Patent Description:
<NUM>-(<NUM>-fluoro-phenyl)-<NUM>-((6bR,10aS)-<NUM>-methyl-<NUM>,<NUM>,6b,<NUM>,<NUM>,10a-hexahydro-<NUM>,<NUM>-pyrido[<NUM>',<NUM>':<NUM>,<NUM>]pyrrolo[<NUM>,<NUM>,<NUM>-de]quinoxalin-<NUM>-yl)-butan-<NUM>-one (sometimes referred to as <NUM>-((6bR,10aS)-<NUM>-methyl-<NUM>,<NUM>,6b,<NUM>,<NUM>,10a-hexahydro-<NUM>-pyrido[<NUM>',<NUM>':<NUM>,<NUM>]pyrrolo[<NUM>,<NUM>,<NUM>-de]quinoxalin-<NUM>(<NUM>)-yl)-<NUM>-(<NUM>-fluorophenyl)-<NUM>-butanone, or Lumateperone or as ITI-<NUM>), has the following structure:
<CHM>.

ITI-<NUM> is a potent <NUM>-HT2A receptor ligand (Ki=<NUM>) with strong affinity for dopamine (DA) D2 receptors (Ki=<NUM>) and the serotonin transporter (SERT) (Ki=<NUM>), but negligible binding to receptors associated with cognitive and metabolic side effects of antipsychotic drugs (e.g., H1 histaminergic, <NUM>-HT2C, and muscarinic receptors). ITI-<NUM> is currently in clinical trials, i.e., for the treatment of schizophrenia. While ITI-<NUM> is a promising drug, its production and formulation present distinct challenges. In free base form, ITI-<NUM> is an oily, sticky solid, with poor solubility in water. Making salts of the compound has proven to be unusually difficult. A hydrochloride salt form of ITI-<NUM> was disclosed in <CIT>, but this salt was hygroscopic and shows poor stability. A toluenesulfonic acid addition salt (tosylate) of ITI-<NUM> was finally identified and described in <CIT>.

Nevertheless, there remains a need for alternative stable, pharmaceutically acceptable solid forms of ITI-<NUM> which can be readily incorporated into galenic formulations.

It has been disclosed that for a number of drugs, amorphous forms exhibits different dissolution characteristics, and in some cases different bioavailability patterns, compared to crystalline forms of the same drug. For some therapeutic indications, one bioavailability pattern may be favored over another. For example, an amorphous form of Cefuroxime axetil exhibits higher bioavailability than the crystalline form. Thus, amorphous solid dispersions are a promising alternative to traditional crystalline active pharmaceutical ingredients.

Pure amorphous drug forms tend to be unstable. As amorphous forms are thermodynamically unstable relative to the corresponding crystal forms, it is well known that amorphous forms would revert back to the stable crystalline form. This usually occurs during storage under various humidity and temperature conditions. Therefore, in order to utilize the amorphous form of a drug, it is necessary to stabilize it to inhibit crystallization of the drug active during the period of product storage.

Discovering suitable excipients that will stabilize the amorphous form of a pharmaceutical drug is a challenge, as some excipients will chemically react with the drug or promote its decomposition, while other excipients will form uniform solid dispersions that are not physically stable, not chemically stable or both.

Given the difficulties involved in making salts of ITI-<NUM>, it was decided to explore whether the compound could be formulated as a physically and chemically stable amorphous solid dispersion. An extensive screen of excipients was undertaken, using various combinations of agents at different ratios and using different production methods. Dispersions were evaluated based on physical appearance and texture, X-ray powder diffraction (XRPD), modulated differential scanning calorimetry (mDSC), thermogravimetric analysis (TGA), and high-performance liquid chromatography (HPLC). Sixteen potential excipients were screened under a total of forty-four conditions, and three pharmaceutically acceptable amorphous solid dispersions were discovered.

The present disclosure provides three amorphous solid dispersions of ITI-<NUM> free base comprising (<NUM>) ITI-<NUM> free base at a <NUM>:<NUM> to <NUM>:<NUM> weight ratio to cellulose acetate excipient; (<NUM>) ITI-<NUM> free base at a <NUM>:<NUM> to <NUM>:<NUM> weight ratio to cellulose acetate phthalate excipient; and (<NUM>) ITI-<NUM> free base at a <NUM>:<NUM> to <NUM>:<NUM> weight ratio to hydroxypropylmethyl cellulose phthalate excipient.

The disclosure thus provides novel amorphous solid dispersion forms of ITI-<NUM> free base, which dispersions are especially advantageous for use in the preparation of galenic formulations, together with methods of making and using the same.

In a first embodiment, the present disclosure provides <NUM>-(<NUM>-fluoro-phenyl)-<NUM>-((6bR,10aS)-<NUM>-methyl-<NUM>,<NUM>,6b,<NUM>,<NUM>,10a-hexahydro-<NUM>,<NUM>-pyrido[<NUM>',<NUM>':<NUM>,<NUM>]pyrrolo[<NUM>,<NUM>,<NUM>-de]quinoxalin-<NUM>-yl)-butan-<NUM>-one (ITI-<NUM>) free base in the form of an amorphous solid dispersion comprising cellulose acetate excipient in a ratio of <NUM>:<NUM> to <NUM>:<NUM> ITI-<NUM> free base to cellulose acetate (Dispersion <NUM>). The present disclosure further provides the following Compositions:.

In a second embodiment, the present disclosure provides ITI-<NUM> free base in the form of an amorphous solid dispersion comprising cellulose acetate phthalate excipient in a ratio of <NUM>:<NUM> to <NUM>:<NUM> ITI-<NUM> free base to cellulose acetate phthalate (Dispersion <NUM>). The present disclosure further provides the following Compositions:.

In a third embodiment, the present disclosure provides ITI-<NUM> free base in the form of an amorphous solid dispersion comprising hydroxypropylmethyl cellulose phthalate (HPMC-P) excipient in a ratio of <NUM>:<NUM> to <NUM>:<NUM> ITI-<NUM> free base to HPMC-P (Dispersion <NUM>). The present disclosure further provides the following Compositions:.

In a second aspect, the present disclosure provides a process (Process <NUM>) for the production of Dispersion <NUM>, et seq. , or Dispersion <NUM>, et seq. , or Dispersion <NUM>, et seq. , comprising the steps of:.

In another embodiment of the second aspect, the solvent or mixture of solvents for Process <NUM> is selected from dioxane, methanol or a dioxane/methanol mixture, e.g., a <NUM>:<NUM> to <NUM>:<NUM> ratio of dioxane to methanol, or a <NUM>:<NUM> to <NUM>:<NUM> ratio, or about a <NUM>:<NUM> ratio of dioxane to methanol, optionally wherein the solvent is removed by lyophilization.

Solid dispersion, as used herein, refers to the dispersion of an active pharmaceutical ingredient, i.e., ITI-<NUM>, in an inert excipient or matrix (carrier), where the active ingredient could exist in a finely crystalline, solubilized or amorphous state. The excipient in a solid dispersion is typically a polymer. The most important role of the polymer in a solid dispersion is to reduce the molecular mobility of the pharmaceutical active to avoid phase separation and re-crystallization of the active during storage. The amorphous form of the active is associated with a higher energy state as compared to its crystalline counterpart, and therefore, significantly less external energy is required to effect dissolution (e.g., in the gastrointestinal tract or elsewhere in the body).

In a third aspect, the present disclosure provides a pharmaceutical composition (Composition <NUM>) comprising Dispersion <NUM>, et seq. , or Dispersion <NUM>, et seq. , or Dispersion <NUM>, et seq. , in combination or association with a pharmaceutically acceptable diluent or carrier. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule for oral administration. In some embodiments, the pharmaceutical composition is in the form of a depot formulation for use as a long-acting injectable (LAI). The pharmaceutical composition may further comprise any suitable pharmaceutically acceptable excipient, such as: 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, gelatin, polyvinylpyrrolidones such as polyvinylpyrrolidones(PVP K-<NUM>,K-<NUM>), poly (vinyl pyrrolidone-co-vinyl acetate) (PVP-VA) and the like, hydroxypropyl celluloses, hydroxypropyl methylcellulose, cellulose acetate, hydroxypropyl methylcellulose 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 or wetting enhancers such as anionic or cationic or neutral surfactants; maltodextrin, complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like; and film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

In another embodiment of the third aspect, the composition may further comprise one or more anti-oxidants, for example, tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), or and ascorbic acid, or the like. The inclusion of an anti-oxidant may further improve the chemical stability of the dispersions by preventing oxidative chemical degradation of the ITI-<NUM> active. In another embodiment, the dispersion itself is formulated to include such an anti-oxidant.

In another aspect, the present disclosure provides Dispersion <NUM>, et seq. , or Dispersion <NUM>, et seq. , or Dispersion <NUM>, et seq. , or a pharmaceutical composition comprising Dispersion <NUM>, et seq. , or Dispersion <NUM>, et seq. , or Dispersion <NUM>, et seq. , e.g., Composition <NUM>, for use in treating a disease or abnormal condition involving or mediated by the <NUM>-HT2A receptor, serotonin transporter (SERT), and/or dopamine D<NUM>/D<NUM> receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorders, depression, schizophrenia, migraine, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, sleep disorders, conditions associated with cephalic pain, social phobias, or dementia.

In another embodiment, the invention provides a method for the prophylaxis or treatment of a human suffering from a disease or abnormal condition involving or mediated by the <NUM>-HT2A receptor, serotonin transporter (SERT), and/or dopamine D<NUM>/D<NUM> receptor signaling pathways, e.g., a disorder selected from obesity, anorexia, bulimia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorders, depression, schizophrenia, migraine, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, sleep disorders, conditions associated with cephalic pain, social phobias, or dementia, comprising administering to a patient in need thereof a therapeutically effective amount of Dispersion <NUM>, et seq. , or Dispersion <NUM>, et seq. , or Dispersion <NUM>, et seq. , or a pharmaceutical composition comprising Dispersion <NUM>, et seq. , or Dispersion <NUM>, et seq. , or Dispersion <NUM>, et seq, e.g., Composition <NUM>.

The following equipment and methods are used to isolate and characterize the exemplified co-crystal forms:.

Solubility of ITI-<NUM> free base and various excipients is first evaluated in various solvents. It is found that ITI-<NUM> free base shows good solubility (> <NUM>/mL) in acetone, ethanol, methanol, dioxane, and <NUM>,<NUM>,<NUM>-trifluoroethanol (TFE), but relatively poor solubility (<NUM>-<NUM>/mL) in tert-butanol/water mixtures. However, it is found that solutions of ITI-<NUM> free base in TFE rapidly discolor due to decomposition of the active.

The excipients evaluated are Eudragit L100, polyvinyl acetate, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone K-<NUM>, polyvinylpyrrolidone S-<NUM>, cellulose acetate, cellulose acetate phthalate, Gelucire <NUM>/<NUM>, glyceryl monostearate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate (HPMC-P), hydroxypropyl methyl acetate succinate (HPMC-AS), polyethylene glycol (PEG), PEG-<NUM> succinate, Pluronic F-<NUM>, and Soluplus. Excipients were evaluated at one or more of the ratios <NUM>:<NUM>, <NUM>:<NUM> and <NUM>:<NUM> ITI-<NUM> free base to excipient.

Based on the solubility analyses, solutions of various excipients with ITI-<NUM> free base are prepared in <NUM>:<NUM> acetone-ethanol. Rotary evaporation is attempted to remove the solvent, but this results in oily materials, instead of solids, in all cases.

Solid dispersions are successfully prepared by lyophilization from solutions of ITI-<NUM> free base and excipient in either dioxane or dioxane-methanol (<NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM> or <NUM>:<NUM>). Solutions are initially frozen in a dry ice/acetone bath, and then placed in a freeze dryer with the shelf pre-cooled to -<NUM>. Samples are dried overnight at -<NUM>, followed by -<NUM>, then <NUM> over a period of two days. Samples are then secondary dried at <NUM> for four hours, purged with nitrogen then stored in a freezer over desiccant until testing.

Solid dispersions obtained from Example <NUM> are first evaluated by XRPD to determine if they are amorphous. All lyophilization samples using amorphous excipients are found to be x-ray amorphous by XRPD. Lyophilization samples using crystalline excipients (Gelucire <NUM>/<NUM>, PEG, PEG-<NUM> succinate, Pluronic F-<NUM>) are found to be disordered with peaks present corresponding only to the excipient. Further observations of the appearance of the solids are shown in Table <NUM> below. The <NUM>:<NUM> ITI-<NUM>/PEG-<NUM> succinate dispersion is found to be very sticky and is not further evaluated.

Solid dispersions from Example <NUM> are placed into uncapped clear glass vials and the vials are placed into a container maintained for seven days at <NUM>% relative humidity and a temperature of <NUM>. As a control, a sample of ITI-<NUM> free base is analyzed in parallel. Samples were observed visually as well as by polarized light microscopy (<NUM>-<NUM> x magnification with crossed polarizers and a first order red compensator). Observations are shown in Table <NUM>. The majority of samples display changes in appearance or texture, indicating the formation of physically unstable amorphous dispersions. For example, some show visible crystallization while others become sticky solids or oils.

Dispersions which are physically stable free-flowing solids are further analyzed by XRPD to confirm that they remain x-ray amorphous or disordered with excipient peaks only. The XRPD results confirm that the visually stable samples remain X-ray amorphous dispersions.

mDSC and TGA analysis is conducted on the physically stable free-flowing samples. A single glass transition temperature in mDSC supports the conclusion that the solid is a non-crystalline miscible dispersion. The two PEG dispersions show an unacceptable low-temperature glass transition at <NUM> or <NUM>, while the glyceryl monostearate dispersion shows no glass transition. The <NUM>:<NUM> cellulose acetate dispersion shows two glass transition temperatures, which suggests a phase-separated material, which is unacceptable. Only the <NUM>:<NUM> cellulose acetate, <NUM>:<NUM> cellulose acetate phthalate, <NUM>:<NUM> cellulose acetate phthalate, <NUM>:<NUM> HPMC-AS, <NUM>:<NUM> HPMC-AS, <NUM>:<NUM> HPMC-P and <NUM>:<NUM> HPMC-P dispersions show acceptable single glass transition temperatures above <NUM>.

All samples submitted to mDSC and TGA are then submitted to HPLC analysis to determine the chemical stability of the ITI-<NUM> active agent during the seven-day study. As a control, the ITI-<NUM> free base sample is also analyzed by HPLC. All results are normalized to the ITI-<NUM> content shown by HPLC prior to the seven-day study. A loss of less than <NUM>% ITI-<NUM> by HPLC is considered satisfactory.

Both HPMC-AS dispersions, as well as the <NUM>:<NUM> HPMC-P dispersion show very high material losses by HPLC. The <NUM>:<NUM> cellulose acetate phthalate dispersion shows a low but unacceptable loss of material. Only seven dispersions produce satisfactory results: <NUM>:<NUM> cellulose acetate, <NUM>:<NUM> cellulose acetate, <NUM>:<NUM> cellulose acetate phthalate, <NUM>:<NUM> HPMC-P, <NUM>:<NUM> PEG, <NUM>:<NUM> PEG and <NUM>:<NUM> glyceryl stearate. These dispersions are thus chemically stable.

The combined tests results are shown in Table <NUM> below.

Of the tested dispersions, it is found that only three are both chemically stable and physically stable: <NUM>:<NUM> cellulose acetate, <NUM>:<NUM> cellulose acetate phthalate, and <NUM>:<NUM> HPMC-P.

Claim 1:
<NUM>-(<NUM>-fluoro-phenyl)-<NUM>-((6bR,10aS)-<NUM>-methyl-<NUM>,<NUM>,6b,<NUM>,<NUM>,10a-hexahydro-<NUM>,<NUM>-pyrido[<NUM>',<NUM>':<NUM>,<NUM>]pyrrolo[<NUM>,<NUM>,<NUM>-de]quinoxalin-<NUM>-yl)-butan-<NUM>-one (ITI-<NUM>) free base in the form of an amorphous solid dispersion comprising:
(a) cellulose acetate excipient in a ratio of <NUM>:<NUM> to <NUM>:<NUM> ITI-<NUM> free base to cellulose acetate; or
(b) cellulose acetate phthalate excipient in a ratio of <NUM>:<NUM> to <NUM>:<NUM> ITI-<NUM> free base to cellulose acetate phthalate; or
(c) HPMC-P excipient in a ratio of <NUM>:<NUM> to <NUM>:<NUM> ITI-<NUM> free base to HPMC-P.