Novel compositions and methods

Abstract

To provide a transdermal pharmaceutical preparation for treating or preventing disorders related to dementia or the like.SOLUTION: The present invention provides a composition comprising a compound represented by the following formula (I) in a free base form, cocrystal form, or salt form, or a compound in which a portion of the structure is substituted with deuterium.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This international patent application claims priority to and the benefit of U.S. Provisional Application No. 62 / 724,472, filed August 29, 2018, the contents of which are incorporated herein by reference in their entirety.

[0002] Technical Field The present disclosure relates to certain novel transdermal pharmaceutical formulations comprising substituted heterocyclic fused γ-carbolines, the preparation of such formulations, and the use of such formulations in the treatment of, for example, 5-HT 2A The invention relates to methods of use thereof in the treatment of diseases or abnormal conditions involving or mediated by the receptor, serotonin transporter (SERT), and / or dopamine D1 / D2 receptor signaling pathways. The invention includes methods for the treatment and / or prevention of diseases and disorders including, but not limited to, anxiety, psychoses, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with head pain, social phobia, gastrointestinal disorders such as gastrointestinal 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 disorders (e.g., bipolar depression); and other psychiatric and neurological conditions, as well as combinations with other drugs. [Background technology]

[0003] 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]quinoxalin-8-yl)-butan-1-one (often referred to as 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone, or ITI-007 or lumateperone) has the following structure: [ka] has.

[0004] The compounds of formula I are potent 5-HT 2A It is a receptor ligand (Ki=0.5 nM) with strong affinity for the dopamine (DA) D2 receptor (Ki=32 nM) and the serotonin transporter (SERT) (Ki=26 nM, measured using 3H-imipramine binding displacement on human recombinant SERT), but does not bind to receptors associated with the cognitive and metabolic side effects of antipsychotics (e.g., H1 histaminergic receptors, 5-HT 2C The compound is currently undergoing clinical trials for the treatment of schizophrenia, bipolar disorder, and dementia, including Alzheimer's disease. Compounds of formula I, and analogs thereof, salts thereof, and methods of treatment including and methods of making the compounds, are disclosed, for example, in U.S. Pat. No. 5,399,411; U.S. Pat. No. 5,499,623; U.S. Pat. No. 5,523,366; U.S. Pat. No. 5,633,636; U.S. Pat. No. 5,711,1 ...

[0005] Patent Documents 18 and 19 (Patent Document 20) generally disclose deuterated variants of ITI-007. Deuterated compounds are designed to slow or inhibit metabolism in vivo by replacing hydrogen atoms of ITI-007 with deuterium atoms at molecular positions targeted for metabolic activity. Natural metabolites of ITI-007 are pharmacologically active, but have somewhat different receptor selectivity profiles. Thus, these deuterated derivatives can provide altered pharmacokinetic profiles due to altered metabolic rates or pathways, and altered overall pharmacological profiles due to altered balance between active parent and active metabolite species.

[0006] One such deuterated compound is a compound of formula II: [ka] 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)-butan-1-one.

[0007] Another such deuterated compound is a compound of formula III: [ka] 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]quinoxalin-8-yl)-butan-1-one.

[0008] Each of the compounds of formula I, II and III undergoes significant first-pass metabolism in the liver, as well as significant intraluminal metabolism. For example, the oral bioavailability of the compound of formula I has been found to be about 5% or less. High metabolic rates require the administration of higher oral doses of the drug than would otherwise be required, which can result in increased liver burden, increased manufacturing costs, formulation difficulties, and increased patient-to-patient variability in dose response. Therefore, there is a need for new routes of administration that can avoid first-pass hepatic metabolism and GI intraluminal metabolism, and accordingly reduce the required dose.

[0009] For many drugs, transdermal delivery, such as transdermal patches, transdermal gels or ointments, and transdermal sprays, has been disclosed as an effective alternative to traditional dosage forms such as parenteral and oral administration. Parenteral administration (intravenous administration) is very effective in avoiding first-pass and GI metabolism, but its usefulness is limited because it usually needs to be administered by trained professionals in a clinical setting. In contrast, transdermal delivery systems can be used to formulate drugs that can be taken by patients without professional supervision and can minimize first-pass metabolism to provide stable, long-term drug absorption.

[0010] The use of transdermal drug delivery formulations is well known, with a transdermal patch formulation of scopolamine dating back to 1979. These formulations involve the movement of the active agent across the epidermal and dermal layers of the skin to reach the capillaries deep in the dermis, which differs from transdermal drug delivery, which simply delivers the active ingredient to the skin itself. Transdermal drug delivery is a method of systemic drug administration rather than local administration. Transdermal drug delivery is difficult to achieve due to the natural impermeability of the skin to foreign bodies, including water. Thus, transdermal drug delivery is particularly challenging for water-soluble drug substances. In contrast to transdermal drug delivery is transmucosal drug delivery, in which the drug substance is transported across mucosal membranes, including the oral, nasal and vaginal mucosa. Transdermal drug delivery, like transmucosal drug delivery, has the distinct advantage of avoiding first-pass hepatic and GI metabolism, and common formulations such as patches are patient-friendly, as they can be applied by the patient and do not need to be replaced frequently. Many transdermal drug delivery systems can be optimized to ensure constant, stable systemic drug delivery for extended periods of time (e.g., days or weeks).

[0011] Existing transdermal delivery systems include patches, gels, ointments and sprays. Examples of such delivery systems include those disclosed in US Pat. No. 5,399,433 to Lee et al., US Pat. No. 5,399,422 to Jain et al., US Pat. No. 5,399,433 to Mo, US Pat. No. 5,399,443 to Hwang et al., and US Pat. No. 5,399,453 to Ito. To ensure delivery accuracy and reliability, each formulation needs to be fine-tuned to a specific active pharmaceutical ingredient. Thus, although the field of transdermal drug delivery has a long history, it takes considerable effort to adapt a selected transdermal delivery technology to a specific active pharmaceutical ingredient.

[0012] The use of transdermal drug delivery is particularly useful when treating patients for whom daily oral medication is unreliable or expected to be unreliable, most importantly those with psychiatric or neurological disorders such as psychosis, schizophrenia, and cognitive and memory disorders (e.g., dementia such as Alzheimer's disease).

[0013] The compounds of formula I, II and III in the form of free base are hydrophobic and have good lipophilicity, but are difficult to crystallize and tend to exist as oil.In contrast, the compounds of formula I, II and III can exist in a stable solid crystalline salt form that is easy to handle, but are not lipophilic.As a result, it may not be an easy task to develop a transdermal formulation of these compounds.

[0014] There is a need for improved pharmaceutical delivery systems for the safe, effective and reliable delivery of compounds of Formula I and / or Formula II, especially for long-term treatment of patients where daily oral dosing is unreliable. The present disclosure provides novel transdermal formulations for the delivery of these compounds without the drawbacks of existing parenteral and oral delivery systems. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] U.S. Patent No. 6,548,493 [Patent Document 2] U.S. Patent No. 7,238,690 [Patent Document 3] U.S. Patent No. 6,552,017 [Patent Document 4] U.S. Patent No. 6,713,471 [Patent Document 5] U.S. Patent No. 7,183,282 [Patent Document 6] U.S. Reissue Patent No. 39,680 [Patent Document 7] U.S. Reissue Patent Invention No. 39,679 [Patent Document 8] US Patent Application Publication No. 2004 / 209864 [Patent Document 9] US Patent Application Publication No. 2010 / 113781 [Patent Document 10] US Patent Application Publication No. 2011 / 071080 [Patent Document 11] US Patent Application Publication No. 2011 / 112105 [Patent Document 12] US Patent Application Publication No. 2013 / 0202692 [Patent Document 13] US Patent Application Publication No. 2015 / 0079172 [Patent Document 14] US Patent Application Publication No. 2017 / 0183350 [Patent Document 15] International Publication No. 2017 / 165843 [Patent Document 16] US Patent Application Publication No. 2019 / 0231780 [Patent Document 17] International Publication No. 2017 / 117514 [Patent Document 18] US Patent Application Publication No. 2017 / 0183350 [Patent Document 19] International Publication No. 2017 / 165843 [Patent Document 20] US Patent Application Publication No. 2019 / 0231780 [Patent Document 21] U.S. Patent No. 9,993,466 [Patent Document 22] U.S. Patent No. 9,913,840 [Patent Document 23] U.S. Patent No. 9,693,970 [Patent Document 24] U.S. Patent No. 9,585,862 [Patent Document 25] U.S. Patent No. 7,858,114 Summary of the Invention

[0016] Quick Overview The present disclosure relates to novel transdermal pharmaceutical formulations 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]quinoxalin-8-yl)-butan-1-one (lumateperone) in free base form, co-crystal form or salt form, and deuterated variants thereof. Transdermal formulations include, but are not limited to, patches, gels, ointments and sprays.

[0017] Further areas of applicability of the present invention will become apparent 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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Detailed Description The following description of the preferred embodiments is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.

[0019] As used throughout, ranges are used as a shorthand way of describing all values ​​within a range. Values ​​within a range can be selected as the termini of the range. Furthermore, all documents cited herein are incorporated herein by reference in their entirety. In the event of a discrepancy between a definition in this disclosure and a definition in a cited document, this disclosure shall control.

[0020] Unless otherwise specified, all percentages and amounts expressed herein and elsewhere should be understood to mean percent by weight. The amounts given are based on the active weight of the material in free base equivalent form.

[0021] In a first embodiment, the present disclosure provides a transdermal pharmaceutical formulation (Formulation 1) 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]quinoxalin-8-yl)-butan-1-one (compound of formula I) in free base, co-crystal or salt form. The present disclosure further provides the following formulation:

[0022] 1.1. Formulation 1, wherein the formulation comprises a compound of formula I in the free base form.

[0023] 1.2. Formulation 1, wherein the formulation comprises a compound of formula I in a salt form, e.g. a pharma- ceutically acceptable salt form, optionally an amorphous solid or crystalline salt form; or in a co-crystal form, e.g. a nicotinamide or isonicotinamide co-crystal form.

[0024] 1.3. Formulation 1.2, wherein the salt form is a tosylate, oxalate, cyclamate, 4-aminosalicylate or hydrochloride salt, optionally wherein the salt form is a crystalline salt form.

[0025] 1.4. Any of the above formulations, wherein the formulation contains 1 to 1000 mg, for example, 1 to 750 mg, 1 to 500 mg, 1 to 300 mg, 1 to 200 mg, 10 to 200 mg, 50 to 200 mg, 100 to 200 mg, 100 to 300 mg, 200 to 300 mg, 200 to 500 mg, or 500 to 1000 mg of the compound represented by formula I (free base equivalent amount).

[0026] 1.5. Any of the above formulations, wherein the formulation comprises 1 to 100 mg, for example, 10 to 70 mg, or 40 to 70 mg, of the compound of formula I (free base equivalent amount).

[0027] 1.6. Any of the above formulations, wherein the formulation comprises 1 to 80 mg, for example, 1 to 50 mg, or 5 to 50 mg, of the compound of formula I (free base equivalent amount).

[0028] 1.7. Any of the above formulations, wherein the composition further comprises one or more excipients, such as materials that stabilize the compound of Formula I and / or increase absorption of the compound of Formula I into the skin.

[0029] 1.8. Formulation 1.7, wherein the one or more excipients are selected from the group consisting of solvents, solubilizers, plasticizers, surfactants, binders, humectants (e.g., polyols), antioxidants, buffering agents (e.g., acids, bases and / or salts thereof), emollients and thickening agents (e.g., gelling agents).

[0030] 1.9. Formulation 1.7, wherein the one or more excipients are selected from any of the following: alcohols (ethanol, isopropanol, propanol, glycerol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, polyethylene glycol), non-alcoholic solvents (e.g., dimethylsulfoxide, dimethylformamide, acetonitrile), gums (e.g., acacia, guar, agar, xanthan, tragacanth, karaya, gellan), polysaccharides and polysaccharide derivatives (e.g., starch, dextran, pectin, alginate, glycerol, sorbitol ... gelatin, including non-gelling and gelling types (e.g., mammalian gelatin, such as bovine gelatin, porcine gelatin, trigelatin, fish gelatin (e.g., mixed high and low molecular weight gelatins), synthetic polymers (e.g., polyvinylpyrrolidone, polyethylene oxide, and / or cellulose derivatives (e.g., carboxymethylcellulose, methylcellulose, hydroxyalkylcellulose (e.g., hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose)), ... or polypropylene oxide polymers and copolymers (e.g., poloxamers, e.g., poloxamer 188), polyacrylate polymers (e.g., carbopol), 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 (e.g., citric acid, acids, lactic acid, malic acid, mandelic acid, tropic acid, glycolic 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 (e.g., sodium, potassium, calcium, magnesium, lithium, ammonium salts of the abovementioned acids) and esters (e.g., methyl or ethyl esters, or fatty acid esters), inorganic or organic bases (e.g., carbonates, bicarbonates, hydroxides of alkali metals or alkaline earth metals,oxides), anionic surfactants (e.g., sodium lauryl sulfate, sodium laureth sulfate, sodium dodecylbenzenesulfonate, sodium lauroyl sarcosinate, sodium stearate), cationic surfactants (e.g., benzalkonium halides, cetylpyridinium halides, cetrimonium halides, benzethonium halides), zwitterionic surfactants (e.g., cocamidoalkyl betaines, e.g., cocamidopropyl betaine, or amine oxides, e.g., dimethyldodecylamine oxide and myristamine oxide), nonionic surfactants (e.g., fatty alcohol ethoxylates (e.g., polyethylene glycol polydodecyl ether)), sorbitan esters (e.g., sorbitol monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate), polyethoxylated sorbitan esters (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80), fatty acid esters (e.g., lauryl lactate, isopropyl myristate, oleyl oleate, methyl laurate, isopropyl palmitate, ethyl oleate), fatty alcohols (e.g., dodecanol, octyldecanol, lauryl alcohol), and antioxidants (e.g., ascorbic acid, citric acid, ascorbyl palmitate, sodium metabisulfite, BHT, BHA, TBHQ, propyl gallate, beta-carotene, tocopherol, tocotrienol).

[0031] 1.10. Any of formulations 1.7-1.9, wherein any one or more of the excipients is present in an amount of 0.1-80% by weight of the formulation, for example 0.1-60%, or 0.1-40%, or 0.1-20%, or 0.1-15% or 0.1-10%.

[0032] 1.11. Any of the above formulations, wherein the formulation comprises an adhesive polymer, optionally in an amount of 25-80% by weight.

[0033] 1.12. Formulation 1.11, wherein the adhesive polymer comprises a polymer selected from the group consisting of acrylate polymers or copolymers (e.g., polymers in which at least one monomer unit is an acrylic acid or ester and one or more other monomer units may be non-acrylate monomers, e.g., vinyl monomers), polyvinylpyrrolidones (e.g., linear or crosslinked), copolymers of maleic acid or maleic esters with vinyl ethers (e.g., copolymers of maleic acid or anhydride with methyl vinyl ether), cellulose derivatives (e.g., carboxymethylcellulose), silicone polymers (e.g., dimethyl silicone), and mixtures thereof, such as mixtures of polyacrylate polymers and silicone polymers.

[0034] 1.13. Any of the above formulations, wherein the formulation is an ointment.

[0035] 1.14. Any of formulations 1 or 1.1 to 1.11, wherein the formulation is a spray.

[0036] 1.15. Any of formulations 1 or 1.1 to 1.11, wherein the formulation is a gel.

[0037] 1.16. Any of formulations 1 or 1.1-1.11, wherein the formulation is contained in a patch, e.g., an adhesive patch.

[0038] 1.17. Formulation 1.16, wherein the patch comprises at least one drug reservoir layer and the formulation is the drug reservoir layer.

[0039] 1.18. Formulation 1.17, wherein the drug reservoir layer is adhesive.

[0040] 1.19. Any of the above formulations, wherein the compound of formula I is incorporated into the formulation as microparticles (e.g., particles having an average diameter of less than 50 μm, less than 30 μm, less than 10 μm, or less than 5 μm, or less than 1 μm).

[0041] 1.20. Any of the above formulations, wherein said formulation further comprises a compound of formula II or a compound of formula III, or a combination thereof.

[0042] 1.21. Any of the above formulations, wherein the formulation comprises a compound of Formula I in a tosylate salt form, e.g., the monotosylate salt form or the ditosylate salt form, or a mixture thereof.

[0043] 1.22. Formulation 1.21, wherein the formulation further comprises toluenesulfonic acid, for example, the formulation comprises the tosylate salt form of the compound of formula I 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.

[0044] 1.23. Any of the above formulations wherein the compound of formula I is enriched with deuterium at one or more hydrogen atom positions, e.g., at any one or more hydrogen atom positions, substantially greater than the natural incorporation level of deuterium at such positions in the structure (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%).

[0045] 1.24. Formulation 1.23, wherein the compound of formula I incorporates more than 50% deuterium (i.e., more than 50 atomic % D) at any one or more hydrogen atom positions of 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% deuterium.

[0046] 1.25. A compound of Formula I, any of Formulations 1 or 1.1-1.24, in which all hydrogen atom positions are not enriched with deuterium (i.e., all hydrogen atom positions contain natural abundance deuterium or less than 0.1% deuterium).

[0047] 1.26. Any of Formulations 1 or 1.1-1.25, wherein the formulation systemically delivers an average daily dose of a compound of Formula I of 0.1-5.0 mg per day (free base equivalent), e.g., 0.5-2.0 mg per day, or 0.1-0.5 mg per day, or 1.0-2.0 mg per day, or about 1.8 mg per day.

[0048] 1.27. Any of Formulations 1 or 1.1-1.26, wherein the formulation delivers the compound of Formula I at a rate sufficient to maintain a steady-state maximum plasma concentration of the compound of Formula I (free base) of 5-50 ng / mL, e.g., 10-40 ng / mL, or 20-40 ng / mL (e.g., about 30 ng / mL), and / or a steady-state 24-hour mean area under the plasma concentration curve (AUC) of the compound of Formula I (free base) of 5-100 ng-hr / mL, e.g., 20-90 ng-hr / mL, or 40-90 ng-hr / mL, or 70-90 ng-hr / mL (e.g., about 80 ng-hr / mL).

[0049] In a second embodiment, the present disclosure provides a transdermal 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-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (compound of formula II) in free base form, co-crystal form or salt form. The present disclosure further provides the following formulation:

[0050] 2.1. Formulation 2, wherein the formulation comprises the compound of formula II in free base form.

[0051] 2.2. Formulation 2, wherein the formulation comprises a compound of formula II in a salt form, e.g., a pharma- ceutically acceptable salt form, optionally an amorphous solid or crystalline salt form; or in a co-crystal form, e.g., a nicotinamide or isonicotinamide co-crystal form.

[0052] 2.3. Formulation 2.2, wherein the salt form is a tosylate, oxalate, cyclamate, 4-aminosalicylate or hydrochloride salt, optionally wherein the salt form is a crystalline salt form.

[0053] 2.4. Any of the above formulations, wherein the formulation contains 1 to 1000 mg, for example, 1 to 750 mg, 1 to 500 mg, 1 to 300 mg, 1 to 200 mg, 10 to 200 mg, 50 to 200 mg, 100 to 200 mg, 100 to 300 mg, 200 to 300 mg, 200 to 500 mg, or 500 to 1000 mg of the compound represented by formula II (free base equivalent amount).

[0054] 2.5. Any of the above formulations, wherein the formulation comprises 1 to 100 mg, for example, 10 to 70 mg, or 40 to 70 mg, of the compound of formula II (free base equivalent amount).

[0055] 2.6. Any of the above formulations, wherein the formulation comprises 1 to 80 mg, for example, 1 to 50 mg, or 5 to 50 mg, of the compound of formula II (free base equivalent amount).

[0056] 2.7. Any of the above formulations, wherein the composition further comprises one or more excipients, such as materials that stabilize the compound of Formula II and / or increase absorption of the compound of Formula II into the skin.

[0057] 2.8. Formulation 2.7, wherein the one or more excipients are selected from the group consisting of solvents, solubilizers, plasticizers, surfactants, binders, humectants (e.g., polyols), antioxidants, buffering agents (e.g., acids, bases and / or salts thereof), emollients and thickening agents (e.g., gelling agents).

[0058] 2.9. Formulation 2.7, wherein the one or more excipients are selected from any of the following: alcohols (ethanol, isopropanol, propanol, glycerol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, polyethylene glycol), non-alcoholic solvents (e.g., dimethylsulfoxide, dimethylformamide, acetonitrile), gums (e.g., acacia, guar, agar, xanthan, tragacanth, karaya, gellan), polysaccharides and polysaccharide derivatives (e.g., starch, dextran, pectin, alginate, glycerol, sorbitol ... gelatin, including non-gelling and gelling types (e.g., mammalian gelatin, such as bovine gelatin, porcine gelatin, trigelatin, fish gelatin (e.g., mixed high and low molecular weight gelatins), synthetic polymers (e.g., polyvinylpyrrolidone, polyethylene oxide, and / or cellulose derivatives (e.g., carboxymethylcellulose, methylcellulose, hydroxyalkylcellulose (e.g., hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose)), ... or polypropylene oxide polymers and copolymers (e.g., poloxamers, e.g., poloxamer 188), polyacrylate polymers (e.g., carbopol), 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 (e.g., quercetin, glycerol ... acid, lactic acid, malic acid, mandelic acid, tropic acid, glycolic 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 (e.g., sodium, potassium, calcium, magnesium, lithium, ammonium salts of the abovementioned acids) and esters (e.g., methyl or ethyl esters, or fatty acid esters), inorganic or organic bases (e.g., carbonates, bicarbonates, hydroxides of alkali metals or alkaline earth metals,oxides), anionic surfactants (e.g., sodium lauryl sulfate, sodium laureth sulfate, sodium dodecylbenzenesulfonate, sodium lauroyl sarcosinate, sodium stearate), cationic surfactants (e.g., benzalkonium halides, cetylpyridinium halides, cetrimonium halides, benzethonium halides), zwitterionic surfactants (e.g., cocamidoalkyl betaines, e.g., cocamidopropyl betaine, or amine oxides, e.g., dimethyldodecylamine oxide and myristamine oxide), nonionic surfactants (e.g., fatty alcohol ethoxylates (e.g., polyethylene glycol polydodecyl ether), 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), fatty acid esters (e.g., lauryl lactate, isopropyl myristate, oleyl oleate, methyl laurate, isopropyl palmitate, ethyl oleate), fatty alcohols (e.g., dodecanol, octyldecanol, lauryl alcohol), and antioxidants (e.g., ascorbic acid, citric acid, ascorbyl palmitate, sodium metabisulfite, BHT, BHA, TBHQ, propyl gallate, beta-carotene, tocopherol, tocotrienol).

[0059] 2.10. Any of formulations 2.7-2.9, wherein any one or more of the excipients is present in an amount of 0.1-80% by weight of the formulation, such as 0.1-60%, or 0.1-40%, or 0.1-20%, or 0.1-15% or 0.1-10%.

[0060] 2.11. Any of the above formulations, wherein the formulation comprises an adhesive polymer, optionally in an amount of 25-80% by weight.

[0061] 2.12. Formulation 2.11, wherein the adhesive polymer comprises a polymer selected from the group consisting of acrylate polymers or copolymers (e.g., polymers in which at least one monomer unit is an acrylic acid or ester and one or more other monomer units may be non-acrylate monomers, e.g., vinyl monomers), polyvinylpyrrolidones (e.g., linear or crosslinked), copolymers of maleic acid or maleic esters with vinyl ethers (e.g., copolymers of maleic acid or anhydride with methyl vinyl ether), cellulose derivatives (e.g., carboxymethylcellulose), silicone polymers (e.g., dimethyl silicone), and mixtures thereof, e.g., mixtures of polyacrylate polymers and silicone polymers.

[0062] 2.13. Any of the above formulations, wherein the formulation is an ointment.

[0063] 2.14. Any of formulations 2 or 2.1 to 2.11, wherein the formulation is a spray.

[0064] 2.15. Any of formulations 2 or 2.1-2.11, wherein the formulation is a gel.

[0065] 2.16. Any of formulations 2 or 2.1-2.11, wherein the formulation is contained in a patch, e.g., an adhesive patch.

[0066] 2.17. Formulation 2.16, wherein the patch comprises at least one drug reservoir layer and the formulation is the drug reservoir layer.

[0067] 2.18. Formulation 2.17, wherein the drug reservoir layer is adhesive.

[0068] 2.19. Any of the above formulations, wherein the compound of formula II is incorporated into the formulation as microparticles (e.g., particles having an average diameter of less than 50 μm, less than 30 μm, less than 10 μm, or less than 5 μm, or less than 1 μm).

[0069] 2.20. Any of the above formulations, wherein said formulation further comprises a compound of Formula I or a compound of Formula III, or a combination thereof.

[0070] 2.21. Any of the above formulations, wherein the formulation comprises a compound of Formula II in a tosylate salt form, e.g., the monotosylate salt form or the ditosylate salt form, or a mixture thereof.

[0071] 2.22. Formulation 2.21, wherein the formulation further comprises toluenesulfonic acid, for example, the formulation comprises the compound of formula II in tosylate salt form 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.

[0072] 2.23. Any of the above formulations, wherein the compound of formula II is enriched with deuterium at one or more hydrogen atom positions, e.g., at any one or more hydrogen atom positions, substantially greater than the natural incorporation level of deuterium at such positions in the structure (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%).

[0073] 2.24. Formulation 2.23, wherein the compound of formula II incorporates more than 50% deuterium (i.e., more than 50 atomic % D) at any one or more hydrogen atom positions of 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% deuterium.

[0074] 2.25. A compound of formula II, in which all hydrogen atom positions are not enriched with deuterium (i.e., all hydrogen atom positions contain natural abundance deuterium or less than 0.1% deuterium); formulation 2 or any of 2.1-2.24;

[0075] 2.26. Any of Formulations 2 or 2.1-2.25, wherein the formulation systemically delivers an average daily dose of the compound of Formula II of 0.1-5.0 mg per day (free base equivalent), e.g., 0.5-2.0 mg per day, or 0.1-0.5 mg per day, or 1.0-2.0 mg per day, or about 1.8 mg per day.

[0076] 2.27. Any of Formulations 2 or 2.1-2.26, wherein the formulation delivers the compound of Formula II at a rate sufficient to maintain a steady-state maximum plasma concentration of the compound of Formula II (free base) of 5-50 ng / mL, e.g., 10-40 ng / mL, or 20-40 ng / mL (e.g., about 30 ng / mL), and / or a steady-state 24-hour mean area under the plasma concentration curve (AUC) of the compound of Formula II (free base) of 5-100 ng-hr / mL, e.g., 20-90 ng-hr / mL, or 40-90 ng-hr / mL, or 70-90 ng-hr / mL (e.g., about 80 ng-hr / mL).

[0077] In a third embodiment, the present disclosure provides a transdermal pharmaceutical formulation (Formulation 3) comprising 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]quinoxalin-8-yl)-butan-1-one (compound of formula III) in free base form, co-crystal form or salt form. The present disclosure further provides the following formulation:

[0078] 3.1. Formulation 3, wherein the formulation comprises the compound of formula III in free base form.

[0079] 3.2. Formulation 3, wherein the formulation comprises a compound of formula III in a salt form, e.g., a pharma- ceutically acceptable salt form, optionally an amorphous solid or crystalline salt form; or in a co-crystal form, e.g., a nicotinamide or isonicotinamide co-crystal form.

[0080] 3.3. Formulation 3.2, in which the salt form is a tosylate, oxalate, cyclamate, 4-aminosalicylate or hydrochloride salt, optionally wherein the salt form is a crystalline salt form.

[0081] 3.4. Any of the above formulations, wherein the formulation contains 1 to 1000 mg, for example, 1 to 750 mg, 1 to 500 mg, 1 to 300 mg, 1 to 200 mg, 10 to 200 mg, 50 to 200 mg, 100 to 200 mg, 100 to 300 mg, 200 to 300 mg, 200 to 500 mg, or 500 to 1000 mg of the compound represented by formula III (free base equivalent amount).

[0082] 3.5. Any of the above formulations, wherein the formulation comprises 1 to 100 mg, for example, 10 to 70 mg, or 40 to 70 mg, of the compound of formula III (free base equivalent amount).

[0083] 3.6. Any of the above formulations, wherein the formulation comprises 1 to 80 mg, e.g., 1 to 50 mg, or 5 to 50 mg, of the compound of formula III (free base equivalent amount).

[0084] 3.7. Any of the above formulations, wherein the composition further comprises one or more excipients, such as materials that stabilize the compound of formula III and / or increase absorption of the compound of formula III into the skin.

[0085] 3.8. Formulation 3.7, wherein the one or more excipients are selected from the group consisting of solvents, solubilizers, plasticizers, surfactants, binders, humectants (e.g., polyols), antioxidants, buffering agents (e.g., acids, bases and / or salts thereof), emollients and thickening agents (e.g., gelling agents).

[0086] 3.9. Formulation 3.7, wherein the one or more excipients are selected from any of the following: alcohols (ethanol, isopropanol, propanol, glycerol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, polyethylene glycol), non-alcoholic solvents (e.g., dimethylsulfoxide, dimethylformamide, acetonitrile), gums (e.g., acacia, guar, agar, xanthan, tragacanth, karaya, gellan), polysaccharides and polysaccharide derivatives (e.g., starch, dextran, pectin, alginate, glycerol, sorbitol ... gelatin, including non-gelling and gelling types (e.g., mammalian gelatin, such as bovine gelatin, porcine gelatin, trigelatin, fish gelatin (e.g., mixed high and low molecular weight gelatins), synthetic polymers (e.g., polyvinylpyrrolidone, polyethylene oxide, and / or cellulose derivatives (e.g., carboxymethylcellulose, methylcellulose, hydroxyalkylcellulose (e.g., hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose)), ... or polypropylene oxide polymers and copolymers (e.g., poloxamers, e.g., poloxamer 188), polyacrylate polymers (e.g., carbopol), 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 (e.g., quercetin, glycerol ... acid, lactic acid, malic acid, mandelic acid, tropic acid, glycolic 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 (e.g., sodium, potassium, calcium, magnesium, lithium, ammonium salts of the abovementioned acids) and esters (e.g., methyl or ethyl esters, or fatty acid esters), inorganic or organic bases (e.g., carbonates, bicarbonates, hydroxides of alkali metals or alkaline earth metals,oxides), anionic surfactants (e.g., sodium lauryl sulfate, sodium laureth sulfate, sodium dodecylbenzenesulfonate, sodium lauroyl sarcosinate, sodium stearate), cationic surfactants (e.g., benzalkonium halides, cetylpyridinium halides, cetrimonium halides, benzethonium halides), zwitterionic surfactants (e.g., cocamidoalkyl betaines, e.g., cocamidopropyl betaine, or amine oxides, e.g., dimethyldodecylamine oxide and myristamine oxide), nonionic surfactants (e.g., fatty alcohol ethoxylates (e.g., polyethylene glycol polydodecyl ether), 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), fatty acid esters (e.g., lauryl lactate, isopropyl myristate, oleyl oleate, methyl laurate, isopropyl palmitate, ethyl oleate), fatty alcohols (e.g., dodecanol, octyldecanol, lauryl alcohol), and antioxidants (e.g., ascorbic acid, citric acid, ascorbyl palmitate, sodium metabisulfite, BHT, BHA, TBHQ, propyl gallate, beta-carotene, tocopherol, tocotrienol).

[0087] 3.10. Any of formulations 3.7-3.9, wherein any one or more of the excipients is present in an amount of 0.1-80% by weight of the formulation, for example 0.1-60%, or 0.1-40%, or 0.1-20%, or 0.1-15% or 0.1-10%.

[0088] 3.11. Any of the above formulations, wherein the formulation comprises an adhesive polymer, optionally in an amount of 25-80% by weight.

[0089] 3.12. Formulation 3.11, wherein the adhesive polymer comprises a polymer selected from the group consisting of acrylate polymers or copolymers (e.g., polymers in which at least one monomer unit is an acrylic acid or ester and one or more other monomer units may be non-acrylate monomers, e.g., vinyl monomers), polyvinylpyrrolidones (e.g., linear or crosslinked), copolymers of maleic acid or maleic esters with vinyl ethers (e.g., copolymers of maleic acid or anhydride with methyl vinyl ether), cellulose derivatives (e.g., carboxymethylcellulose), silicone polymers (e.g., dimethyl silicone), and mixtures thereof, e.g., mixtures of polyacrylate polymers and silicone polymers.

[0090] 3.13. Any of the above formulations, wherein the formulation is an ointment.

[0091] 3.14. Any of formulations 3 or 3.1 to 3.11, wherein the formulation is a spray.

[0092] 3.15. Any of formulations 3 or 3.1-3.11, wherein the formulation is a gel.

[0093] 3.16. Any of formulations 3 or 3.1-3.11, wherein the formulation is contained in a patch, e.g., an adhesive patch.

[0094] 3.17. Formulation 3.16, wherein the patch comprises at least one drug reservoir layer, and the formulation is the drug reservoir layer.

[0095] 3.18. Formulation 3.17, wherein the drug reservoir layer is adhesive.

[0096] 3.19. Any of the above formulations, wherein the compound of formula III is incorporated into the formulation as microparticles (e.g., particles having an average diameter of less than 50 μm, less than 30 μm, less than 10 μm, or less than 5 μm, or less than 1 μm).

[0097] 3.20. Any of the above formulations, wherein said formulation further comprises a compound of Formula I or a compound of Formula II, or a combination thereof.

[0098] 3.21. Any of the above formulations, wherein the formulation comprises a compound of Formula III in a tosylate salt form, e.g., the monotosylate salt form or the ditosylate salt form, or a mixture thereof.

[0099] 3.22. Formulation 3.21, wherein the formulation further comprises toluenesulfonic acid, for example, the formulation comprises the compound of formula III in tosylate salt form 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.

[0100] 3.23. Any of the above formulations, wherein the compound of formula III is enriched with deuterium at one or more hydrogen atom positions, e.g., at any one or more hydrogen atom positions, substantially greater than the natural incorporation level of deuterium at such positions in the structure (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%).

[0101] 3.24. Formulation 3.23, wherein the compound of formula III incorporates greater than 50% deuterium (i.e., greater than 50 atomic % D) at any one or more hydrogen atom positions of the structure, for example, 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% deuterium.

[0102] 3.25. A compound of Formula III, wherein all hydrogen atom positions are not enriched with deuterium (i.e., all hydrogen atom positions contain natural abundance deuterium or less than 0.1% deuterium).

[0103] 3.26. Any of Formulations 3 or 3.1-3.25, wherein the formulation systemically delivers an average daily dose of the compound of Formula III of 0.1-5.0 mg per day (free base equivalent), e.g., 0.5-2.0 mg per day, or 0.1-0.5 mg per day, or 1.0-2.0 mg per day, or about 1.8 mg per day.

[0104] 3.27. Any of Formulations 3 or 3.1-3.26, wherein the formulation delivers the compound of Formula III at a rate sufficient to maintain a steady-state maximum plasma concentration of the compound of Formula III (free base) of 5-50 ng / mL, e.g., 10-40 ng / mL, or 20-40 ng / mL (e.g., about 30 ng / mL), and / or a steady-state 24-hour mean area under the plasma concentration curve (AUC) of the compound of Formula III (free base) of 5-100 ng-hr / mL, e.g., 20-90 ng-hr / mL, or 40-90 ng-hr / mL, or 70-90 ng-hr / mL (e.g., about 80 ng-hr / mL).

[0105] In a fourth embodiment, the present disclosure provides a transdermal pharmaceutical device (Device 1) comprising any of Formulation 1 or later, Formulation 2 or later, or Formulation 3 or later. In certain embodiments, the present disclosure further provides:

[0106] 1.1. Device 1, wherein the device comprises at least two layers, at least one layer being a drug reservoir layer (e.g., a layer comprising a compound of Formula I or Formula II or Formula III) and at least one layer being a backing layer (e.g., an inactive layer, substantially free of and substantially impermeable to the compound of Formula I, Formula II and Formula III).

[0107] 1.2. Device 1.1, wherein the drug reservoir layer comprises or consists of formulation 1 or any of 1.1-1.27.

[0108] 1.3. Device 1.1, wherein the drug reservoir layer comprises or consists of formulation 2 or any of 2.1-2.27.

[0109] 1.4. Device 1.1, wherein the drug reservoir layer comprises or consists of formulation 3 or any of 3.1-3.27.

[0110] 1.5. Any of the above devices, wherein said drug reservoir layer comprises an adhesive polymer as defined above, and said drug reservoir layer is the skin contact layer of said device.

[0111] 1.6. Device 1.5, wherein the drug reservoir layer comprises the adhesive polymer in an amount of 25-80% by weight, e.g., 30-65% by weight, or 40-60% by weight.

[0112] 1.7. Any of Devices 1 or 1.1-1.4, wherein the device further comprises a third layer separate from the drug reservoir layer, the third layer being a skin contact layer, the layer comprising an adhesive polymer as defined above, and the layer being substantially free of compounds of Formula I, Formula II and Formula III prior to use of the device.

[0113] 1.8. Device 1.7, wherein the skin contact layer comprises the adhesive polymer in an amount of 25-90% by weight, e.g., 50-90% by weight, or 65-90% by weight.

[0114] 1.9. Device 1.7 or 1.8, wherein the device further comprises an intermediate layer disposed between the skin-contacting layer and the drug reservoir layer, said layer being a rate-controlling layer which may comprise any of the excipients listed above.

[0115] 1.10. Device 1.9, wherein the intermediate layer is a microporous polymer layer, for example, the polymer layer comprises polyethylene, polypropylene, polyurethane, polyester, vinyl acetate polymer or copolymer, or combinations thereof.

[0116] 1.11. Any of the above devices, wherein the drug reservoir layer and / or the skin contact layer comprise one or more permeation enhancing excipients, such as fatty acid esters (e.g., lauryl lactate), alcohols (e.g., propylene glycol), amine oxides (e.g., dimethyldodecylamine oxide), and / or carboxylic acids (e.g., alpha hydroxy acids, such as lactic acid).

[0117] 1.12. Any of the above devices, wherein said drug reservoir layer comprises the free base form of a compound of formula I, or a compound of formula II, or a compound of formula III.

[0118] 1.13. Any of the above devices, wherein the drug reservoir layer comprises a compound of formula I, or a compound of formula II, or a compound of formula III in a pharma- ceutically acceptable salt form (e.g., a tosylate salt form), e.g., mixed with at least one organic or inorganic base to slowly form the free base form of the compound.

[0119] 1.14. Any of the above devices, wherein said backing layer is flexible or partially flexible.

[0120] 1.15. Any of the above devices, wherein the backing layer is composed of one or more of a film, a nonwoven, a woven, a laminate, or a combination thereof.

[0121] 1.16. Any of the above devices, wherein the backing layer comprises one or more polymers selected from polyester, polyamide, polyvinylidene chloride, polyvinyl chloride, polyethylene, polypropylene, polyurethane, polyetheramide, polyvinyl acetate, nylon.

[0122] 1.17. Any of the above devices further comprising a release liner in at least partial contact with the skin contact layer or the drug reservoir layer and which protects the adhesive elements of the device prior to use and prevents migration of components of the device from the device prior to use.

[0123] 1.18. Device 1.17, wherein the release liner is a non-permeable polymeric film.

[0124] 1.19. Any of the above devices, wherein the device comprises 1 to 1000 mg, for example, 1 to 750 mg, 1 to 500 mg, 1 to 300 mg, 1 to 200 mg, 10 to 200 mg, 50 to 200 mg, 100 to 200 mg, 100 to 300 mg, 200 to 300 mg, 200 to 500 mg, or 500 to 1000 mg of a compound represented by formula I, a compound represented by formula II, or a compound represented by formula III (free base equivalent amount).

[0125] 1.20. Any of the above devices, wherein the device is formulated to deliver the compound of formula I or the compound of formula II or the compound of formula III to a patient for a period of 1 to 30 days, for example, 1 to 20 days, or 1 to 15 days, or 1 to 10 days, or 1 to 7 days, or 1 to 5 days, or 1 to 3 days.

[0126] 1.21. Any of the above devices, wherein the device is formulated to deliver to a patient an average daily dose of 1-60 mg per day (free base equivalent) of the compound of formula I or the compound of formula II or the compound of formula III, e.g., 1-40 mg per day, or 1-30 mg per day, or 1-20 mg per day, or 1-15 mg per day, or 1-10 mg per day.

[0127] 1.22. The device has a luminance of 10 to 500 μg / hr / cm 2 Any of the above devices providing an in vitro flux of the compound of formula I or the compound of formula II or the compound of formula III (in free base equivalent amounts).

[0128] 1.23. Any of the above devices, wherein the device systemically delivers an average daily dose of the compound of formula I or the compound of formula II or the compound of formula III of 0.1-5.0 mg per day (free base equivalent), e.g., 0.5-2.0 mg per day, or 0.1-0.5 mg per day, or 1.0-2.0 mg per day, or about 1.8 mg per day.

[0129] 1.24. Any of the above devices, wherein the device delivers the compound of formula I or the compound of formula II or the compound of formula III at a rate sufficient to maintain a steady-state maximum plasma concentration of the compound of formula I or the compound of formula II or the compound of formula III (free base) of 5-50 ng / mL, e.g., 10-40 ng / mL, or 20-40 ng / mL (e.g., about 30 ng / mL), and / or a steady-state 24-hour average area under the plasma concentration curve (AUC) of the compound (free base) of 5-100 ng-hr / mL, e.g., 20-90 ng-hr / mL, or 40-90 ng-hr / mL, or 70-90 ng-hr / mL (e.g., about 80 ng-hr / mL).

[0130] As used herein, the term "transdermal formulation" or "transdermal delivery" does not encompass "transmucosal" routes of administration such as sublingual, oral, buccal, intravaginal, nasal and pulmonary. Transdermal delivery refers to the transport of a drug substance through the skin, e.g., keratinous epithelium, for absorption in the capillaries within or below the dermal layer of the skin for systemic delivery of the drug substance.

[0131] As used herein, "deuteration" refers to the removal of hydrogen (protium, 1 H) atom deuterium atom ( 2H). A hydrogen atom position of a structure is considered to be substituted with deuterium if the abundance of deuterium at that position is enriched. Since the natural abundance of deuterium is about 0.02%, a compound is "enriched" with deuterium at a particular position if the frequency of deuterium incorporation at that position is greater than 0.02%. Thus, in embodiments of deuterated compounds provided herein, one or more hydrogen atoms may be enriched with deuterium at a level of 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%.

[0132] In all aspects and embodiments of the present disclosure comprising a compound of formula I, the compound of formula I may be deuterated at one or more hydrogen atoms.

[0133] In all aspects and embodiments of the present disclosure comprising a compound of formula II, the compound of formula II is enriched only at the designated position (2,2-d2).

[0134] In all aspects and embodiments of the present disclosure comprising a compound of formula III, the compound of formula III is enriched only at the designated positions (1,1,2,2-d4).

[0135] In some embodiments, the formulation may further comprise one or more antioxidants, such as tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), citric acid, and / or ascorbic acid, or the like.In some embodiments, the formulation does not comprise an antioxidant compound.The inclusion of an antioxidant can further improve the chemical stability of the formulation by preventing the oxidative chemical degradation of the active ingredient.

[0136] In another aspect, the present disclosure provides a method for the treatment of 5-HT 2A In one embodiment, the present invention provides a method for treating a disease or abnormal condition involving or mediated by a serotonin receptor, a serotonin transporter (SERT), and / or a dopamine D1 / D2 receptor signaling pathway, such as obesity, anorexia, bulimia, depression (including major depressive disorder (MDD)), anxiety, psychosis, schizophrenia, obsessive-compulsive disorder, sexual disorder, migraine, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, conditions associated with head pain, social phobia, dementia (including Alzheimer's disease and Parkinson's dementia), gastrointestinal disorders, such as gastrointestinal motility disorders, and obesity, or a bipolar disorder (e.g., bipolar depression).

[0137] In another embodiment, the present invention provides 5-HT 2A The present invention provides a method for preventing or treating a disease or abnormal condition involving or mediated by the receptor, serotonin transporter (SERT), and / or dopamine D1 / D2 receptor signaling pathway in a patient in need of such prevention or treatment, comprising administering to the patient 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 transdermal route (Method 1). Further embodiments of Method 1 include:

[0138] 1.1 Method 1, in which a compound of formula I and / or a compound of formula II and / or a compound of formula III is administered by a transdermal route (e.g., administered using a transdermal delivery device such as a patch, gel, ointment or spray).

[0139] 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 formulations 1 or later, or formulations 2 or later, or formulations 3 or later.

[0140] 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 by device 1 or later.

[0141] 1.4 Any of Methods 1 or 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, sexual disorder, migraine, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, head pain related conditions, social phobia, dementia (including Alzheimer's disease and Parkinson's dementia), gastrointestinal disorders such as gastrointestinal motility disorders, and obesity, or bipolar disorders (e.g. bipolar depression).

[0142] 1.5 Any of methods 1 or 1.1 et seq., where the daily dose administered by the transdermal route (e.g. by device 1 et seq.) provides 1-50% of the dose administered under the same conditions by the oral route, e.g. 1-40%, or 5-25%, or 5-15%, or 1-5%, or 2.5-7.5% of the daily oral dose (due to reduced first pass metabolism and GI metabolism).

[0143] 1.6 Any of methods 1 or 1.1 et seq., wherein the method comprises transdermal application of a transdermal delivery device once every 30 days or less, e.g., once every 20 days or less, or once every 15 days or less, or once every 10 days or less, or once every 7 days or less, or once every 5 days or less, once every 3 days or less.

[0144] 1.7 Any of Methods 1 or 1.1 et seq., wherein the method comprises delivery to the patient of a compound of Formula I or a compound of Formula II or a compound of Formula III in an average daily amount of 5 to 60 mg per day (free base equivalent), e.g., 5 to 40 mg per day, or 5 to 30 mg per day, or 5 to 20 mg per day, or 5 to 15 mg per day, or 5 to 10 mg per day, or 1 to 5 mg per day, or 1 to 3 mg per day, or 2 to 3 mg per day, or about 1.8 mg per day, or 0.1 to 2 mg per day, or 0.1 to 1 mg per day, or 0.1 to 0.7 mg per day, or about 0.6 mg per day.

[0145] A compound of formula I or a compound of formula II and / or a compound of formula III for use in any of method 1 or method 1.1 onwards.

[0146] A pharmaceutical composition selected from any of Formulation 1 or later, Formulation 2 or later, or Formulation 3 or later, or Device 1 or later, for use in any of Method 1 or Method 1.1 or later.

[0147] Use of a compound of formula I or a compound of formula II or a compound of formula III in the manufacture of a medicament for transdermal administration, for example a medicament according to any of Formulation 1 or later, Formulation 2 or later, or Formulation 3 or later, or Device 1 or later for use in a method of treatment according to any of Method 1 or Method 1.1 or later.

[0148] Methods for synthesizing compounds of Formula I and compounds of Formulas II and III are known in the art and include those described in U.S. Patent Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; 7,081,455; 8,309,722; U.S. Reissue Patent No. 39680, and U.S. Reissue Patent No. 39679, and U.S. Patent Application Publication No. 2017 / 183350, the contents of each 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. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; 8,648,077; U.S. Reissue Patent No. 39680; and U.S. Reissue Patent No. 39679, the contents of each of which are incorporated herein by reference in their entirety.

[0149] Isolation or purification of the diastereomers of the compounds of the present invention can be achieved by conventional methods known in the art, such as column purification, preparative thin layer chromatography, preparative HPLC, crystallization, trituration, simulated moving bed, and the like.

[0150] The pharma- ceutically acceptable salts of the compounds of formula I, II and III can be synthesized from parent compounds containing basic or acid moieties by conventional chemical methods.Generally, such salts can be prepared by reacting the free base forms of these compounds with stoichiometric amounts of suitable acids in water or in organic solvents or in mixtures thereof; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.More detailed descriptions of the preparation of these salts, such as the toluenesulfonate salt in amorphous or crystalline form, can be found in U.S. Pat. No. 8,309,722 and / or U.S. Pat. No. 8,648,077.

[0151] Transdermal dosage forms are known to those skilled in the art, and the general procedures for preparing these dosage forms have been described.Examples of such delivery systems include those disclosed in U.S. Patent No. 9,993,466 to Lee et al., U.S. Patent No. 9,913,840 to Jain et al., U.S. Patent No. 9,693,970 to Mo, U.S. Patent No. 9,585,862 to Hwang et al., and U.S. Patent No. 7,858,114 to Ito.The contents of each of these documents are incorporated herein by reference in their entirety. EXAMPLES

[0152] Example 1A: Comparison of pharmacokinetics between subcutaneous (SC) and sublingual (SL) administration in dogs The in vivo absorption and distribution of a compound of formula I and a compound of formula II (both in the tosylate salt form) was compared following subcutaneous and sublingual administration in a non-crossover sequential study in dogs.

[0153] SC administration: Six male beagle dogs, aged 2-5 years, were randomized into two groups of 3. Dogs in group 1 were administered a compound of formula I at a dose of 1 mg / kg (free base equivalent) in a 0.5% methylcellulose / distilled water vehicle. Dogs in group 2 were administered a compound of formula II at a dose of 1 mg / kg (free base equivalent) in a 0.5% methylcellulose / distilled water vehicle. Administration was subcutaneous in the interscapular region with a 22 or 23 gauge needle. Whole blood samples were collected from the cephalic vein of the dogs before administration and at 5, 15 and 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours after administration. After a minimum washout period of 7 days, the dogs were transferred to the sublingual test.

[0154] SL administration: Dogs in group 1 are administered a compound of formula I at a dose of 1 mg / kg (free base equivalent) in a 0.5% methylcellulose / distilled water vehicle. Dogs in group 2 are administered a compound of formula II at a dose of 1 mg / kg (free base equivalent) in a 0.5% methylcellulose / distilled water vehicle. Animals are anesthetized using propofol (6 mg / kg) prior to administration, and anesthesia is maintained for 30 minutes using 3-4.5% isoflurane. Administration is sublingual, with the dose applied for 30 minutes and then wiped off using nonwoven gauze. Whole blood samples are collected from the cephalic vein of the dogs prior to administration, and at 5, 15, and 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 36 hours, and 48 hours after administration.

[0155] Whole blood samples are processed to plasma and analyzed for drug concentrations using liquid chromatography tandem mass spectrometry (LC-MS / MS). Areas under the curve (AUC) for parent and metabolites based on plasma versus time data are calculated using Prism 5.04 software (GraphPad Software, Inc.).

[0156] The results are summarized in Table 1 below (AUC is shown for 0-24 hours):

[0157] [Table 1]

[0158] The results show that both SC and SL administration result in high plasma concentrations and high plasma AUC. SL administration also results in significantly higher maximum drug plasma concentrations (Cmax) for both compounds compared to SC administration. For the compound of formula II, SL administration also results in significantly higher overall AUC, while the AUC of the compound of formula I shows comparable AUC between SC and SL administration. The time to maximum plasma concentration is also the same for both compounds with SC and SL administration.

[0159] Example 1B: Pharmacokinetic comparison of subcutaneous and sublingual administration in dogs with metabolite analysis The second study is performed essentially as described in Example 1A, except that plasma samples are analyzed for the parent (administered) compound and the major known metabolite. Following administration of a compound of Formula I or a compound of Formula II, the major circulating species are found to be the parent and the N-desmethyl metabolite. The results are summarized in Table 1B below (AUC is shown for 0-24 hours):

[0160] [Table 2]

[0161] These results further show that both SC and SL administration result in high plasma concentrations and high plasma AUC of the administered compounds. SL administration also results in higher maximum plasma drug concentrations (Cmax) for both compounds compared to SC administration. Furthermore, the results show that both SC and SL administration result in a very low rate of metabolite formation, indicating that these pathways effectively bypass the primary site of metabolic degradation of these compounds (hepatic metabolism). Compounds of formula I circulate in plasma with an AUC of the parent that is about 22-fold higher than the metabolites after SL administration and 27-fold higher for SC administration. In contrast, when administered orally, compounds of formula I and their desmethyl metabolites have been found to circulate in plasma with an AUC of about 1:1 or less. Similarly, results are shown for compound of formula II (parent / metabolite ratio of about 12 for SL and about 16 for SC).

[0162] Example 2: Pharmacokinetics of oral administration in dogs In contrast to the subcutaneous and sublingual pharmacokinetics shown in Example 1, this example shows that oral administration results in substantially lower systemic drug exposure due to extensive hepatic first-pass metabolism, even using doses 2.5-15 times higher than those used in the SC and SL studies.

[0163] For the large-scale long-term toxicity portion, 20 male and female beagle dogs are administered a control or a compound of formula I in the tosylate salt form at doses of 2.5 mg / kg, 5 mg / kg, 10 mg / kg, or 15 mg / kg. For the control, the dogs are administered an empty capsule. For the compound of formula I, the dogs are administered a normal release oral capsule. Blood samples are collected at 0.25, 0.5, 1, 4, 8, and 24 hours. The blood samples are processed to plasma and analyzed for the 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.

[0164] [Table 3]

[0165] The compound of formula I exhibits dose-dependent oral absorption, with the plasma concentrations achieved even at the highest oral dose being much lower than the plasma concentrations and AUC achieved at sublingual and subcutaneous administration as shown in Example 1. Sublingual and subcutaneous administration of only 1.0 mg / kg of the compound of formula I results in a 24-hour AUC that is more than 18-fold higher than the oral dose of 2.5 mg / kg. Sublingual and subcutaneous administration of 1.0 mg / kg provides a 24-hour AUC that is approximately 3-fold higher than the oral dose of 15 mg / kg.

[0166] Collectively, these results indicate a large loss of exposure due to hepatic first-pass metabolism and an unexpectedly high improvement in exposure achieved by the use of a transmucosal delivery system.

[0167] Example 3: Pharmacokinetics of SC and IV Administration in Monkeys Monkeys are also tested to determine the plasma concentrations of both the compound of formula I and its major metabolites after both SL and SC administration at 0.5 mg / kg. Six cynomolgus monkeys are divided into two groups for IV and SC administration of the compound of formula I. The animals are dosed in the fasting state. Blood samples are taken before dosing and at 5 minutes, 15 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 36 hours and 48 hours after dosing. Whole blood samples are processed into plasma and later analyzed by liquid chromatography tandem mass spectrometry. Samples are tested for the concentrations of the compound of formula I and its five major known metabolites. PK parameters are calculated using PK Solutions 2.0 software (Summit Research Services, Colorado, US).

[0168] The results indicate that the bioavailability (based on IV vs. SC pharmacokinetic comparison) is about 74% for the compound of Formula I or SC administration. The majority of metabolites tested are found to be present at levels below the limit of quantification. Only the desmethyl and amide metabolites (oxidation of the methylene adjacent to the N-methyl group to a carbonyl) are found to be present in significant concentrations. The concentrations of both metabolites are found to be lower after SC administration than after IV administration. The results are shown in Table 3 below:

[0169] [Table 4]

[0170] The results show that SC administration to monkeys results in substantially lower formation levels of major metabolites compared to IV administration.

[0171] All of the above results demonstrate the effectiveness of administering compounds of the present disclosure in a manner that avoids first-pass metabolism.

[0172] Example 4: In vitro permeability study A bilayer transdermal patch is prepared that includes an adhesive drug reservoir layer and a backing layer protected by a release liner. Permeation testing is performed by removing the release liner from a sample patch and immediately applying the patch to the stratum corneum of human cadaver skin fixed to the donor chamber side of a modified Franz diffusion cell. A mesh is applied over the patch to ensure that the patch remains attached to the skin for the duration of the experiment. The lower chamber of the cell contains the receptor solution that is sampled at various time points and analyzed for lumateperone content. The cell contains a magnetic mixer bar to ensure complete mixing. These measurements are used to calculate drug flux and cumulative delivery over the course of the experiment. A Franz cell with a diffusion area of ​​2 square centimeters, a capacity of 5.0 mL of receptor solution is used for all experiments. The transdermal patch measures 1 square centimeter. The temperature is maintained at 32°C and humidity is ambient. The receptor solution consists of 20% v / v polyethylene glycol 400 in phosphate buffer at pH 7.4. Solution samples are analyzed by HPLC.

[0173] Study 1. Prepare a patch containing a binary drug reservoir layer consisting of 2.5% w / w lumateperone free base in a single vehicle. 25 different vehicles are tested. Samples from the receptor solution are taken at 3, 6, 12 and 24 hours after application. The cumulative permeability results are shown in the table below:

[0174] [Table 5]

[0175] The results show that of the 25 excipients selected, 8 excipients have a significantly better enhancing effect than the other 16 excipients. The other 16 excipients, all of which had cumulative permeation amounts ranging from 2 to 15 μg, are butylene glycol, diethylene glycol monomethyl ether, diisopropyl adipate, dipropylene glycol, glyceryl monooleate, glycerol, isostearic acid, laureth-4, levulinic acid, octyzalate, oleic acid, oleyl alcohol, propylene glycol monolaurate, sorbitan monooleate, and triacetin.

[0176] Study 2. Prepare a patch containing a ternary drug reservoir layer consisting of 10% w / w lumateperone free base and 20% w / w excipients in a polyacrylate vehicle. The eight preferred excipients from Study 1 are tested along with a control containing 10% w / w lumateperone free base in a polyacrylate vehicle. Samples are taken from the receptor solution at 6, 24, 48, and 72 hours after application. Significant differences are seen when the excipient is present compared to when it is not present. Optimal results are obtained with the lauryl lactate excipient, which gives a drug delivery of 114 μg at 72 hours, followed by propylene glycol and methyl laurate (50-70 μg), with the remaining excipients giving results similar to the control (all 25-40 μg).

[0177] Test 3. A patch is prepared containing a quaternary drug reservoir layer consisting of 10% w / w lumateperone free base and 0-10% w / w lauryl lactate excipient in a mixed vehicle of polyacrylate and silicone adhesive. Samples from the receptor solution are taken at 6, 24, 48, and 72 hours after application. As expected, samples with 0% excipient have the lowest permeation values, all below 30 μg at 72 hours, while samples with 10% excipient have the highest permeation values, all above 70 μg at 72 hours. The combination of 10% lauryl lactate, 40% acrylate adhesive, and 40% silicone adhesive gave optimal results.

[0178] Further studies are conducted investigating the permeation enhancing effect of 20 additional excipients. Of these additional excipients, only methyl caprate and Labrafac PG® (propylene glycol dicaprate / dicaprylate) are found to significantly enhance permeability.

[0179] Further studies will also evaluate lumateperone 10% w / w in various excipient mixtures in a polyacrylate / silicone adhesive vehicle. Each mixture contains a combination of excipients selected from lauryl lactate (LL), propylene glycol (PG), methyl laurate (ML), and propylene glycol dicaprate / dicaprylate (PGDD). It is found that there is an unexpected synergistic effect on permeation resulting from the combination of lauryl lactate and propylene glycol, as shown in the summary below:

[0180] [Table 6]

[0181] Further studies also evaluate dimethyldodecylamine oxide (DDAO) as an enhancing excipient. Unexpectedly, the addition of just 2 wt% DDAO to a formulation containing 20% ​​lumateperone, 15% lauryl lactate, and 10% propylene glycol was found to nearly double permeation at 72 hours, from approximately 300 μg to over 550 μg.

[0182] Moreover, lactic acid is unexpectedly found to enhance permeation, which is believed to be due to the fact that lactic acid prevents cohesion of the adhesive matrix. Further comparative testing shows that lactic acid provides more favorable permeation enhancement than the similar acids glycolic acid, mandelic acid, and tropic acid.

[0183] Finally, the six final drug reservoir layer formulations, each with 20 wt% lumateperone, are tested in a three-day porcine irritation and drug delivery study. The patches are also tested for stability in a two-month aging study. For the porcine study, the patches, approximately 2" x 2", are placed adjacent to each other in series on the animals' backs and the edges are secured with medical adhesive tape. An additional control of adhesive only is used for comparison of irritation results. Drug delivery is determined by measuring the amount of drug remaining in the patch and on the skin surface (taken with a cotton swab) compared to the amount of drug originally contained in each patch (which varies slightly depending on the exact size of each patch). The six formulations are shown in the table below (w / w%):

[0184] [Table 7]

[0185] All six formulations show similar irritation and stability results: no significant irritation or discoloration of the skin 72 hours after application (similar to the control), and the patches show less than 0.3% degradation at room temperature for up to two weeks of storage. When stored at room temperature for up to two months, the patches show 0.1-0.7% degradation. Thus, lumateperone is stable at room temperature storage in these patch formulations, and the patch formulations do not significantly irritate the skin. Drug delivery results show that both lactic acid and DDAO enhance in vivo delivery in an unexpected synergistic way compared to the excipient-only patch. The excipient-free patch (adhesive only) shows very low drug delivery.

Claims

1. The compound of formula I, which comprises 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]quinoxalin-8-yl)-butan-1-one, in free base form, co-crystal form or salt form, or 1-(4-fluoro-phenyl)-4-((6bR,10aS)-2,2-d 2 -3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (compound represented by formula II) or -(4-fluoro-phenyl)-4-((6bR,10aS)-1,1,2,2-d in free base form, co-crystal form or salt form. 4 A transdermal pharmaceutical formulation comprising 3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (a compound represented by formula III).

2. 2. The formulation of claim 1, wherein the formulation comprises a compound of formula I, a compound of formula II, or a compound of formula III in free base form.

3. The formulation of claim 1, wherein the formulation comprises a compound of formula I or a compound of formula II or a compound of formula III in a salt form, e.g., a pharma- ceutically acceptable salt form, or a co-crystal form.

4. 4. The formulation of claim 3, wherein the salt form is the tosylate, e.g. a crystalline salt form.

5. 20. A formulation according to any preceding claim, wherein the formulation comprises 1-1000 mg, for example 1-750 mg, 1-500 mg, 1-300 mg, 1-200 mg, 10-200 mg, 50-200 mg, 100-200 mg, 100-300 mg, 200-300 mg, 200-500 mg, or 500-1000 mg of a compound of formula I (free base equivalent amount) or a compound of formula II (free base equivalent amount) or a compound of formula III (free base equivalent amount).

6. 10. The formulation of any preceding claim, further comprising one or more excipients selected from the group consisting of solvents, solubilizers, plasticizers, surfactants, binders, humectants (e.g., polyols), antioxidants, buffering agents (e.g., acids, bases and / or their salts), emollients, and thickening agents (e.g., gelling agents).

7. 7. The formulation of claim 6, wherein the one or more excipients are selected from any of the following: alcohols (ethanol, isopropanol, propanol, glycerol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, polyethylene glycol), non-alcoholic solvents (e.g., dimethylsulfoxide, dimethylformamide, acetonitrile), gums (e.g., acacia, guar, agar, xanthan, tragacanth, karaya, gellan), polysaccharides and polysaccharide derivatives (e.g., starch, dextran, pectin, alginate, carrageenan, cellulose, cellulose derivatives (e.g., carboxymethylcellulose, methylcellulose, hydroxyalkylcelluloses (e.g., hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose)), gelatins including non-gelling and gelling types (e.g., mammalian gelatins, e.g., bovine gelatin, porcine gelatin, trigelatin, fish gelatins (e.g., mixed high and low molecular weight gelatins), synthetic polymers (e.g., polyvinylpyrrolidone, polyethylene oxide, and and / or polypropylene oxide polymers and copolymers (e.g., poloxamers, e.g., poloxamer 188), polyacrylate polymers (e.g., carbopol), 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 (e.g., For example, citric acid, lactic acid, malic acid, mandelic acid, tropic acid, glycolic 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 (e.g., sodium, potassium, calcium, magnesium, lithium, ammonium salts of the abovementioned acids) and esters (e.g., methyl or ethyl esters, or fatty acid esters), inorganic or organic bases (e.g., carbonates, bicarbonates, salts of alkali metals or alkaline earth metals,hydroxides, oxides), anionic surfactants (e.g. sodium lauryl sulfate, sodium laureth sulfate, sodium dodecylbenzenesulfonate, sodium lauroyl sarcosinate, sodium stearate), cationic surfactants (e.g. benzalkonium halides, cetylpyridinium halides, cetrimonium halides, benzethonium halides), zwitterionic surfactants (e.g. cocamidoalkyl betaines, e.g. cocamidopropyl betaine, or amine oxides, e.g. dimethyldodecylamine oxide and myristamine oxide), nonionic surfactants (e.g. fatty alcohol ethoxylates (e.g. polyethylene glycol polydodecyl ether), sorbitan esters (e.g. monolaurate sol sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate), polyethoxylated sorbitan esters (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80), fatty acid esters (e.g., lauryl lactate, isopropyl myristate, oleyl oleate, methyl laurate, isopropyl palmitate, ethyl oleate), fatty alcohols (e.g., dodecanol, octyldecanol, lauryl alcohol), and antioxidants (e.g., ascorbic acid, citric acid, ascorbyl palmitate, sodium metabisulfite, BHT, BHA, TBHQ, propyl gallate, beta-carotene, tocopherol, tocotrienol).

8. A formulation according to any preceding claim, wherein the formulation comprises an adhesive polymer, optionally in an amount of 25-80% by weight.

9. 9. The formulation of claim 8, wherein the adhesive polymer comprises a polymer selected from the group consisting of acrylate polymers or copolymers (e.g., polymers in which at least one monomer unit is an acrylic acid or ester and one or more other monomer units may be non-acrylate monomers, such as vinyl monomers); polyvinylpyrrolidones (e.g., linear or crosslinked), copolymers of maleic acid or maleic esters with vinyl ethers (e.g., copolymers of maleic acid or anhydride with methyl vinyl ether), cellulose derivatives (e.g., carboxymethylcellulose), silicone polymers (e.g., dimethyl silicone), and mixtures thereof, such as mixtures of polyacrylate polymers and silicone polymers.

10. The formulation according to any one of claims 1 to 9, wherein the formulation is an ointment, a spray or a gel.

11. The formulation according to any one of claims 1 to 9, wherein the formulation is comprised in a patch, such as an adhesive patch.

12. A transdermal pharmaceutical device comprising the formulation according to any one of claims 1 to 11.

13. 13. The device of claim 12, wherein the device comprises at least two layers, at least one layer being a drug reservoir layer and at least one layer being a backing layer.

14. 14. The device of claim 13, wherein the drug reservoir layer comprises an adhesive polymer, and the drug reservoir layer is a skin contact layer of the device.

15. 14. The device of claim 13, wherein the device further comprises a third layer separate from the drug reservoir layer, the third layer being a skin contact layer, the layer comprising an adhesive polymer, and the layer being substantially free of compounds of Formula I, Formula II and Formula III prior to use of the device.

16. 16. The device of claim 15, wherein the device further comprises an intermediate layer disposed between the skin-contacting layer and the drug reservoir layer, the intermediate layer being a rate-controlling layer.

17. 17. The device of any of claims 13 to 16, wherein the drug reservoir layer and / or the skin contact layer comprises one or more permeation enhancing excipients, such as fatty acid esters (e.g., lauryl lactate), alcohols (e.g., propylene glycol), amine oxides (e.g., dimethyldodecylamine oxide), and / or carboxylic acids (e.g., alpha hydroxy acids, e.g., lactic acid).

18. 18. The device of any one of claims 13 to 17, wherein the device comprises 1 to 1000 mg, for example 1 to 750 mg, 1 to 500 mg, 1 to 300 mg, 1 to 200 mg, 10 to 200 mg, 50 to 200 mg, 100 to 200 mg, 100 to 300 mg, 200 to 300 mg, 200 to 500 mg, or 500 to 1000 mg of a compound of formula I or a compound of formula II or a compound of formula III (free base equivalent amount).

19. 19. The device of any of claims 13 to 18, wherein the device is formulated to deliver the compound of formula I or the compound of formula II or the compound of formula III to a patient for a period of from 1 to 30 days, such as from 1 to 20 days, or from 1 to 15 days, or from 1 to 10 days, or from 1 to 7 days, or from 1 to 5 days, or from 1 to 3 days.

20. 20. The device of any of claims 13 to 19, wherein the device is formulated to deliver to a patient an average daily dose of 1 to 60 mg per day (free base equivalent) of the compound of formula I or the compound of formula II or the compound of formula III, e.g., 1 to 40 mg per day, or 1 to 30 mg per day, or 1 to 20 mg per day, or 1 to 15 mg per day, or 1 to 10 mg per day.

21. 21. The device of any of claims 13 to 20, wherein the device systemically delivers an average daily dose of the compound of formula I or the compound of formula II or the compound of formula III of 0.1 to 5.0 mg per day (free base equivalent), e.g., 0.5 to 2.0 mg per day, or 0.1 to 0.5 mg per day, or 1.0 to 2.0 mg per day, or about 1.8 mg per day.

22. 22. The device of any of claims 13-21, wherein the device delivers the compound of formula I or the compound of formula II or the compound of formula III (free base) at a rate sufficient to maintain a steady state maximum plasma concentration of the compound of formula I or the compound of formula II or the compound of formula III (free base) of 5-50 ng / mL, e.g., 10-40 ng / mL, or 20-40 ng / mL (e.g., about 30 ng / mL), and / or a steady state 24 hour mean area under the plasma concentration curve (AUC) of the compound (free base) of 5-100 ng-hr / mL, e.g., 20-90 ng-hr / mL, or 40-90 ng-hr / mL, or 70-90 ng-hr / mL (e.g., about 80 ng-hr / mL).

23. 5-HT 2A A method for the prevention or treatment of a disease or abnormal condition involving or mediated by the serotonin receptor, serotonin transporter (SERT), and / or dopamine D1 / D2 receptor signaling pathway in a patient in need of such prevention or treatment, comprising administering to the patient 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 transdermal route.

24. The method according to claim 21, 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 formulation according to any one of claims 1 to 11.

25. The method according to claim 21, wherein the compound of formula I and / or the compound of formula II and / or the compound of formula III is administered using a device according to any of claims 12 to 22.

26. 26. The method of any one of claims 23 to 25, wherein the disease or condition is selected from obesity, anorexia, bulimia, depression (including major depressive disorder (MDD)), anxiety, psychosis, schizophrenia, obsessive-compulsive disorder, sexual disorder, migraine, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, head pain related conditions, social phobia, dementia (including Alzheimer's disease and Parkinson's dementia), gastrointestinal disorders, such as gastrointestinal motility disorders, and obesity, or bipolar disorders (e.g. bipolar depression).

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