WO2020123952A1 - Dispersions solides amorphes - Google Patents

Dispersions solides amorphes Download PDF

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Publication number
WO2020123952A1
WO2020123952A1 PCT/US2019/066247 US2019066247W WO2020123952A1 WO 2020123952 A1 WO2020123952 A1 WO 2020123952A1 US 2019066247 W US2019066247 W US 2019066247W WO 2020123952 A1 WO2020123952 A1 WO 2020123952A1
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WIPO (PCT)
Prior art keywords
dispersion
iti
dioxane
methanol
ratio
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PCT/US2019/066247
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English (en)
Inventor
Peng Li
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Intra-Cellular Therapies, Inc.
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Application filed by Intra-Cellular Therapies, Inc. filed Critical Intra-Cellular Therapies, Inc.
Priority to MX2021006886A priority Critical patent/MX2021006886A/es
Priority to EP19897052.7A priority patent/EP3893878A4/fr
Priority to AU2019398451A priority patent/AU2019398451A1/en
Priority to CA3123085A priority patent/CA3123085A1/fr
Priority to KR1020217021918A priority patent/KR20210103501A/ko
Priority to CN201980092118.2A priority patent/CN113473988A/zh
Priority to JP2021533470A priority patent/JP7523440B2/ja
Publication of WO2020123952A1 publication Critical patent/WO2020123952A1/fr
Priority to IL283927A priority patent/IL283927A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • This disclosure relates to certain novel amorphous solid dispersion formulations of a substituted heterocycle fused gamma-carboline, the manufacture of such dispersions, pharmaceutical compositions comprising such dispersions, and uses thereof, e.g., in the treatment of diseases or abnormal conditions involving or mediated by the 5-HT 2A receptor, serotonin transporter (SERT), and/or dopamine D1/D2 receptor signaling pathways.
  • SERT serotonin transporter
  • ITI- 007 is currently in or has recently completed several clinical trials, i.e., for the treatment of schizophrenia and bipolar depression.
  • GP-007 is a promising drug, its production and formulation present distinct challenges.
  • free base form GP-007 is an oily, sticky solid, with poor solubility in water.
  • Making salts of the compound has proven to be unusually difficult.
  • a hydrochloride salt form of ITI-007 was disclosed in US Patent 7,183,282, but this salt was hygroscopic and showed poor stability.
  • a stable, crystalline toluenesulfonic acid addition salt (tosylate) of ITI-007 was finally identified and described in WO 2009/114181 and U.S. Patent 8,648,077. Each of these publications are incorporated by reference in their entirety.
  • amorphous forms exhibit different dissolution characteristics, and in some cases different bioavailability patterns, compared to crystalline forms of the same drug.
  • one bioavailability pattern may be favored over another.
  • an amorphous form of Cefuroxime axetil exhibits higher bioavailability than the crystalline form.
  • amorphous solid dispersions are a promising alternative to traditional crystalline active pharmaceutical ingredients.
  • amorphous drug forms tend to be unstable. As amorphous forms are thermodynamically unstable relative to the corresponding crystal forms, it is well known that amorphous forms would revert back to the stable crystalline form. This usually occurs during storage under various humidity and temperature conditions. Therefore, in order to utilize the amorphous form of a drug, it is necessary to stabilize it to inhibit crystallization of the drug active during the period of product storage.
  • the present disclosure therefore provides amorphous solid dispersions of ITI-007 in free base form or in tosylate salt form, in admixture with one or more excipients, such as stabilizing excipients.
  • the present disclosure provides three particularly stable amorphous solid dispersions of GP-007 free base comprising (1) ITI-007 free base at a 5:95 to 50:50 weight ratio to cellulose acetate excipient; (2) ITI-007 free base at a 25:75 to 75:25 weight ratio to cellulose acetate phthalate excipient; and (3) ITI-007 free base at a 25:75 to 75:25 weight ratio to hydroxypropyl methyl cellulose phthalate excipient.
  • the present disclosure further provides several amorphous solid dispersions of GP-007 tosylate, optionally further comprising an antioxidant and/or a surfactant.
  • the disclosure thus provides amorphous solid dispersion forms of ITI-007 free base and tosylate salt, which dispersions are especially advantageous for use in the preparation of galenic formulations, together with methods of making and using the same.
  • Figure 1 depicts an overlay of X-ray powder diffraction patterns for dispersions of GP-007 free base with cellulose acetate.
  • Figure 2 depicts an overlay of X-ray powder diffraction patterns for dispersions of GGI-007 free base with cellulose acetate phthalate.
  • Figure 3 depicts an overlay of X-ray powder diffraction patterns for dispersions of GGI-007 free base with hydroxypropyl methyl cellulose phthalate (grade 55) (HPMC-P).
  • the top pattern is the 25:75 ITI-007 free base/excipient dispersion as-generated; the second pattern is the 25:75 dispersion post-stress; the third pattern is the 50:50 ITI-007 free base/excipient dispersion as-generated; the bottom pattern is the 50:50 dispersion post-stress.
  • Figure 4 depicts mDSC and TGA thermograms for a 25:75 dispersion of ITI-007 free base with cellulose acetate.
  • Figure 5 depicts mDSC and TGA thermograms for a 50:50 dispersion of ITI-007 free base with cellulose acetate phthalate.
  • Figure 6 depicts mDSC and TGA thermograms for a 50:50 dispersion of ITI-007 free base with HPMC-P.
  • the present disclosure provides amorphous solid dispersions of l-(4-fluoro-phenyl)-4- ((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH,7H-pyrido[3 , ,4':4,5]pyrrolo[l,2,3- de]quinoxalin-8-yl)-butan-l-one (ITI-007), either in free base form or in tosylate salt form, in admixture with one or more excipients, such as stabilizing excipients
  • the present disclosure provides l-(4-fluoro-phenyl)-4-((6bR,10aS)- B-methyl-l ⁇ bb ⁇ lthlOa-hexahydro-lH H-pyridoP ⁇ SJpyrrolof l ⁇ B-deJquinoxalin-S-yl)- butan-l-one (ITI-007) free base in the form of an amorphous solid dispersion comprising cellulose acetate excipient in a ratio of 5:95 to 50:50 ITI-007 free base to cellulose acetate (Dispersion 1).
  • the present disclosure further provides the following Compositions:
  • Dispersion 1 wherein the dispersion comprises ITI-007 free base and cellulose acetate in a weight ratio of 5:95 up to 50:50, but 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.
  • any foregoing dispersion wherein the dispersion shows a single glass transition temperature (T g ) above 75 °C, e.g., at a temperature above 100 °C, or at a temperature above 150 °C, e.g., as shown by mDSC analysis.
  • T g single glass transition temperature
  • Dispersion 1.5 wherein the dispersion shows a single glass transition temperature above 160 °C, or between 165 °C and 170 °C, or at about 167 °C.
  • ACp change in heat capacity
  • Dispersion 1.8 wherein the dispersion shows less than 8% weight loss up to a temperature of 100 °C, e.g., less than 7% weight loss, or less than 6% weight loss, or less than 5% weight loss, or less than 4% weight loss, or less than 3% weight loss, up to a temperature of 100 °C. 1.10. Any foregoing dispersion, wherein the dispersion shows no changes in appearance or texture after 7 days at 75% relative humidity at 40 °C.
  • Dispersion 1.11 wherein the dispersion shows greater than 95%, or greater than 96%, or greater than 97% or greater than 98%, or greater than 99% chemical stability of ITI-007 after 7 days at 75% relative humidity at 40 °C.
  • any foregoing dispersion wherein the dispersion is manufactured by a method comprising dissolving ITI-007 free base and the selected excipient in a suitable solvent or mixture of solvents and removing the solvent, e.g., by lyophilizing the solution, to obtain the amorphous solid dispersion.
  • Dispersion 1.13 wherein the solvent or mixture of solvents is selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof.
  • Dispersion 1.13 wherein the solvent or mixture of solvents is selected from dioxane, methanol or a dioxane/methanol mixture, e.g., 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.
  • the solvent or mixture of solvents is selected from dioxane, methanol or a dioxane/methanol mixture, e.g., 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.
  • the present disclosure provides GP-007 free base in the form of an amorphous solid dispersion comprising cellulose acetate phthalate excipient in a ratio of 25:75 to 75:25 GP-007 free base to cellulose acetate phthalate (Dispersion 2).
  • the present disclosure further provides the following Compositions:
  • Dispersion 2 wherein the dispersion comprises ITI-007 free base and cellulose acetate phthalate in a weight ratio of from 25:75 up to 75:25, but excluding the ratios 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.
  • Any foregoing dispersion, wherein the dispersion is x-ray amorphous, e.g., as shown by XRPD analysis.
  • any foregoing dispersion wherein the dispersion shows a single glass transition temperature (T g ) above 75 °C, e.g., at a temperature above 85 °C, or at a temperature above 95 °C, e.g., as shown by mDSC analysis.
  • T g single glass transition temperature
  • Dispersion 2.5 wherein the dispersion shows a single glass transition temperature above 100 °C, or between 105 °C and 115 °C, or at about 107 °C.
  • any foregoing dispersion wherein the dispersion shows a change in heat capacity (ACp) of 0.1 to 0.6 J/g-°C, e.g., from 0.2 to 0.5 J/g-°C, or about 0.4 J/g-°C, e.g., as shown by mDSC.
  • ACp change in heat capacity
  • any foregoing dispersion wherein the dispersion shows less than 10% weight loss up to a temperature of 100 °C, e.g., as shown by TGA analysis.
  • Dispersion 2.8 wherein the dispersion shows less than 8% weight loss up to a temperature of 100 °C, e.g., less than 7% weight loss, or less than 6% weight loss, or less than 5% weight loss, or less than 4% weight loss, or less than 3% weight loss, up to a temperature of 100 °C.
  • any foregoing dispersion wherein the dispersion shows greater than 90% chemical stability of ITI-007 after 7 days at 75% relative humidity at 40 °C, e.g., as judged by HPLC.
  • Dispersion 2.11 wherein the dispersion shows greater than 95%, or greater than 96%, or greater than 97% or greater than 98%, or greater than 99% chemical stability of ITI-007 after 7 days at 75% relative humidity at 40 °C.
  • any foregoing dispersion wherein the dispersion is manufactured by a method comprising dissolving ITI-007 free base and the selected excipient in a suitable solvent or mixture of solvents and removing the solvent, e.g., by lyophilizing the solution, to obtain the amorphous solid dispersion.
  • Dispersion 2.13 wherein the solvent or mixture of solvents is selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof.
  • Dispersion 2.13 wherein the solvent or mixture of solvents is selected from dioxane, methanol or a dioxane/methanol mixture, e.g., 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.
  • the solvent or mixture of solvents is selected from dioxane, methanol or a dioxane/methanol mixture, e.g., 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.
  • the present disclosure provides ITI-007 free base in the form of an amorphous solid dispersion comprising hydroxypropyl methyl cellulose phthalate (HPMC-P) excipient in a ratio of 25:75 to 75:25 GP-007 free base to HPMC-P (Dispersion 3).
  • HPMC-P hydroxypropyl methyl cellulose phthalate
  • the present disclosure further provides the following Compositions:
  • Dispersion 3 wherein the dispersion comprises ITI-007 free base and HPMC-P in a weight ratio of from 25:75 up to 75:25, but excluding the ratios 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.
  • 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
  • any foregoing dispersion wherein the dispersion shows a single glass transition temperature (T g ) above 75 °C, e.g., at a temperature above 80 °C, or at a temperature above 85 °C, e.g., as shown by mDSC analysis.
  • T g single glass transition temperature
  • Dispersion 3.5 wherein the dispersion shows a single glass transition temperature above 90 °C, or between 92 °C and 98 °C, or at about 95 °C.
  • ACp change in heat capacity
  • Dispersion 3.8 Any foregoing dispersion, wherein the dispersion shows less than 10% weight loss up to a temperature of 100 °C, e.g., as shown by TGA analysis. 3.9. Dispersion 3.8, wherein the dispersion shows less than 8% weight loss up to a temperature of 100 °C, e.g., less than 7% weight loss, or less than 6% weight loss, or less than 5% weight loss, or less than 4% weight loss, or less than 3% weight loss, up to a temperature of 100 °C.
  • Dispersion 3.11 wherein the dispersion shows greater than 95%, or greater than 96%, or greater than 97% or greater than 98%, or greater than 99% chemical stability of ITI-007 after 7 days at 75% relative humidity at 40 °C.
  • any foregoing dispersion wherein the dispersion is manufactured by a method comprising dissolving ITI-007 free base and the selected excipient in a suitable solvent or mixture of solvents and removing the solvent, e.g., by lyophilizing the solution, to obtain the amorphous solid dispersion.
  • Dispersion 3.13 wherein the solvent or mixture of solvents is selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof.
  • Dispersion 3.13 wherein the solvent or mixture of solvents is selected from dioxane, methanol or a dioxane/methanol mixture, e.g., 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.
  • the solvent or mixture of solvents is selected from dioxane, methanol or a dioxane/methanol mixture, e.g., 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.
  • the present disclosure provides ITI-007 tosylate salt in the form of an amorphous solid dispersion comprising a stabilizing excipient and optionally further comprising an anti-oxidant and/or a surfactant (Dispersion 4).
  • the stabilizing excipient is an excipient which stabilizes the amorphous form of ITI-007 tosylate to prevent conversion of the amorphous form to the crystal form.
  • the present disclosure further provides the following Compositions:
  • Dispersion 4 wherein the dispersion comprises GP-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 methyl cellulose, hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), hydroxypropyl methyl cellulose phthalate (HPMC-P), polyvinyl acetate, polyvinyl pyrrolidone, polyvinyl pyrrolidone/vinyl acetate copolymer, and polyethylene glycol/polyvinyl acetate/polyvinylcaprolactam copolymer.
  • a stabilizing excipient selected from the group consisting of cellulose acetate, cellulose acetate phthalate, methacrylate/methyl acrylate copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
  • Dispersion 4 or 4.1 wherein the composition comprises ITI-007 tosylate salt in admixture with a single stabilizing excipient.
  • Dispersion 4 or 4.1 wherein the composition comprises ITI-007 tosylate salt in admixture with two stabilizing excipients.
  • Dispersion 4 or any of 4.1 to 4.3, wherein the dispersion comprises ITI-007 tosylate salt in admixture 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.
  • the dispersion comprises ITI-007 tosylate salt in admixture 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
  • Dispersion 4 or any of 4.1 to 4.3, wherein the dispersion comprises ITI-007 tosylate salt 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.
  • the dispersion comprises ITI-007 tosylate salt 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:
  • Dispersion 4 or any of 4.1 to 4.3, wherein the dispersion comprises ITI-007 tosylate salt in admixture 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.
  • the dispersion comprises ITI-007 tosylate salt in admixture 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.
  • the stabilizing excipient comprises one or more of cellulose acetate, cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), and hydroxypropyl methyl cellulose phthalate (HPMC-P).
  • the stabilizing excipient comprises one or more of cellulose acetate, cellulose acetate phthalate, and hydroxypropyl methyl cellulose phthalate.
  • Dispersion 4.9 wherein the anti-oxidant is selected from one or more of tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), and ascorbic acid.
  • BHT butylated hydroxytoluene
  • OPG propyl gallate
  • Dispersion 4.9 or 4.10 wherein the dispersion comprises the antioxidant in an amount of 0.1 to 10% by weight, e.g., 0.5 to 5% or 0.5 to 3% by weight of the dispersion.
  • a surfactant for example, an anionic or cationic or neutral surfactants, such as a surfactant which stabilizes the amorphous form of ITI-007 tosylate (e.g., to prevent conversion to an ITI-007 tosylate crystal form).
  • a surfactant for example, an anionic or cationic or neutral surfactants, such as a surfactant which stabilizes the amorphous form of ITI-007 tosylate (e.g., to prevent conversion to an ITI-007 tosylate crystal form).
  • the dispersion is x-ray amorphous, e.g., as shown by XRPD analysis.
  • any foregoing dispersion wherein the dispersion shows a single glass transition temperature (T g ) above 75 °C, e.g., at a temperature above 80 °C, or at a temperature above 90 °C, or a temperature about 100 °C, or at a temperature above 110 °C, e.g., as shown by mDSC analysis.
  • T g single glass transition temperature
  • ACp change in heat capacity
  • Dispersion 4.17 wherein the dispersion shows 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 up to a temperature of 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.
  • any foregoing dispersion wherein the dispersion shows greater than 85% chemical stability of ITI-007 after 7 days at 75% relative humidity at 40 °C, e.g., as judged by HPLC. 4.21.
  • Dispersion 4.20 wherein the dispersion shows greater than 90%, or greater than 95%, or greater than 96%, or greater than 97% or greater than 98%, or greater than 99% chemical stability of ITI-007 after 7 days at 75% relative humidity at 40 °C.
  • any foregoing dispersion wherein the dispersion is manufactured by a method comprising dissolving ITI-007 tosylate salt and the selected excipient(s) in a suitable solvent or mixture of solvents and removing the solvent, e.g., by lyophilizing the solution or evaporating the solvent (e.g., by rotary evaporation), to obtain the amorphous solid dispersion.
  • Dispersion 4.22 wherein the solvent or mixture of solvents is selected from dioxane, methanol, ethanol, tetrahydrofuran, acetone, and mixtures thereof.
  • Dispersion 4.23 wherein the solvent or mixture of solvents is selected from dioxane, methanol or a dioxane/methanol mixture, e.g., 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.
  • the solvent or mixture of solvents is selected from dioxane, methanol or a dioxane/methanol mixture, e.g., 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.
  • Dispersion 4.22, 4.23, or 4.24 wherein the method further comprises adding an anti-oxidant or a surfactant to the solvent mixture prior to removing the solvent.
  • Dispersion 4 may comprise an antioxidant to improve the stability of the ITI-007 tosylate salt amorphous form.
  • the anti-oxidant is selected from one or more of tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), and ascorbic acid.
  • the antioxidant may be selected from additional suitable antioxidants, such as butylated hydroxyanisole (BHA), tert-Butylhydroquinone (TBHQ), carotenoids, glutathione, a metabisulfite salt (e.g., sodium), an ethylenediaminetetraacetate salt (e.g., sodium), cysteine, methionine, sesamol, and citric acid.
  • BHA butylated hydroxyanisole
  • TBHQ tert-Butylhydroquinone
  • carotenoids glutathione
  • glutathione a metabisulfite salt (e.g., sodium)
  • an ethylenediaminetetraacetate salt e.g., sodium
  • cysteine methionine
  • sesamol e.g., sodium
  • citric acid e.g., cysteine, methionine, sesamol
  • the antioxidant may be ethylenediaminetetraacetic acid.
  • Dispersion 4, and any of 4.1-4.26 may comprise a surfactant to improve the stability of the ITI-007 tosylate salt amorphous form.
  • the surfactant is a surfactant which stabilizes the amorphous form ITI-007 tosylate (e.g., to prevent conversion to an ITI-007 tosylate crystal form).
  • the surfactant is selected from one or more of an anionic or cationic or neutral surfactant.
  • Dispersion 4, or any of 4.1-4.26 may further comprise any other excipient which can prevent or inhibit the formation of the crystal form of ITI-007 tosylate, or which can prevent or inhibit the conversion of the amorphous form of ITI-007 tosylate to a crystal form of ITI-007 tosylate.
  • excipients may include polymers, gums, surfactants, wetting agents, drying agents, pH modifiers, fillers, disintegrants, coatings, binders, or any other suitable pharmaceutically acceptable excipients.
  • the present disclosure provides a process (Process 1) for the production of Dispersion 1, et seq., or Dispersion 2, et seq., or Dispersion 3, et seq., comprising the steps of:
  • the present disclosure provides a process (Process 2) for the production of Dispersion 4, et seq., comprising the steps of:
  • Process 2 further comprises the step of adding one or more anti oxidants and/or one or more surfactants to the solvent or mixture of solvents in step (a).
  • the anti-oxidant is selected from one or more of tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), and ascorbic acid.
  • the one or more surfactants may comprise an anionic or cationic or neutral surfactant.
  • the surfactant may be a surfactant which stabilizes the amorphous form ITI-007 tosylate, such as to prevent conversion of the amorphous form to an ITI-007 tosylate crystal form.
  • the antioxidant may be selected from additional suitable antioxidants, such as butylated hydroxyanisole (BHA), tert-Butylhydroquinone (TBHQ), carotenoids, glutathione, a metabisulfite salt (e.g., sodium), an ethylenediaminetetraacetate salt (e.g. sodium), cysteine, methionine, sesamol, and citric acid.
  • BHA butylated hydroxyanisole
  • TBHQ tert-Butylhydroquinone
  • carotenoids glutathione
  • glutathione a metabisulfite salt (e.g., sodium)
  • an ethylenediaminetetraacetate salt e.g. sodium
  • cysteine methionine
  • sesamol e.g. sodium
  • citric acid e.g. sodium
  • the antioxidant may be ethylenediaminetetraacetic acid.
  • the solvent or mixture of solvents for Process 1 is selected from dioxane, methanol or a dioxane/methanol mixture, e.g., 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.
  • the solvent or mixture of solvents for Process 2 is selected from dioxane, methanol or a dioxane/methanol mixture, e.g., 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.
  • Solid dispersion refers to the dispersion of an active pharmaceutical ingredient, i.e., ITI-007, in an inert excipient or matrix (carrier), where the active ingredient could exist in a finely crystalline, solubilized or amorphous state.
  • the excipient in a solid dispersion is typically a polymer.
  • the most important role of the polymer in a solid dispersion is to reduce the molecular mobility of the pharmaceutical active to avoid phase separation and re-crystallization of the active during storage.
  • the amorphous form of the active is associated with a higher energy state as compared to its crystalline counterpart, and therefore, significantly less external energy is required to effect dissolution (e.g., in the gastrointestinal tract or elsewhere in the body).
  • composition 1 comprising Dispersion 1, et seq., or Dispersion 2, et seq., or Dispersion 3, et seq., or Dispersion 4, et seq., in combination or association with a pharmaceutically acceptable diluent or carrier.
  • the pharmaceutical composition is in the form of a tablet or capsule for oral administration.
  • the pharmaceutical composition is in the form of a depot formulation for use as a long-acting injectable (LAI).
  • LAI long-acting injectable
  • the pharmaceutical composition may further comprise any suitable pharmaceutically acceptable excipient, such as: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, xylitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones such as polyvinylpyrrolidones (PVP K-30,K-90), poly(vinyl pyrrolidone-co-vinyl acetate) (PVP-VA) and the like, hydroxypropyl celluloses, hydroxypropyl methylcellulose, cellulose acetate, hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones,
  • the composition may further comprise one or more anti-oxidants, for example, tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), and ascorbic acid, or the like.
  • BHT butylated hydroxytoluene
  • OPG propyl gallate
  • ascorbic acid or the like.
  • the inclusion of an anti-oxidant may further improve the chemical stability of the dispersions by preventing oxidative chemical degradation of the ITI-007 active.
  • the dispersion itself is formulated to include such an anti-oxidant.
  • Suitable anti-oxidants include butylated hydroxyanisole (BHA), tert-Butylhydroquinone (TBHQ), carotenoids, glutathione, a metabisulfite salt (e.g., sodium), an ethylenediamine- tetraacetate salt (e.g. sodium), ethylenediaminetetraacetic acid, cysteine, methionine, sesamol, and citric acid.
  • BHA butylated hydroxyanisole
  • TBHQ tert-Butylhydroquinone
  • carotenoids glutathione
  • glutathione a metabisulfite salt
  • an ethylenediamine- tetraacetate salt e.g. sodium
  • ethylenediaminetetraacetic acid cysteine, methionine, sesamol, and citric acid.
  • the composition may further comprise any excipient which can prevent or inhibit the formation of the crystal form of ITI-007 free base or ITI-007 tosylate, or which can prevent or inhibit the conversion of the amorphous form of ITI-007 free base or ITI-007 tosylate to a crystal form thereof.
  • excipients may include polymers, gums, surfactants, wetting agents, drying agents, pH modifiers, fillers, disintegrants, coatings, binders, or any other suitable pharmaceutically acceptable excipients.
  • excipients include any one or more of the excipients described in paragraph [0038] above.
  • the present disclosure provides Dispersion 1, et seq., or Dispersion 2, el seq., or Dispersion 3, et seq., or Dispersion 4, et seq., or a pharmaceutical composition comprising Dispersion 1, et seq., or Dispersion 2, et seq., or Dispersion 3, et seq., or Dispersion 4, et seq., e.g., Composition 1, for use in treating a disease or abnormal condition involving or mediated by the 5- HT2 A receptor, serotonin transporter (SERT), and/or dopamine D1/D2 receptor signaling pathways (including Di-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-compul
  • 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., a short-duration anxious episode associated with generalized anxiety disorder, panic disorder, specific phobias, or social anxiety disorder, or social avoidance), including treatment resistant depression (e.g., depression which has not responded to treatment with an antidepressant agent 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 SR I/NR I, an SR I/DR I, an NRI/DRI, an SR I/NR I/DR I (triple reuptake inhibitor), a serotonin receptor antagonist, or any combination thereof
  • the invention provides a method for the prophylaxis or treatment of a human suffering from a disease or abnormal condition involving or mediated by the 5-HT 2A receptor, serotonin transporter (SERT), and/or dopamine D1/D2 receptor signaling pathways (including Di-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 disorders, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, social phobias, 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, et seq., or Dispersion 2, et seq., or Dispersion
  • 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., a short- duration anxious episode associated with generalized anxiety disorder, panic disorder, specific phobias, or social anxiety disorder, or social avoidance), including treatment resistant depression (e.g., depression which has not responded to treatment with an antidepressant agent 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 SR I/NR I/DR I (triple reuptake inhibitor), a serotonin receptor antagonist, or any combination thereof), bipolar
  • X-ray powder diffraction (XRPD): The X-ray powder diffraction studies are performed using a PANalytical X’Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror is used to focus Cu Koc X-ray radiation through the specimen and onto the detector. Prior to analysis, a silicon specimen is analyzed to verify the observed position of the Si (111) peak (consistent with the NIST-certified position, NIST SM 640e). A specimen of the sample is sandwiched between 3-micron thick films and analyzed in transmission geometry.
  • TGA Thermogravimetry analysis: TGA is performed using a TA Instruments Q5000 or Discovery thermogravimetric analyzer. The sample is placed in an aluminum sample pan and is inserted into the TG furnace. Samples are heated from ambient temperature to 250 °C at a rate of 10 °C/minute. Nickel and Alumel are used as the calibration standards.
  • mDSC data is 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. The sample is placed into an aluminum T-zero DSC pan, covered with a lid, and the weight is accurately recorded. A weighed aluminum pan configured as the sample pan is placed on the reference side of the cell. Typically, the start temperature is - 50 °C and the end temperature is 250 °C, with a modulation amplitude of ⁇ 1°C and a 50 second period with an underlying heating rate of 2 °C per minute.
  • High performance liquid chromatography HPLC: The high-performance liquid chromatography analyses are performed using an Agilent 1100 series liquid chromatograph equipped with a diode array detector, degasser, quaternary pump, and an auto sampler.
  • the column is a 4.6 x 100mm CSH C18 column with 2.5-micron packing (XSelect) running with a 0.1% TFA in water mobile phase A and a 0.1% TFA in acetonitrile mobile phase B, at a flow rate of 0.500 mL/minute.
  • the gradient runs from 95% A to 73% over the first 22 minutes, followed by 6 minutes at 73% A, and followed by 73% A to 30% A over the next 22 minutes.
  • the column temperature is set to 15.0 °C, and the detector wavelength is 254 nm with a bandwidth of 100 nm and a reference wavelength of 360 nm.
  • the injection volume is 2.0 microliters.
  • Solubility of ITI-007 free base and various excipients is first evaluated in various solvents. It is found that ITI-007 free base shows good solubility (> 50 mg/mL) in acetone, ethanol, methanol, dioxane, and 2,2,2-trifluoroethanol (TFE), but relatively poor 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.
  • the excipients evaluated are Eudragit L100, polyvinyl acetate, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone K-90, polyvinylpyrrolidone S-630, cellulose acetate, cellulose acetate phthalate, Gelucire 50/13, glyceryl monostearate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose 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 the ratios 25:75, 50:50 and 75:25 ITI-007 free base to excipient.
  • Solid dispersions are successfully prepared by lyophilization from solutions of ITI-007 free base and excipient in either dioxane or dioxane-methanol (90: 10, 91:9, 92:8, 93:7 or 94:6). Solutions are initially frozen in a dry ice/acetone bath, and then placed in a freeze dryer with the shelf pre-cooled to -75 °C. Samples are dried overnight at -50 °C, followed by -20 °C, then 0 °C over a period of two days. Samples are then secondary dried at 20 °C for four hours, purged with nitrogen then stored in a freezer over desiccant until testing.
  • Solid dispersions obtained from Example 1 are first evaluated by XRPD to determine if they are amorphous. All lyophilization samples using amorphous excipients are found to be x-ray amorphous by XRPD. Lyophilization samples using crystalline excipients (Gelucire 50/13, PEG, PEG- 1000 succinate, Pluronic F-127) are found to be disordered with peaks present corresponding only to the excipient. Further observations of the appearance of the solids are shown in Table 1 below. The 50:50 ITI-007/PEG-1000 succinate dispersion is found to be very sticky and is not further evaluated.
  • Example 1 Solid dispersions from Example 1 are placed into uncapped clear glass vials and the vials are placed into a container maintained for seven days at 75% relative humidity and a temperature of 40 °C.
  • a sample of ITI-007 free base is analyzed in parallel. Samples were observed visually as well as by polarized light microscopy (0.8-10 x magnification with crossed polarizers and a first order red compensator). Observations are shown in Table 1. The majority of samples display changes in appearance or texture, indicating the formation of physically unstable amorphous dispersions. For example, some show visible crystallization while others become sticky solids or oils.
  • Dispersions which are physically stable free-flowing solids are further analyzed by XRPD to confirm that they remain x-ray amorphous or disordered with excipient peaks only.
  • the XRPD results confirm that the visually stable samples remain X-ray amorphous dispersions.
  • mDSC and TGA analysis is conducted on the physically stable free-flowing samples.
  • a single glass transition temperature in mDSC supports the conclusion that the solid is a non crystalline miscible dispersion.
  • the two PEG dispersions show an unacceptable low-temperature glass transition at 9 or 10 °C, while the glyceryl monostearate dispersion shows no glass transition.
  • the 50:50 cellulose acetate dispersion shows two glass transition temperatures, which suggests a phase-separated material, which is unacceptable.
  • HPMC-AS dispersions as well as the 25:75 HPMC-P dispersion show very high material losses by HPLC.
  • the 25:75 cellulose acetate phthalate dispersion shows a low but unacceptable loss of material. Only seven dispersions produce 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 thus chemically stable.
  • the 25:75 dispersion of ITI-007 tosylate with cellulose acetate produced crystallization of ITI-007 during the aging study; the 50:50 dispersion of ITI- 007 tosylate with cellulose acetate phthalate showed about a 52% decrease in ITI-007 content by HPLC; and the 50:50 dispersion of ITI-007 tosylate with HPMC-P showed about a 68% decrease in P ⁇ -007 content by HPLC.
  • ITI-007 tosylate is chemically more stable than ITI-007 free base.
  • the three specific amorphous solid dispersions of ITI-007 free base are physically and chemically stable whereas the corresponding dispersions of ITI-007 tosylate salt are not.
  • ITI-007 tosylate salt as the active ingredient. It is found that ITI-007 tosylate has good solubility (> 50 mg/mL) in 2,2,2-trifluoroethanol (TFE) and in a 60:40 v/v mixture of tert-butanol/water, but relatively poor solubility (20-40 mg/mL) in acetone, ethanol, dioxane and other tert-butanol/water mixtures. However, it is also found that solutions of GP-007 tosylate salt in TFE rapidly discolor due to decomposition of the active.
  • TFE 2,2,2-trifluoroethanol
  • a pharmaceutical formulation comprising ITI-007 tosylate salt in 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 a surfactant and/or an anti oxidant as described herein.

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Abstract

L'invention concerne de nouvelles dispersions solides amorphes,stables, pharmaceutiquement acceptables de 1-(4-fluoro-phényl)-4-((6bR,10aS)-3-méthyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3'4':4,5]pyrrolo[1,2,3-dé]quinoxalin-8-yl)-butan-1-one, ainsi que leurs procédés de production et d'utilisation, et des compositions pharmaceutiques les comprenant.
PCT/US2019/066247 2018-12-14 2019-12-13 Dispersions solides amorphes WO2020123952A1 (fr)

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AU2019398451A AU2019398451A1 (en) 2018-12-14 2019-12-13 Amorphous solid dispersions
CA3123085A CA3123085A1 (fr) 2018-12-14 2019-12-13 Dispersions solides amorphes
KR1020217021918A KR20210103501A (ko) 2018-12-14 2019-12-13 비결정성 고체 분산체
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EP3843738A4 (fr) * 2018-08-31 2022-06-01 Intra-Cellular Therapies, Inc. Nouvelles méthodes

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WO2018031535A1 (fr) * 2016-08-09 2018-02-15 Assia Chemical Industries Ltd. Formes à l'état solide de sel de ditosylate lumateperone
WO2018071233A1 (fr) * 2016-10-12 2018-04-19 Intra-Cellular Therapies, Inc. Dispersions solides amorphes
WO2018189646A1 (fr) * 2017-04-10 2018-10-18 Dr. Reddy's Laboratories Limited Forme amorphe et dispersions solides de p-tosylate de lumateperone
WO2019102240A1 (fr) * 2017-11-27 2019-05-31 Egis Gyógyszergyár Zrt. Procédé pour la fabrication de lumatépérone et de ses sels

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KR20210052471A (ko) * 2018-08-31 2021-05-10 인트라-셀룰라 써래피스, 인코퍼레이티드. 신규한 방법

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WO2018031535A1 (fr) * 2016-08-09 2018-02-15 Assia Chemical Industries Ltd. Formes à l'état solide de sel de ditosylate lumateperone
WO2018071233A1 (fr) * 2016-10-12 2018-04-19 Intra-Cellular Therapies, Inc. Dispersions solides amorphes
WO2018189646A1 (fr) * 2017-04-10 2018-10-18 Dr. Reddy's Laboratories Limited Forme amorphe et dispersions solides de p-tosylate de lumateperone
WO2019102240A1 (fr) * 2017-11-27 2019-05-31 Egis Gyógyszergyár Zrt. Procédé pour la fabrication de lumatépérone et de ses sels

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EP3843738A4 (fr) * 2018-08-31 2022-06-01 Intra-Cellular Therapies, Inc. Nouvelles méthodes

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