formula I (free base equivalent), for example, 0.1 to 5 mg or 5 to 10 mg.

1.7. Any preceding formulation, further comprising one or more hydrophilic water-soluble or water-swellable polymers.

1.8. Formula 1.7, wherein the polymer is selected from the group consisting of natural or modified cellulosic polymers, polymers of ethylene oxide and/or propylene oxide, polymers that iviA/a/zuzz/uiuiai comprise acrylic acid monomers, natural gums or modified (for example, xanthan gum), natural or modified starches (for example, pregelatinized starches), or any mixture thereof.

1.9. Any preceding formulation, further comprising a hydrophobic polymer or poorly water-soluble polymer, for example, a Silicon polymer or polyalkylene polymer (for example, polyethylene).

1.10. Any preceding formulation, further comprising one or more excipients selected from the group consisting of plasticizers, surfactants, drying agents, flavors, sweeteners, binders, disintegrants, humectants (e.g., polyols), wetting agents, antioxidants, buffering agents (e.g. for example, acids, bases and/or salts thereof) and thickening agents (for example, gelling agents).

1.11. Formula 1.10, wherein one or more excipients are selected from any of the following: alcohols (ethanol, glycerol, propylene glycol), gums (e.g. arabic, guar, agar, xanthan, tragacanth, karaya, gellan), polysaccharides and polysaccharide derivatives (e.g. starches, dextrans, pectins, alginates, carrageenans, cellulose, cellulose derivatives (e.g. carboxymethylcellulose, methylcellulose, hydroxyalkylcelluloses (e.g. hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose)), gelatins including non-gelling and gelling types (e.g., mammalian gelatins, such as bovine gelatin, porcine gelatins, avian gelatins, fish gelatins (e.g., mixed high molecular weight and low molecular weight gelatins), synthetic polymers (e.g. for example, polyvinylpyrrolidones, polymers and copolymers of polyethylene oxide and/or polypropylene oxide (for example, poloxamers, such as poloxamer 188), polyacrylate polymers (for example, carbopoles), polyamide polymers), sugars and sugar alcohols (e.g., dextrose, lactose, galactose, glucose, ribose, sucrose, trehalose, mannitol, maltitol, lactitol, sorbitol, xylitol, erythritol, galactitol, inositol), polypeptides/proteins, amino acids , inorganic or organic acids (for example, citric acid, lactic acid, malic acid, gluconic acid, benzoic acid, toluenesulfonic acid, phosphoric acid, sulfuric acid, hydrochloric acid, tartaric acid, oxalic acid, cyclamic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, formic acid) and their salts (for example, sodium, potassium, calcium, magnesium, lithium, ammonium salts of the aforementioned acids), inorganic or organic bases (for example, carbonates, bicarbonates, hydroxides, oxides of alkali metals or alkaline earth metals), cationic surfactants (for example, benzalkonium halides, cetylpyridinium halides, cetrimonium halides, benzethonium halides), zwitterionic surfactants (for example, cocamidoalkyl betaines, such as cocamidopropyl betaine), nonionic surfactants (for example, fatty alcohol ethoxylates (for example, polyethylene glycol polydodecyl ethers), sorbitan esters (for example, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate), 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, beta-carotene, tocopherols, tocotrienols).

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

1.13. Any preceding formulation, which is free of plasticizer, surfactant or humectant (for example, polyol).

1.14. Any preceding formulation, wherein the formulation comprises from 0.01 to 99% water, for example, from 0.01 to 10% water, or from 0.01 to 5% water, or from 50 to 99% water, or from 75 to 99% water, or 25 to 75% water.

1.15. Any preceding formulation, wherein the formulation is a rapidly dissolving tablet or wafer, for example, a sublingual tablet or wafer.

1.16. Any formulation 1 or 1.1 to 1.14, wherein the formulation is an oral spray, for example, a sublingual spray or buccal spray.

1.17. Any formulation 1 or 1.1 to 1.14, wherein the formulation is a rapidly dissolving film, for example, a sublingual film or buccal film.

1.18. Formula 1.17, wherein the film is a single layer or multi-layer film.

1.19. Formulation 1.17 or 1.18, wherein the film has uniform or substantially uniform thickness.

1.20. Formulation 1.17, 1.18 or 1.19, wherein the compound of formula I is distributed uniformly or substantially uniformly.

1.21. Any formulation 1 or 1.1 to 1.14, wherein the formulation is an intranasal spray.

1.22. Any formulation 1 or 1.1 to 1.14, wherein the formulation is an oral gel, for example, a rapidly dissolving sublingual or buccal gel.

1.23. Any of formulations 1 or 1.1 to 1.14, wherein the formulation is an intravaginal formulation, for example, a rapidly dissolving intravaginal tablet, wafer or gel, or an intravaginal spray or a rapidly dissolving intravaginal film.

1.24. Any preceding formulation wherein the compound of formula I is incorporated into the formulation as microparticles (for example, particles having an average diameter of less than 50 pm, less than 30 pm, less than 10 pm, or less than 5 pm, or less than 1 pm).

1.25. Any preceding formulation wherein the compound of formula I is incorporated into the formulation as nanoparticles (for example, particles having an average diameter of less than 100 pm, or less than 50 pm, or less than 10 pm).

1.26. Any preceding formulation, wherein the formulation is absorbed by the mucosa (e.g., dissolves) in less than 30 seconds after administration.

1.27. Any preceding formulation, wherein the dosage of the compound of formula I is 1 to 20% of the unit daily dosage for oral administration, for example, 5 to 15% of the oral dosage.

1.28. Any preceding formulation, wherein the formulation further comprises the compound of formula II or the compound of formula III or a combination thereof.

1.29. Any preceding formulation, wherein the formulation is formulated for administration once a day, or twice a day, or three times a day, or four times a day, or once every two days or once every three days.

1.30. Any preceding formulation, wherein the formulation comprises the compound of formula I in tosylate salt form, for example, in monotosylate salt form or ditosylate salt form or a mixture thereof.

1.31. Formulation 1.30, wherein the formulation further comprises toluenesulfonic acid, for example, the formulation comprises the compound of formula I in the form of a tosylate salt 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 approximately 1:1.

1.32. Any preceding formulation, wherein the compound of formula I is enriched in deuterium at one or more hydrogen atom positions, for example, where at any one or more hydrogen atom positions there exists a level of deuterium incorporation substantially greater than the natural level at such positions in the structure (for example, greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%).

1.33. Formulation 1.32, wherein the compound of formula I has more than 50% deuterium incorporation at any one or more hydrogen atom positions of the structure (i.e., greater than 50% D atom), e.g. 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 %.

1.34. Any of formulations 1 or 1.1 to 1.31, wherein all hydrogen atom positions of the compound of formula I are not enriched in deuterium (i.e., each hydrogen atom position contains the natural abundance of deuterium or less than 0.1% of deuterium).

In a second embodiment, the present disclosure provides a transmucosal pharmaceutical formulation (formulation 2) comprising 1-(4-fluoro-phenyl)-4-((6bR,10aS) 2,2-o^3-methyl2,3,6b ,9,10,1 Oa-hexahydro-1 H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-íl)-butan-1 -one (compound of formula II), in the form of free base, cocrystal or salt. The present disclosure further provides the following formulations:

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

2.2. Formulation 2, wherein the formulation comprises the compound of formula II in salt form, for example, in pharmaceutically acceptable salt form, optionally in solid or crystal amorphous salt form; or in cocrystal form, for example, in the form of a nicotinamide or isonicotinamide cocrystal.

23. Formulation 2.2, wherein the salt form is a tosylate, oxalate, cyclamate, 4-aminosalicylate, or hydrochloride salt form, optionally, wherein said salt form is a crystalline salt form.

2.4. Any preceding form, wherein the formulation comprises 0.01 to 100 mg of the compound of formula II (free base equivalent), for example, 0.01 to 75 mg, 0.01 to 50 mg, 0.01 to 30 ινΐΛ/a/zuzz/uiuiai mg, 0.01 to 20 mg, 0.1 to 20 mg, 5 to 20 mg, 10 to 20 mg, 10 to 30 mg, 20 to 30 mg, 20 to 50 mg or 50 to 100 mg.

2.5. Any preceding formulation, wherein the formulation comprises 0.01 to 10 mg of the compound of formula II (free base equivalent).

2.6. Any preceding formulation, wherein the formulation comprises 0.05 to 8 mg of the compound of formula II (free base equivalent), for example, 0.1 to 5 mg or 5 to 10 mg.

2.7. Any preceding formulation, further comprising one or more hydrophilic water-soluble or water-swellable polymers.

2.8. Formula 2.7, wherein the polymer is selected from the group consisting of natural or modified cellulosic polymers, polymers of ethylene oxide and/or propylene oxide, polymers comprising acrylic acid monomers, natural or modified gums (for example, xanthan gum ), natural or modified starches (for example, pregelatinized starches), or any mixture thereof.

2.9. Any preceding formulation, further comprising a hydrophobic polymer or poorly water-soluble polymer, for example, a Silicon polymer, or polyalkylene polymer (for example, polyethylene).

2.10. Any preceding formulation, further comprising one or more excipients selected from the group consisting of plasticizers, surfactants, drying agents, flavors, sweeteners, binders, disintegrants, humectants (e.g., polyols), wetting agents, antioxidants, buffering agents (e.g. for example, acids, bases and/or salts thereof) and thickening agents (for example, gelling agents).

2.11. Formula 2.10, wherein one or more excipients are selected from any of the following: alcohols (ethanol, glycerol, propylene glycol), gums (e.g. arabic, guar, agar, xanthan, tragacanth, karaya, gellan), polysaccharides and polysaccharide derivatives (e.g. starches, dextrans, pectins, alginates, carrageenans, cellulose, cellulose derivatives (e.g. carboxymethylcellulose, methylcellulose, hydroxyalkylcelluloses (e.g. hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose)), gelatins including non-gelling and gelling types (e.g., mammalian gelatins, such as bovine gelatin, porcine gelatins, avian gelatins, fish gelatins (e.g., mixed high molecular weight and low molecular weight gelatins), synthetic polymers (e.g. for example, polyvinylpyrrolidones, polymers and copolymers of polyethylene oxide and/or polypropylene oxide (for example, poloxamers, such as poloxamer 188), polyacrylate polymers (for example, carbopoles), polyamide polymers), sugars and sugar alcohols (e.g., dextrose, lactose, galactose, glucose, ribose, sucrose, trehalose, mannitol, maltitol, lactitol, sorbitol, xylitol, erythritol, galactitol, inositol), polypeptides/proteins, amino acids , inorganic or organic acids (for example, citric acid, lactic acid, malic acid, gluconic acid, benzoic acid, toluenesulfonic acid, phosphoric acid, sulfuric acid, hydrochloric acid, tartaric acid, oxalic acid, cyclamic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, formic acid) and their salts (for example, sodium, potassium, calcium, magnesium, lithium, ammonium salts of the aforementioned acids), inorganic or organic bases (for example

MA/a/zuzz/ui uiyi e.g. carbonates, bicarbonates, hydroxides, oxides of alkali metals or alkaline earth metals), cationic surfactants (e.g. benzalkonium halides, cetylpyridinium halides, cetrimonium halides, benzethonium halides), zwitterionic surfactants (e.g., cocamidoalkyl betaines, such as cocamidopropyl betaine), nonionic surfactants (e.g., fatty alcohol ethoxylates (e.g., polyethylene glycol polydodecyl ethers), sorbitan esters (e.g., sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate), 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, beta-carotene, tocopherols, tocotrienols).

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

2.13. Any preceding formulation, which is free of plasticizer, surfactant or humectant (for example, polyol).

2.14. Any preceding formulation, wherein the formulation comprises from 0.01 to 99% water, for example, from 0.01 to 10% water, or from 0.01 to 5% water, or from 50 to 99% water, or from 75 to 99% water, or 25 to 75% water.

2.15. Any preceding formulation, wherein the formulation is a rapidly dissolving tablet or wafer, for example, a sublingual tablet or wafer.

2.16. Any formulation 2 or 2.1 to 2.14, wherein the formulation is an oral spray, for example, a sublingual spray or buccal spray.

2.17. Any formulation 2 or 2.1 to 2.14, wherein the formulation is a rapidly dissolving film, for example, a sublingual film or buccal film.

2.18. Formula 2.17, wherein the film is a single layer or multi-layer film.

2.19. Formulation 2.17 or 2.18, wherein the film has uniform or substantially uniform thickness.

2.20. Formulation 2.17, 2.18 or 2.19, wherein the compound of formula II is distributed uniformly or substantially uniformly.

2.21. Any formulation 2 or 2.1 to 2.14, wherein the formulation is an intranasal spray.

2.22. Any formulation 2 or 2.1 to 2.14, wherein the formulation is an oral gel, for example, a rapidly dissolving sublingual or buccal gel.

2.23. Any of formulations 2 or 2.1 to 2.14, wherein the formulation is an intravaginal formulation, for example, a rapidly dissolving intravaginal tablet, wafer or gel, or an intravaginal spray or a rapidly dissolving intravaginal film.

2.24. Any preceding formulation wherein the compound of formula II is incorporated into the formulation as microparticles (for example, particles having an average diameter of less than 50 pm, less than 30 pm, less than 10 pm, or less than 5 pm, or less than 1 pm).

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2.25. Any preceding formulation wherein the compound of formula II is incorporated into the formulation as nanoparticles (for example, particles having an average diameter of less than 100 pm, or less than 50 pm, or less than 10 pm).

2.26. Any preceding formulation, wherein the formulation is absorbed by the mucosa (e.g., dissolves) in less than 30 seconds after administration.

2.27. Any preceding formulation, wherein the dosage of the compound of formula II is 1 to 20% of the unit daily dosage for oral administration, for example, 5 to 15% of the oral dosage.

2.28. Any preceding formulation, wherein the formulation further comprises the compound of formula I or the compound of formula III or a combination thereof.

2.29. Any preceding formulation, wherein the formulation is formulated for administration once a day, or twice a day, or three times a day, or four times a day, or once every two days or once every three days.

2.30. Any preceding formulation, wherein the formulation comprises the compound of formula II in tosylate salt form, for example, in monotosylate salt form or ditosylate salt form or a mixture thereof.

2.31. Formulation 2.30, wherein the formulation further comprises toluenesulfonic acid, for example, the formulation comprises the compound of formula II in the form of a tosylate salt 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 approximately 1:1.

In a third embodiment, the present disclosure provides a subcutaneous pharmaceutical formulation (formulation 3) comprising 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9, 10,10ahexah¡dro-1H,7H-p¡r¡do[3',4':4,5]pyrrolo[1,2,3-de]quinoxal¡n-8-¡l)-butan- 1-or na (compound of formula I), in the form of free base, cocrystal or salt. The present disclosure further provides the following formulations:

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

3.2. Formulation 3, wherein the formulation comprises the compound of formula I in salt form, for example, in pharmaceutically acceptable salt form, optionally in solid or crystal amorphous salt form; or in cocrystal form, for example, in the form of a nicotinamide or isonicotinamide cocrystal.

3.3. Formulation 3.2, wherein the salt form is a tosylate, oxalate, cyclamate, 4-aminosalicylate, or hydrochloride salt form, optionally, wherein said salt form is a crystalline salt form.

3.4. Any preceding form, wherein the formulation comprises 0.01 to 100 mg of the compound of formula I (free base equivalent), for example, 0.01 to 75 mg, 0.01 to 50 mg, 0.01 to 30 mg, 0.01 to 20 mg, 0.1 to 20 mg, 5 to 20 mg, 10 to 20 mg, 10 to 30 mg, 20 to 30 mg, 20 to 50 mg or 50 to 100 mg.

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3.5. Any preceding formulation, wherein the formulation comprises 0.01 to 10 mg of the compound of formula I (free base equivalent).

3.6. Any preceding formulation, wherein the formulation comprises 0.05 to 8 mg of the compound of formula I (free base equivalent), for example, 0.1 to 5 mg or 5 to 10 mg.

3.7. Any preceding formulation, further comprising one or more of water, water-soluble polymers (e.g., modified celluloses, polyvinylpyrrolidones, polyethylene glycols), water-miscible alcohols (e.g., ethanol, glycerin and propylene glycol), fillers (e.g. , sugars, sugar alcohols and amino acids), inorganic salts (for example, sodium chloride, calcium chloride, potassium chloride), buffers (for example, carbonate and bicarbonate salts, citrate salts, phosphate salts, Tris salts), preservatives, antioxidants, chelating agents and mixtures thereof.

3.8. Any preceding formulation, wherein the formulation comprises from 0.01 to 99% water, for example, from 0.01 to 10% water, or from 0.01 to 5% water, or from 50 to 99% water, or from 75 to 99% water, or 25 to 75% water.

3.9. Any preceding formulation, wherein a substantial amount (for example, greater than 75% or greater than 85%, or greater than 90%) of the compound of formula I is absorbed immediately (for example, in less than 1 minute, or less than 5 minutes).

3.10. Any preceding formulation, wherein a significant amount (for example, greater than 25% or greater than 50%, or greater than 75%) of the compound of formula I is not absorbed immediately (for example, in more than 5 minutes, or more 10 minutes, or less than 30 minutes, or greater than 1 hour or greater than 5 hours).

3.11. Any preceding formulation, wherein the formulation is packaged for use in a prefilled syringe, a prefilled autoinjector, or a sealed vial or similar container.

3.12. Any preceding formulation, wherein the formulation is packaged for use as a dry solid, for example, a lyophilized solid, for reconstitution in a pharmaceutically acceptable solvent (for example, sterile water for injection) at the point of use.

3.13. Any preceding formulation, wherein the dosage of the compound of formula I is 1 to 20% of the unit daily dosage for oral administration, for example, 5 to 15% of the oral dosage.

3.14. Any preceding formulation, wherein the formulation further comprises the compound of formula II or the compound of formula III or a combination thereof.

3.15. Any formulation, wherein the formulation is formulated for administration once a day, or once every two days, or once every three days, or once a week, or once every two weeks, or once every three weeks, or once a month, or once every two months, or once every three months, or once every six months.

3.16. Any preceding formulation, wherein the formulation comprises the compound of formula I in tosylate salt form, for example, in monotosylate salt form or ditosylate salt form or a mixture thereof.

3.17. Formulation 3.16, wherein the formulation further comprises toluenesulfonic acid, for example, the formulation comprises the compound of formula I in the form of a tosylate salt 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 approximately 1:1.

3.18. Any preceding formulation, wherein the compound of formula I is enriched in deuterium at one or more hydrogen atom positions, for example, where at any one or more hydrogen atom positions there exists a level of deuterium incorporation substantially greater than the natural level at such positions in the structure (for example, greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%).

3.19. Formulation 3.18, wherein the compound of formula I has more than 50% deuterium incorporation at any one or more hydrogen atom positions of the structure (i.e., greater than 50% D atom), e.g. 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 %.

3.20. Any of formulations 3 or 3.1 to 3.17, wherein all hydrogen atom positions of the compound of formula I are not enriched in deuterium (i.e., each hydrogen atom position contains the natural abundance of deuterium or less than 0.1% of deuterium).

In a fourth embodiment, the present disclosure provides a subcutaneous pharmaceutical formulation (formulation 4) comprising 1 -(4-fluoro-phenyl)-4-((6bR, 10aS) 2,2-cfe-3-methyl-2 ,3,6b,9,10,10ahexahydro-1 H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1 -one (compound of formula II), in the form of free base, cocrystal or salt. The present disclosure further provides the following formulations:

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

4.2. Formulation 4, wherein the formulation comprises the compound of formula II in salt form, for example, in pharmaceutically acceptable salt form, optionally in solid or crystal amorphous salt form; or in cocrystal form, for example, in the form of a nicotinamide or isonicotinamide cocrystal.

4.3. Formulation 4.2, wherein the salt form is a tosylate, oxalate, cyclamate, 4-aminosalicylate, or hydrochloride salt form, optionally, wherein said salt form is a crystalline salt form.

4.4. Any preceding form, wherein the formulation comprises 0.01 to 100 mg of the compound of formula II (free base equivalent), for example, 0.01 to 75 mg, 0.01 to 50 mg, 0.01 to 30 mg, 0.01 to 20 mg, 0.1 to 20 mg, 5 to 20 mg, 10 to 20 mg, 10 to 30 mg, 20 to 30 mg, 20 to 50 mg or 50 to 100 mg.

4.5. Any preceding formulation, wherein the formulation comprises 0.01 to 10 mg of the compound of formula II (free base equivalent).

4.6. Any preceding formulation, wherein the formulation comprises 0.05 to 8 mg of the compound of formula II (free base equivalent), for example, 0.1 to 5 mg or 5 to 10 mg.

4.7. Any preceding formulation, further comprising one or more of water, water-soluble wuua/zuzz/ui uiai polymers (for example, modified celluloses, polyvinylpyrrolidones, polyethylene glycols), water-miscible alcohols (for example, ethanol, glycerin and propylene glycol), filling agents (e.g. sugars, sugar alcohols and amino acids), inorganic salts (e.g. sodium chloride, calcium chloride, potassium chloride), buffers (e.g. carbonate and bicarbonate salts, citrate salts, phosphate salts, Tris salts), preservatives, antioxidants, chelating agents and mixtures thereof.

4.8. Any preceding formulation, wherein the formulation comprises from 0.01 to 99% water, for example, from 0.01 to 10% water, or from 0.01 to 5% water, or from 50 to 99% water, or from 75 to 99% water, or 25 to 75% water.

4.9. Any preceding formulation, wherein a substantial amount (for example, greater than 75% or greater than 85%, or greater than 90%) of the compound of formula II is absorbed immediately (for example, in less than 1 minute, or less than 5 minutes).

4.10. Any preceding formulation, wherein a significant amount (for example, greater than 25% or greater than 50%, or greater than 75%) of the compound of formula II is not absorbed immediately (for example, in more than 5 minutes, or more 10 minutes, or less than 30 minutes, or greater than 1 hour or greater than 5 hours).

4.11. Any preceding formulation, wherein the formulation is packaged for use in a prefilled syringe, a prefilled autoinjector, or a sealed vial or similar container.

4.12. Any preceding formulation, wherein the formulation is packaged for use as a dry solid, for example, a lyophilized solid, for reconstitution in a pharmaceutically acceptable solvent (for example, sterile water for injection) at the point of use.

4.13. Any preceding formulation, wherein the dosage of the compound of formula II is 1 to 20% of the unit daily dosage for oral administration, for example, 5 to 15% of the oral dosage.

4.14. Any preceding formulation, wherein the formulation further comprises the compound of formula I or the compound of formula III or a combination thereof.

4.15. Any formulation, wherein the formulation is formulated for administration once a day, or once every two days, or once every three days, or once a week, or once every two weeks, or once every three weeks, or once a month, or once every two months, or once every three months, or once every six months.

4.16. Any preceding formulation, wherein the formulation comprises the compound of formula II in tosylate salt form, for example, in monotosylate salt form or ditosylate salt form or a mixture thereof.

4.17. Formulation 4.16, wherein the formulation further comprises toluenesulfonic acid, for example, the formulation comprises the compound of formula II in the form of a tosylate salt 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 approximately 1:1.

In a fifth embodiment, the present disclosure provides a transmucosal pharmaceutical formulation (formulation 5) comprising 1-(4-fluoro-phenyl)-4-((6bR,10aS) 1,1,2,2-dr3-methylινΐΛ/a /zuzz/uiuiyi

2,3,6b,9,10,10a-hexahydro-1 H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan- 1-one (compound of formula III), in the form of free base, cocrystal or salt. The present disclosure further provides the following formulations:

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

5.2. Formulation 5, wherein the formulation comprises the compound of formula III in salt form, for example, in pharmaceutically acceptable salt form, optionally in solid or crystal amorphous salt form; or in cocrystal form, for example, in the form of a nicotinamide or isonicotinamide cocrystal.

5.3. Formulation 5.2, wherein the salt form is a tosylate, oxalate, cyclamate, 4-aminosalicylate, or hydrochloride salt form, optionally, wherein said salt form is a crystalline salt form.

5.4. Any preceding form, wherein the formulation comprises 0.01 to 100 mg of the compound of formula III (free base equivalent), for example, 0.01 to 75 mg, 0.01 to 50 mg, 0.01 to 30 mg, 0.01 to 20 mg, 0.1 to 20 mg, 5 to 20 mg, 10 to 20 mg, 10 to 30 mg, 20 to 30 mg, 20 to 50 mg or 50 to 100 mg.

5.5. Any preceding formulation, wherein the formulation comprises 0.01 to 10 mg of the compound of formula III (free base equivalent).

5.6. Any preceding formulation, wherein the formulation comprises 0.05 to 8 mg of the compound of formula III (free base equivalent), for example, 0.1 to 5 mg or 5 to 10 mg.

5.7. Any preceding formulation, further comprising one or more hydrophilic water-soluble or water-swellable polymers.

5.8. Formula 5.7, wherein the polymer is selected from the group consisting of natural or modified cellulosic polymers, polymers of ethylene oxide and/or propylene oxide, polymers comprising acrylic acid monomers, natural or modified gums (for example, xanthan gum ), natural or modified starches (for example, pregelatinized starches), or any mixture thereof.

5.9. Any preceding formulation, further comprising a hydrophobic polymer or poorly water-soluble polymer, for example, a Silicon polymer or polyalkylene polymer (for example, polyethylene).

5.10. Any preceding formulation, further comprising one or more excipients selected from the group consisting of plasticizers, surfactants, drying agents, flavors, sweeteners, binders, disintegrants, humectants (e.g., polyols), wetting agents, antioxidants, buffering agents (e.g. for example, acids, bases and/or salts thereof) and thickening agents (for example, gelling agents).

5.11. Formula 5.10, wherein one or more excipients are selected from any of the following: alcohols (ethanol, glycerol, propylene glycol), gums (e.g. arabic, guar, agar, xanthan, tragacanth, karaya, gelana), polysaccharides and polysaccharide derivatives (e.g. starches, dextrans, iviA/a/zuzz/uiuiyi pectins , alginates, carrageenans, cellulose, cellulose derivatives (e.g. carboxymethylcellulose, methylcellulose, hydroxyalkylcelluloses (e.g. hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose)), gelatins including non-gelling and gelling types (e.g., mammalian gelatins, such as bovine gelatin, porcine gelatins, avian gelatins, fish gelatins (e.g., mixed high molecular weight and low molecular weight gelatins), synthetic polymers (e.g. for example, polyvinylpyrrolidones, polymers and copolymers of polyethylene oxide and/or polypropylene oxide (for example, poloxamers, such as poloxamer 188), polyacrylate polymers (for example, carbopoles), polyamide polymers), sugars and sugar alcohols (e.g., dextrose, lactose, galactose, glucose, ribose, sucrose, trehalose, mannitol, maltitol, lactitol, sorbitol, xylitol, erythritol, galactitol, inositol), polypeptides/proteins, amino acids , inorganic or organic acids (for example, citric acid, lactic acid, melic acid, gluconic acid, benzoic acid, toluenesulfonic acid, phosphoric acid, sulfuric acid, hydrochloric acid, tartaric acid, oxalic acid, cyclamic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, formic acid) and their salts (for example, sodium, potassium, calcium, magnesium, lithium, ammonium salts of the aforementioned acids), inorganic or organic bases (for example, carbonates, bicarbonates, hydroxides, oxides of alkali metals or alkaline earth metals), cationic surfactants (for example, benzalkonium halides, cetylpyridinium halides, cetrimonium halides, benzethonium halides), zwitterionic surfactants (for example, cocamidoalkyl betaines, such as cocamidopropyl betaine), nonionic surfactants (for example, fatty alcohol ethoxylates (for example, polyethylene glycol polydodecyl ethers), sorbitan esters (for example, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate), 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, beta-carotene, tocopherols, tocotrienols).

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

5.13. Any preceding formulation, which is free of plasticizer, surfactant or humectant (for example, polyol).

5.14. Any preceding formulation, wherein the formulation comprises from 0.01 to 99% water, for example, from 0.01 to 10% water, or from 0.01 to 5% water, or from 50 to 99% water, or from 75 to 99% water, or 25 to 75% water.

5.15. Any preceding formulation, wherein the formulation is a rapidly dissolving tablet or wafer, for example, a sublingual tablet or wafer.

5.16. Any formulation 5 or 5.1 to 5.14, wherein the formulation is an oral spray, for example, a sublingual spray or buccal spray.

5.17. Any formulation 5 or 5.1 to 5.14, wherein the formulation is a rapidly dissolving film, for example, a sublingual film or buccal film.

5.18. Formula 5.17, wherein the film is a single layer or multi-layer film.

5.19. Formulation 5.17 or 5.18, wherein the film has uniform or substantially uniform thickness.

5.20. Formulation 5.17, 5.18 or 5.19, wherein the compound of formula III is distributed uniformly or substantially uniformly.

5.21. Any formulation 5 or 5.1 to 5.14, wherein the formulation is an intranasal spray.

5.22. Any formulation 5 or 5.1 to 5.14, wherein the formulation is an oral gel, for example, a rapidly dissolving sublingual or buccal gel.

5.23. Any of formulations 5 or 5.1 to 5.14, wherein the formulation is an intravaginal formulation, for example, a rapidly dissolving intravaginal tablet, wafer or gel, or an intravaginal spray or a rapidly dissolving intravaginal film.

5.24. Any preceding formulation wherein the compound of formula III is incorporated into the formulation as microparticles (for example, particles having an average diameter of less than 50 pm, less than 30 pm, less than 10 pm, or less than 5 pm, or less than 1 pm).

5.25. Any preceding formulation wherein the compound of formula III is incorporated into the formulation as nanoparticles (for example, particles having an average diameter of less than 100 pm, or less than 50 pm, or less than 10 pm).

5.26. Any preceding formulation, wherein the formulation is absorbed by the mucosa (e.g., dissolves) in less than 30 seconds after administration.

5.27. Any preceding formulation, wherein the dosage of the compound of formula III is 1 to 20% of the unit daily dosage for oral administration, for example, 5 to 15% of the oral dosage.

5.28. Any preceding formulation, wherein the formulation further comprises the compound of formula II or the compound of formula I or a combination thereof.

5.29. Any preceding formulation, wherein the formulation is formulated for administration once a day, or twice a day, or three times a day, or four times a day, or once every two days or once every three days.

5.30. Any preceding formulation, wherein the formulation comprises the compound of formula III in tosylate salt form, for example, in monotosylate salt form or ditosylate salt form or a mixture thereof.

5.31. Formulation 5.30, wherein the formulation further comprises toluenesulfonic acid, for example, the formulation comprises the compound of formula III in the form of a tosylate salt 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 approximately 1:1.

In a sixth embodiment, the present disclosure provides a subcutaneous pharmaceutical formulation (formulation 6) comprising 1-(4-fluoro-phenyl)-4-((6bR,10aS) 1,1,2,2-dr3-methyl2,3 ,6b,9,10,1 Oa-hexahydro-1 H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1- one (compound of formula III), in the form of a free base, cocrystal or salt. The present disclosure further provides the following formulations:

ινΐΛ/a/zuzz/uiuiai

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

6.2. Formulation 6, wherein the formulation comprises the compound of formula III in salt form, for example, in pharmaceutically acceptable salt form, optionally in solid or crystal amorphous salt form; or in cocrystal form, for example, in the form of a nicotinamide or isonlcotinamide cocrystal.

6.3. Formulation 6.2, wherein the salt form is a tosylate, oxalate, cyclamate, 4-aminosalicylate, or hydrochloride salt form, optionally, wherein said salt form is a crystalline salt form.

6.4. Any preceding form, wherein the formulation comprises 0.01 to 100 mg of the compound of formula III (free base equivalent), for example, 0.01 to 75 mg, 0.01 to 50 mg, 0.01 to 30 mg, 0.01 to 20 mg, 0.1 to 20 mg, 5 to 20 mg, 10 to 20 mg, 10 to 30 mg, 20 to 30 mg, 20 to 50 mg or 50 to 100 mg.

6.5. Any preceding formulation, wherein the formulation comprises 0.01 to 10 mg of the compound of formula III (free base equivalent).

6.6. Any preceding formulation, wherein the formulation comprises 0.05 to 8 mg of the compound of formula III (free base equivalent), for example, 0.1 to 5 mg or 5 to 10 mg.

6.7. Any preceding formulation, further comprising one or more of water, water-soluble polymers (e.g., modified celluloses, polyvinylpyrrolidones, polyethylene glycols), water-miscible alcohols (e.g., ethanol, glycerin and propylene glycol), fillers (e.g. , sugars, sugar alcohols and amino acids), inorganic salts (for example, sodium chloride, calcium chloride, potassium chloride), buffers (for example, carbonate and bicarbonate salts, citrate salts, phosphate salts, Tris salts), preservatives, antioxidants, chelating agents and mixtures thereof.

6.8. Any preceding formulation, wherein the formulation comprises from 0.01 to 99% water, for example, from 0.01 to 10% water, or from 0.01 to 5% water, or from 50 to 99% water, or from 75 to 99% water, or 25 to 75% water.

6.9. Any preceding formulation, wherein a substantial amount (e.g., greater than 75% or greater than 85%, or greater than 90%) of the compound of formula III is absorbed immediately (e.g., in less than 1 minute, or less than 5 minutes).

6.10. Any preceding formulation, wherein a significant amount (e.g., greater than 25% or greater than 50%, or greater than 75%) of the compound of formula III is not absorbed immediately (e.g., in more than 5 minutes, or more 10 minutes, or less than 30 minutes, or greater than 1 hour or greater than 5 hours).

6.11. Any preceding formulation, wherein the formulation is packaged for use in a prefilled syringe, a prefilled autoinjector, or a sealed vial or similar container.

6.12. Any preceding formulation, wherein the formulation is packaged for use as a dry solid, e.g., a lyophilized solid, for reconstitution in a pharmaceutically acceptable solvent (e.g., sterile water for injection) at the point of use.

6.13. Any preceding formulation, wherein the dosage of the compound of formula III is 1 to 20% of the unit daily dosage for oral administration, for example, 5 to 15% of the oral dosage.

6.14. Any preceding formulation, wherein the formulation further comprises the compound of formula II or the compound of formula I or a combination thereof.

6.15. Any formulation, wherein the formulation is formulated for administration once a day, or once every two days, or once every three days, or once a week, or once every two weeks, or once every three weeks, or once a month, or once every two months, or once every three months, or once every six months.

6.16. Any preceding formulation, wherein the formulation comprises the compound of formula III in tosylate salt form, for example, in monotosylate salt form or ditosylate salt form or a mixture thereof.

6.17. Formulation 4.16, wherein the formulation further comprises toluenesulfonic acid, for example, the formulation comprises the compound of formula III in the form of a tosylate salt 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 approximately 1:1.

As used herein, “deuteration” refers to the substitution of a hydrogen atom (protium,¹H) in a chemical structure with a deuterium atom (²H). A hydrogen atom position of a deuterium-substituted structure is considered when the deuterium abundance at that position is enriched. The natural abundance of deuterium is approximately 0.02%, so a compound is “enriched” with deuterium at a specific position when the frequency of deuterium incorporation at that position exceeds 0.02%. Therefore, in any embodiment of a deuterated compound provided herein, any one or more hydrogen atoms may be enriched with deuterium to a level of greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%, such as, 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%.

In all aspects and embodiments of the present disclosure comprising the compound of formula I, said compound of formula I may be optionally deuterated at one or more hydrogen atom positions.

In all aspects and embodiments of the present disclosure comprising the compound of formula II, said compound of formula II is enriched only at the designated positions (2,2-d₂).

In all aspects and embodiments of the present disclosure comprising the compound of formula III, said compound of formula III is enriched only at the designated positions (1,1,2,2d^).

In a second aspect, the present disclosure provides a process (process 1) for the production of the transmucosal formulation of formulation 1, etseq., or formulation 2, etseq., or formulation 5, etseq., comprising the steps of:

(a) combining the compound of formula I, in pharmaceutically acceptable or free salt form and/or the compound of formula II, in pharmaceutically acceptable or free salt form and/or the compound of formula III in salt form pharmaceutically acceptable or free, with suitable pharmaceutically acceptable excipients, optionally in a suitable solvent or mixture of solvents; and (b) either (1) remove the solvent to provide a dry film, or (2) remove the solvent to provide a dry powder suitable for compression into tablets or wafers, or (3) remove the solvent, or some portion of the same, to provide a solution suitable for administration via an aerosol spray device.

In a third aspect, the present disclosure provides a process (process 2) for the production of the subcutaneous formulation of formulation 3, et seq., or formulation 4, et seq., or formulation 6, et seq., comprising the steps from either:

(a) Combine the compound of formula I, in pharmaceutically acceptable or free salt form and/or the compound of formula II in pharmaceutically acceptable or free salt form and/or the compound of formula III in pharmaceutically acceptable salt form or free, with suitable pharmaceutically acceptable excipients in a solvent or mixture of solvents suitable for injection and then package the resulting solution for use (for example, in a prefilled syringe, or in a sealed vial or similar container, or in a prefilled autoinjector); or (b) Combine the compound of formula I, in pharmaceutically acceptable or free salt form and/or the compound of formula II in pharmaceutically acceptable or free salt form and/or the compound of formula III in pharmaceutical salt form acceptable or free, optionally with suitable pharmaceutically acceptable excipients in a solvent or mixture of solvents and then removing said solvent(s) to obtain a dry solid (e.g. a freeze-dried solid) for packaging.

The pharmaceutical formulations described herein, for example, formulation 1, et seq., formulation 2, et seq., formulation 3, et seq., formulation 4, et seq., formulation 5, et seq. and formulation 6, etc., may comprise any suitable pharmaceutically acceptable excipient, including but not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, xylitol, sugar and the like; binders such as acacia, guar gum, tragacanth gum, gelatin, polyvinylpyrrolidones such as polyvinylpyrrolidones (PVP, K-30, K-90), poly(vinyl pyrrolidone-co-vinyl acetate) (PVP-VA) and the like, hydroxypropyl celluloses , hydroxypropylmethylcellulose, cellulose acetate, hydroxypropylmethylcellulose acetate succinate (HPMC-AS) and the like, disintegrants, such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility enhancers or humectants such as anionic or cationic or neutral surfactants; maltodextrin, complexing agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropylcelluloses, hydroxymethylcelluloses, hydroxypropylmethylcelluloses, ethylcelluloses, methylcelluloses, ινΐΛ/a/zuzz/uiuiyi various grades of methyl methacrylates, waxes and the like; and film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, buffering agents, filling agents and the like.

In some embodiments, the formulations may comprise one or more antioxidants, for example, tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), ascorbic acid, or the like. The inclusion of an antioxidant can further improve the stability of formulations by preventing oxidative chemical degradation of the active ingredient.

In another aspect, the present disclosure provides formulation 1, et seq., formulation 2, et seq., formulation 3, et seq., formulation 4, et seq., formulation 5, et seq., or formulation 6, et seq. ., for use to treat a disease or abnormal condition that involves or is mediated by 5-HT receptor signaling pathways₂A, serotonin transporter (SERT)) and/or dopamine D1/D2 receptor, for example, a disorder selected from obesity, anorexia, bulimia, depression (including major depressive disorder (MDD)), anxiety, psychosis, schizophrenia, disorder obsessive-compulsive, sexual disorders, migraine, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with head pain, social phobias, dementia (including Alzheimer's disease and Parkinson's dementia), gastrointestinal disorders, such as gastrointestinal tract motility dysfunction and obesity, or bipolar disorder (for example, bipolar depression).

In another embodiment, the invention provides a method (method 1) for the prophylaxis or treatment of a disease or abnormal condition that involves or is mediated by 5-HT receptor signaling pathways.₂A, serotonin transporter (SERT) and/or dopamine D1/D2 receptor, in a patient in need thereof, comprising administering to the patient via a transmucosal or subcutaneous route, a therapeutically effective amount of the compound of formula I and /or the compound of formula II and/or the compound of formula III. Additional modalities of method 1 include:

1.1 Method 1, wherein the compound of formula I and/or the compound of formula II and/or the compound of formula III is administered via a transmucosal route (for example, intraorally, intranasally, by buccal absorption or by sublingual absorption).

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 is administered in the form of a composition selected from any of formulation 1, et seq., or formulation 2, et seq., or formulation 4, et seq.

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, via a sublingual film, sublingual spray, tablet or sublingual wafer (e.g., fast-dissolving tablet or wafer), or a sublingual solution (e.g., aqueous solution).

1.4 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 buccally, for example, via buccal film, buccal spray, tablet or buccal sublingual wafer (e.g., fast-dissolving tablet or wafer).

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 intraorally, for example, via an intraoral spray (for example, a aerosol spraying).

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, via an intranasal spray (for example, a aerosol spraying).

1.7 Method 1, wherein the compound of formula I and/or the compound of formula II and/or the compound of formula III is administered via a subcutaneous route (for example, a subcutaneous injection).

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 is administered in the form of a composition selected from any of formulation 3, etc., or formulation 4, etseq., or formulation 6, etseq.

1.9 Method 1.7 or 1.8, 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, via a prefilled syringe, an autoinjector, a portable injector.

1.10 Method 1.7, 1.8 or 1.9, wherein the compound of formula I and/or the compound of formula II and/or the compound of formula III is administered by the patient (e.g., is self-administered).

1.11 Method 1 or any of 1.1, et seq., wherein the disease or condition is selected from obesity, anorexia, bulimia, depression (including major depressive disorder (MDD)), anxiety, psychosis, schizophrenia, obsessive-compulsive disorder, disorders sexual activity, migraine, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with head pain, social phobias, dementia (including Alzheimer's disease and Parkinson's dementia), gastrointestinal disorders, such as gastrointestinal tract motility dysfunction and obesity, or bipolar disorder (for example, bipolar depression).

1.12 Method 1 or any of 1.1, et seq., where the disease or condition to be treated requires rapid intervention, for example, acute anxiety, acute agitation or acute psychosis.

1.13 Method 1 or any of 1.1, et seq., wherein the dosage administered via the transmucosal (e.g., sublingual, buccal, intranasal, or intraoral) or subcutaneous route is 1 to 20% of the dosage administered for the same condition by the orally, for example, 5 to 15% of the oral dosage.

A compound of formula I or a compound of formula II and/or a compound of formula III for use in method 1 or any of method 1.1 etseq.

A pharmaceutical composition selected from any of formulation 1, et seq., formulation 2, et seq., formulation 3, et seq., formulation 4, et seq., formulation 5, et seq., or formulation 6, et seq., for be used in method 1 or any of method 1.1, etseq.

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, a medicament according to any of formulation 1, et seq ., formulation 2, et seq., formulation 3, et seq., formulation 4, et seq., formulation 5, et seq., or formulation 6, et seq., for use in the treatment method according to the method 1 or any of method 1.1 et seq.

Methods for synthesizing compounds of formula I and compounds of formula II are known in the art and include the methods described in WO PCT/US08/03340 (WO 2008/112280), US application no. serial 10/786,935, U.S. Patents No. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; US RE39680, and US RE39679, and WO 2015/154025, the contents of each of which are incorporated by reference in their entirety. Salts of the compounds of the invention may also be prepared as similarly described in US Pat. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; US RE39680, US RE39679 and WO 2009/114181, the contents of each of which are incorporated by reference in their entirety.

Isolation or purification of diasteromers of the compounds of the invention can be achieved by conventional methods known in the art, for example, column purification, preparative thin layer chromatography, preparative HPLC, crystallization, grinding, simulated moving beds and the like.

Pharmaceutically acceptable salts of the compounds of formulas I, II and III can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water or an organic solvent, or in a mixture of the two, generally, non-aqueous media are preferred. such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Additional details for the preparation of these salts, for example, toluenesulfonic salt in amorphous or crystal form, can be found in PCT/US08/03340 and/or provisional US application no. 61/036,069.

Transmucosal dosage forms are known to those skilled in the art and general procedures have been described by which these dosage forms can be prepared. Examples of dissolved film delivery systems include those described in US Patent 4,136,145 to Fuchs, US Patent 4,849,246 to Schmidt, US Patent 5,629,003 to Horstmann, US Patent 5,948,430 to Zerbe, US Patent 9,108,340 to Yang, US Patent 8,906,277 to Yang, US Pat. Yang US Patent 8,900,498, Yang US Patent 8,900,497, Yang US Patent 8,652,378, U.S. Patent 8,603,514 to Yang, U.S. Patent 9,427,412 to Bryson, and U.S. Patent 8,414,922 to Bryson. The preparation of other transmucosal systems is described in US 5,763,476 to Delbressine (sublingual and buccal solutions and solids), US Patent 9,216,175 to Amancha (sublingual spray), US Patent 8,835,459 to Kottayil (sublingual spray) and US 6,552,024 to Chen (various transmucosal systems). mucosa delivery). The contents of each of these references are incorporated by reference herein in their entirety.

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Examples

Example 1 A: Pharmacokinetic Comparison Between Subcutaneous (SC) and Sublingual (SL) Dosing in Dogs

The in vivo absorption and distribution of the compound of formula I and the compound of formula II, both in their tosylate salt forms, are compared between subcutaneous and sublingual administration in sequential non-crossover studies in dogs.

SC Administration: Six male beagle dogs between 2 and 5 years of age are randomized into two groups of three dogs each. Dogs in group 1 are administered with the compound of formula I at a dose of 1 mg/kg (free base equivalent) in a vehicle of 0.5% methylcellulose/distilled water. Dogs in group 2 are administered the compound of formula II at a dose of 1 mg/kg (free base equivalent) in a vehicle of 0.5% methylcellulose/distilled water. Administration is subcutaneous in the intrascapular region via a 22 or 23 gauge needle. Whole blood samples are collected via the dog's cephalic vein before the dose and at the 5, 15, and 30 post-dose time points. minutes, 1, 2, 4, 6, 8 and 24 hours. Following a minimum clearance period of 7 days, dogs are transferred to the sublingual portion of the study.

SL Administration: Dogs in group 1 are administered with the compound of formula I at a dose of 1 mg/kg (free base equivalent) in a vehicle of 0.5% methylcellulose/distilled water. Dogs in group 2 are administered the compound of formula II at a dose of 1 mg/kg (free base equivalent) in a vehicle of 0.5% methylcellulose/distilled water. Animals are anesthetized before dosing using propofol (6 mg/kg) and anesthesia is maintained for 30 minutes using 3 to 4.5% isoflurane. Administration is sublingual and the dosage is applied for 30 minutes, then cleaned using non-woven gauze. Whole blood samples are collected via the dog's cephalic vein before the dose and at the post-dose time points of 5, 15 and 30 minutes, 1,2,4, 6, 8, 24, 36 and 48 hours.

All samples are processed to plasma and analyzed for drug concentration using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The area under the curve (AUC) of plasma-based precursor and metabolites against time data is calculated using Prism 5.04 software (GraphPad Software, Inc.).

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

Table 1A

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<td></td><td>Test compound (1 mg/kg):</td><td>Formula I</td><td>Formula II</td>

<td rowspan="3">SL</td><td>AUC (ng-h/mL)</td><td> 734</td><td> 1262</td>

<td>Cmax (ng/mL)</td><td> 259</td><td> 562</td>

<td>Tmax (h)</td><td> 1.0</td><td> 1.0</td>

<td rowspan="3">S.C.</td><td>AUC (ng-h/mL)</td><td> 813</td><td> 785</td>

<td>Cmax (ng/mL)</td><td> 110</td><td> 79</td>

<td>Tmax (h)</td><td> 1.0</td><td> 1.0</td>

The results demonstrate that both SC and SL dosing results in high plasma concentration and high plasma AUC. SL dosing also results in significantly higher maximum plasma drug concentration (Cmax) compared to SC dosing for both compounds. For the compound of formula II, SL dosing also results in significantly higher overall AUC, while the AUC for the compound of formula I shows comparable AUC between SC and SL dosing. The time to maximum plasma concentration is also the same between SC and SL dosing for both compounds.

Example 1B: Comparison of Pharmacokinetics Between Subcutaneous and Sublingual Dosing in Dogs with Metabolite Analysis

A second study was performed substantially as described for Example 1A, except that plasma samples are analyzed for the precursor (administered) compounds as well as for the major known metabolites. Following administration of either the compound of formula I or the compound of formula II, the major circulating species are found to be the precursor and the N-desmethyl metabolite. The results are summarized in Table 1B below (AUC shown for 0-24 hours):

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Table 1B

<td></td><td>Test compound (1 mg/kg):</td><td>Formula I</td><td>Formula II</td>

<td rowspan="6">SL</td><td>AUC (ng-h/mL)-Precursor</td><td> 507</td><td> 1262</td>

<td>Cmax (ng/mL)-Precursor</td><td> 179</td><td> 562</td>

<td>Tmax (h)-Precursor</td><td> 1.0</td><td> 1.0</td>

<td>AUC (ng-h/mL)-Desmethyl</td><td> 23</td><td> 104</td>

<td>Cmax (ng/mL)-Desmethyl</td><td> 4.0</td><td> 27</td>

<td>Tmax (h)-Desmethyl</td><td> 1.0</td><td> 1.0</td>

<td rowspan="6">S.C.</td><td>AUC (ng-h/mL)-Precursor</td><td> 560</td><td> 785</td>

<td>Cmax (ng/mL)-Precursor</td><td> 76</td><td> 79</td>

<td>Tmax (h)-Precursor</td><td> 1.0</td><td> 1.0</td>

<td>AUC (ng-h/mL)-Desmethyl</td><td> 20</td><td> 49</td>

<td>Cmax (ng/mL)-Desmethyl</td><td> 4.0</td><td> 1.0</td>

<td>Tmax (h)-Desmethyl</td><td> 1.7</td><td> 1.0</td>

The results further demonstrate that both SC and SL dosing results in high plasma concentration and high plasma AUC for the administered compounds. SL dosing also results in higher maximum plasma drug concentration (Cmax) compared to SC dosing for both compounds. Furthermore, the results show that both SC and SL dosing result in very low rates of metabolite formation, indicating that these pathways effectively bypass the primary site of metabolic degradation of these compounds (hepatic metabolism). The compound of formula I circulated in plasma at an AUC approximately 22 times higher for the precursor than for the metabolite after SL dosing and 27 times higher for SC dosing. In contrast, when administered orally, the compound of formula I and its desmethyl metabolite were found to circulate in plasma with AUC of approximately 1:1 or less. Similarly, results are shown for the compound of formula II (parent/metabolite ratio of about 12 for SL and about 16 for SC).

Example 2: Pharmacokinetics of Oral Dosing in Dogs

In contrast to the subcutaneous and sublingual pharmacokinetics presented in Example 1, this example demonstrates that oral administration results in substantially lower systemic drug exposure due to the high degree of first-pass hepatic metabolism. This is even true using doses 2.5 times to 15 times higher than the dose used in the SC and SL study.

As part of a larger long-term toxicology study, 20 male and female beagle dogs are administered with either control, or the compound of formula I, tosylate salt form, at a dose of 2.5, 5, 10 or 15 mg/kg. For control, empty capsules are administered to dogs. For the compound of formula I, normal release oral capsules are administered to dogs. Blood samples are obtained at 0.25 hour, 0.5 hour, 1 hour, 4 hours, 8 hours and 24 hours. Blood samples are processed to plasma and analyzed for concentration of the compound of formula I by high-performance liquid chromatography mass spectrometry. Cmax, Tmax and area under the curve (AUC, 0-24 hours) are calculated using Phoenix WinNonlin software. The results are shown in table 1 below:

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Table 1

<td>Dosage:</td><td>2.5mg/kg</td><td>5mg/kg</td><td>10mg/kg</td><td>15mg/kg</td>

<td>AUC (ng-h/mL)</td><td> 40.05</td><td> 52.45</td><td> 142.5</td><td> 248</td>

<td>Cmax (ng/mL)</td><td> 5.51</td><td> 7.72</td><td> 29.0</td><td> 44.5</td>

<td>Tmax (h)</td><td> 0.469</td><td> 0.875</td><td> 0.813</td><td> 1.63</td>

The compound of formula I shows dose-dependent oral absorption and that the plasma concentration achieved with even the highest oral dose is well below the plasma concentration and AUC achieved from sublingual and subcutaneous administration as shown in Example 1. Sublingual and subcutaneous dosing of the compound of formula I at only 1.0 mg/kg results in 24-hour AUC that is more than 18 times greater than oral dosing at 2.5 mg/kg. Sublingual and subcutaneous dosing even provide about three times greater 24-hour AUC at 1.0 mg/kg than oral dosing at 15 mg/kg.

These results taken together clearly demonstrate the large loss in exposure that results from first-pass hepatic metabolism and the unexpectedly high improvement in exposures that are achieved from using transmucosal dosing systems.

Example 3: Pharmacokinetics of SC and IV Dosing in Monkeys

A study was also performed in monkeys to determine plasma concentrations of both the compound of formula I and its major metabolites after both SL and SC dosing at 0.5 mg/kg. Six cynomolgus monkeys are divided into two groups for IV and SC dosing with the compound of formula I. The animals are dosed in a fasting state. Blood samples are collected before the dose and at 5 minutes, 15 minutes, 1,2,4, 6, 8, 24, 36 and 48 hours after the dose. All samples are processed to plasma and subsequently analyzed by liquid tandem chromatography mass spectrometry. Samples are tested for the concentration of the compound of formula I as well as its five major known metabolites. PK parameters are calculated using the PK Solutions 2.0 software (Summit Research Services, Colorado, USA).

The results show that the bioavailability (based on a comparison of IV to SC pharmacokinetics) is approximately 74% for the compound of formula I or SC administration. The most tested metabolites are present at levels below the limit of quantification. Only the desmethyl metabolite and the amide metabolite (oxidation of methylene adjacent to the N-methyl group to a carbonyl) are present in significant concentration. The concentrations of both metabolites are found to be lower after SC dosing than after IV dosing. The results are shown in table 3 below:

Table 3

<td></td><td>Analyte:</td><td>Precursor compound</td><td>Demethyl metabolite</td><td>amide metabolite</td>

<td rowspan="3">IV</td><td>AUC (ng-h/mL)</td><td> 297</td><td> 9.2</td><td> 20</td>

<td>Cmax (ng/mL)</td><td> 94</td><td> 1.5</td><td> 1.9</td>

<td>Tmax (h)</td><td> 0.083</td><td> 1.0</td><td> 4.0</td>

<td rowspan="3">S.C.</td><td>AUC (ng-h/mL)</td><td> 220</td><td> 2.3</td><td> 3.3</td>

<td>Cmax (ng/mL)</td><td> 23</td><td> 0.3</td><td> 0.3</td>

<td>Tmax (h)</td><td> 2.0</td><td> 2.0</td><td> 6.0</td>

The results show that SC administration in monkeys results in substantially lower levels of formation of the main metabolites compared to IV administration.