JP7523440B2 - Amorphous solid dispersions - Google Patents

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a PCT international application claiming priority to and benefit of U.S. Provisional Application No. 62/779,930, filed December 14, 2018, the contents of which are incorporated herein by reference in their entirety.
FIELD The present disclosure relates to certain novel amorphous solid dispersion formulations of substituted heterocycle-fused γ-carbolines, methods for making the dispersions, pharmaceutical compositions comprising the dispersions, and their uses in treating diseases or abnormal conditions involving or mediated by the 5- _HT2A receptor, the serotonin transporter (SERT), and/or the dopamine _D1 / _D2 receptor signaling pathways, for example.

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 lumateperone or ITI-007) has the following structure:
has.

ITI-007 is a potent 5-HT _2A receptor ligand (K _i =0.5 nM) with strong affinity for dopamine (DA) D ₂ receptors (K _i =32 nM), dopamine D ₂ receptors (K _i =52 nM), and serotonin transporter (SERT) (K _i =62 nM), but only weak binding to receptors associated with the cognitive and metabolic side effects of antipsychotics (e.g., H1 histaminergic, 5-HT _2C , and muscarinic receptors). ITI-007 is currently in or has recently been completed in several clinical trials, namely for the treatment of schizophrenia and bipolar depression. Recent evidence also indicates that ITI-007 enhances glutamatergic neurotransmission through D ₁ -mediated indirect effects on both NMDA and AMPA receptor conductances in rat mPFC slices. These effects of lumateperone are consistent with those of other fast-acting antidepressant therapies, including olanzapine (a _D2 receptor antagonist antipsychotic) in combination with fluoxetine (a selective serotonin reuptake inhibitor) and ketamine, thus supporting the molecular effects of lumateperone being consistent with acute therapeutic effects for anxiety and treatment-resistant depression. Such effects are described in PCT/US2019/022480, the contents of which are incorporated herein by reference in their entirety.

Although ITI-007 is a promising drug, its manufacture and formulation pose distinct challenges. In its free base form, ITI-007 is an oily, sticky solid with low solubility in water. Making salts of the compound has proven to be very difficult. A hydrochloride form of ITI-007 was disclosed in US Pat. No. 5,399,623, but this salt was shown to be hygroscopic and of low stability. A stable, crystalline toluenesulfonic acid addition salt (tosylate) of ITI-007 was eventually identified and described in US Pat. No. 5,499,623 and US Pat. No. 5,499,623, each of which is incorporated herein by reference in its entirety. Nevertheless, there remains a need for alternative stable, pharma- ceutically acceptable solid forms of ITI-007 that can be easily incorporated into galenic formulations.

For many drugs, amorphous forms have been disclosed to exhibit different dissolution properties and in some cases different bioavailability patterns compared to the crystalline forms of the same drug. For some therapeutic indications, one bioavailability pattern may be preferred over another. For example, the amorphous form of cefuroxime axetil exhibits higher bioavailability than the crystalline form. Thus, amorphous solid dispersions are promising alternatives to traditional crystalline active pharmaceutical ingredients.

Pure amorphous drug forms tend to be unstable. Since the amorphous form is thermodynamically unstable compared to the corresponding crystalline form, it is well known that the amorphous form reverts to a 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 and inhibit the crystallization of the active drug during the shelf life of the product.

Finding suitable excipients to stabilize the amorphous form of a pharmaceutical is a challenge, since some excipients react chemically with the drug or promote its degradation, while others are not physically or chemically stable or both.

International Publication No. 2019/178484 U.S. Patent No. 7,183,282 International Publication No. 2009/114181 U.S. Pat. No. 8,648,077

Considering the difficulties involved in preparing salts of ITI-007, it was decided to investigate whether the compound could be formulated as a physically and chemically stable amorphous solid dispersion. Extensive screening of excipients was performed using various combinations of drugs in various ratios and using a variety of 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 promising excipients were screened under a total of 44 conditions, and three pharma- ceutically acceptable amorphous solid dispersions were discovered.

The present disclosure thus provides an amorphous solid dispersion of ITI-007 in free base or tosylate form mixed with one or more excipients, such as stabilizing excipients.

In one aspect, the disclosure provides three particularly stable amorphous solid dispersions of ITI-007 free base, including (1) ITI-007 free base in a weight ratio of 5:95 to 50:50 to a cellulose acetate excipient; (2) ITI-007 free base in a weight ratio of 25:75 to 75:25 to a cellulose acetate phthalate excipient; and (3) ITI-007 free base in a weight ratio of 25:75 to 75:25 to a hydroxypropylmethylcellulose phthalate excipient. The disclosure further provides several amorphous solid dispersions of ITI-007 tosylate, which may further include an antioxidant and/or a surfactant.

Thus, the present disclosure provides amorphous solid dispersion forms of ITI-007 free base and tosylate salts that are particularly advantageous for use in preparing galenical formulations, along with methods of making and using them.

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.

The present invention will become more fully understood from the detailed description and the accompanying drawings, in which:

FIG. 1 shows the overlaid powder X-ray diffraction patterns for a dispersion of ITI-007 free base and cellulose acetate.

FIG. 2 shows overlaid powder X-ray diffraction patterns for a dispersion of ITI-007 free base and cellulose acetate phthalate.

FIG. 3 shows an overlay of powder X-ray diffraction patterns for a dispersion of ITI-007 free base and hydroxypropyl methylcellulose phthalate (grade 55) (HPMC-P).

For each of Figures 1, 2 and 3, the top pattern is the as-made 25:75 ITI-007 free base/excipient dispersion; the second pattern is the 25:75 dispersion after stress; the third pattern is the as-made 50:50 ITI-007 free base/excipient dispersion; and the bottom pattern is the 50:50 dispersion after stress.

FIG. 4 shows the mDSC and TGA thermograms for a 25:75 dispersion of ITI-007 free base and cellulose acetate.

FIG. 5 shows the mDSC and TGA thermograms for a 50:50 dispersion of ITI-007 free base and cellulose acetate phthalate.

FIG. 6 shows the mDSC and TGA thermograms for a 50:50 dispersion of ITI-007 free base and HPMC-P.

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.

As used throughout, ranges are used as a shorthand for describing all values within that range. Any value within a range may be selected as an endpoint of the range. Additionally, all references cited herein are incorporated by reference in their entirety. In the event of a discrepancy between a definition in this disclosure and a definition in a cited reference, this disclosure controls.

Unless otherwise specified, all percentages and amounts expressed herein and elsewhere herein should be understood to mean percent by weight. The amounts given are based on the active weight of the material.

The present disclosure provides an amorphous solid dispersion of 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 (ITI-007) in either the free base form or the tosylate salt form mixed with one or more excipients, such as stabilizing excipients.

In a first embodiment, the disclosure provides 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 (ITI-007) in the form of an amorphous solid dispersion comprising a cellulose acetate excipient in a ratio of 5:95 to 50:50 of ITI-007 free base to cellulose acetate (Dispersion 1). The disclosure further provides the following compositions:
1.1. Dispersion 1, wherein the dispersion comprises ITI-007 free base and cellulose acetate in a weight ratio of 5:95 to 50:50, excluding the ratio 50:50.
Dispersion 1 or 1.1, wherein the dispersion comprises ITI-007 free base and cellulose acetate in a weight ratio of 5:95 to 49:51, e.g., 5:95 to 45:55, or 10:90 to 40:60, or 15:85 to 35:65, or 20:80 to 30:70, or 22:78 to 28:82, or 23:77 to 27:83, or 24:76 to 26:74, or about 25:75.
1.3 Any of the above dispersions, wherein the dispersion is x-ray amorphous, for example as shown by XRPD analysis.
1.4 Any of the above dispersions whose X-ray diffraction pattern does not contain peaks characteristic of the excipients.
1.5. Any of the above dispersions, wherein the dispersion exhibits a single glass transition temperature (T _g ) above 75° C., such as above 100° C., or above 150° C., as shown, for example, by mDSC analysis.
1.6. Dispersion 1.5, wherein the dispersion exhibits a single glass transition temperature above 160°C, or between 165°C and 170°C, or at about 167°C.
1.7. Any of the above dispersions, wherein the dispersion exhibits a change in heat capacity (ΔC _p ) of 0.1 to 0.5 J/g·°C, such as 0.2 to 0.3 J/g·°C, or about 0.2 J/g·°C, as indicated, for example, by mDSC.
1.8 Any of the above dispersions, wherein the dispersion exhibits less than 10% weight loss up to a temperature of 100° C., as shown, for example, by TGA analysis.
1.9. Dispersion 1.8, wherein the dispersion exhibits less than 8% weight loss up to a temperature of 100° C., such as less than 7% weight loss up to a temperature of 100° C., or less than 6%, or less than 5%, or less than 4%, or less than 3% weight loss.
1.10. Any of the above dispersions, wherein the dispersion exhibits no change in appearance or texture after 7 days at 75% relative humidity and 40° C.
1.11 Any of the above dispersions, wherein the dispersion exhibits greater than 90% chemical stability of ITI-007 after 7 days at 75% relative humidity and 40° C., as determined, for example, by HPLC.
Dispersion 1.11, wherein the dispersion exhibits a chemical stability of ITI-007 after 7 days at 75% relative humidity and 40° C. of greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.
1.13. Any of the above dispersions, wherein the dispersion is prepared by a process comprising dissolving ITI-007 free base and selected excipients in a suitable solvent or solvent mixture and removing the solvent, for example, by lyophilizing the solution, to obtain an amorphous solid dispersion.
1.14. Dispersion 1.13, wherein the solvent or solvent mixture is selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof.
1.15. Dispersion 1.13, wherein the solvent or solvent mixture is selected from dioxane, methanol, or a dioxane/methanol mixture (e.g., a ratio of dioxane to methanol of 90:10 to 98:2, or a ratio of 92:8 to 95:5, or a ratio of about 93:7).
1.16 Any of the above dispersions, wherein the dispersion exhibits any combination of the characteristics recited in 1.1 to 1.15.

In a second embodiment, the disclosure provides ITI-007 free base in the form of an amorphous solid dispersion comprising cellulose acetate phthalate excipient in a ratio of ITI-007 free base to cellulose acetate phthalate of 25:75 to 75:25 (Dispersion 2). The disclosure further provides the following compositions:
2.1. Dispersion 2, wherein the dispersion comprises ITI-007 free base and cellulose acetate phthalate in a weight ratio of 25:75 to 75:25, excluding the ratios of 25:75 and 75:25.
Dispersion 2 or 2.1, wherein the dispersion comprises ITI-007 free base and cellulose acetate phthalate in a weight ratio of 26:74 to 74:26, e.g., 30:70 to 70:30, or 35:65 to 65:35, or 40:60 to 60:40, or 42:58 to 58:42, or 44:56 to 56:44, or 45:55 to 55:45, or 47:53 to 53:47, or 48:52 to 52:48, or 49:51 to 51:49, or about 50:50.
2.3 Any of the above dispersions, wherein the dispersion is x-ray amorphous, for example as shown by XRPD analysis.
2.4 Any of the above dispersions whose X-ray diffraction pattern does not contain peaks characteristic of the excipients.
2.5 Any of the above dispersions, wherein the dispersion exhibits a single glass transition temperature (T _g ) above 75° C., such as above 85° C., or above 95° C., as shown, for example, by mDSC analysis.
2.6. Dispersion 2.5, wherein the dispersion exhibits a single glass transition temperature above 100°C, or between 105°C and 115°C, or at about 107°C.
2.7 Any of the above dispersions, wherein the dispersion exhibits a change in heat capacity (ΔC _p ) of 0.1 to 0.6 J/g·°C, for example, 0.2 to 0.5 J/g·°C, or about 0.4 J/g·°C, as indicated, for example, by mDSC.
2.8 Any of the above dispersions, wherein the dispersion exhibits less than 10% weight loss up to a temperature of 100° C., as shown, for example, by TGA analysis.
Dispersion 2.8, wherein the dispersion exhibits less than 8% weight loss up to a temperature of 100° C., such as less than 7% weight loss up to a temperature of 100° C., or less than 6%, or less than 5%, or less than 4%, or less than 3% weight loss.
2.10. Any of the above dispersions, wherein the dispersion exhibits no change in appearance or texture after 7 days at 75% relative humidity and 40° C.
2.11 Any of the above dispersions, wherein the dispersion exhibits greater than 90% chemical stability of ITI-007 after 7 days at 75% relative humidity and 40° C., as determined, for example, by HPLC.
Dispersion 2.11, wherein the dispersion exhibits a chemical stability of ITI-007 after 7 days at 75% relative humidity and 40° C. of greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.
2.13 Any of the above dispersions, wherein the dispersion is prepared by a process comprising dissolving ITI-007 free base and selected excipients in a suitable solvent or solvent mixture and removing the solvent, for example, by lyophilizing the solution, to obtain an amorphous solid dispersion.
2.14. Dispersion 2.13, wherein the solvent or solvent mixture is selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof.
2.15. Dispersion 2.13, wherein the solvent or solvent mixture is selected from dioxane, methanol, or a dioxane/methanol mixture (e.g., a ratio of dioxane to methanol of 90:10 to 98:2, or a ratio of 92:8 to 95:5, or a ratio of about 93:7).
2.16 Any of the above dispersions, wherein the dispersion exhibits any combination of the characteristics set forth in 2.1 through 2.15.

In a third embodiment, the disclosure provides ITI-007 free base in the form of an amorphous solid dispersion comprising hydroxypropyl methylcellulose phthalate (HPMC-P) excipient in a ratio of ITI-007 free base to HPMC-P of 25:75 to 75:25 (Dispersion 3). The disclosure further provides the following compositions:
3.1 Dispersion 3, wherein the dispersion comprises ITI-007 free base and HPMC-P in a weight ratio of 25:75 to 75:25, excluding the ratios of 25:75 and 75:25.
Dispersion 3 or 3.1, wherein the dispersion comprises ITI-007 free base and HPMC-P in a weight ratio of 26:74 to 74:26, e.g., 30:70 to 70:30, or 35:65 to 65:35, or 40:60 to 60:40, or 42:58 to 58:42, or 44:56 to 56:44, or 45:55 to 55:45, or 47:53 to 53:47, or 48:52 to 52:48, or 49:51 to 51:49, or about 50:50.
3.3 Any of the above dispersions, wherein the dispersion is x-ray amorphous, e.g., as indicated by XRPD analysis.
3.4 Any of the above dispersions whose X-ray diffraction pattern does not contain peaks characteristic of the excipients.
3.5 Any of the above dispersions, wherein the dispersion exhibits a single glass transition temperature (T _g ) above 75° C., such as above 80° C., or above 85° C., as shown, for example, by mDSC analysis.
3.6 Dispersion 3.5, wherein the dispersion exhibits a single glass transition temperature above 90°C, or between 92°C and 98°C, or at about 95°C.
3.7 Any of the above dispersions, wherein the dispersion exhibits a change in heat capacity (ΔC _p ) of 0.1 to 0.5 J/g·°C, for example, 0.2 to 0.4 J/g·°C, or about 0.3 J/g·°C, as indicated, for example, by mDSC.
3.8 Any of the above dispersions, wherein the dispersion exhibits less than 10% weight loss up to a temperature of 100° C., as shown, for example, by TGA analysis.
3.9. Dispersion 3.8, wherein the dispersion exhibits less than 8% weight loss up to a temperature of 100° C., such as less than 7% weight loss up to a temperature of 100° C., or less than 6%, or less than 5%, or less than 4%, or less than 3% weight loss.
3.10. Any of the above dispersions, wherein the dispersion exhibits no change in appearance or texture after 7 days at 75% relative humidity and 40° C.
3.11 Any of the above dispersions, wherein the dispersion exhibits greater than 90% chemical stability of ITI-007 after 7 days at 75% relative humidity and 40° C., as determined, for example, by HPLC.
Dispersion 3.12, wherein the dispersion exhibits a chemical stability of ITI-007 after 7 days at 75% relative humidity and 40° C. of greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.
3.13. Any of the above dispersions, wherein the dispersion is prepared by a process comprising dissolving ITI-007 free base and selected excipients in a suitable solvent or solvent mixture and removing the solvent, for example, by lyophilizing the solution, to obtain an amorphous solid dispersion.
3.14. Dispersion 3.13, wherein the solvent or solvent mixture is selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof.
3.15. Dispersion 3.13, wherein the solvent or solvent mixture is selected from dioxane, methanol, or a dioxane/methanol mixture (e.g., a ratio of dioxane to methanol of 90:10 to 98:2, or a ratio of 92:8 to 95:5, or a ratio of about 93:7).
3.16 Any of the above dispersions, wherein the dispersion exhibits any combination of the characteristics described in 3.1 through 3.15.

In a fourth embodiment, the present disclosure provides ITI-007 tosylate in the form of an amorphous solid dispersion (Dispersion 4), comprising a stabilizing excipient and optionally further comprising an antioxidant and/or a surfactant. For example, the stabilizing excipient is an excipient that stabilizes the amorphous form of ITI-007 tosylate and prevents conversion from the amorphous form to a crystalline form. The present disclosure further provides the following compositions:
Dispersion 4, wherein the dispersion comprises ITI-007 tosylate salt and a stabilizing excipient selected from the group consisting of cellulose acetate, cellulose acetate phthalate, methacrylate/methyl acrylate copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate (HPMC-P), polyvinyl acetate, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, and polyethylene glycol/polyvinyl acetate/polyvinylcaprolactam copolymer.
4.2 Dispersion 4 or 4.1, wherein the composition comprises ITI-007 tosylate mixed with one stabilizing excipient.
4.3 Dispersion 4 or 4.1, where the composition comprises ITI-007 tosylate mixed with two stabilizing excipients.
4.4. Any of Dispersions 4 or 4.1-4.3, wherein the dispersion comprises ITI-007 tosylate salt mixed with one or more stabilizing excipients in a weight ratio of 25:75 to 75:25, e.g., 26:74 to 74:26, or 30:70 to 70:30, or 35:65 to 65:35, or 40:60 to 60:40, or 42:58 to 58:42, or 44:56 to 56:44, or 45:55 to 55:45, or 47:53 to 53:47, or 48:52 to 52:48, or 49:51 to 51:49, or about 50:50.
4.5. Any of Dispersions 4 or 4.1-4.3, wherein the dispersion comprises ITI-007 tosylate in admixture with one or more stabilizing excipients in a weight ratio of 5:95 to 50:50, e.g., 5:95 to 49:51, or 5:95 to 45:55, or 10:90 to 40:60, or 15:85 to 35:65, or 20:80 to 30:70, or 22:78 to 28:82, or 23:77 to 27:83, or 24:76 to 26:74, or about 25:75. Any of Dispersions 4 or 4.1-4.3, wherein the dispersion comprises ITI-007 tosylate salt mixed with one or more stabilizing excipients in a weight ratio of 50:50 to 95:5, e.g., 51:49 to 95:5, or 55:45 to 95:5, or 60:40 to 90:10, or 65:45 to 85:15, or 70:30 to 80:20 or about 75:25.
4.7. Any of the above dispersions wherein the stabilizing excipient comprises one or more of cellulose acetate, cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), and hydroxypropyl methylcellulose phthalate (HPMC-P).
4.8. Any of the above dispersions wherein the stabilizing excipient comprises one or more of cellulose acetate, cellulose acetate phthalate, and hydroxypropyl methylcellulose phthalate.
4.9. Any of the above dispersions further comprising an antioxidant.
4.10. Dispersion 4.9, wherein the antioxidant is selected from one or more of tocopherol, butylhydroxytoluene (BHT), propyl gallate (OPG), and ascorbic acid.
4.11. Dispersion 4.9 or 4.10, wherein the dispersion comprises an antioxidant in an amount of 0.1 to 10% by weight of the dispersion, e.g., 0.5 to 5% by weight or 0.5 to 3% by weight.
4.12. Any of the above dispersions further comprising a surfactant, e.g., an anionic, cationic or neutral surfactant, such as a surfactant that stabilizes the amorphous form of ITI-007 tosylate (e.g., to prevent conversion to a crystalline form of ITI-007 tosylate).
4.13 Any of the above dispersions, wherein the dispersion is x-ray amorphous, e.g., as indicated by XRPD analysis.
4.14 Any of the above dispersions, wherein the X-ray diffraction pattern does not contain peaks characteristic of the excipients.
4.15. Any of the above dispersions, wherein the dispersion exhibits a single glass transition temperature (T g ) at a temperature greater than 75° C., for example greater than 80° C., or greater than 90° C., or at a temperature of about 100° C., or greater than 110° C., as shown, for example, by _mDSC analysis.
4.16. Any of the above dispersions, wherein the dispersion exhibits a change in heat capacity (ΔC p ) of from 0.1 to 2.0 J/g·°C, e.g., from 0.1 to 1.5 J/g·°C, or from 0.1 to 1.0 J/g·°C, or from 0.1 to 0.5 J/g·°C, e.g., as indicated by _mDSC .
4.17 Any of the above dispersions, wherein the dispersion exhibits less than 20% weight loss up to a temperature of 150° C., as shown, for example, by TGA analysis.
Dispersion 4.17, wherein the dispersion exhibits less than 15% weight loss up to a temperature of 150° C., e.g., less than 15% weight loss up to a temperature of 100° C., or less than 10% weight loss at 150° C., or less than 10% weight loss up to a temperature of 100° C., or less than 5% weight loss up to a temperature of 150° C., or less than 5% weight loss up to a temperature of 100° C.
4.19. Any of the above dispersions, wherein the dispersion exhibits no change in appearance or texture after 7 days at 75% relative humidity and 40° C.
4.20 Any of the above dispersions, wherein the dispersion exhibits greater than 85% chemical stability of ITI-007 after 7 days at 75% relative humidity and 40° C., as determined, for example, by HPLC.
Dispersion 4.20, wherein the dispersion exhibits a chemical stability of ITI-007 after 7 days at 75% relative humidity and 40° C. of greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.
4.22 Any of the above dispersions, wherein the dispersion is prepared by a process comprising dissolving ITI-007 tosylate and selected excipients in a suitable solvent or solvent mixture and removing the solvent, for example by lyophilization of the solution or evaporation of the solvent (e.g., by rotary evaporation), to obtain an amorphous solid dispersion.
4.23. Dispersion 4.22, wherein the solvent or solvent mixture is selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof.
4.24. Dispersion 4.23, wherein the solvent or solvent mixture is selected from dioxane, methanol, or a dioxane/methanol mixture (e.g., a ratio of dioxane to methanol of 90:10 to 98:2, or a ratio of 92:8 to 95:5, or a ratio of about 93:7).
4.25. Dispersion 4.22, 4.23 or 4.24, wherein the method further comprises adding an antioxidant or a surfactant to the solvent mixture prior to removing the solvent.
4.26 Any of the above dispersions, wherein the dispersion exhibits any combination of the characteristics set forth in 4.1 through 4.25.

Dispersions 4, and any of 4.1-4.26, include an antioxidant to improve the stability of the ITI-007 tosylate amorphous form. In some embodiments, the antioxidant is selected from one or more of tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), and ascorbic acid.

In other embodiments, the antioxidant may be selected from additional suitable antioxidants such as butyl hydroxyanisole (BHA), tert-butyl hydroxyquinoline (TBHQ), carotenoids, glutathione, salts of metabisulfite (e.g., sodium), salts of ethylenediaminetetraacetic acid (e.g., sodium), cysteine, methionine, sesamol, and citric acid. Alternatively, the antioxidant may be ethylenediaminetetraacetic acid.

Dispersions 4, and any of 4.1-4.26 may include a surfactant to improve the stability of the amorphous form of ITI-007 tosylate. In some embodiments, the surfactant is a surfactant that stabilizes the amorphous form of ITI-007 tosylate (e.g., to prevent conversion to a crystalline form of ITI-007 tosylate). In some embodiments, the surfactant is selected from one or more of anionic, cationic, or neutral surfactants.

In some embodiments of the present disclosure, Dispersion 4, or any of Dispersions 4.1-4.26, may further include other excipients that can prevent or inhibit the formation of a crystalline form of ITI-007 tosylate or prevent or inhibit the conversion of an amorphous form of ITI-007 tosylate to a crystalline form of ITI-007 tosylate. Such excipients may include polymers, gums, surfactants, wetting agents, drying agents, pH adjusters, fillers, disintegrants, coating agents, binders, or other suitable pharma- ceutically acceptable excipients.

In a second aspect, the present disclosure provides a method for producing a pharmaceutical composition comprising:
There is provided a method for preparing Dispersion 1 et seq., or Dispersion 2 et seq., or Dispersion 3 et seq. (Preparation Method 1), comprising the steps of: (a) combining 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 (ITI-007) free base with selected excipients in a suitable solvent or mixture of solvents, for example selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof; and (b) removing the solvent and recovering the amorphous solid dispersion thus formed, for example by lyophilization of the solution.

In another embodiment of the second aspect, the present disclosure provides a method for producing a composition comprising:
The present invention provides a method for producing Dispersion 4 et seq. (Production Method 2), comprising the steps of: (a) combining 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 (ITI-007) tosylate salt (e.g., monotosylate salt), optionally in crystalline form, with selected excipients in a suitable solvent or mixture of solvents, for example selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof; and (b) removing the solvent to recover the formed amorphous solid dispersion, for example by lyophilizing the solution or evaporating the solvent (e.g., by rotary evaporation).

In some embodiments, the method of preparation 2 further comprises adding one or more antioxidants and/or one or more surfactants to the solvent or solvent mixture in step (a). In some embodiments, the antioxidant is selected from one or more of tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), and ascorbic acid. In some embodiments, the one or more surfactants may comprise an anionic or cationic or neutral surfactant. For example, the surfactant may be a surfactant to stabilize the amorphous form ITI-007 tosylate, e.g., to prevent conversion of the amorphous form to an ITI-007 tosylate crystalline form.

In other embodiments, the antioxidant may be selected from additional suitable antioxidants such as butyl hydroxyanisole (BHA), tert-butyl hydroxyquinoline (TBHQ), carotenoids, glutathione, salts of metabisulfite (e.g., sodium), salts of ethylenediaminetetraacetic acid (e.g., sodium), cysteine, methionine, sesamol, and citric acid. Alternatively, the antioxidant may be ethylenediaminetetraacetic acid.

In another embodiment of the second aspect, the solvent or solvent mixture for production method 1 is selected from dioxane, methanol, or a dioxane/methanol mixture (e.g., a dioxane to methanol ratio of 90:10 to 98:2, or 92:8 to 95:5, or about 93:7), which may be removed by lyophilization. In another embodiment of the second aspect, the solvent or solvent mixture for production method 2 is selected from dioxane, methanol, or a dioxane/methanol mixture (e.g., a dioxane to methanol ratio of 90:10 to 98:2, or 92:8 to 95:5, or about 93:7), which may be removed by lyophilization.

A solid dispersion, as used herein, refers to a dispersion of an active pharmaceutical ingredient (i.e., ITI-007) in an inert excipient or matrix (carrier) in which the active pharmaceutical ingredient may exist in a microcrystalline, 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 recrystallization of the pharmaceutical active during storage. The amorphous form of the active is associated with a higher energy state compared to its crystalline form, 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 disclosure provides a pharmaceutical composition (Composition 1) comprising Dispersion 1 or later, or Dispersion 2 or later, or Dispersion 3 or later, or Dispersion 4 or later, in combination or association with a pharma- ceutically 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 suitable pharma- ceutically acceptable excipients, such as: diluents, such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, xylitol, sugars, and the like; binders, such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidone, such as polyvinylpyrrolidone (PVP), and the like. K-30, K-90), poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA), hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose acetate, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), etc.; disintegrants, for example, starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, etc.; lubricants, for example, stearic acid, magnesium stearate, zinc stearate, etc.; glidants, for example, colloidal silicon dioxide, etc.; solubility or wetting enhancers, for example, anionic, cationic or neutral surfactants; maltodextrin, complex forming agents, agents), such as various grades of cyclodextrin and resins; release rate controlling agents, such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylate, waxes, and the like; as well as film formers, plasticizers, colorants, flavors, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

In another embodiment of the third aspect, the composition may further include one or more antioxidants, such as tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), and ascorbic acid. The inclusion of an antioxidant may further improve the chemical stability of the dispersion by preventing oxidative chemical degradation of the ITI-007 active. In another embodiment, the dispersion itself is formulated to include such an antioxidant. Other suitable antioxidants include butylated hydroxyanisole (BHA), tert-butylated hydroxyquinoline (TBHQ), carotenoids, glutathione, salts of metabisulfite (e.g., sodium), salts of ethylenediaminetetraacetic acid (e.g., sodium), ethylenediaminetetraacetic acid, cysteine, methionine, sesamol, and citric acid.

In another embodiment of the third aspect, the composition may further comprise an excipient capable of preventing or inhibiting the formation of a crystalline form of ITI-007 free base or ITI-007 tosylate salt or preventing or inhibiting the conversion of an amorphous form of ITI-007 free base or ITI-007 tosylate salt to its crystalline form. Such excipients may include polymers, gums, surfactants, wetting agents, drying agents, pH adjusters, fillers, disintegrants, coating agents, binders, or other suitable pharma- ceutically acceptable excipients. Such excipients may include one or more of the excipients described in paragraph [0038] above.

In another aspect, the present disclosure provides a method for treating a disease or abnormal condition involving or mediated by the 5-HT _2A receptor, the serotonin transporter (SERT), and/or the dopamine D ₁ /D ₂ receptor signaling pathway (including D ₁ mediated NMDA or AMPA receptor modulation), such as obesity, anorexia, bulimia, depression (bipolar depression, major depressive disorder, treatment-refractory depression, In one embodiment, a pharmaceutical composition is provided comprising Dispersion 1 or later, or Dispersion 2 or later, or Dispersion 3 or later, or Dispersion 4 or later, e.g. Composition 1, for use in the treatment of a disorder selected from: chronic obstructive pulmonary disease (COPD), acute depression (including acute depression, and/or acute depression), anxiety (including acute anxiety), psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorder, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, conditions associated with head pain, social phobia, or dementia (e.g. Alzheimer's disease or Parkinson's disease dementia). In some embodiments, the disease or abnormal condition or disorder being treated is acute depression (e.g., acute major depressive episode, acute brief depressive episode, acute recurrent brief depressive episode) and/or acute anxiety (e.g., brief anxiety episodes associated with generalized anxiety disorder, panic disorder, specific phobia, or social anxiety disorder, or social avoidance), including treatment-resistant depression (e.g., depression that has not responded to treatment with an antidepressant selected from selective serotonin reuptake inhibitors (SSRIs), serotonin reuptake inhibitors (SRIs), tricyclic antidepressants, monoamine oxidase inhibitors, norepinephrine reuptake inhibitors (NRIs), dopamine reuptake inhibitors (DRIs), SRI/NRIs, SRI/DRIs, NRI/DRIs, SRI/NRI/DRIs (triple reuptake inhibitors), serotonin receptor antagonists, or combinations thereof), bipolar depression, or major depressive disorder. Other embodiments of the methods provided by the present disclosure are those described in PCT/US2019/022480 (WO2019/178484), the contents of which are incorporated herein by reference in their entirety.

In another embodiment, the present invention provides a method for treating _{rheumatoid arthritis} , comprising administering to _a patient a therapeutically effective amount of a rheumatoid arthritis medication, comprising administering to _a patient a therapeutically effective amount of a rheumatoid arthritis medication, the patient being treated with a medicament for treating rheumatoid arthritis ... In _{one embodiment, the present invention provides a method for the prevention or treatment of a human suffering from a disease or abnormal condition in which a cellular signaling pathway is implicated or mediated by NMDA or AMPA receptor modulation (including NMDA or AMPA receptor modulation 1} mediated NMDA or AMPA receptor modulation), e.g. a disorder selected from obesity, anorexia, bulimia, depression (including bipolar depression, major depressive disorder, treatment-refractory depression, and/or acute depression), anxiety (including acute anxiety), psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorder, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, conditions associated with head pain, social phobia, or dementia (e.g. Alzheimer's disease or Parkinson's disease dementia), comprising administering to a patient in need of said prevention or treatment a therapeutically effective amount of a pharmaceutical composition comprising Dispersion 1 or later, or Dispersion 2 or later, or Dispersion 3 or later, or Dispersion 1 or later, or Dispersion 2 or later, or Dispersion 3 or later, or Dispersion 4 or later, e.g. Composition 1. In some embodiments, the disease or abnormal condition or disorder being treated is acute depression (e.g., acute major depressive episode, acute brief depressive episode, acute recurrent brief depressive episode) and/or acute anxiety (e.g., brief anxiety episodes associated with generalized anxiety disorder, panic disorder, specific phobia, or social anxiety disorder, or social avoidance), including treatment-resistant depression (e.g., depression that has not responded to treatment with an antidepressant selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), an SRI/NRI, an SRI/DRI, an NRI/DRI, an SRI/NRI/DRI (triple reuptake inhibitor), a serotonin receptor antagonist, or a combination thereof), bipolar depression, or major depressive disorder. Other embodiments of the methods provided by the present disclosure are those described in PCT/US2019/022480 (WO2019/178484), the contents of which are incorporated herein by reference in their entirety.

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

X-ray Powder Diffraction (XRPD): Powder X-ray diffraction studies are performed using a PANalytical X'Pert PRO MPD diffractometer with an incident beam of Cu radiation generated with an Optix long, fine-focus source. An elliptically graded multilayer mirror is used to focus the CuKα X-rays through the specimen onto the detector. Prior to analysis, a silicon sample is analyzed to confirm the location of the observed Si(111) peak (NIST certified location, consistent with NIST SM 640e). Sample specimens are sandwiched between 3 micron thick films and analyzed in transmission geometry. A beam stop, short anti-scatter extensions, and an anti-scatter knife edge are used to minimize background caused by air. Soller slits for the incident and diffracted beams are used to minimize spread from axial divergence. Diffraction patterns are collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen. Data Collector software v. 2.2b is used for analysis.

Thermogravimetry (TGA) Analysis: TGA is performed using a TA Instruments Q5000 or Discovery Thermogravimetry Analyzer. Samples are placed in aluminum sample pans and inserted into the TG furnace. Samples are heated from ambient temperature to 250°C at a rate of 10°C/min. Nickel and Alumel are used as calibration standards.

Modulated Differential Scanning Calorimetry (mDSC): mDSC data are obtained on a TA Instruments Q2000 or 2920 Differential Scanning Calorimeter equipped with a refrigerated cooling system. Temperature calibration is performed using NIST traceable indium metal. Samples are placed into aluminum T-zero DSC pans, covered, and weights accurately recorded. A weighed aluminum pan configured as the sample pan is placed on the reference side of the cell. Typically, the starting temperature is -50°C, the ending temperature is 250°C, the modulation amplitude is ±1°C for 50 seconds, and the underlying heating rate is 2°C/min.

High Performance Liquid Chromatography (HPLC): High performance liquid chromatography analysis is performed using an Agilent 1100 series liquid chromatograph equipped with a diode array detector, degasser, quaternary pump and autosampler. The column is a 4.6 x 100 mm CSH C18 column with 2.5 micron packing (XSelect) and is run with 0.1% TFA in water mobile phase A and 0.1% TFA in acetonitrile mobile phase B at a flow rate of 0.500 mL/min. The gradient is run from 95% A to 73% in the first 22 minutes, then 73% A for 6 minutes, then 73% A to 30% A in the next 22 minutes. The column temperature is set at 15.0°C, the detector wavelength is 254 nm, the bandwidth is 100 nm, and the reference wavelength is 360 nm. The injection volume is 2.0 microliters.

Example 1: Preparation of Free Base Dispersion First, the solubility of ITI-007 free base and various excipients in various solvents is evaluated. It is found that ITI-007 free base has good solubility (>50 mg/mL) in acetone, ethanol, methanol, dioxane, and 2,2,2-trifluoroethanol (TFE), but relatively low solubility (5-50 mg/mL) in tert-butanol/water mixtures. However, it is found that solutions of ITI-007 free base in TFE rapidly discolor due to decomposition of the active agent.

The excipients evaluated were Eudragit L100, polyvinyl acetate, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone K-90, polyvinylpyrrolidone S-630, cellulose acetate, cellulose acetate phthalate, Gelucire 50/13, glyceryl monostearate, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate (HPMC-P), hydroxypropylmethyl acetate succinate (HPMC-AS), polyethylene glycol (PEG), PEG-100 succinate, Pluronic F-127, and Soluplus. The excipients were evaluated at one or more of the following ITI-007 free base to excipient ratios: 25:75, 50:50, and 75:25.

Based on solubility analysis, solutions of various excipients containing ITI-007 free base are prepared in acetone-ethanol (3:1). Rotary evaporation is attempted to remove the solvent, but in all cases this results in an oily material rather than a solid.

Solid dispersions are successfully prepared by lyophilization from solutions of ITI-007 free base and excipients in either dioxane or dioxane-methanol (90:10, 91:9, 92:8, 93:7, or 94:6). The solution is first frozen in a dry ice/acetone bath and then placed in a lyophilizer with shelves precooled to -75°C. Samples are dried at -50°C overnight, then at -20°C overnight, then at 0°C for 2 days. Samples are then secondary dried at 20°C for 4 hours, purged with nitrogen, and then stored over desiccant in a freezer until testing.

Example 2: Preliminary Screening of Free Base Dispersions The solid dispersions from Example 1 are first evaluated by XRPD to determine if they are amorphous. All lyophilized samples using amorphous excipients are found to be x-ray amorphous by XRPD. Lyophilized samples using crystalline excipients (Gelucire 50/13, PEG, PEG-1000 succinate, Pluronic F-127) are found to be disordered with peaks corresponding only to the excipients. Further observations of the appearance of the solids are shown in Table 1 below. The 50:50 ITI-007/PEG-1000 succinate dispersion was found to be very sticky and was not further evaluated.

Example 3: Stability evaluation of free base dispersions The solid dispersions from Example 1 are placed in uncapped clear glass vials and the vials are placed in a container maintained at 75% relative humidity and 40°C for 7 days. A sample of ITI-007 free base is analyzed in parallel as a control. The samples were observed visually and by polarized light microscopy (0.8-10x magnification, with crossed polarizers and a first order red compensator). The observations are shown in Table 1. The majority of the samples showed changes in appearance or texture, indicating the formation of physically unstable amorphous dispersions. For example, some showed visible crystallization while others became sticky solids or oils.

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

mDSC and TGA analysis are performed on physically stable flowable 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 unacceptable low temperature glass transitions at 9 or 10°C, while the glyceryl monostearate dispersion shows no glass transition. The 50:50 cellulose acetate dispersion shows two glass transition temperatures, suggesting a phase separated material, which is unacceptable. The 25:75 cellulose acetate dispersion, 25:75 cellulose acetate phthalate dispersion, 50:50 cellulose acetate phthalate dispersion, 25:75 HPMC-AS dispersion, 50:50 HPMC-AS dispersion, 25:75 HPMC-P dispersion, and 50:50 HPMC-P dispersion show acceptable single glass transition temperatures above 75°C.

All samples subjected to mDSC and TGA are then subjected to HPLC analysis to determine the chemical stability of the ITI-007 active agent during the 7-day study. An ITI-007 free base sample is also analyzed by HPLC as a control. All results are normalized to the ITI-007 content shown by HPLC prior to the 7-day study. Less than 5% loss of ITI-007 by HPLC is considered satisfactory.

Both the HPMC-AS and 25:75 HPMC-P dispersions show very high material loss by HPLC. The 25:75 cellulose acetate phthalate dispersion shows low but unacceptable material loss. Only seven dispersions give satisfactory results: 25:75 cellulose acetate, 50:50 cellulose acetate, 50:50 cellulose acetate phthalate, 50:50 HPMC-P, 25:75 PEG, 50:50 PEG and 25:75 glyceryl stearate. These dispersions are therefore chemically stable.

The test results are shown in Table 1 below.

Of the dispersions tested, only three are found to be both chemically and physically stable: 25:75 cellulose acetate, 50:50 cellulose acetate phthalate, and 50:50 HPMC-P.

It is noted that similar tests performed using ITI-007 tosylate salt instead of ITI-007 free base did not result in completely stable amorphous dispersions. These results are shown in more detail in Example 4 below. Although most of the ITI-007 tosylate salt dispersions pass the initial screen (exhibiting only X-ray amorphous or X-ray peaks due to excipients), all of the resulting initial dispersions show strong physical instability (changes in color and appearance, including crystallization of the active agent from the dispersion) or chemical instability (10-68% decomposition by HPLC). For example, a 25:75 dispersion of ITI-007 tosylate with cellulose acetate results in crystallization of ITI-007 during aging studies; a 50:50 dispersion of ITI-007 tosylate with cellulose acetate phthalate shows approximately a 52% reduction in ITI-007 content by HPLC; and a 50:50 dispersion of ITI-007 tosylate with HPMC-P shows approximately a 68% reduction in ITI-007 content by HPLC. These results are unexpected since ITI-007 tosylate is more chemically stable than ITI-007 free base. Thus, it is particularly unexpected that these three particular amorphous solid dispersions of ITI-007 free base are physically and chemically stable, whereas the corresponding dispersions of ITI-007 tosylate are not.

Example 4: Preparation, Preliminary Screening and Stability Evaluation of Tosylate Dispersions The procedures described in Examples 1, 2 and 3 are repeated using ITI-007 tosylate as the active agent. It is found that ITI-007 tosylate has good solubility (>50 mg/mL) in 2,2,2-trifluoroethanol (TFE) and a 60:40 v/v mixture of tert-butanol/water, but relatively low solubility (20-40 mg/mL) in acetone, ethanol, dioxane and other tert-butanol/water mixtures. However, it is also found that solutions of ITI-007 tosylate in TFE rapidly discolor due to decomposition of the active agent.

The same excipients are evaluated as described in Example 1. As seen for the free base, rotary evaporation from solvent (3:1 acetone-methanol) does not result in amorphous material, but lyophilization from dioxane and dioxane/methanol mixtures results in amorphous material using each of the excipients tested. The screening and stability evaluations are shown in Table 2 below.

Of the dispersions tested using ITI-007 tosylate, most were found to be amorphous, and some were visually observed to have undergone some degree of crystallization under harsh storage conditions at 75% relative humidity and 40°C. Additionally, other dispersions were observed to have undergone minor color or texture changes. However, further evaluation suggests that these changes in physical appearance may be prevented by incorporating antioxidants into the composition to prevent air-promoted oxidation, forming the dispersion into a coated tablet, encapsulating the dispersion in a gel caplet or capsule, adding excipients such as polymers to prevent partial conversion of the amorphous formulation to a crystalline form, and/or mixing the dispersion with a surfactant to prevent particle aggregation.

Without being bound by theory, it is believed that pharmaceutical formulations comprising ITI-007 tosylate salt in an amorphous solid dispersion form can be effectively prepared using one or more of cellulose acetate, cellulose acetate phthalate, HPC, HPMC-AS, HPMC-P, PVAc, PVP S-630, PVP K-90, or PVP-co-VA in combination with surfactants and/or antioxidants as described herein.
The present application also includes the following aspects.
[Aspect 1]
1. An amorphous solid dispersion 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 (ITI-007) tosylate and a stabilizing excipient, and optionally further comprising an antioxidant and/or a surfactant.
[Aspect 2]
2. The dispersion of embodiment 1, wherein the dispersion comprises ITI-007 tosylate salt and one or more stabilizing excipients selected from the group consisting of cellulose acetate, cellulose acetate phthalate, methacrylate/methyl acrylate copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate (HPMC-P), polyvinyl acetate, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, and polyethylene glycol/polyvinyl acetate/polyvinylcaprolactam copolymer.
[Aspect 3]
2. The dispersion of embodiment 1, further comprising an antioxidant which may be selected from one or more of tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), ascorbic acid, butylated hydroxyanisole (BHA), tert-butylated hydroxyquinoline (TBHQ), carotenoids, glutathione, salts of metabisulfite (e.g., sodium), salts of ethylenediaminetetraacetic acid (e.g., sodium), ethylenediaminetetraacetic acid, cysteine, methionine, sesamol, and citric acid.
[Aspect 4]
2. The dispersion of embodiment 1, further comprising a surfactant, which may be an anionic or cationic or neutral surfactant.
[Aspect 5]
2. The dispersion of embodiment 1, wherein the dispersion is x-ray amorphous.
[Aspect 6]
The dispersion 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 (ITI-007) tosylate, and
(a) a cellulose acetate phthalate excipient in a ratio of ITI-007 tosylate to cellulose acetate phthalate of 5:95 to 75:25 (e.g., excluding the ratio 75:25); or
(b) HPMC-AS vehicle with a ratio of ITI-007 tosylate to HPMC-AS of 25:75 to 50:50 (e.g., excluding the ratio of 50:50); or
(c) HPMC-P excipient at a ratio of ITI-007 tosylate to HPMC-P of 5:95 to 75:25 (e.g., excluding the ratio of 75:25).
2. The dispersion of embodiment 1, comprising:
[Aspect 7]
The dispersion of embodiment 6, wherein the dispersion is x-ray amorphous.
[Aspect 8]
7. The dispersion of claim 6, wherein the X-ray diffraction pattern does not include peaks characteristic of excipients.
[Aspect 9]
7. The dispersion of embodiment 6, further comprising an antioxidant which may be selected from one or more of tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), ascorbic acid, butylated hydroxyanisole (BHA), tert-butylated hydroxyquinoline (TBHQ), carotenoids, glutathione, salts of metabisulfite (e.g., sodium), salts of ethylenediaminetetraacetic acid (e.g., sodium), ethylenediaminetetraacetic acid, cysteine, methionine, sesamol, and citric acid.
[Aspect 10]
7. The dispersion of embodiment 6, further comprising a surfactant, which may be an anionic or cationic or neutral surfactant.
[Aspect 11]
A pharmaceutical composition comprising the dispersion according to embodiment 1 in combination or association with a pharma- ceutically acceptable diluent or carrier.
[Aspect 12]
A pharmaceutical composition comprising the dispersion according to embodiment 6 in combination or association with a pharma- ceutically acceptable diluent or carrier.
[Aspect 13]
13. The composition of embodiment 11 or 12, in the form of a tablet or capsule for oral administration.
[Aspect 14]
2. A method for the prevention or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT2A _receptor , the serotonin transporter (SERT), and/or the dopamine D1 _/ D2 _receptor signaling pathway (including D1 _- mediated NMDA or AMPA receptor modulation), e.g. a disorder selected from obesity, anorexia, bulimia, depression (including bipolar depression, major depressive disorder, treatment-refractory depression, and/or acute depression), anxiety (including acute anxiety), psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorder, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, conditions associated with head pain, social phobia, or dementia (e.g. Alzheimer's disease or Parkinson's disease dementia), comprising administering to a patient in need of said prevention or treatment a therapeutically effective amount of the dispersion of embodiment 1.
[Aspect 15]
10. A method for the prevention or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT2A _receptor , serotonin transporter (SERT), and/or dopamine D1 _/ D2 _receptor signaling pathways (including D1 _- mediated NMDA or AMPA receptor modulation), e.g. a disorder selected from obesity, anorexia, bulimia, depression (including bipolar depression, major depressive disorder, treatment-refractory depression, and/or acute depression), anxiety (including acute anxiety), psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorder, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, conditions associated with head pain, social phobia, or dementia (e.g. Alzheimer's disease or Parkinson's disease dementia), comprising administering to a patient in need of said prevention or treatment a therapeutically effective amount of the dispersion of embodiment 6.
[Aspect 16]
A method for producing the dispersion according to embodiment 1, comprising the steps of:
(a) combining 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 (ITI-007) tosylate, e.g., monotosylate, optionally in crystalline form, with selected excipients in a suitable solvent or solvent mixture, e.g., selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof; and
(b) removing the solvent, for example by lyophilizing the solution or evaporating the solvent (e.g., by rotary evaporation), to recover the formed amorphous solid dispersion.
A method comprising:
[Aspect 17]
17. The process of embodiment 16, wherein the solvent or mixture of solvents is selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof.
[Aspect 18]
17. The process of embodiment 16, wherein the solvent or solvent mixture is selected from dioxane, methanol, or a dioxane/methanol mixture.
[Aspect 19]
17. The process of embodiment 16, wherein the solvent or solvent mixture is dioxane or methanol in a ratio of dioxane to methanol of from 90:10 to 98:2, or in a ratio of dioxane to methanol of from 92:8 to 95:5, or 93:7.

Claims (19)

1. An amorphous solid dispersion 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 (ITI-007) tosylate and a stabilizing excipient, and optionally further comprising an antioxidant and/or a surfactant ,
the stabilizing excipient is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate (HPMC-P), polyvinyl acetate, polyvinylpyrrolidone/vinyl acetate copolymer, and polyethylene glycol/polyvinyl acetate/polyvinylcaprolactam copolymer, wherein the dispersion comprises ITI-007 tosylate and the stabilizing excipient in a weight ratio of 25:75 to 75:25;
provided that if the stabilizing excipient is cellulose acetate phthalate or hydroxypropylmethylcellulose phthalate, the weight ratio of ITI-007 tosylate to the stabilizing excipient is about 75:25;
However, if the stabilizing excipient is hydroxypropylmethylcellulose acetate succinate, the weight ratio of ITI-007 tosylate to the stabilizing excipient is 50:50 to 75:25.
A dispersion. 2. The dispersion of claim 1, wherein the dispersion comprises ITI-007 tosylate salt and one or more stabilizing excipients selected from the group consisting of polyvinylpyrrolidone /vinyl acetate copolymer, and polyethylene glycol/polyvinyl acetate/polyvinylcaprolactam copolymer. The dispersion of claim 1 or 2, further comprising an antioxidant that may be selected from one or more of tocopherol, butylhydroxytoluene (BHT), propyl gallate (OPG), ascorbic acid, butylhydroxyanisole (BHA), tert-butylhydroxyquinoline (TBHQ), carotenoids, glutathione, salts of metabisulfite (e.g., sodium), salts of ethylenediaminetetraacetic acid (e.g., sodium), ethylenediaminetetraacetic acid, cysteine, methionine, sesamol, and citric acid. The dispersion according to any one of claims 1 to 3, further comprising a surfactant, which may be an anionic, cationic or neutral surfactant. The dispersion according to any one of claims 1 to 4, wherein the dispersion is X-ray amorphous. the dispersion is a mixture of 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 (ITI-007) tosylate, and (a) a cellulose acetate phthalate vehicle with a ratio of ITI-007 tosylate to cellulose acetate phthalate of about 7.5 : 2.5 ; or (b) an HPMC-AS vehicle with a ratio of ITI-007 tosylate to HPMC-AS of about 5.0 :50 to 75:25 ; or (c) an HPMC-P vehicle with a ratio of ITI-007 tosylate to HPMC-P of about 7.5 :2. 5. The dispersion of claim 1, further comprising HPMC-P excipient. The dispersion of claim 6, wherein the dispersion is X-ray amorphous. The dispersion according to claim 6 or 7, wherein the X-ray diffraction pattern does not include peaks characteristic of the excipient. The dispersion of any one of claims 6 to 8, further comprising an antioxidant that may be selected from one or more of tocopherol, butylhydroxytoluene (BHT), propyl gallate (OPG), ascorbic acid, butylhydroxyanisole (BHA), tert-butylhydroxyquinoline (TBHQ), carotenoids, glutathione, salts of metabisulfite (e.g., sodium), salts of ethylenediaminetetraacetic acid (e.g., sodium), ethylenediaminetetraacetic acid, cysteine, methionine, sesamol, and citric acid. The dispersion according to any one of claims 6 to 9, further comprising a surfactant, which may be an anionic, cationic or neutral surfactant. A pharmaceutical composition comprising the dispersion of any one of claims 1 to 5 in combination or association with a pharma- ceutically acceptable diluent or carrier. A pharmaceutical composition comprising the dispersion according to any one of claims 6 to 10 in combination or association with a pharma- ceutically acceptable diluent or carrier. The composition of claim 11 or 12, in the form of a tablet or capsule for oral administration. 14. The composition of claim 11 or 13 for the prevention or treatment of a human suffering from a disease or abnormal condition in which the 5- _HT2A receptor, the serotonin transporter (SERT), and/or the dopamine _D1 / _D2 receptor signaling pathway (including _D1- mediated NMDA or AMPA receptor modulation) is implicated or mediated, such as a disorder selected from obesity, anorexia, bulimia, depression (including bipolar depression, major depressive disorder, treatment-refractory depression, and/or acute depression), anxiety (including acute anxiety), psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorder, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, conditions associated with head pain, social phobia, or dementia (e.g. Alzheimer's or Parkinson's dementia). 14. The composition of claim 12 or 13 for the prevention or treatment of a human suffering from a disease or abnormal condition in which the 5- _HT2A receptor, serotonin transporter (SERT), and/or dopamine _D1 / _D2 receptor signaling pathways (including _D1- mediated NMDA or AMPA receptor modulation) are implicated or mediated, such as a disorder selected from obesity, anorexia, bulimia, depression (including bipolar depression, major depressive disorder, treatment-refractory depression, and/or acute depression), anxiety (including acute anxiety), psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorder, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder, conditions associated with head pain, social phobia, or dementia (e.g. Alzheimer's disease or Parkinson's disease dementia). A method for producing the dispersion according to claim 1, comprising the steps of:
20. A method comprising the steps of: (a) combining 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 (ITI-007) tosylate salt, e.g., monotosylate salt, optionally in crystalline form, with selected excipients in a suitable solvent or solvent mixture, e.g., selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof; and (b) removing the solvent to recover the formed amorphous solid dispersion, e.g., by lyophilization of the solution or evaporation of the solvent (e.g., by rotary evaporation). 17. The method of claim 16, wherein the solvent or mixture of solvents is selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof. 17. The method of claim 16, wherein the solvent or solvent mixture is selected from dioxane, methanol, or a dioxane/methanol mixture. The method of claim 16, wherein the solvent or solvent mixture is dioxane or methanol in a ratio of dioxane to methanol of 90:10 to 98:2, or in a ratio of dioxane to methanol of 92:8 to 95:5, or 93:7.