CN113473988A

CN113473988A - Amorphous solid dispersion

Info

Publication number: CN113473988A
Application number: CN201980092118.2A
Authority: CN
Inventors: 李鹏
Original assignee: Intra Cellular Therapies Inc
Current assignee: Intra Cellular Therapies Inc
Priority date: 2018-12-14
Filing date: 2019-12-13
Publication date: 2021-10-01
Also published as: WO2020123952A1; CA3123085A1; JP2022512239A; KR20210103501A; MX2021006886A; AU2019398451A1; IL283927A; EP3893878A1; EP3893878A4

Abstract

Provided herein are novel stable pharmaceutically acceptable amorphous solid dispersions of 1- (4-fluoro-phenyl) -4- ((6bR,10aS) -3-methyl-2, 3,6b,9,10,10 a-hexahydro-1H, 7H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8-yl) -butan-1-one, and methods of making and using the same, aS well aS pharmaceutical compositions comprising the same.

Description

Amorphous solid dispersion

Cross Reference to Related Applications

Priority of U.S. provisional application No. 62/779,930 filed on 12, 14, 2018, the contents of which are incorporated herein by reference in their entirety, and the benefit of this application.

Technical Field

The present invention relates to certain novel amorphous solid dispersion (dispersion) formulations of substituted heterocycle fused gamma-carbolines, methods of making such dispersions, pharmaceutical compositions comprising such dispersions and uses thereof, for example in the treatment of disorders involving or resulting from 5-HT_2AReceptors, serotonin transporters (SERT) and/or dopamine D₁/D₂A disease or abnormal condition mediated by a receptor signaling pathway.

Background

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

ITI-007 is an effective 5-HT_2AReceptor ligands (K)_i0.5nM), vs Dopamine (DA) D₂Receptor (K)_i32nM), dopamine D₂Receptor (K)_i52nM) and serotonin transporter (SERT) (K)_i62nM) have strong affinity but are associated with cognitive and metabolic side effects of antipsychotics (e.g., H1 histaminergic receptor, 5-HT_2CAnd muscarinic receptors) are negligible. ITI-007 is currently on-going or has recently completed a number of clinical trials, namely, for the treatment of schizophrenia and bipolar depression. Recent evidence also suggests that ITI-007 passes through D₁-mediated indirect effects on NMDA and AMPA receptor conductance in rat mPFC slices to enhance glutamatergic neurotransmission. These effects of lumeplerenone are consistent with those of other rapid-acting antidepressant therapies, including the combined use of olanzapine (a D)₂Receptor antagonist antipsychotic) with fluoxetine (a selective serotonin reuptake inhibitor) and ketamine, supporting the molecular mechanism of lumeparone and its resistance to anxiety and treatmentThe acute therapeutic action of depression is consistent. This effect is described in PCT/US2019/022480(WO 2019/178484), the contents of which are incorporated herein by reference in their entirety.

Although ITI-007 is a promising drug, its production and formulation presents different challenges. In its free base form, ITI-007 is an oily viscous solid that is poorly soluble in water. The preparation of salts of this compound has proven to be exceptionally difficult. The hydrochloride salt form of ITI-007 is disclosed in U.S. patent 7,183,282, but this salt is hygroscopic and has poor stability. The stable crystalline tosylate addition salt of ITI-007 (tosylate) was finally identified and described in WO 2009/114181 and U.S. Pat. No. 8,648,077. Each of these publications is incorporated by reference herein in its entirety.

However, there remains a need for alternative stable, pharmaceutically acceptable solid forms of ITI-007 that can be easily incorporated into galenic formulations.

It has been disclosed that for many drugs, amorphous forms exhibit different dissolution profiles, and in some cases different bioavailability patterns, compared to crystalline forms of the same drug. For certain therapeutic indications, one bioavailability pattern may be more favorable than another. For example, the amorphous form of cefuroxime axetil exhibits higher bioavailability than the crystalline form. Amorphous solid dispersions are therefore a promising alternative to traditional crystalline active pharmaceutical ingredients.

Pure amorphous drug forms tend to be unstable. It is well known that amorphous forms revert back to the stable crystalline form due to their thermodynamic instability relative to the corresponding crystalline form. This typically 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 the product during storage to inhibit crystallization of the pharmaceutically active substance.

Finding suitable excipients that stabilize the amorphous form of the drug is a challenge because some excipients will chemically react with or promote decomposition of the drug, while other excipients will form a homogeneous solid dispersion that is physically unstable, chemically unstable, or both.

SUMMARY

In view of the difficulties involved in preparing the salts of ITI-007, it was decided to explore whether the compounds could be formulated as physically and chemically stable amorphous solid dispersions. Excipients were extensively screened using various combinations of active agents in different ratios and using different manufacturing methods. These 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). A total of 44 conditions were used to screen 16 potential excipients and three pharmaceutically acceptable amorphous solid dispersions were found.

Thus, the present invention provides amorphous solid dispersions of ITI-007 in free base form or in tosylate form with one or more excipients, such as excipients for stabilization (stabilizing excipients).

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

Accordingly, provided herein are amorphous solid dispersion forms of ITI-007 free base and tosylate, which are particularly advantageous for use in the preparation of galenical forms, and methods of making and using the same.

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 the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.

Brief Description of Drawings

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

FIG. 1 depicts the X-ray powder diffraction pattern superposition of a dispersion of ITI-007 free base and cellulose acetate.

Figure 2 depicts the superposition of the X-ray powder diffraction patterns of a dispersion of ITI-007 free base and cellulose acetate phthalate.

Figure 3 depicts the X-ray powder diffraction pattern overlay of a dispersion of ITI-007 free base and hydroxypropylmethylcellulose phthalate (grade 55) (HPMC-P).

For each of fig. 1,2 and 3, the top pattern is the resulting 25:75ITI-007 free base/excipient resulting dispersion; the second pattern was a 25:75 dispersion after stress; the third pattern was the resulting 50:50ITI-007 free base/excipient dispersion; the bottom pattern was a stressed 50:50 dispersion.

FIG. 4 depicts mDSC and TGA thermogravimetric analysis plots of a 25:75 dispersion of ITI-007 free base with cellulose acetate.

FIG. 5 depicts mDSC and TGA thermogravimetric analysis of a 50:50 dispersion of the ITI-007 free base with cellulose acetate phthalate.

FIG. 6 depicts mDSC and TGA thermogravimetric analysis of a 50:50 dispersion of ITI-007 free base with HPMC-P.

Detailed Description

The following description of the preferred embodiment(s) 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 shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range. In addition, all references cited herein are incorporated by reference in their entirety. In the event that a definition herein conflicts with a definition in a cited reference, the definition herein controls.

Unless otherwise indicated, all percentages and amounts expressed herein and elsewhere in the specification are to be understood as referring to weight percentages. The amounts given are based on the active weight of the material.

Provided herein are amorphous solid dispersions of a mixture of 1- (4-fluoro-phenyl) -4- ((6bR,10aS) -3-methyl-2, 3,6b,9,10,10 a-hexahydro-1H, 7H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8-yl) -butan-1-one (ITI-007) in free base form or in tosylate form with one or more excipients, for example, for stabilization.

In a first embodiment, provided herein is 1- (4-fluoro-phenyl) -4- ((6bR,10aS) -3-methyl-2, 3,6b,9,10,10 a-hexahydro-1H, 7H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8-yl) -butan-1-one (ITI-007) free base in the form of an amorphous solid dispersion comprising a cellulose acetate excipient wherein the ratio of ITI-007 free base to cellulose acetate is from 5:95 to 50:50 (dispersion 1). Also provided herein are 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 a ratio of 50: 50.

1.2. 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 one of the above dispersions, wherein the dispersion is X-ray amorphous, as shown, for example, by XRPD analysis.

1.4. Any one of the above dispersions, wherein the X-ray diffraction pattern is free of excipient peak characteristics.

1.5. Any one of the above dispersions, wherein the dispersion exhibits a single glass transition temperature (T)_g) Temperatures above 75 ℃, such as above 100 ℃ or temperatures above 150 ℃, as shown, for example, by mDSC analysis.

1.6. Dispersion 1.5, wherein the dispersion exhibits a single glass transition temperature above 160 ℃ or between 165 ℃ and 170 ℃ or at about 167 ℃.

1.7. Any one of the above dispersions, wherein the dispersion exhibits a change in heat capacity (Δ Cp) of 0.1 to 0.5J/g- ° C, e.g., 0.2 to 0.3J/g- ° C or about 0.2J/g- ° C, e.g., as indicated by mDSC.

1.8. Any one of the above dispersions, wherein the dispersion exhibits a weight loss of less than 10% up to a temperature of 100 ℃, as shown, for example, by TGA analysis.

1.9. Dispersion 1.8, wherein the dispersion shows a weight loss of less than 8% up to a temperature of 100 ℃, for example less than 7% or less than 6% or less than 5% or less than 4% or less than 3% up to a temperature of 100 ℃.

1.10. Any one of the above dispersions, wherein the dispersion exhibits no change in appearance or texture after 7 days at 40 ℃ and 75% relative humidity.

1.11. Any one of the above dispersions, wherein the dispersion exhibits a chemical stability of ITI-007 at 40 ℃, 75% relative humidity of greater than 90% after 7 days, for example as judged by HPLC.

1.12. Dispersion 1.11, wherein the dispersion exhibits an ITI-007 chemical stability of greater than 95% or greater than 96% or greater than 97% or greater than 98% or greater than 99% after 7 days at 40 ℃ and 75% relative humidity.

1.13. Any one of the above dispersions, wherein the dispersion is prepared by the following process: the process comprises dissolving ITI-007 free base and the selected excipient in a suitable solvent or solvent mixture and removing the solvent, for example by lyophilizing the solution, to yield an amorphous solid dispersion.

1.14. Dispersion 1.13, wherein the solvent or solvent mixture is selected from the group consisting of 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, for example a 90:10 to 98:2 ratio of dioxane to methanol or a 92:8 to 95:5 ratio or about a 93:7 ratio of dioxane to methanol.

1.16. Any of the above dispersions, wherein the dispersion exhibits any combination of the features as described in 1.1-1.15.

In a second embodiment, provided herein is ITI-007 free base in the form of an amorphous solid dispersion comprising a cellulose acetate phthalate excipient wherein the ratio of ITI-007 free base to cellulose acetate phthalate is from 25:75 to 75:25 (dispersion 2). Also provided herein are 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.

2.2. 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 one of the above dispersions, wherein the dispersion is X-ray amorphous, as shown, for example, by XRPD analysis.

2.4. Any one of the above dispersions, wherein the X-ray diffraction pattern is free of excipient peak characteristics.

2.5. Any one of the above dispersions, wherein the dispersion exhibits a single glass transition temperature (T)_g) Above 75 ℃, e.g. at a temperature above 85 ℃ or above 95 ℃, e.g. as shown by mDSC analysis.

2.6. Dispersion 2.5, wherein the dispersion exhibits a single glass transition temperature above 100 ℃ or between 105 ℃ and 115 ℃ or at about 107 ℃.

2.7. Any one of the above dispersions, wherein the dispersion exhibits a change in heat capacity (Δ Cp) of 0.1 to 0.6J/g- ° C, e.g., 0.2 to 0.5J/g- ° C or about 0.4J/g- ° C, e.g., as indicated by mDSC.

2.8. Any one of the above dispersions, wherein the dispersion exhibits a weight loss of less than 10% up to a temperature of 100 ℃, as shown, for example, by TGA analysis.

2.9. Dispersion 2.8, wherein the dispersion shows a weight loss of less than 8% up to a temperature of 100 ℃, for example less than 7% or less than 6% or less than 5% or less than 4% or less than 3% up to a temperature of 100 ℃.

2.10. Any one of the above dispersions, wherein the dispersion exhibits no change in appearance or texture after 7 days at 40 ℃ and 75% relative humidity.

2.11. Any one of the above dispersions, wherein the dispersion exhibits a chemical stability of ITI-007 at 40 ℃, 75% relative humidity, as judged, for example, by HPLC, of greater than 90% after 7 days.

2.12. Dispersion 2.11, wherein the dispersion exhibits an ITI-007 chemical stability of greater than 95% or greater than 96% or greater than 97% or greater than 98% or greater than 99% after 7 days at 40 ℃ and 75% relative humidity.

2.13. Any one of the above dispersions, wherein the dispersion is prepared by the following process: the process comprises dissolving ITI-007 free base and the selected excipient in a suitable solvent or solvent mixture and removing the solvent, for example by lyophilizing the solution, to yield an amorphous solid dispersion.

2.14. Dispersion 2.13, wherein the solvent or solvent mixture is selected from the group consisting of 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, for example a 90:10 to 98:2 ratio of dioxane to methanol or a 92:8 to 95:5 ratio or about a 93:7 ratio of dioxane to methanol.

2.16. Any of the above dispersions, wherein the dispersion exhibits any combination of the features as described in 2.1-2.15.

In a third embodiment, provided herein is ITI-007 free base in the form of an amorphous solid dispersion comprising a hydroxypropylmethylcellulose phthalate (HPMC-P) excipient, wherein the ratio of ITI-007 free base to HPMC-P is from 25:75 to 75:25 (dispersion 3). Also provided herein are 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.

3.2. 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 one of the above dispersions, wherein the dispersion is X-ray amorphous, as shown, for example, by XRPD analysis.

3.4. Any one of the above dispersions, wherein the X-ray diffraction pattern is free of excipient peak characteristics.

3.5. Any one of the above dispersions, wherein the dispersion exhibits a single glass transition temperature (T)_g) Above 75 ℃, e.g. at a temperature above 80 ℃ or above 85 ℃, e.g. as shown by mDSC analysis.

3.6. Dispersion 3.5, wherein the dispersion exhibits a single glass transition temperature above 90 ℃ or between 92 ℃ and 98 ℃ or at about 95 ℃.

3.7. Any one of the above dispersions, wherein the dispersion exhibits a change in heat capacity (Δ Cp) of 0.1 to 0.5J/g- ° C, e.g., 0.2 to 0.4J/g- ° C or about 0.3J/g- ° C, e.g., as indicated by mDSC.

3.8. Any one of the above dispersions, wherein the dispersion exhibits a weight loss of less than 10% up to a temperature of 100 ℃, as shown, for example, by TGA analysis.

3.9. Dispersion 3.8, wherein the dispersion shows a weight loss of less than 8% up to a temperature of 100 ℃, for example less than 7% or less than 6% or less than 5% or less than 4% or less than 3% up to a temperature of 100 ℃.

3.10. Any one of the above dispersions, wherein the dispersion exhibits no change in appearance or texture after 7 days at 40 ℃ and 75% relative humidity.

3.11. Any one of the above dispersions, wherein the dispersion exhibits a chemical stability of ITI-007 at 40 ℃, 75% relative humidity, as judged, for example, by HPLC, of greater than 90% after 7 days.

3.12. Dispersion 3.11, wherein the dispersion shows a chemical stability of more than 95% or more than 96% or more than 97% or more than 98% or more than 99% after 7 days at 40 ℃, 75% relative humidity.

3.13. Any one of the above dispersions, wherein the dispersion is prepared by the following process: the process comprises dissolving ITI-007 free base and the selected excipient in a suitable solvent or solvent mixture and removing the solvent, for example by lyophilizing the solution, to yield 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, for example a 90:10 to 98:2 ratio of dioxane to methanol or a 92:8 to 95:5 ratio or about a 93:7 ratio of dioxane to methanol.

3.16. Any of the above dispersions, wherein the dispersion exhibits any combination of the features as described in 3.1-3.15.

In a fourth embodiment, provided herein is ITI-007 tosylate in the form of an amorphous solid dispersion comprising excipients for stabilization and optionally further comprising an antioxidant and/or surfactant (dispersion 4). For example, the excipient used for stabilization is an excipient that stabilizes the amorphous form of ITI-007 tosylate salt to prevent conversion of the amorphous form to a crystalline form. Also provided herein are the following compositions:

4.1. dispersion 4, wherein the dispersion comprises ITI-007 tosylate and an excipient for stabilization selected from the group consisting of cellulose acetate, cellulose acetate phthalate, methacrylate/methyl acrylate copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate (HPMC-P), polyvinyl acetate, polyvinylpyrrolidone/vinyl acetate copolymer, and polyethylene glycol/polyvinyl acetate/polyvinyl caprolactam copolymer.

4.2. Dispersion 4 or 4.1, wherein the composition comprises ITI-007 tosylate in admixture with a single excipient for stabilization.

4.3. Dispersion 4 or 4.1, wherein the composition comprises ITI-007 tosylate in admixture with two excipients for stabilization.

4.4. Any one of dispersions 4 or 4.1-4.3, wherein the dispersion comprises a mixture of ITI-007 tosylate and one or more excipients for stabilization, wherein the weight ratio of ITI-007 tosylate to one or more excipients for stabilization is from 25:75 to 75:25, such as from 26:74 to 74:26, or from 30:70 to 70:30, or from 35:65 to 65:35, or from 40:60 to 60:40, or from 42:58 to 58:42, or from 44:56 to 56:44, or from 45:55 to 55:45, or from 47:53 to 53:47, or from 48:52 to 52:48, or from 49:51 to 51:49, or about 50: 50.

4.5. Dispersion 4 or any of 4.1-4.3, wherein the dispersion comprises a mixture of ITI-007 tosylate and one or more excipients for stabilization, wherein the weight ratio of ITI-007 tosylate to one or more excipients for stabilization is from 5:95 to 50:50, such as from 5:95 to 49:51, or from 5:95 to 45:55, or from 10:90 to 40:60, or from 15:85 to 35:65, or from 20:80 to 30:70, or from 22:78 to 28:82, or from 23:77 to 27:83, or from 24:76 to 26:74, or about 25: 75.

4.6. Any of dispersion 4 or 4.1-4.3, wherein the dispersion comprises a mixture of ITI-007 tosylate and one or more excipients for stabilization, wherein the weight ratio of ITI-007 tosylate to one or more excipients for stabilization is from 50:50 to 95:5, such as from 51:49 to 95:5, or from 55:45 to 95:5, or from 60:40 to 90:10, or from 65:45 to 85:15, or from 70:30 to 80:20, or about 75: 25.

4.7. Any one of the above dispersions, wherein the excipient for stabilization comprises one or more of: cellulose acetate, cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and hydroxypropyl methylcellulose phthalate (HPMC-P).

4.8. Any one of the above dispersions, wherein the excipient for stabilization comprises one or more of: cellulose acetate, cellulose acetate phthalate and hydroxypropylmethylcellulose 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, Butylated Hydroxytoluene (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, such as 0.5 to 5% or 0.5 to 3% by weight of the dispersion.

4.12. Any of the above dispersions, further comprising a surfactant, e.g., an anionic or cationic or neutral surfactant, such as a surfactant that stabilizes the amorphous form of ITI-007 tosylate (e.g., prevents conversion to the crystalline form of ITI-007 tosylate).

4.13. Any one of the above dispersions, wherein the dispersion is x-ray amorphous, as shown, for example, by XRPD analysis.

4.14. Any one of the above dispersions, wherein the X-ray diffraction pattern is free of excipient peak characteristics.

4.15. Any one of the above dispersions, wherein the dispersion exhibits a single glass transition temperature (T)_g) Above 75 ℃, e.g. at a temperature above 80 ℃ or at a temperature above 90 ℃ or at a temperature of about 100 ℃ or at a temperature above 110 ℃, as shown for example by mDSC analysis.

4.16. Any one of the above dispersions, wherein the dispersion exhibits a change in heat capacity (Δ Cp) of from 0.1 to 2.0J/g- ° C, e.g., from 0.1 to 1.5J/g- ° C, or from 0.1 to 1.0J/g- ° C, or from 0.1 to 0.5J/g- ° C, e.g., as indicated by mDSC.

4.17. Any one of the above dispersions, wherein the dispersion exhibits a weight loss of less than 20% up to a temperature of 150 ℃, as shown, for example, by TGA analysis.

4.18. Dispersion 4.17, wherein the dispersion shows a weight loss of less than 15% up to a temperature of 150 ℃, for example less than 15% up to a temperature of 100 ℃, or less than 10% up to a temperature of 150 ℃, or less than 10% up to a temperature of 100 ℃, or less than 5% up to a temperature of 150 ℃, or less than 5% up to a temperature of 100 ℃.

4.19. Any one of the above dispersions, wherein the dispersion exhibits no change in appearance or texture after 7 days at 40 ℃ and 75% relative humidity.

4.20. Any one of the above dispersions, wherein the dispersion exhibits a chemical stability of ITI-007 at 40 ℃, 75% relative humidity of greater than 85% after 7 days, as judged by HPLC, for example.

4.21. Dispersion 4.20, wherein the dispersion exhibits an ITI-007 chemical stability of greater than 90% or greater than 95% or greater than 96% or greater than 97% or greater than 98% or greater than 99% after 7 days at 40 ℃ and 75% relative humidity.

4.22. Any one of the above dispersions, wherein the dispersion is prepared by the following process: the process comprises dissolving ITI-007 tosylate and the selected excipient in a suitable solvent or mixture of solvents and removing the solvent, for example by lyophilizing the solution or evaporating the solvent (e.g. by rotary evaporation), to give an amorphous solid dispersion.

4.23. Dispersion 4.22, wherein the solvent or solvent mixture is selected from the group consisting of 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, for example a 90:10 to 98:2 ratio of dioxane to methanol or a 92:8 to 95:5 ratio or about a 93:7 ratio of dioxane to methanol.

4.25. Dispersion 4.22, 4.23 or 4.24, wherein the process further comprises: an antioxidant or surfactant is added to the solvent mixture prior to solvent removal.

4.26. Any of the above dispersions, wherein the dispersion exhibits any combination of the features recited in 4.1 to 4.25.

Any of dispersions 4 and 4.1-4.26, may contain an antioxidant to improve the stability of the amorphous form of ITI-007 tosylate. 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 Butylated Hydroxyanisole (BHA), tertiary-butylhydroquinone (TBHQ), carotenoids, glutathione, metabisulfites (e.g., sodium), edetates (e.g., sodium), cysteine, methionine, sesamol, and citric acid. Alternatively, the antioxidant may be ethylenediaminetetraacetic acid.

Any of dispersions 4 and 4.1-4.26, may contain 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 the ITI-007 tosylate salt (e.g., prevents conversion to the crystalline form of the ITI-007 tosylate salt). In some embodiments, the surfactant is selected from one or more of anionic or cationic or neutral surfactants.

In some embodiments herein, any of dispersion 4 or 4.1-4.26 may further comprise any other excipient that can prevent or inhibit the formation of a crystalline form of ITI-007 tosylate or that can 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 adjusting agents, fillers, disintegrants, coatings, binders or any other suitable pharmaceutically acceptable excipient.

In a second aspect, provided herein is a process (process 1) for producing dispersion 1 or the like or dispersion 2 or the like or dispersion 3 or the like, comprising the steps of:

(a) combining 1- (4-fluoro-phenyl) -4- ((6bR,10aS) -3-methyl-2, 3,6b,9,10,10 a-hexahydro-1H, 7H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8-yl) -butan-1-one (ITI-007) free base with a selected excipient in a suitable solvent or mixture of solvents, for example selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone and mixtures thereof; and

(b) the solvent is removed (e.g., by lyophilizing the solution) and the amorphous solid dispersion thus formed is recovered.

In another embodiment of the second aspect, provided herein is a process (process 2) for producing dispersion 4 and the like, comprising the steps of:

(a) combining 1- (4-fluoro-phenyl) -4- ((6bR,10aS) -3-methyl-2, 3,6b,9,10,10 a-hexahydro-1H, 7H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8-yl) -butan-1-one (ITI-007) tosylate (e.g., monotoluenesulfonate), optionally in crystalline form, with a selected excipient in a suitable solvent or mixture of solvents, e.g., selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof; and

(b) the solvent is removed (e.g., by lyophilizing the solution or evaporating the solvent (e.g., by rotary evaporation)) and the amorphous solid dispersion thus formed is recovered.

In some embodiments, method 2 further comprises the step of 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 that stabilizes the amorphous form of ITI-007 tosylate, for example to prevent conversion of the amorphous form to the crystalline form of ITI-007 tosylate.

In other embodiments, the antioxidant may be selected from other suitable antioxidants, such as Butylated Hydroxyanisole (BHA), tertiary-butylhydroquinone (TBHQ), carotenoids, glutathione, metabisulfites (e.g., sodium), edetates (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 used in method 1 is selected from dioxane, methanol or a dioxane/methanol mixture, for example a 90:10 to 98:2 ratio of dioxane to methanol or a 92:8 to 95:5 ratio or about a 93:7 ratio of dioxane to methanol, optionally wherein the solvent is removed by lyophilization. In another embodiment of the second aspect, the solvent or solvent mixture used in method 2 is selected from dioxane, methanol or a dioxane/methanol mixture, for example a 90:10 to 98:2 ratio of dioxane to methanol or a 92:8 to 95:5 ratio or about a 93:7 ratio of dioxane to methanol, optionally wherein the solvent is removed by lyophilization.

As used herein, a solid dispersion refers to a dispersion of the active pharmaceutical ingredient, ITI-007, in an inert excipient or matrix (carrier), wherein the active ingredient may be present in a finely crystalline, dissolved or amorphous state. The excipient in the solid dispersion is typically a polymer. The most important role of the polymer in solid dispersions is to reduce the molecular mobility of the pharmaceutically active ingredient to avoid phase separation and recrystallization of the active ingredient during storage. Amorphous forms of the active ingredient are associated with higher energy states than their crystalline counterparts, and therefore, significantly less external energy is required to achieve dissolution (e.g., in the gastrointestinal tract or elsewhere in the body).

In a third aspect, provided herein is a pharmaceutical composition (composition 1) comprising dispersion 1 (and preferred embodiments thereof) or dispersion 2 (and preferred embodiments thereof) or dispersion 3 (and preferred embodiments thereof) or dispersion 4 (and preferred embodiments thereof) 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 Injection (LAI). The pharmaceutical composition may also comprise any suitable pharmaceutically acceptable excipient, such as: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, xylitol, sugar, and the like; binders, such AS acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, such AS polyvinylpyrrolidone (PVP K-30, K-90), poly (vinylpyrrolidone-co-vinyl acetate) (PVP-VA), and the like, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), and the like; disintegrants, for example starch, sodium starch glycolate, pregelatinized starch, crospovidone, 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; dissolution or wetting enhancers, such as anionic or cationic or neutral surfactants; maltodextrins, complex forming agents such as different grades of cyclodextrins and resins, and the like; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, different grades of methyl methacrylate, waxes, and the like; and film forming agents, plasticizers, colorants, flavorants, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

In another embodiment of the third aspect, the composition may further comprise one or more antioxidants, such as tocopherol, Butylated Hydroxytoluene (BHT), propyl gallate (OPG), ascorbic acid, and the like. The inclusion of an antioxidant may further improve the chemical stability of the dispersion by preventing oxidative chemical degradation of the ITI-007 active ingredient. In another embodiment, the dispersion itself is formulated to include such an antioxidant. Other suitable antioxidants include Butylated Hydroxyanisole (BHA), tertiary-butylhydroquinone (TBHQ), carotenoids, glutathione, metabisulfites (e.g., sodium), edetates (e.g., sodium), ethylenediaminetetraacetic acid, cysteine, methionine, sesamol, and citric acid.

In another embodiment of the third aspect, the composition may further comprise any excipient that prevents or inhibits the formation of the crystalline form of the ITI-007 free base or the ITI-007 tosylate salt, or that prevents or inhibits the conversion of the amorphous form of the ITI-007 free base or the ITI-007 tosylate salt to its crystalline form. The excipients may include polymers, gums, surfactants, wetting agents, drying agents, pH adjusting agents, fillers, disintegrants, coatings, binders or any other suitable pharmaceutically acceptable excipient. Such excipients include any one or more of the excipients described in paragraph [0038] above.

In another aspect, provided herein is dispersion 1 (and preferred embodiments thereof) or dispersion 2 (and preferred embodiments thereof) or dispersion 3 (and preferred embodiments thereof) or dispersion 4 (and preferred embodiments thereof), or a pharmaceutical composition, e.g. composition 1, comprising dispersion 1 (and preferred embodiments thereof) or dispersion 2 (and preferred embodiments thereof) or dispersion 3 (and preferred embodiments thereof) or dispersion 4 (and preferred embodiments thereof), for use in the treatment of a condition involving 5-HT_2AReceptors, serotonin transporters (SERT) and/or dopamine D₁/D₂Receptor signaling pathways (including D)₁-mediated modulation of NMDA or AMPA receptors) or a disease or abnormal condition mediated thereby, such as a disorder selected from: obesity, anorexia, bulimia, depression (including bipolar depression, major depressive disorder, treatment-resistant depression, and/or acute depression), anxiety (including acute anxiety), psychosis, schizophrenia, migraine, obsessive compulsive disorder, sexual dysfunction, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with head pain, social phobia, or dementia (e.g., dementia in Alzheimer's disease or Parkinson's disease). In some embodiments, the disease or abnormal condition or disorder is acute depression (e.g., acute major depressive episode, acute short-duration depressive episode, acute recurrent brief depressive episode) and/or acute anxiety (e.g., short-duration anxiety episode associated with generalized anxiety disorder, panic disorder, specific phobia or social anxiety disorder, or social avoidance), including depression that is resistant to treatment (e.g., depression that is not responsive to treatment with an antidepressant selected from the group consisting of Selective Serotonin Reuptake Inhibitors (SSRI), Serotonin Reuptake Inhibitors (SRI), tricyclic antidepressants, monoamine oxidase inhibitors, Norepinephrine Reuptake Inhibitors (NRI), Dopamine Reuptake Inhibitors (DRI), SRI/NRI, SRI/DRI, NRI/DRI, SRI/NRI/DRI (triple reuptake inhibitors), Serotonin receptor antagonists or any combination thereof), bipolar depression or major depressive disorder. Other embodiments of the methods provided herein are PCT/US2019/022480(WO 2019)178484), the contents of which are incorporated herein by reference in their entirety.

In another embodiment, the invention provides a method of preventing or treating a human suffering from a disease or abnormal condition involving 5-HT_2AReceptors, serotonin transporters (SERT) and/or dopamine D₁/D₂Receptor signaling pathways (including D)₁-mediated NMDA or AMPA receptor modulation) or mediated thereby, e.g. a condition selected from: obesity, anorexia, bulimia, depression (including bipolar depression, major depressive disorder, treatment-resistant depression and/or acute depression), anxiety (including acute anxiety), psychosis, schizophrenia, migraine, obsessive compulsive disorder, sexual dysfunction, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with head pain, social phobia or dementia (e.g., dementia of Alzheimer's disease or Parkinson's disease), comprising administering to a patient in need thereof a therapeutically effective amount of dispersion 1 (and preferred embodiments thereof) or dispersion 2 (and preferred embodiments thereof) or dispersion 3 (and preferred embodiments thereof) or a pharmaceutical composition comprising dispersion 1 (and preferred embodiments thereof) or dispersion 2 (and preferred embodiments thereof) or dispersion 3 (and preferred embodiments thereof) or dispersion 4 (and preferred embodiments thereof), such as composition 1. In some embodiments, the disease or abnormal condition or disorder treated is acute depression (e.g., acute major depressive episode, acute short-duration depressive episode, acute recurrent brief depressive episode) and/or acute anxiety (e.g., short-duration anxiety episode associated with generalized anxiety disorder, panic disorder, specific phobia or social anxiety disorder, or social avoidance), including depression resistant to treatment (e.g., depression unresponsive to treatment with an antidepressant selected from the group consisting of 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/DRI, NRI/DRI, SRI/NRI/DRI (triple reuptake inhibitors), Serotonin receptor antagonists or any of themCombination), bipolar depression or major depressive disorder. Other embodiments of the methods provided herein are those described in PCT/US2019/022480(WO 2019/178484), the contents of which are incorporated herein by reference in their entirety.

Examples

The following apparatus and methods were used to separate and characterize exemplary eutectic forms:

x-ray powder diffraction (XRPD): x-ray powder diffraction studies were performed using a PANalytical X' Pert PRO MPD diffractometer using an incident beam of Cu radiation generated by an Optix long fine focus light source. An elliptical graded multilayer mirror is used to focus Cu ka X-ray radiation through the sample onto the detector. Prior to analysis, the silicon samples were analyzed to verify the observed Si (111) peak positions (consistent with NIST-certified position NIST SM 640 e). A sample of the sample was sandwiched between 3-micron thick films and analyzed in transmission geometry. Beam brakes, short anti-scatter extensions and anti-scatter blades are used to minimize the background of air generation. Soller slits for the incident and diffracted beams are used to minimize broadening of the axial divergence. The diffractogram was collected using a scanning position sensitive detector (X' Celerator) 240mm from the sample. Data Collector software v.2.2b was used for the analysis.

TGA was performed using a TA Instruments Q5000 or Discovery thermogravimetric Analyzer. The samples were placed in an aluminum sample pan and inserted into a TG furnace. The sample was heated from ambient temperature to 250 ℃ at a rate of 10 ℃/min. Nickel and nickel-aluminum alloys were used as calibration standards.

Modulated differential scanning calorimetry (mDSC). mDSC data were obtained on a TA Instruments Q2000 or 2920 differential scanning calorimeter equipped with a cryogenic cooling system. Temperature calibration was performed using NIST traceable indium metal. The sample was placed in an aluminum T-zero DSC pan, covered with a lid and the weight was recorded accurately. A weighing aluminum pan configured as a sample pan was placed on the reference side of the cell. Typically, the start temperature is-50 deg.C, the end temperature is 250 deg.C, the modulation amplitude is + -1 deg.C, the period is 50 seconds, and the base heating rate is 2 deg.C/min.

High Performance Liquid Chromatography (HPLC) analysis was performed using an Agilent 1100 series liquid chromatograph equipped with a diode array detector, degasser, quaternary pump and autosampler. The column was a 4.6x100mm CSH C18 column with 2.5-micron packing (xselectrode) run with 0.1% TFA in water as mobile phase a and 0.1% TFA in acetonitrile as mobile phase B, flow rate 0.500 mL/min. The gradient was run from 95% a to 73% in the first 22 minutes, then 6 minutes at 73% a, and from 73% a to 30% a in the subsequent 22 minutes. The column temperature was set at 15.0 deg.C, the detector wavelength at 254nm, the bandwidth at 100nm, and the reference wavelength at 360 nm. The injection volume was 2.0 microliters.

Example 1 preparation of free base Dispersion

The solubility of the ITI-007 free base and various excipients in different solvents was first evaluated. The ITI-007 free base was found to have good solubility (>50mg/mL) in acetone, ethanol, methanol, dioxane and 2,2, 2-Trifluoroethanol (TFE), but relatively poor solubility in the tert-butanol/water mixture (5-50 mg/mL). However, it was found that solutions of ITI-007 free base in TFE discolor rapidly due to decomposition of the active ingredient.

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

Based on the solubility analysis, solutions of various excipients with ITI-007 free base in 3:1 acetone-ethanol were prepared. Attempts were made to remove the solvent by rotary evaporation, but this resulted in an oil in all cases, rather than a solid.

Solid dispersions were successfully prepared by freeze-drying a solution of ITI-007 free base and excipient in dioxane or dioxane-methanol (90:10, 91:9, 92:8, 93:7, or 94: 6). The solution was initially frozen in a dry ice/acetone bath and then placed in a freeze dryer with a shelf pre-cooled to-75 ℃. The samples were dried overnight at-50 ℃ and then at-20 ℃ and then 0 ℃ for two days. The samples were then dried twice at 20 ℃ for 4 hours, purged with nitrogen, and then stored on a desiccant in a refrigerator until tested.

Example 2 preliminary screening of free base Dispersion

The solid dispersions obtained from example 1 were first evaluated by XRPD to determine whether they were amorphous. All lyophilized samples using amorphous excipients were found to be x-ray amorphous by XRPD. Lyophilized samples using crystalline excipients (Gelucire 50/13, PEG-1000 succinate, Pluronic F-127) were found to be disordered and peaks were present only corresponding 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 viscous and was not evaluated further.

Example 3 evaluation of stability of free base Dispersion

The solid dispersion from example 1 was placed into an uncapped clear glass vial, and the vial was placed into a container maintained at 75% relative humidity and a temperature of 40 ℃ for 7 days. A parallel analysis was performed with the ITI-007 free base sample as a control. The samples were observed visually and by polarization microscopy (0.8-10 times magnification, with cross-polarizer and first-order red compensator). The observation results are shown in table 1. Most samples exhibited changes in appearance or texture indicating the formation of a physically unstable amorphous dispersion. For example, some show visible crystallization, while others become viscous solids or oils.

Dispersions of physically stable free-flowing solids were further analyzed by XRPD to confirm that they remained x-ray amorphous or had only a disordered state of excipient peaks. XRPD results confirmed that the visually stable sample remained an X-ray amorphous dispersion.

mDSC and TGA analysis were performed on physically stable free flowing samples. The single glass transition temperature in mDSC supports the conclusion that the solid is a non-crystalline, miscible dispersion. Both PEG dispersions showed an unacceptably low temperature glass transition at 9 or 10 ℃, whereas the glyceryl monostearate dispersion showed no glass transition. The 50:50 cellulose acetate dispersion showed two glass transition temperatures, indicating a phase separated material, which was unacceptable. Only the 25:75 cellulose acetate, 25:75 cellulose acetate phthalate, 50:50 cellulose acetate phthalate, 25:75HPMC-AS, 50:50HPMC-AS, 25:75HPMC-P and 50:50HPMC-P dispersions showed acceptable single glass transition temperatures above 75 ℃.

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

HPMC-AS dispersions AS well AS the 25:75HPMC-P dispersion showed very high loss of material by HPLC. The 25:75 cellulose acetate phthalate dispersion showed low but unacceptable loss of material. Only seven dispersions produced satisfactory results: 25:75 cellulose acetate, 50:50 cellulose acetate phthalate, 50:50HPMC-P, 25:75PEG, 50:50PEG and 25:75 glyceryl stearate. Thus, these dispersions are chemically stable.

The combined test results are shown in table 1 below.

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

It should be noted that a similar experiment using the ITI-007 tosylate salt instead of the ITI-007 free base did not result in a completely stable amorphous dispersion. These results are shown in more detail in example 4 below. While most ITI-007 tosylate dispersions passed the initial screening (X-ray amorphous or only showing X-ray peaks due to excipients), all of the resulting initial dispersions showed strong physical instability (color and appearance changes, including crystallization of the active agent out of the dispersion) or chemical instability (HPLC showed 10-68% decomposition). For example, a 25:75 dispersion of ITI-007 tosylate and cellulose acetate produced crystallization of ITI-007 during the aging study; a 50:50 dispersion of ITI-007 tosylate and cellulose acetate phthalate showed about a 52% reduction in ITI-007 content by HPLC; a50: 50 dispersion of ITI-007 tosylate and HPMC-P showed about a 68% reduction in ITI-007 content by HPLC. These results are unexpected because the ITI-007 tosylate salt is chemically more stable than the ITI-007 free base. Thus, it is particularly unexpected that three specific amorphous solid dispersions of the ITI-007 free base are physically and chemically stable, while the corresponding dispersions of the ITI-007 tosylate salt are unstable.

Example 4 preparation of tosylate Dispersion, preliminary screening and stability evaluation

The procedures described in examples 1,2 and 3 were repeated using ITI-007 tosylate as active ingredient. It was found that ITI-007 tosylate has good solubility (>50mg/mL) in 2,2, 2-Trifluoroethanol (TFE) and 60:40v/v t-butanol/water mixtures, but relatively poor solubility in acetone, ethanol, dioxane and other t-butanol/water mixtures (20-40 mg/mL). However, it was also found that the solution of ITI-007 tosylate in TFE discolored rapidly due to decomposition of the active ingredient.

The same excipients were evaluated as described in example 1. As observed for the free base, rotary evaporation from the solvent (3:1 acetone-methanol) did not produce amorphous material, but lyophilization from dioxane and dioxane/methanol mixtures resulted in amorphous material using each excipient tested. Screening and stability evaluation are shown in table 2 below.

In the test dispersions using the ITI-007 tosylate salt, it was found to be mostly amorphous and under stringent storage conditions of 75% relative humidity and temperature of 40 ℃, a small amount of crystallization was visually observed for several of the dispersions. In addition, minor discoloration or texture changes were found to occur with other dispersions. However, further evaluation indicates that prevention of these changes in physical appearance can be achieved by incorporating antioxidants into the composition to prevent air-promoted oxidation, forming the dispersion into coated tablets, encapsulating the dispersion into gel sachets or capsules, adding excipients such as polymers to prevent partial conversion of the amorphous formulation into a crystalline form, and/or mixing the dispersion with surfactants to inhibit particle agglomeration.

Without being bound by theory, it is believed that 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 may be used to effectively prepare a pharmaceutical formulation comprising ITI-007 tosylate in the form of an amorphous solid dispersion with a surfactant and/or an antioxidant AS described herein.

Claims

1. An amorphous solid dispersion comprising 1- (4-fluoro-phenyl) -4- ((6bR,10aS) -3-methyl-2, 3,6b,9,10,10 a-hexahydro-1H, 7H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8-yl) -butan-1-one (ITI-007) tosylate and an excipient for stabilization and optionally further comprising an antioxidant and/or a surfactant.

2. The dispersion of claim 1, wherein the dispersion comprises ITI-007 tosylate and one or more excipients for stabilization selected from the group consisting of cellulose acetate, cellulose acetate phthalate, methacrylate/methyl acrylate copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate (HPMC-P), polyvinyl acetate, polyvinylpyrrolidone/vinyl acetate copolymer, and polyethylene glycol/polyvinyl acetate/polyvinyl caprolactam copolymer.

3. The dispersion of claim 1, further comprising an antioxidant, optionally selected from one or more of tocopherol, Butylated Hydroxytoluene (BHT), propyl gallate (OPG), ascorbic acid, Butylated Hydroxyanisole (BHA), Tertiary Butylhydroquinone (TBHQ), carotenoids, glutathione, metabisulfites (e.g., sodium), edetates (e.g., sodium), ethylenediaminetetraacetic acid, cysteine, methionine, sesamol, and citric acid.

4. The dispersion of claim 1, further comprising a surfactant, optionally an anionic or cationic or neutral surfactant.

5. The dispersion of claim 1, wherein the dispersion is x-ray amorphous.

6. The dispersion of claim 1, wherein the dispersion is 1- (4-fluoro-phenyl) -4- ((6bR,10aS) -3-methyl-2, 3,6b,9,10,10 a-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 wherein the ratio of ITI-007 tosylate to cellulose acetate phthalate is from 5:95 to 75:25 (e.g. excluding a ratio of 75: 25); or

(b) An HPMC-AS excipient, wherein the ratio of ITI-007 tosylate to HPMC-AS is from 25:75 to 50:50 (e.g., excluding a 50:50 ratio); or

(c) An HPMC-P excipient wherein the ratio of ITI-007 tosylate to HPMC-P is from 5:95 to 75:25 (e.g. excluding the ratio of 75: 25).

7. The dispersion of claim 6, wherein the dispersion is x-ray amorphous.

8. The dispersion of claim 6, wherein the X-ray diffraction pattern is free of excipient peak characteristics.

9. The dispersion of claim 6, further comprising an antioxidant, optionally selected from one or more of tocopherol, Butylated Hydroxytoluene (BHT), propyl gallate (OPG), ascorbic acid, Butylated Hydroxyanisole (BHA), Tertiary Butylhydroquinone (TBHQ), carotenoids, glutathione, metabisulfites (e.g., sodium), edetates (e.g., sodium), ethylenediaminetetraacetic acid, cysteine, methionine, sesamol, and citric acid.

10. The dispersion of claim 6, further comprising a surfactant, optionally an anionic or cationic or neutral surfactant.

11. A pharmaceutical composition comprising the dispersion of claim 1 in association with a pharmaceutically acceptable diluent or carrier.

12. A pharmaceutical composition comprising the dispersion of claim 6 in association with a pharmaceutically acceptable diluent or carrier.

13. The composition of claim 11 or 12, wherein the composition is in the form of a tablet or capsule for oral administration.

14. Methods for preventing or treating a human suffering from a disease or abnormal condition involving 5-HT_2AReceptors, serotonin transporters (SERT) and/or dopamine D₁/D₂Receptor signaling pathways (including D)₁-mediated NMDA or AMPA receptor modulation) or mediated thereby, e.g. a condition selected from: obesity, anorexia, bulimia, depression (including bipolar depression, major depressive disorder, treatment-resistant depression and/or acute depression), anxiety (including acute anxiety), psychosis, schizophrenia, migraine, obsessive compulsive disorder, sexual dysfunction, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with head pain, social phobia, or dementia (e.g., dementia of alzheimer's disease or parkinson's disease), comprising administering to a patient in need thereof a therapeutically effective amount of the dispersion of claim 1.

15. Methods for preventing or treating a human suffering from a disease or abnormal condition involving 5-HT_2AReceptors, serotonin transporters (SERT) and/or dopamine D₁/D₂Receptor signaling pathways (including D)₁-mediated NMDA or AMPA receptor modulation) or mediated thereby, e.g. a condition selected from: obesity, anorexia, bulimia, depression (including bipolar depression, major depressive disorder, treatment-resistant depression and/or acute depression), anxiety (including acute anxiety), psychosis, schizophrenia, migraine, obsessive compulsive disorder, sexual dysfunction, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with head pain, social phobia, or dementia (e.g., dementia of alzheimer's disease or parkinson's disease), comprising administering to a patient in need thereof a therapeutically effective amount of the dispersion of claim 6.

16. A process for producing the dispersion of claim 1, comprising the steps of:

17. The process of claim 16, wherein the solvent or solvent mixture is selected from the group consisting of dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof.

18. The process of claim 16, wherein the solvent or solvent mixture is selected from dioxane, methanol or a dioxane/methanol mixture.

19. The process of claim 16, wherein the solvent or solvent mixture is dioxane and methanol, wherein the ratio of dioxane to methanol is from 90:10 to 98:2, or the ratio of dioxane to methanol is from 92:8 to 95:5, or the ratio of dioxane to methanol is 93: 7.