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WO2025052301A1 - Compositions comprising aticaprant for use in treating major depressive disorder - Google Patents

Compositions comprising aticaprant for use in treating major depressive disorder Download PDF

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Publication number
WO2025052301A1
WO2025052301A1 PCT/IB2024/058663 IB2024058663W WO2025052301A1 WO 2025052301 A1 WO2025052301 A1 WO 2025052301A1 IB 2024058663 W IB2024058663 W IB 2024058663W WO 2025052301 A1 WO2025052301 A1 WO 2025052301A1
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WIPO (PCT)
Prior art keywords
aticaprant
weight
pharmaceutical composition
patient
filler
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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PCT/IB2024/058663
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French (fr)
Inventor
Anne-Gaëlle DOSNE
Navinkumar Subhash GOYAL
Chakradhar Lagishetty
Xia Li
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Janssen Pharmaceuticals Inc
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Janssen Pharmaceuticals Inc
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Publication of WO2025052301A1 publication Critical patent/WO2025052301A1/en
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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61P25/24—Antidepressants

Definitions

  • the present disclosure relates to methods of treating major depressive disorder in certain patient populations by administration of aticaprant, including oral compositions of aticaprant in the form of tablets.
  • KOR Kappa opioid receptors
  • KOR native ligand dynorphin
  • chronic stress, substance abuse, and acute withdrawal lead to increased dynorphin expression, activating KORs and subsequent downstream signaling pathways to inhibit mesolimbic dopamine surge, contributing to negative affective states.
  • the behavioral pharmacology of KOR antagonism has been tested in animal models of anhedonia, depression, and anxiety and found to have meaningful effects that may translate to therapeutic benefit in humans.
  • KOR antagonists may be effective for the treatment of patients with mood disorders, perhaps by modulating the negative affective state associated with stress response.
  • the disclosure provides methods of treating major depressive disorder in a human patient, comprising administering a pharmaceutical composition comprising about 5 mg of aticaprant to the human patient, wherein the human patient had a previous inadequate response to other antidepressant therapy and wherein the human patient has a weight less than about 55 kg.
  • patient populations typically comprise adolescents, including those from 12 years old to less than 18 years old.
  • the disclosure provides oral tablets comprising about 5 mg aticaprant, wherein the oral tablet comprises a core tablet of about 100 mg, wherein the core tablet comprises an intragranular and extragranular phase, wherein the intragranular phase comprises about 30 mg microcrystalline cellulose, about 30 mg lactose monohydrate, about 2.5 mg croscarmellose sodium, and about 0.5 mg silica, colloidal anhydrous; and wherein the extragranular phase comprises about 28.5 mg silicified microcrystalline cellulose, about 2.5 mg croscarmellose sodium, about 0.5 mg silica, colloidal anhydrous, and about 0.5 mg magnesium stearate.
  • the disclosure provides methods of treating major depressive disorder (MDD) in a human patient comprising administering to the patient the pharmaceutical composition, oral tablet, or solid pharmaceutical composition described herein.
  • MDD major depressive disorder
  • FIG. 1 is the flow chart for the process for preparing tablets containing aticaprant.
  • a refers to microfine, i.e., milled aticaprant.
  • FIG. 2 is a schematic for the adult population pharmacokinetic model development.
  • FIG. 3 is a schematic of the workflow for the simulation of aticaprant exposures in adult and adolescent populations.
  • Fig. 4 are graphs showing the matching aticaprant exposures in adolescent and adult populations.
  • left figures 90% prediction interval of simulated aticaprant steady-state AUC(0-24h) in adolescents (shaded areas) as function of body weight (upper left) and age (lower left), compared to the adult simulated median exposure value (dashed line) and 5th and 95th percentiles (dotted lines) for Scenario 5 (aticaprant 5 mg QD for ⁇ 45 kg and 10 mg QD for >45 kg).
  • Scenario 5 (aticaprant 5 mg QD for ⁇ 45 kg and 10 mg QD for >45 kg).
  • right figures Proportion of adolescents within the 5th and 95th simulated percentiles of steady-state AUC(0-24h) in adults as function of body weight (upper right) and age (lower right), for the five different dosing regimens scenarios.
  • FIG. 5 is a graph showing the body weight distributions in adolescents and the proportion P of adolescents 12 to ⁇ 18 years below 45 (green) and 50 (red) kg, respectively.
  • compositions comprising pure crystalline Form of III aticaprant that are anhydrous and stable in the solid form.
  • crystalline refers to a solid form of a chemical moiety that contains a highly ordered intermolecular structure.
  • polymorph refers to a crystalline form of a molecule having one specific crystal structure.
  • a crystalline compound may have one crystal form or may have two or more crystal forms, i.e., polymorphs.
  • polymorphs of a chemical compound may distinguished from each other by compared physicochemical properties such as solubility, dissolution rate, stability, bioavailability, among others.
  • Polymorphs also may have different spectra selected from, without limitation, x-ray powder diffraction (XRPD), single crystal x-ray diffraction, thermogravimetric analysis (TGA), infrared spectroscopy, Raman spectroscopy, solid state nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), polarized light microscopy (PLM), hot stage microscopy, or dynamic solvent sorption.
  • XRPD x-ray powder diffraction
  • TGA thermogravimetric analysis
  • infrared spectroscopy Raman spectroscopy
  • NMR solid state nuclear magnetic resonance
  • DSC differential scanning calorimetry
  • PLM polarized light microscopy
  • hot stage microscopy or dynamic solvent sorption.
  • crystalline refers to solid state form of a chemical moiety wherein the atoms, molecules, or ions are assembled in a highly ordered structure that extends in all directions.
  • crystalline includes all crystalline forms of Compound I, including salts thereof. Characterization of crystalline forms may be performed by those skilled in the art including, without limitation, XRPD or DSC. Typically, the XRPD pattern contains sharp intensity peaks. This contrasts to the XRPD pattern of an amorphous form that often contains a broad, peak, without no identifying peaks.
  • a crystalline form may be completely crystalline or partially crystalline. In some aspects, a crystalline sample may be 100% w/w crystalline.
  • a crystalline sample may also contain solids that are amorphous.
  • a crystalline form may contain solids such that the sample is at least about 99% w/w crystalline, at least about 95% w/w amorphous, at least about 90% w/w crystalline, at least about 85% w/w crystalline, at least about 80% w/w crystalline, or the like.
  • anhydrous or “anhydrate” as used herein refers to a crystalline as described herein that substantially lacks water.
  • an anhydrous form contains less than about 1% w/w of water.
  • an anhydrous form contains less than about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1% w/w of water.
  • temperatures may vary. Such variations may depend on instrument type, instrument parameters, laboratory techniques, and/or laboratory conditions. Unless otherwise defined, a recited temperature may vary. In some aspects, the temperatures noted herein vary by about 0.1°, about 0.5°, about 1°, about 2°, about 3°, about 4°, or about 5°.
  • 20 values obtained from the XRPD patterns also may vary. Such variations may depend on instrument type, instrument parameters, laboratory techniques, sample (including particle size, impurities, etc.), and/or laboratory conditions. Unless otherwise defined, the XRPD patterns and/or the 20 peak values may vary. In certain aspects, the 20 peak values vary (higher or lower) by about 0.05°, about 0.1°, about 0.15°, or about 0.2°. In other aspects, one or more of the 20 peak values are higher by about 0.05°, about 0.1°, about 0.15°, or about 0.2°. In further aspects, one or more of the 20 peak values are lower by about 0.05°, about 0.1°, about 0.15°, or about 0.2°.
  • the term “corresponds to” may be used in reference to certain spectra.
  • “corresponds to” includes a spectrum that is identical or substantially similar to another spectrum.
  • One skilled in the art would be able to compare such spectra and determine if a spectrum corresponds to another.
  • the term “corresponds to” is used herein to compare XRPD patterns, DSC thermograms, among others.
  • one XRPD pattern corresponds to another XRPD pattern when their 20 values are within the margin of error as described above.
  • one XRPD pattern corresponds to another XRPD pattern when the peaks have the same 20 peak value, but one or more peaks have a different height (intensity).
  • one XRPD pattern corresponds to another XRPD pattern when the peaks have the same 20 peak value, but one or more peaks have a different peak area.
  • one XRPD pattern corresponds to another XRPD pattern when the peaks have the same 20 peak value, but one or more peak is obscured. Such obscured peaks may be due to impurities, excipients, or the like. Such obscured peaks typically do not prevent characterization of the crystalline form.
  • aticaprant refers to 3- fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-l-yl-methylphenoxybenzamide, i.e. , the following compound: and is also known as JNJ-67953964, 67953964- AAA, CERC-501, and LY-2456302.
  • “aticaprant” refers to the (S)-enantiomer of aticaprant, i.e., the following also known as (S)-aticaprant or (S)-3-fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-l-yl- methylphenoxybenzamide.
  • the aticaprant used in the methods described herein is substantially free of the (R)-enantiomer, i.e., (R)-aticaprant or (R)-3- fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-l-yl-methylphenoxybenzamide having the following structure:
  • the aticaprant contains less than about 10% by weight, based on the weight of aticaprant, of the (R)-enantiomer of aticaprant. In further embodiments, aticaprant contains less than about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, about 1, about 0.5, about 0.1, about 0.005, or about 0.001% by weight, based on the weight of aticaprant, of the (R)-enantiomer of aticaprant. In yet other embodiments, the aticaprant contains about 0.001 to about 10% by weight, based on the weight of aticaprant, of the (R)-enantiomer of aticaprant.
  • the aticaprant contains about 0.001 to about 10%, about 0.001 to about 5%, about 0.001 to about 1%, about 0.001 to about 0.5%, about 0.001 to about 0.1%, about 0.1 to about 5%, about 0.1 to about 1%, about 0.1 to about 5%, or about 0.5 to about 5% by weight, based on the weight of aticaprant.
  • compositions of aticaprant are also contemplated by the present invention, which may be readily selected by those skilled in the art.
  • a “pharmaceutically acceptable salt” refers a salt of aticaprant that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, G.S. Paulekuhn, “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665-72, S.M. Berge, “Pharmaceutical Salts”, J. Pharm.
  • salts examples include those that are pharmacologically effective and suitable for administration to patients without undue toxicity, irritation, or allergic response.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, bromides (such as hydrobromides), iodides (such as hydroiodides), acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4-dioates, hexyne- 1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylene
  • the aticaprant is crystalline Form III of aticaprant.
  • Crystalline Form III of aticaprant may be characterized by a number of techniques including, without limitation, x-ray diffraction and differential scanning calorimetry.
  • crystalline Form III of aticaprant is characterized by x-ray diffraction.
  • crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 20 ( ⁇ 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4°.
  • crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 20 ( ⁇ 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° and one or more additional peaks at 16.4°, 20.1°, 20.3°, 24.1°, and 25.7°.
  • crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 20 ( ⁇ 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° and one or more additional peaks at 15.1°, 16.4°, 20.0°, 20.1°, 20.3°, 24.1°, 25.0°, 25.7°, 26.2°, and 28.8°.
  • crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 20 ( ⁇ 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° and one or more additional peaks at 8.2°, 9.7°, 12.0°, 13.5°, 15.1°, 16.4°, 19.4°, 28.4°, 20.0°, 20.1°, 20.3°, 24.1°, 25.0°, 25.7°, 26.2°, 28.8°, and 30.0°.
  • crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 20 ( ⁇ 0.2) of In still other embodiments, crystalline Form III of aticaprant is characterized the x-ray diffraction pattern peaks in Table 2. ,
  • Crystalline Form III of aticaprant may also be characterized by differential scanning calorimetry.
  • the differential scanning calorimetry thermogram comprises a peak temperature (T m ) at about 121 °C.
  • composition comprising aticaprant and one or more pharmaceutically acceptable excipient.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • the preferred pharmaceutical composition contains crystalline Form III of aticaprant as the active ingredient intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
  • the amount of aticaprant present in the compositions is about 5 mg, and, in particular embodiments, the amount is 5 mg.
  • the composition contains about 4.9 mg to about 5.1 mg of aticaprant. In other embodiments, the composition contains about 4.9, about 5, or about 5.1 mg of aticaprant.
  • the composition contains about 4.9% to about 5.1% by weight of aticaprant, based on a 100 mg core tablet. In some embodiments, the composition contains about 4.9, about 5, or about 5.1% by weight, based on the weight of the composition, of aticaprant.
  • the composition contains about 4.9 to about 5.1, about 4.9 to about 5, or about 5 to about 5.1% by weight, based on the weight of the composition, of aticaprant. In further embodiments, the composition contains about 5% by weight of aticaprant. In yet other embodiments, the composition contains about 4.9% by weight of aticaprant. In still further embodiments, the composition contains about 5.1% by weight of aticaprant.
  • the amount of aticaprant for administration according to the methods described herein may be determined by one skill in the art and, unless otherwise noted, are set forth on an aticaprant free base basis. That is, the amounts indicate that amount of the aticaprant molecule administered, exclusive of, for example, solvent (such as in solvates) or counterions (such as in pharmaceutically acceptable salts).
  • the pharmaceutical compositions have a particular pharmacokinetic (PK) profile at a specific dose.
  • the pharmaceutical compositions have a PK profile that is dose-proportional.
  • the pharmaceutical compositions have a PK profile comprising parameters, e.g., exposure parameters such as Cmax or AUC, that are dose-proportional.
  • the pharmaceutical compositions have a PK profile or PK parameter that is dose -proportional to about 5 mg aticaprant, about 4.9 mg aticaprant, or about 5.1 mg aticaprant.
  • Some embodiments include pharmaceutical compositions comprising aticaprant that are bioequivalent to any one of the pharmaceutical compositions described herein. Bioequivalence may be demonstrated by any method known to one skilled in the art, for example, as described in Chow, Bioavailability and Bioequivalence in Drug Development, Wiley interdisciplinary reviews, Computational statistics, 6, 4 (2014): 304-
  • the pharmaceutical composition comprises about 5 mg aticaprant, wherein when the pharmaceutical composition is compared to a reference composition, the 90% confidence interval of the ratio of geometric means of one or more PK parameters of the pharmaceutical composition and reference composition is within the bioequivalence limits of 80% and 125%.
  • the PK profile is based on administration of the composition, containing about 5 mg aticaprant, to a human after at least a 10-hour fast. In other embodiments, the PK profile is based on administration of the composition, containing about 5 mg aticaprant, to a human about 30 minutes after the start of a high-fat meal following at least a 10-hour fast. In further embodiments, the PK profile is based on administration of the composition, containing about 5 mg aticaprant, to a human after at least a 10-hour fast. In yet other embodiments, the PK profile is based on administration of a composition containing about 5 mg aticaprant to a human. In still further embodiments the PK profile is based on administration of a composition containing 4.9 to about 5.1, about 4.9 to about 5, or about 5 to about 5.1 mg of aticaprant to a human.
  • the PK profile is determined after an at least 10-hour food fast.
  • the food fast is at least about 1, about 2, about 4, about 5, about 10, about 12, about 15, about 18, about 20, about 22, about 24, about 28, or about 32 hours.
  • the compositions contain a pharmaceutically acceptable excipient, one of which may be a filler.
  • the filler is the filler is microcrystalline cellulose, lactose monohydrate, or silicified microcrystalline cellulose, or a combination thereof.
  • the filler is microcrystalline cellulose.
  • the filler is lactose monohydrate.
  • the filler is silicified microcrystalline cellulose.
  • the composition comprises between about 10% to about 99.9% filler by weight, based on the weight of the composition.
  • the composition contains about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, or about 99.9% by weight, based on the weight of the composition, of a filler
  • the composition comprises about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 99.9, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 99.9, about 30
  • the composition comprises about 90% by weight, based on the weight of the composition, of the filler. In other embodiments, the composition comprises about 88.5% by weight, based on the weight of the composition, of the filler.
  • the aticaprant to filler ratio is between about 0.005 and about 9 by weight.
  • the aticaprant to filler ratio is about 0.008 and 0.8 about by weight. In other embodiments, the aticaprant to filler ratio is about 0.005 to about 8, about 0.005 to about 7, about 0.005 to about 6, about 0.005 to about 5, about 0.005 to about 4, about 0.005 to about 3, about 0.005 to about 2, about 0.005 to about 1, about 0.005 to about 0.5, about 0.005 to about 0.1, about 0.005 to about 0.05, about 0.005 to about 0.01, about 0.01 to about 9, about 0.01 to about 8, about 0.01 to about 7, about 0.01 to about 6, about 0.01 to about 5, about 0.01 to about 4, about 0.01 to about 3, about 0.01 to about 2, about 0.01 to about 1, about 0.01 to about 0.5, about 0.01 to about 0.1, about 0.01 to about 0.05, about 0.05 to about 9, about 0.05 to about 8, about 0.05 to about 7, about 0.05 to about 6, about 0.05 to about 5, about 0.05 to about 4, about 0.05 to about 3, about 0.005 to about
  • the composition may further comprise one or more of a filler, disintegrant, glidant, lubricant, solvent, coloring agent, binder buffers, preservatives, penetration agents, wetting agents, surfactants, solubilizing agents, thickening agents, colorants, antioxidants, emulsifying agents, isotonizing agents, suspending agents, and/or viscosity increasing agents.
  • a filler disintegrant, glidant, lubricant, solvent, coloring agent, binder buffers, preservatives, penetration agents, wetting agents, surfactants, solubilizing agents, thickening agents, colorants, antioxidants, emulsifying agents, isotonizing agents, suspending agents, and/or viscosity increasing agents.
  • the composition further comprises one or more of a disintegrant.
  • disintegrants useful in the compositions include, e.g., the disintegrant is croscarmellose sodium.
  • the composition comprises between about 0.5% to about 50% by weight, based on the weight of the composition, of the disintegrant.
  • the composition comprises about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50% by weight, based on the weight of the composition, of the disintegrant.
  • the composition comprises about 0.5 to about 40%, about 0.5 to about 30%, about 0.5 to about 20%, about 0.5 to about 10%, about 0.5 to about 5%, about 0.5 to about 4%, about 0.5 to about 3%, about 0.5 to about 2%, about 0.5 to about 1%, about 5 to about 50%, about 5 to about 40%, about 5 to about 30%, about 5 to about 20%, about 5 to about 10%, about 10 to about 50%, about 10 to about 40%, about 10 to about 30%, about 10 to about 20%, about 20 to about 50%, about 20 to about 40%, about 20 to about 30%, about 30 to about 50%, about 30 to about 40%, or about 40 to about 50% by weight, based on the weight of the composition of the disintegrant.
  • the composition comprises about 5% by weight, based on the weight of the composition, of the disintegrant.
  • the aticaprant to disintegrant ratio is between about 0.1 and 10 by weight. In some embodiments, the aticaprant to disintegrant ratio is about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 by weight.
  • the aticaprant to disintegrant ratio is about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 10, about 0.5 to about 9, about 0.5 to about 8, about 0.5 to about 7, about 0.5 to about 6, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 6, about 3 to about 5, about 3 to about 4, about 4 to to to about 4 to to about
  • the composition further comprises one or more of a glidant.
  • glidants useful in the compositions include, e.g., silica, colloidal anhydrous.
  • the composition comprises between about 0.1% to about 10% glidant by weight, based on the weight of the composition.
  • the composition contains about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10% by weight, based on the weight of the composition, of the glidant.
  • the composition contains about 0.1 to about 9, about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about
  • the composition contains about 1 % by weight, based on the weight of the composition, of the glidant.
  • the aticaprant to glidant ratio is between 0.5 and 50 by weight. In some embodiments, the aticaprant to glidant ratio is about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 by weight.
  • the aticaprant to glidant ratio is about 0.5 to about 50, about 0.5 to about 45, about 0.5 to about 40, about 0.5 to about 35, about 0.5 to about 30, about 0.5 to about 25, about 0.5 to about 20, about 0.5 to about 15, about 0.5 to about 10, about 0.5 to about 5, about 0.5 to about 1, about 1 to about 50, about 1 to about 45, about 1 to about 40, about 1 to about 35, about 1 to about 30, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 5, about 5 to about 50, about 5 to about 45, about 5 to about 40, about 5 to about 35, about 5 to about 30, about 5 to about 25, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 50, about 10 to about 45, about 10 to about 40, about 10 to about 35, about 10 to about 30, about 10 to about 25, about 10 to about 20, about 10 to about 15, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about about
  • the composition further comprises one or more of a lubricant.
  • lubricants useful in the compositions include, e.g., the lubricant is magnesium stearate.
  • the composition comprises between about 0.05% to about 5% lubricant by weight, based on the weight of the composition. In some embodiments, the composition comprises about 0.05, about 0.1, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5 or about 5% by weight, based on the weight of the composition, of lubricant.
  • the composition comprises about 0.05 to about 4.5, about 0.05 to about 4, about 0.05 to about 3, about 0.05 to about 2, about 0.05 to about 1, about 0.05 to about 0.5, about 0.05 to about 0.1, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5% by weight, based on the weight of the composition, of lubricant.
  • the composition comprises about 0.5% by weight, based on the weight of the composition, of the lubricant.
  • the aticaprant to lubricant ratio is between about 1 and about 100 by weight. In some embodiments, the aticaprant to lubricant ratio is about 1, about 5, 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100 by weight.
  • the aticaprant to lubricant ratio is 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 5 to about 100, about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 5 to about 100, about 5 to about 90, about 5 to about 80, about 5 to about 70, about 5 to about 60, about 5 to about 50, about 5 to about 40, about 5 to about 30, about 5 to about 20, about 5 to about 10, about 10 to about 100, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 100, about 20 to about 90,
  • the composition comprises one or more of an aticaprant to filler ratio between 0.005 and 9 by weight; an aticaprant to disintegrant ratio between 0.1 and 10 by weight; an aticaprant to glidant ratio between 0.5 and 50 by weight; and an aticaprant to lubricant ratio between 1 and 100 by weight.
  • the composition comprises one or more of an aticaprant to filler ratio of about 0.06 by weight; an aticaprant to disintegrant ratio of about 1 by weight; an aticaprant to glidant ratio of about 5 by weight; and an aticaprant to lubricant ratio of about 10 by weight.
  • the composition comprises about 5% by weight of aticaprant, about 88.5% by weight of filler, about 5% by weight of disintegrant by weight, about 1% by weight of glidant, and about 0.5% by weight of lubricant, based on the weight of the composition.
  • the pharmaceutical composition comprises one or more of a filler, disintegrant, glidant, lubricant, binder, and/or coloring agent.
  • the filler is microcrystalline cellulose, lactose monohydrate, or silicified microcrystalline cellulose;
  • the disintegrant is croscarmellose sodium;
  • the glidant is silica, colloidal anhydrous;
  • the lubricant is magnesium stearate.
  • the composition is formulated as a solid composition.
  • the solid composition is a tablet, capsule, or caplet.
  • the solid composition is a tablet such as an oral tablet.
  • the solid composition is a capsule such as an oral capsule.
  • the solid composition is a caplet such as an oral caplet.
  • the solid compositions are coated.
  • the coating is an enteric coating.
  • the coating provides a film coat on the solid composition.
  • the film coat comprises a coating powder.
  • the film coat comprises Opadry II Orange.
  • the coating powder is Opadry II Orange.
  • Exemplary aticaprant tablet and capsule formulations, including excipients, are disclosed in U.S. Patent Application No. 18/179,093, filed March 6, 2023, the disclosure of which is incorporated by reference herein.
  • the tablet may comprise one or more layers.
  • the tablet comprises a core tablet and a film coat to provide a film coated tablet.
  • the ratio of the film coat to core tablet is between about 0.03 to 10 by weight. In some embodiments, the ratio of the film coat to core tablet is about 0.03, 0.05, 0.08, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 by weight, based on the weight of the composition.
  • the ratio of the film coat to core tablet is about 0.03 to about 9, about 0.03 to about 8, about 0.03 to about 7, about 0.03 to about 6, about 0.03 to about 6, about 0.03 to about 5, about 0.03 to about 4, about 0.03 to about 3, about 0.03 to about 2, about 0.03 to about 1, about 0.03 to about 0.5, about 0.03 to about 0.1, about 0.05 to about 10, 0.05 to about 9, about 0.05 to about 8, about 0.05 to about 7, about 0.05 to about 6, about 0.05 to about 6, about 0.05 to about 5, about 0.05 to about 4, about 0.05 to about 3, about 0.05 to about 2, about 0.05 to about 1, about 0.05 to about 0.5, about 0.05 to about 0.1, about 0.1 to about 10, 0.1 to about 9, about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, 0.05 to about 0.1, about 0.1 to about 10,
  • the core tablet may contain one or more phases.
  • the core tablet comprises a first phase such as an intragranular phase.
  • the core tablet comprises a second phase such as an extragranular phase.
  • the core tablet comprises intragranular and extragranular phases.
  • the ratio of the intragranular phase to extragranular phase in the core tablet is between about 1.5 and about 3 by weight. In some embodiments, the ratio of the intragranular phase to extragranular phase in the core tablet is about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, or about 3 by weight.
  • the ratio of the intragranular phase to extragranular phase in the core tablet is about 1.5 to about 2.8, about 1.5 to about 2.5, about 1.5 to about 2.3, about 1.5 to about 2, about 1.5 to about 1.8, about 1.8 to about 3, about 1.8 to about 2.8, about 1.8 to about 2.5, about 1.8 to about 2.3, about 2 to about 3, about 2 to about 2.8, about 2 to about 2.5, about 2 to about 2.3, about 2 to about 2.1, about 2.1 to about 3, about 2.1 to about 2.8, about 2.1 to about 2.5, about 2.1 to about 2.3, about 2.3 to about 3, about 2.3 to about 2.8, about 2.3 to about 2.5 to about 2.5 to about 3, about 2.5 to about 2.8, and about 2.8 to about 3 by weight.
  • the ratio of the intragranular phase to extragranular phase in the core tablet is about 2.1 by weight.
  • the solid composition contains aticaprant and one or more pharmaceutically acceptable excipients.
  • the intragranular phase comprises aticaprant, a filler, a disintegrant, and a glidant.
  • the intragranular phase comprises one filler.
  • the intragranular phase comprises two fillers.
  • the intragranular phase comprises about 10 to about 120 mg of the filler. In some embodiments, the intragranular phase comprises about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, or about 120 mg of the filler.
  • the intragranular phase comprises about 10 to about 110, about 10 to about 100, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 120, about 20 to about 110, about 20 to about 100, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 120, about 30 to about 110, about 30 to about 100, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 40 to about 120, about 40 to about 110, about 40 to about 100, about 40 to about 90, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 50 to about 100, about 50 to about 90, about
  • the intragranular phase contains about 60 mg of filler. In yet other embodiments, the intragranular phase contains about 30 mg of microcrystalline cellulose. In still further embodiments, the intragranular phase contains about 30 mg of lactose monohydrate. In other embodiments, the intragranular phase contains about 60 mg of microcrystalline cellulose. In further embodiments, the intragranular phase contains about 60 mg of lactose monohydrate.
  • the intragranular phase comprises an aticaprant to filler ratio of between about 0.008 and 0.8 by weight.
  • the intragranular phase contains an aticaprant to filler ratio of about 0.008, about 0.005, about 0.001, about 0.01, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, or about 0.8 by weight.
  • the intragranular phase comprises an aticaprant to filler ratio of about 0.008 to about 0.7, about 0.008 to about 0.6, about 0.008 to about 0.5, about 0.008 to about 0.6, about 0.008 to about 0.5, about 0.008 to about 0.4, about 0.008 to about 0.3, about 0.008 to about 0.2, about 0.008 to about 0.1, about 0.008 to about 0.05, about 0.008 to about 0.01, about 0.01 to about 0.8, about 0.01 to about 0.7, 0.01 to about 0.6, about 0.01 to about 0.5, about 0.01 to about 0.4, about 0.01 to about 0.5, about 0.01 to about 0.4, about 0.01 to about 0.3, about 0.01 to about 0.2, about 0.01 to about 0.1, about 0.01 to about 0.05, about 0.05 to about 0.8, about 0.05 to about 0.9, about 0.05 to about 0.8, about 0.05 to about 0.7, about 0.05 to about 0.6, about 0.05 to about 0.6, about 0.05 to
  • the intragranular phase comprises an aticaprant to filler ratio of about 0.08 by weight.
  • the intragranular phase also may contain a disintegrant.
  • the intragranular phase contains about 1 to about 10 mg of the disintegrant.
  • the intragranular phase contains about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, 7, about 7.5, about 8, about 8.5, about 9, about 9.5 or about 10 mg of the disintegrant.
  • the intragranular phase contains about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 2.5 to about 10, about 2.5 to about 9, about 2.5 to about 8, about 2.5 to about 7, about 2.5 to about 6, about 2.5 to about 5, about 2.5 to about 4, about 2.5 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 9, about 7 to
  • the intragranular phase contains about 2.5 mg of the disintegrant. In still further embodiments, the intragranular phase contains about 5 mg of the disintegrant. In other embodiments, the intragranular phase contains about 2.5 mg of croscarmellose sodium. In further embodiments, the intragranular phase contains about 5 mg of croscarmellose sodium.
  • the intragranular phase may further contain a glidant.
  • the intragranular phase contains about 0.1 to about 5 mg of a glidant.
  • the intragranular phase contains about 0.1, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5 mg of a glidant.
  • the intragranular phase contains about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5 mg of a glidant.
  • the intragranular phase contains about 0.5 mg of the glidant.
  • the intragranular phase contains about 1 mg of the glidant.
  • the intragranular phase contains about 0.5 mg of silica, colloidal anhydrous.
  • the intragranular phase contains about 1 mg of silica, colloidal anhydrous.
  • the intragranular phase has an aticaprant to disintegrant ratio of between about 0.2 and 20 by weight; In some embodiments, the intragranular phase has an aticaprant to disintegrant ratio of about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 by weight.
  • the intragranular phase comprises an aticaprant to disintegrant ratio of about 0.2 to about 18, about 0.2 to about 16, about 0.2 to about 14, about 0.2 to about 12, about 0.2 to about 10, about 0.2 to about 8, about 0.2 to about 6, about 0.2 to about 4, about 0.2 to about 3, about 0.2 to about 2, about 0.2 to about 1, about 0.2 to about 0.5, about 0.5 to about 20, about 0.5 to about 18, about 0.5 to about 16, about 0.5 to about 14, about 0.5 to about 12, about 0.5 to about 10, about 0.5 to about 8, about 0.5 to about 6, about 0.5 to about 4, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 20, about 1 to about 18, about 1 to about 16, about 1 to about 14, about 1 to about 12, about 1 to about 10, about 1 to about 8, about 1 to about 6, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 1 to about 1.5, about 2 to about 20, about 2 to about 18, about 2 to about 16, about 2 to about 14, about 2 to about 12, about 2 to about 10, about 2 to about 10, about
  • the intragranular phase comprises an aticaprant to disintegrant ratio of about 2 by weight.
  • the intragranular phase comprises an aticaprant to glidant ratio of between about 1 and 100 by weight. In some embodiments, the intragranular phase comprises an aticaprant to glidant ratio of about 1, about 5, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 by weight.
  • the intragranular phase comprises an aticaprant to glidant ratio of about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 5, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 15, about 2 to about 10, about 2 to about 5, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 80, about 40 to about 60, or about 60 to about 80 by weight.
  • the intragranular phase comprises an aticaprant to glidant ratio of 10 by weight.
  • the extragranular phase comprises one or more of a filler, a disintegrant, a glidant, and a lubricant.
  • the extragranular phase comprises a filler.
  • the extragranular phase comprises a disintegrant.
  • the extragranular phase comprises a glidant.
  • the extragranular phase comprises a lubricant.
  • the extragranular phase may comprise a filler.
  • the extragranular phase contains one filler.
  • the extragranular phase contains about 10 to about 80 mg of a filler.
  • the extragranular phase contains about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 70, or about 80 mg of a filler.
  • the extragranular phase contains about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 10 to about 15, about 15 to about 80, about 15 to about 70, about 15 to about 60, about 15 to about 50, about 15 to about 40, about 15 to about 30, about 15 to about 20, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 25 to about 80, about 25 to about 70, about 25 to about 60, about 25 to about 50, about 25 to about 40, about 25 to about 30, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 35 to about 80, about 35 to about 70, about 35 to about 60, about 35 to about 50, about 35 to about 40, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 40 to about 80, about 40 to about 70, about 40 to
  • the extragranular phase contains about 28.5 mg of the filler. In other embodiments, the extragranular phase contains about 28.5 of silicified microcrystalline cellulose. In further embodiments, the extragranular phase contains about 57 mg of the filler. In still other embodiments, the extragranular phase contains about 57 mg of silicified microcrystalline cellulose.
  • the extragranular phase may additionally contain a disintegrant.
  • the disintegrant is croscarmellose sodium.
  • the extragranular phase contains about 1 to about 10 mg of a disintegrant.
  • the extragranular phase contains about 1, about 2, about 2.5, about 3, about 4, about 5, about 6, about 7, about 7.5, about 8, about 9, or about 10 mg of a disintegrant.
  • the extragranular phase contains about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 2.5 to about 10, about 2.5 to about 9, about 2.5 to about 8, about 2.5 to about 7, about 2.5 to about 6, about 2.5 to about 5, about 2.5 to about 4, about 2.5 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 6 to about 10, about 9, about 6 to about 8, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 about 7 about
  • the extragranular phase contains about 2.5 mg of a disintegrant. In other embodiments, the extragranular phase contains about 5 mg of a disintegrant. In further embodiments, the extragranular phase contains about 2.5 mg of croscarmellose sodium. In still other embodiments, the extragranular phase contains about 5 mg of croscarmellose sodium.
  • the extragranular phase comprises a filler to disintegrant ratio of between about 1 and 100 by weight. In some embodiments, the extragranular phase comprises a filler to disintegrant ratio of 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 by weight.
  • the extragranular phase comprises a filler to disintegrant ratio of about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 5 to about 100, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 10 to about 15, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 by weight.
  • the extragranular phase comprises a filler to disintegrant ratio of about 11.4.
  • the extragranular phase further may contain a glidant.
  • the glidant is silica, colloidal anhydrous.
  • the extragranular phase contains about 0.1 to about 5 mg of the glidant.
  • the extragranular phase contains about 0.1, about 0.25, about 0.5, about 0.75, about 1, about
  • the extragranular phase contains about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about
  • the extragranular phase contains about 0.5 mg of a glidant. In other embodiments, the extragranular phase contains about 1 mg of a glidant. In further embodiments, the extragranular phase contains about 0.5 mg of silica, colloidal anhydrous.
  • the extragranular phase contains about 1 mg of silica, colloidal anhydrous.
  • the extragranular phase comprises a filler to glidant ratio of between about 5 and 500 by weight. In other embodiments, the extragranular phase comprises a filler to glidant ratio of about 5, about 10, about 25, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500.
  • the extragranular phase comprises a filler to glidant ratio of about 5 to about 400, about 5 to about 300, about 5 to about 200, about 5 to about 100, about 5 to about 75, about 5 to about 50, about 10 to about 500, about 10 to about 400, about 10 to about 300, about 10 to about 200, about 10 to about 100, about 10 to about 50, about 25 to about 500, about 25 to about 400, about 25 to about 300, about 25 to about 200, about 25 to about 100, about 25 to about 75, about 25 to about 50, about 50 to about 500, about 50 to about 400, about 50 to about 300, about 50 to about 200, about 50 to about 100, about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200 to about 500, about 200 to about 400, about 200 to about 300, about 300 to about 500, about 300 to about 400, or about 400 to about 500 by weight.
  • the extragranular phase comprises a filler to glidant ratio of about 57
  • the extragranular phase may also contain a lubricant.
  • the lubricant is magnesium stearate.
  • the extragranular phase contains about 0.1 to about 5 mg of the lubricant.
  • the extragranular phase contains about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 2, about 3, about 4, or about 5 mg of a lubricant.
  • the extragranular phase contains about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5 mg of a lubricant.
  • the extragranular phase contains about 0.5 mg of a lubricant.
  • the extragranular phase contains about 1 mg of a lubricant.
  • the extragranular phase contains about 0.5 mg of magnesium stearate.
  • the extragranular phase contains about 1 mg of magnesium stearate.
  • the extragranular phase comprises a filler to lubricant ratio of between about 5 and 500 by weight. In other embodiments, the extragranular phase comprises a filler to lubricant ratio of about 5, about 10, about 25, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500.
  • the extragranular phase comprises a filler to lubricant ratio of about 5 to about 400, about 5 to about 300, about 5 to about 200, about 5 to about 100, about 5 to about 75, about 5 to about 50, about 10 to about 500, about 10 to about 400, about 10 to about 300, about 10 to about 200, about 10 to about 100, about 10 to about 50, about 25 to about 500, about 25 to about 400, about 25 to about 300, about 25 to about 200, about 25 to about 100, about 25 to about 75, about 25 to about 50, about 50 to about 500, about 50 to about 400, about 50 to about 300, about 50 to about 200, about 50 to about 100, about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200 to about 500, about 200 to about 400, about 200 to about 300, about 300 to about 500, about 300 to about 400, or about 400 to about 500 by weight.
  • the extragranular phase comprises a filler to lubricant ratio of about 57
  • the intragranular phase comprises one or more of: an aticaprant to filler ratio of between about 0.008 and 0.8 by weight; an aticaprant to disintegrant ratio of between about 0.2 and 20 by weight; and an aticaprant to glidant ratio of between about 1 and 100 by weight.
  • the extragranular phase comprises one or more of: a filler to disintegrant ratio of between about 1 and 100 by weight; a filler to glidant ratio of between about 5 and 500 by weight; and a filler to lubricant ratio of between about 5 and 500 by weight.
  • the extragranular phase comprises a filler to disintegrant ratio of about 11.4 by weight.
  • the extragranular phase comprises a filler to glidant ratio of about 57 by weight.
  • the extragranular phase comprises a filler to lubricant ratio of about 57 by weight.
  • the core tablet comprises about 5% aticaprant by weight, about 88.5% filler by weight, about 5% disintegrant by weight, about 1% glidant by weight, and about 0.5% lubricant by weight.
  • the oral tablet may be of weight that is suitable for administration by a patient.
  • the oral tablet has a core tablet of about 10 to about 1000 mg.
  • the core tablet is about 10, about 25, about 50, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, or about 1000 mg.
  • the core tablet is about 10 to about 900, about 10 to about 800, about 10 to about 700, about 10 to about 600, about 10 to about 500, about 10 to about 400, about 10 to about 300, about 10 to about 200, about 10 to about 100, about 10 to about 50, about 25 to about 1000, about 25 to about 900, about 25 to about 800, about 25 to about 700, about 25 to about 600, about 25 to about 500, about 25 to about 400, about 25 to about 300, about 25 to about 200, about 25 to about 100, about 25 to about 75, about 50 to about 1000, about 50 to about 900, about 50 to about 800, about 50 to about 700, about 50 to about 600, about 50 to about 500, about 50 to about 400, about 50 to about 300, about 50 to about 200, about 50 to about 100, about 100 to about 1000, about 100 to about 900, about 100 to about 800, about 100 to about 700, about 100 to about 600, about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200, about 50 to
  • the core tablet contains a disintegrant.
  • the core tablet contains about 5 to about 100 mg of a disintegrant.
  • the core tablet contains about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg of a disintegrant.
  • the core tablet contains about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 mg of a disintegrant.
  • the core tablet contains about 5 mg of the disintegrant.
  • the core tablet contains about 10 mg of the disintegrant.
  • the core tablet contains a glidant.
  • the core tablet contains about 1 to about 100 mg of a glidant.
  • the core tablet contains about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg of a glidant.
  • the core tablet contains about 1 to about 100, about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 2 to about 100, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 10, about 2 to about 5, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 mg of a glidant. In further embodiments, the core tablet contains about 1 mg of the glidant. In yet other embodiments, the core tablet contains about 2 mg of the glid
  • the core tablet contains a lubricant.
  • the core tablet contains about 0.5 to about 100 mg of a lubricant.
  • the core tablet contains about 0.5, about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg of a lubricant.
  • the core tablet contains about 0.5 to about 80, about 0.5 to about 60, about 0.5 to about 40, about 0.5 to about 20, about 0.5 to about 10, about 0.5 to about 5, about 0.5 to about 1, about 1 to about 100, about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 2 to about 100, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 10, about 2 to about 5, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 mg
  • the core tablet contains a filler.
  • the core tablet contains about 1 to about 200 mg of a filler.
  • the core tablet contains about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, or about 200 mg of a filler.
  • the core tablet contains about 1 to about 180, about 1 to about 160, about 1 to about 140, about 1 to about 120, 1 to about 100, about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 2 to about 200, about 2 to about 180, about 2 to about 160, about 2 to about 140, about 2 to about 120, about 2 to about 100, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 10, about 2 to about 5, about 5 to about 200m, about 5 to about 180, about 5 to about 160, about 5 to about 140, about 5 to about 120, about 5 to about 100, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 200, about 10 to about 180, about 10 to about 160, about 10 to about 140, about 10 to about 120, about 10 to about 100, about 10 to about 80, about 10 to about 10 to about
  • the oral tablet comprises a core tablet of about 100 mg and comprising about 5 mg aticaprant, about 5 mg disintegrant, about 88.5 mg filler, about 1 mg glidant, and about 0.5 mg lubricant.
  • the core tablet may be coated with a film coat.
  • the oral tablet comprises about 3 mg of film coat.
  • the film coated oral tablet comprises about 80 to about 99.9% by weight of the core tablet and about 0.1 to about 20% by weight, based on the weight of the film coated oral tablet, of the core tablet.
  • the film coated oral tablet comprises about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, or 99.9% by weight, based on the weight of the film coated oral tablet.
  • the film coated oral tablet comprises about 80 to about 99, about 80 to about 96, about 80 to about 94, about 80 to about 92, about 80 to about 90, about 80 to about 88, about 80 to about 86, about 80 to about 84, about 80 to about 82, about 82 to about 99, about 82 to about 96, about 82 to about 94, about 82 to about 92, about 82 to about 90, about 82 to about 88, about 82 to about 86, about 82 to about 84, about 84 to about 99, about 84 to about 99, about 84 to about 96, about 84 to about 94, about 84 to about 92, about 84 to about 90, about 84 to about 88, about 84 to about 86, about 86 to about 99, about 86 to about 96, about 86 to about 94, about 86 to about 92, about 86 to about 90, about 86 to about 92, about 86 to about 90, about 86 to about 88, about 88
  • the film coated oral tablet comprises about 97% core tablet by weight, based on the weight of the film coated oral tablet. In yet other embodiments, the film coated oral tablet comprises about 0.1 to about 20% by weight, based on the weight of the film coated oral tablet, of film coat. In still further embodiments, film coated oral tablet comprises about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20% by weight, based on the weight of the film coated oral tablet, of the film coat.
  • the film coated oral tablet comprises about 0.1 to about 18, about 0.1 to about 16, about 0.1 to about 14, about 0.1 to about 12, about 0.1 to about 10, about 0.1 to about 8, about 0.1 to about 6, about 0.1 to about 4, about 0.1 to about 2, about 0.1 to about 1, about 0.5 to about 20, about 0.5 to about 18, about 0.5 to about 16, about 0.5 to about 14, about 0.5 to about 12, about 0.5 to about 10, about 0.5 to about 8, about 0.5 to about 6, about 0.5 to about 4, about 0.5 to about 2, about 1 to about 20, about 1 to about 18, about 1 to about 16, about 1 to about 14, about 1 to about 12, about 1 to about 10, about 1 to about 8, about 1 to about 6, about 1 to about 4, about 1 to about 2, about 2 to about 20, about 2 to about 18, about 2 to about 16, about 2 to about 14, about 2 to about 12, about 2 to about 10, about 2 to about 8, about 2 to about 8, about 2 to about 6, about 2, about 4 to about 20, about 4 to about 18, about 18, about 4 to about 16, about 4 to about 12, about 4 to about 18, about 18, about 16,
  • the film coated oral tablet comprises about 3% by weight, based on the weight of the film coated oral tablet, of the film coat. In yet other embodiments, the film coated oral tablet comprises about 97% core tablet by weight and about 3% film coat by weight, based on the weight of the film coated oral tablet.
  • the disclosure provides oral tablets comprising about 5 mg aticaprant, wherein the oral tablet comprises a core tablet of about 100 mg, wherein the core tablet comprises an intragranular and extragranular phase, wherein the intragranular phase comprises about 30 mg microcrystalline cellulose, about 30 mg lactose monohydrate, about 2.5 mg croscarmellose sodium, and about 0.5 mg silica, colloidal anhydrous; and wherein the extragranular phase comprises about 28.5 mg silicified microcrystalline cellulose, about 2.5 mg croscarmellose sodium, about 0.5 mg silica, colloidal anhydrous, and about 0.5 mg magnesium stearate.
  • the disclosure provides oral tablets comprising about 10 mg aticaprant, wherein the oral tablet comprises a core tablet of about 200 mg, wherein the core tablet comprises an intragranular and extragranular phase, wherein the intragranular phase comprises about 60 mg microcrystalline cellulose, about 60 mg lactose monohydrate, about 5 mg croscarmellose sodium, and about 1 mg silica, colloidal anhydrous; and wherein the extragranular phase comprises about 57 mg silicified microcrystalline cellulose, about 5 mg croscarmellose sodium, about 1 mg silica, colloidal anhydrous, and about 1 mg magnesium stearate.
  • the solid compositions may also have a desirable dissolution profile that provide the desired release of aticaprant.
  • the solid composition contains about 5 mg of aticaprant and has a dissolution profile comprising a Q value of between about 60% and 90% at 45 minutes, under the dissolution operating conditions of (i) apparatus: Paddle (USP Type 2, Ph. Eur., JP), (ii) dissolution medium: 0.01 M hydrochloric acid, (iii) volume: 900 mL, (iv) temperature: 37 ⁇ 0.5 ° C, (v) rotation speed: 50 rpm, and (vi) analytical finish: UHPLC with UV detection at 247 nm.
  • the Q value is about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, or about 95% at 45 minutes.
  • the Q value is about 60 to about 85, about
  • the Q value is between about 70% and 80% at 45 minutes. In other aspects, the Q value is about 75% at 45 minutes.
  • Aticaprant may be administered once daily, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the composition containing aticaprant is administered once daily.
  • the oral tablet containing aticaprant is administered once daily.
  • the solid pharmaceutical composition containing aticaprant is administered once daily.
  • the disclosure also relates to the use of aticaprant in the manufacture of a medicament, as described herein, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with of aticaprant.
  • the disclosure further relates to a package or pharmaceutical product as described herein, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaprant.
  • antidepressant therapy can be in particular selected from a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.
  • Aticaprant may be used as adjunctive treatment, or in other words, in conjunction, as an add-on, or in combination with one or more antidepressants, for example, the patient may be already, or also, administered one or more antidepressants.
  • the disclosure relates to aticaprant, for use as described herein, comprising administration of aticaprant, as adjunctive treatment with an effective amount of one or more antidepressants.
  • the disclosure relates to aticaprant, for use as described herein, comprising administration of aticaprant, in conjunction with an effective amount of one or more antidepressants.
  • the disclosure relates to aticaprant, for use as described herein, comprising administration of aticaprant, in combination with an effective amount of one or more antidepressants.
  • the disclosure also relates to the use of aticaprant, in the manufacture of a medicament, as described herein, wherein the treatment comprises administration of an effective amount of aticaprant, as adjunctive treatment with an effective amount of one or more antidepressants.
  • the disclosure also relates to the use of aticaprant, as described herein, wherein the treatment comprises administration of an effective amount of aticaprant, in conjunction with an effective amount of one or more antidepressants.
  • the disclosure also relates to the use of aticaprant, as described herein, wherein the treatment comprises administration of an effective amount of aticaprant, in combination with an effective amount of one or more antidepressants.
  • the disclosure further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct the administration of an effective amount of aticaprant, as adjunctive treatment with an effective amount of one or more antidepressants.
  • the disclosure further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct the administration of an effective amount of aticaprant, in conjunction with an effective amount of one or more antidepressants.
  • the disclosure further relates to a package or pharmaceutical as described herein, wherein the instructions for treatment direct administration of an effective amount of aticaprant, in combination with an effective amount of one or more antidepressants.
  • one or more antidepressants can be selected from a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.
  • the disclosure relates to aticaprant, for use as described herein.
  • aticaprant is S-aticaprant.
  • aticaprant, in particular S-aticaprant, for use as described herein is to be administered in an amount of about 5 mg.
  • aticaprant, in particular S-aticaprant, for use as described herein is administered orally.
  • the disclosure relates to aticaprant, in particular S-aticaprant, for use as described herein, administered once daily.
  • the disclosure also relates to the use of aticaprant, in the manufacture of a medicament, as described herein.
  • Aticaprant is S-aticaprant. In a further embodiment of the use as described herein, about 5 mg. In a yet further embodiment of the use, aticaprant is to be administered orally. Furthermore, in a further particular embodiment of the use aticaprant in particular S- aticaprant, is to be administered once daily. In a further particular embodiment, the disclosure further relates to a package or pharmaceutical product as described herein, wherein aticaprant is in particular S-aticaprant. In a further embodiment of the package or pharmaceutical product as described herein, the instructions for treatment direct administration of about 5 mg.
  • the instructions for treatment direct aticaprant in particular S- aticaprant, is for oral administration.
  • the instructions for treatment direct aticaprant in particular S-aticaprant, is for once daily administration.
  • administration of aticaprant does not result in weight gain during treatment, including clinically relevant weight gain.
  • the disclosure relates to aticaprant, for use as described herein, wherein the patient does not experience weight gain during the treatment with aticaprant.
  • the disclosure relates to a use as defined herein, wherein the patient does not experience weight gain during the treatment with aticaprant.
  • the disclosure further relates to a package or pharmaceutical product as described herein, wherein the patient does not experience weight gain during the treatment with aticaprant.
  • the body weight of the patient can in particular be assessed at the time of the initial administration of aticaprant.
  • the patient may have anhedonia.
  • the anhedonia is moderate.
  • the anhedonia is severe.
  • Anhedonia can be measured, through an anhedonia scale, for example, the Snaith Hamilton Pleasure Scale (SHAPS).
  • SHAPS Hamilton Pleasure Scale
  • the disclosure relates to aticaprant, for use as described herein, wherein the anhedonia of the patient is reduced by at least 40%, as measured by the change from baseline in total score in an anhedonia scale following 6 weeks of the treatment with aticaprant, more in particular, the anhedonia of the patient is reduced within about 3 weeks to about 6 weeks as measured by the change from baseline in total score in an anhedonia scale.
  • the anhedonia scale is the Snaith Hamilton Pleasure Scale (SHAPS).
  • SHAPS Snaith Hamilton Pleasure Scale
  • the disclosure relates to the use as described herein, wherein the anhedonia of the patient is reduced by at least 40%, as measured by the change from baseline in total score in an anhedonia scale following 6 weeks of the treatment with aticaprant, more in particular, the anhedonia of the patient is reduced within about 3 weeks to about 6 weeks as measured by the change from baseline in total score in an anhedonia scale.
  • the anhedonia scale is the Snaith Hamilton Pleasure Scale (SHAPS).
  • the disclosure relates to the package or pharmaceutical product as described herein, wherein the anhedonia of the patient is reduced by at least 40%, as measured by the change from baseline in total score in an anhedonia scale following 6 weeks of the treatment with aticaprant, more in particular, the anhedonia of the patient is reduced within about 3 weeks to about 6 weeks as measured by the change from baseline in total score in an anhedonia scale.
  • the anhedonia scale is the Snaith Hamilton Pleasure Scale (SHAPS).
  • methods are provided for treating patients having a more severe type of depression, i.e.. major depressive disorder, using the compounds, compositions, e.g., solid compositions, and tablets, e.g., oral tablets, described herein.
  • the patient also may be experiencing anhedonia.
  • MDD alone is difficult to treat, treatment patients having anhedonia are even more problematic since their ability to gauge pleasure is impaired.
  • antidepressants are known to have a variety of side effects such as weight gain, metabolic side effects, extrapyramidal symptoms, akathisia, cognitive impairment, among others.
  • patients may choose to refrain from or stop taking antidepressants to avoid or prevent any side-effects.
  • the methods described herein are effective in managing the patient’s depression and/or anhedonia using aticaprant.
  • the methods successfully permit the patient to manage their depression while simultaneously reducing anhedonia.
  • the patients treated according to the described methods have moderate to severe anhedonia.
  • the term “anhedonia” as used herein refers to the lack of or decreased ability to experience pleasure in daily activities.
  • the term anhedonia includes loss of pleasure in sensory experiences (z.e., touch, taste, smell), as well as social interactions.
  • anhedonia and depressed mood are diagnostic criteria for a major depressive episode as part of MDD.
  • Anhedonia also describes deficits in one or more components of reward-related behavior, also known as the pleasure cycle, such as wanting, liking, and learning.
  • the pleasure cycle can be divided into three phases: the appetitive phase (dominated by wanting), the consummatory phase (dominated by liking), and the satiety phase (dominated by learning).
  • the appetitive phase is characterized by the initial energy expenditure to attain a reward; the consummatory phase is enjoyment of the reward; and the satiety phase is characterized by learning and feedback integration.
  • an anhedonia scale may be used.
  • the Snaith-Hamilton Pleasure Scale (SHAPS) analysis is a validated scale for the measurement of anhedonia.
  • the SHAPS is a subject completed scale in which subjects score whether or not they experience pleasure in performing a list of activities or experiences.
  • the SHAPS is a self-reported 14-item instrument, developed for the assessment of hedonic capacity. Subjects score whether they experience pleasure in performing a list of activities or experiences. Subjects can rate the answers as 1-4 where 1 indicates “Nonetheless agree”, 2 indicates “Agree”, 3 indicates “Disagree” and 4 indicates “Nonetheless disagree”.
  • the subject's item responses are summed to provide a total score ranging from 14 to 56.
  • a higher total SHAPS score indicates higher levels of current anhedonia.
  • Physician/clinical judgment can be used to assess anhedonia separately or in conjunction with an anhedonia scale.
  • the patient has moderate anhedonia.
  • the patient has severe anhedonia.
  • An assessment of moderate or severe anhedonia is typically determined physician/clinical judgment and/or by one or more tests that provide insight into whether a patient has anhedonia.
  • the severity of the anhedonia may be determined using the SHAPS method.
  • a patient with moderate or severe anhedonia is considered to have a high level of anhedonia.
  • a patient with a SHAPS score of 38 or greater is considered to have moderate to severe anhedonia that can be considered a high level of anhedonia.
  • a high level of anhedonia is reflected by a SHAPS score of at least about 40, about 42, about 44, about 46, about 48, about 50, about 52, about 54, about 56, about 58, or higher.
  • a patient with mild or no anhedonia would be considered to have a low level of anhedonia that is assessed by physician/clinical judgment and/or one or more tests.
  • a patient with a SHAPS score of less than 38 is considered to have low anhedonia.
  • a patient with mild anhedonia may have a SHAPS score of 20 to less than 38, for example, a SHAPS score of 20 to about 36, about 22 to about 36, about 24 to about 36, about 26 to about 36, about 26 to about 34, about 26 to about 32, about 26 to about 30, about 26 to about 28, about 28 to about 36, about 28 to about 36, about 30, to about 36, about 32 to about 36, about 34 to about 36, about 20 to about 34, about 22 to about 34, about 24 to about 34, about 26 to about 32, about 26 to about 30, about 26 to about 28, about 28 to about 36, about 28 to about 34, about 28 to about 32, about 28 to about 30, about 30 to about 36, about 30 to about 34, about 30 to about 32, about 32 to about 36, about 32 to about 34, or about 34 to about 36.
  • a SHAPS score of less than 20 can be considered to correspond to normal hedonic functioning, and for purposes of this disclosure, would fall into the low category of anhedonia, e.g.
  • the patient’s anhedonia is reduced from a high level of anhedonia to a low level of anhedonia. In yet other embodiments, the patient’s anhedonia is reduced by at least about 40%, as measured by the change from baseline in total score in an anhedonia scale following treatment with aticaprant. In yet other embodiments, the patient’s anhedonia is reduced by at least about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, as measured by the change from baseline in total score in an anhedonia scale following treatment with aticaprant.
  • the patient’s anhedonia is reduced by about 40 to about 90%, about 50 to about 90%, about 60 to about 90%, about 70 to about 90%, about 80 to about 90%, about 40 toa bout 80%, about 50 to about 80%, about 60 to about 80%, about 70 to about 80%, about 40 to about 70%, about 50 to about 70%, about 60 to about 70%, about 40 to about 60%, about 50 to about 60%, or about 50 to about 60%, as measured by the change from baseline in total score in an anhedonia scale following treatment with aticaprant.
  • the patient’s anhedonia is ameliorated, i.e., reduced by 100%, as measured by the change from baseline in total score in an anhedonia scale following treatment with aticaprant.
  • Reduction of anhedonia after initiating treatment with aticaprant may be measured relative to the anhedonia of the patient as measured before treatment with aticaprant, i.e., a baseline anhedonia measurement.
  • the treating clinician is able to calculate the change of anhedonia from the baseline to the real time anhedonia measurement at any point after treatment with aticaprant.
  • standard methods for measuring anhedonia may be used, such as an anhedonia scale, e.g., SHAPS.
  • a baseline anhedonia measurement is obtained no more than about 1 week before initiating treatment with aticaprant.
  • a baseline anhedonia measurement is obtained about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day before treatment with aticaprant.
  • a baseline anhedonia measurement is obtained about 24 hours, about 18 hours, about 12 hours, about 8 hours, about 4 hours, about 2 hours, about 1 hours, about 30 minutes, or about 15 minutes before initiating treatment with aticaprant.
  • the patient’s change of anhedonia will depend on several factors including, without limitation, anhedonia severity, patient’ s sensitivity to aticaprant, other pharmaceutical agents being administered, among others.
  • the patient’s anhedonia is reduced after about 3 weeks of treatment with aticaprant.
  • the patient’s anhedonia is reduced after about 3 weeks of treatment with aticaprant.
  • the patient’s anhedonia is reduced after about 3 weeks to about 6 weeks, and, in certain embodiments, through week 6, of treatment with aticaprant.
  • the patient’s anhedonia is reduced by at least about 40%, as measured by the change from baseline in total score in an anhedonia scale following about 6 weeks of the treatment with aticaprant.
  • the anhedonia of the patient is reduced within about 3 weeks, and in some embodiments within about 3 weeks to about 6 weeks, as measured by the change from baseline in total score in an anhedonia scale and/or by physician/clinical judgement.
  • the disclosure provides methods for treating MDD in a human patient by administering to the patient a pharmaceutical composition comprising about 5 mg aticaprant, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaprant.
  • administration of the pharmaceutical composition to the patient achieves a pharmacokinetic (PK) profile comprising one or more of the PK parameters noted above after administration of the composition to a human after at least a 10-hour fast.
  • PK pharmacokinetic
  • the terms “subject” and “patient” refer to a human having a weight of less than about 55 kg, who has been the object of treatment, observation or experiment. Preferably, the patient has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the patient is an adult. As used herein, the term “adult” as used herein refers to a human that is 18 years of age or older. In other embodiments, the patient is an elderly adult, i.e., greater than or equal to 65 years of age. In further embodiments, the patient is a child.
  • the term “child” as used herein refers to a human that has an age under 18 years. Thus, the term “child” includes adolescents. In some embodiments, the patients is 6 to 17 years old. In other embodiments, the patient is 12 years old to less than 18 years old.
  • the methods of treatment and compositions disclosed herein are particularly suited for patients having a weight of less than about 55 kg.
  • the patient has a weight less than about 50, about 45, about 40, about 35, about 30, about 25, about 20, about 15, or about 10 kg.
  • the patient has a weight of 52 kg or less, and, more particularly, a weight of less than 50 kg, or a weight of less than 45 kg.
  • the patient has a weight of about 20 to about 52, about 20 to about 50, about 20 to about 45, about 20 to about 40, about 20 to about 35, about 20 to about 30, about 20 to about 25, about 25 to about 52, about 25 to about 50, about 25 to about 45, about 25 to about 40, about 25 to about 35, about 25 to about 30, about 30 to about 52, about 30 to about 50, about 30 to about 45, about 30 to about 40, about 30 to about 35, about 35 to about 52, about 35 to about 50, about 35 to about 45, about 35 to about 40, about 40 to about 52, about 40 to about 50, about 40 to about 45, about 45 to about 52, or about 45 to about 50 kg.
  • the terms “treating”, “treatment” and the like shall include the management and care of a subject or patient (preferably mammal, more preferably human) for the purpose of combating a disease, condition, or disorder and includes the administration of a compound described herein to prevent the onset of the symptoms or complications, alleviate one or more of the symptoms or complications, or eliminate the disease, condition, or disorder.
  • depression also referred to as depressive disorder
  • depression includes major depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholic, mid-life depression, late-life depression, bipolar depression, depression due to identifiable stressors, treatment resistant depression, or combinations thereof.
  • the depression is major depressive disorder.
  • the major depressive disorder is with melancholic features or anxious distress.
  • the depression is treatment-resistant depression.
  • the depression is major depressive disorder with suicidal ideation.
  • a patient is considered to have major depressive disorder if exhibiting five or more symptoms during the same two week period that are a change from previous functioning; depressed mood and/or loss of interest/pleasure must be present; excluding symptoms clearly attributable to another medical condition. See, e.g., Table 4.
  • Depressed mood Most of the day, nearly every day; may be subjective (e.g., feels sad, empty, hopeless) or observed by others (e.g., appears tearful); in children and adolescents, can be irritable mood
  • Loss of interest/pleasure Markedly diminished interest/pleasure in all (or almost all) activities most of the day, nearly every day; may be subjective or observed by others
  • Weight loss or gain Significant weight loss (without dieting) or gain (change of >5% body weight in a month), or decrease or increase in appetite nearly every day; in children, may be failure to gain weight as expected
  • Insomnia or hypersomnia Nearly every day 5.
  • Psychomotor agitation or retardation Nearly every day and observable by others (not merely subjectively restless or slow)
  • Major depressive disorder may be categorized as mild, moderate, or severe.
  • the MDD is mild.
  • the MDD is moderate.
  • the MDD is severe.
  • “mild MDD” applies to a patient having few, if any, symptoms in excess of those required to make the diagnosis, the intensity of the symptoms is distressing but manageable, and the symptoms result in minor impairment in social or occupational functioning.
  • the mild MDD may be a single episode (ICD-10 F32.0) or a recurrent episode (ICD-10 F33.0).
  • Mode MDD applies to a patient having a number of symptoms, intensity of symptoms, and/or functional impairment are between those specified for “mild” and “severe.”
  • the moderate MDD may be a single episode (ICD-10 F32.1) or a recurrent episode (ICD-10 F33.1).
  • severe MDD applies to a patient where the number of symptoms is substantially in excess of that required to make the diagnosis, the intensity of symptoms is seriously distressing and unmanageable, and the symptoms markedly interfere with social and occupational functioning, and urgent symptom control is necessary.
  • the severe MDD may be a single episode (ICD-10 F32.2) or a recurrent episode (ICD-10 F33.2).
  • MDD is classified according to the DSM-5 definition of Table 5. fable 5: DSM-5 Criteria for MDD
  • MGH Multiple-Asberg Depression Rating Scale
  • CGI-S Clinical Global Impression - Severity
  • SATE Self- Assessment of Treatment Experience
  • MGH Massachusetts General Hospital
  • ATRQ Antidepressant Treatment Response Questionnaire
  • MADRS is utilized to diagnose and/or monitor the patient.
  • MADRS is a 10-item rating scale that is used in antidepressant studies. It is clinician-administered and designed to be used in subjects with MDD to measure the overall severity of depressive symptoms.
  • the MADRS scale is validated, reliable, and acceptable to regulatory health authorities as a primary scale to determine efficacy in major depression.
  • MADRS is administered using the Structured Interview Guide for the MADRS (SIGMA).
  • the scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 60. Higher scores represent a more severe condition.
  • the MADRS evaluates apparent sadness, reported sadness, inner tension, sleep appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts.
  • CGI-S is utilized to diagnose and/or monitor the patient’s depression.
  • CGI-S is a scale that rates the severity of the subject’s illness at the time of assessment, relative to the clinician’s past experience with subjects who have the same diagnosis and improvement with treatment.
  • CGI-S provides an overall clinician-determined summary measure of severity of subject’s illness that considers all available information, including knowledge of subject’s history, psychosocial circumstances, symptoms, behavior, and impact of symptoms on subject’s ability to function.
  • CGI-S evaluates severity of psychopathology on scale of 0 to 7.
  • SMDDS is utilized to diagnose and/or monitor the patient’s depression.
  • SMDDS is a subjective rating of the patient.
  • the SMDDS is a 16-item PRO measure. Each item is rated by the subject according to a 5-point Likert scale. Subjects respond to each question using a rating scale between 0 (“Not at all” or “Never”) to 4 (“Extremely” or “Always”). The total score ranges from 0 to 60.
  • the SMDDS uses a 7-day recall period and verbal rating scales. Higher score indicates more severe depressive symptomatology.
  • SATE is utilized to diagnose and/or monitor the patient’s depression.
  • SATE is a one to three questionnaire administered when the subject is unable to complete other evaluations, i.e., away from the clinical setting such as at home.
  • SATE is useful to evaluate improvement or deterioration of depressive symptoms of the subjects over a short period of time. For rating overall depression, subject selected one option out of Improved, not changed or got worse; for depression improvement, subject selected one option out of slightly improved, much improved, very much improved and for depression worsen subject selected slightly worse, much worse, very much worse. See, Table 6.
  • the MGH-ATRQ is a self-rated scale used to determine treatment resistance in patient’s having MDD. This questionnaire examines the antidepressant treatment history, using specific anchor points to define the adequacy of both dose and duration of each antidepressant trial, and the degree of symptomatic improvement.
  • the MGH-ATRQ permits determining treatment resistance in depression and is known to those skilled in the art.
  • the patient had an inadequate response to other antidepressant therapy.
  • “Inadequate response” as used herein refers to a patient experiencing a less than about 50% reduction in depressive symptom severity from the start of initiating treatment. Typically, the inadequate response is during a current/active episode of the depression. In some embodiments, an inadequate response refers to a patient experiencing about 26 to less than about 50% reduction in depressive symptom severity from the start of initiating treatment.
  • an inadequate response refers to a patient experiencing about 26 to about 49, about 26 to about 45, about 26 to about 40, about 26 to about 35, about 26 to about 30, about 30 to about 49, about 30 to about 45, about 30 to about 40, about 30 to about 35, about 35 to about 49, about 35 to about 45, about 35 to about 40, about 40 to about 49, or about 40 to about 45% reduction in depressive symptom severity from the start of initiating treatment.
  • a patient’s response may be measured by one or more scales described herein and/or by physician/clinical judgment.
  • an inadequate response is measured by MGH-ATRQ, MADRS, or SHAPS.
  • an inadequate response is measured by MGH-ATRQ.
  • other antidepressant therapy refers to an antidepressant medication or non-pharmacological treatment that is used to treat patients having depression.
  • the other antidepressant therapy is an antidepressant medication.
  • the other antidepressant therapy is a non-pharmacological treatment.
  • the other antidepressant therapy is an antidepressant medication other than aticaprant.
  • the antidepressant medication is any pharmaceutical agent which can be used to treat depression. Suitable examples include, without limitation, mono-amine oxidase inhibitors, tricyclics, tetracyclics, non-cyclics, triazolopyridines, selective serotonin reuptake inhibitors (SSRI), serotonin receptor antagonists, serotonin noradrenergic reuptake inhibitors (SNRI), noradrenergic and specific serotonergic agents, noradrenaline reuptake inhibitors, or antipsychotics (typical or atypical antipsychotics).
  • mono-amine oxidase inhibitors include phenelzine, tranylcypromine, moclobemide, and the like.
  • Examples of tricyclics include imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, and the like.
  • Examples of tetracyclics includes maprotiline, and the like.
  • Examples of non-cyclics include nomifensine, and the like.
  • Examples of triazolopyridines include trazodone, and the like.
  • Examples of SSRIs include fluoxetine, sertraline, paroxetine, citalopram, citalopram, escitalopram, fluvoxamine, and the like.
  • Examples of serotonin receptor antagonists include nefazadone, and the like.
  • Examples of SNRIs include venlafaxine, milnacipran, desvenlafaxine, duloxetine, levomilnacipran and the like.
  • Examples of noradrenergic and specific serotonergic agents include mirtazapine, and the like.
  • Examples of noradrenaline reuptake inhibitors include reboxetine, edivoxetine and the like.
  • Typical antipsychotics include phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazin), thioxanthenes e.g., thiothixene, flupentixol), butyrophenones e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), substituted benzamides (e.g., sulpride, amisulpride), and the like.
  • phenothiazines e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazin
  • thioxanthenes e.g., thiothixene, flupentixol
  • antidepressant medication includes natural products such as Kava-Kava, St.
  • the other antidepressant includes neuropeptides such as thyrotropin-releasing hormone and the like or compounds targeting neuropeptide receptors such as neurokinin receptor antagonists and the like.
  • the other antidepressant is a hormone such as triiodothyronine, and the like.
  • the other medication is SSRI, SNRI, or a combination thereof.
  • the other antidepressant is a SSRI that is escitalopram, sertraline, paroxetine, fluoxetine or citalopram.
  • the other antidepressant is a SNRI that is venlafaxine, duloxetine, vortioxeine or desvenlafaxine.
  • the non-pharmacologic treatment for use herein may be selected by one skilled in the art.
  • the non-pharmacologic treatment is psychotherapy, transcranial magnetic stimulation, or the like.
  • Therapeutically effective amounts/dosage levels and dosage regimens for the other antidepressant therapy may be readily determined by one of ordinary skill in the art.
  • therapeutic dosage amounts and regimens for pharmaceutical agents approved for sale are publicly available, for example as listed on packaging labels, in standard dosage guidelines, in standard dosage references such as the Physician’s Desk Reference (Medical Economics Company or online at http:///www.pdrel.com) or other sources.
  • other antidepressant therapy may include one antidepressant medication.
  • other antidepressant therapy includes two or more antidepressant medications.
  • other antidepressant therapy includes two antidepressant medications.
  • other antidepressant therapy includes three antidepressant medications. The attending physician would be able to select suitable antidepressant therapies for use as described herein.
  • the patient was receiving treatment with other antidepressant therapy prior to receiving aticaprant.
  • the patient was receiving treatment with other antidepressant therapy that comprised a SSRI, SNRI, or a combination thereof.
  • the patient stopped treatment with other antidepressant therapy before initiating treatment with aticaprant.
  • adjunctive treatment with an effective amount of one or more antidepressants.
  • adjuctive treatment and “adjunctive therapy” shall mean treatment of a patient in need thereof by administering aticaprant in combination with one or more antidepressant(s), wherein aticaprant and the antidepressant(s) are administered by any suitable means, simultaneously, sequentially, separately, or in a single pharmaceutical formulation.
  • Aticaprant is administered adjunctively with other antidepressant(s) currently being administered to the patient, including current antidepressant(s) to which the patient had an inadequate response, i.e., the antidepressant failed to treat the patient’s depression.
  • aticaprant is administered adjunctively with an antidepressant(s) not previously administered to the patient, i.e., a new antidepressant.
  • aticaprant is administered in a regimen with an antidepressant(s) previously administered to the patient.
  • the number of dosages administered per day for each active compound may be the same or different and more typically different.
  • the antidepressant may be dosed as prescribed by the attending physician and/or by its label and aticaprant is dosed as described herein.
  • the “effective amount” of the antidepressant(s) may be determined by one skilled in the art.
  • a patient is under concurrent treatment with both an antidepressant and aticaprant, where both are administered by their prescribed dosing regimens.
  • the aticaprant and antidepressant(s) may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms.
  • Aticaprant and the antidepressant(s) may be administered via the same or different routes of administration.
  • suitable methods of administration include, but are not limited to, oral, intravenous (iv), intranasal (in) intramuscular (im), subcutaneous (sc), transdermal, buccal, or rectal.
  • aticaprant is administered orally.
  • the patient does not experience many of the side effects that are associated with other antidepressants, i.e., antidepressants other than aticaprant.
  • the patient does not experience weight gain during the treatment with aticaprant.
  • weight gain refers to an increase in the weight of patient, relative to the weight of the patient before taking aticaprant or the weight of the patient that is assessed at the time of the initial administration of aticaprant.
  • the patient may actually see a decrease in overall weight, relative to the weight of the patient before taking aticaprant.
  • the patient’s weight is stable, i.e., does not increase or decrease.
  • the patient does not experience a clinically relevant weight gain which is characterized as a weight increase of > 7%.
  • CPFQ Cognitive and Physical Functioning Questionnaire
  • KSS Karolinska Sleepiness Scale
  • TEPS Temporal Experience of Pleasure Scale
  • the CPFQ is a brief self-report scale that provides additional information regarding the impact of adjunctive treatment on aspects of cognitive and executive function including attention, memory and mental acuity. Subjects with MDD are often reported to have difficulties with functioning in this area.
  • the KSS is a subject-reported assessment used to rate sleepiness on a scale of 1 to 9, ranging from “extremely alert” (1) to “very sleepy, great effort to keep awake, fighting sleep” (9).
  • the TEPS includes 18 items, 2 subscales designed to distinguish between anticipatory and consummatory pleasure.
  • the methods described herein include administering an effective amount of aticaprant to the patient.
  • effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a human that is being sought by a researcher, medical doctor or other clinician, which includes alleviation of one or more of the symptoms of the disease or disorder being treated.
  • aticaprant is utilized in an effective amount as determined by the attending physician.
  • other antidepressant(s) is utilized in an effective amount either separately or in combination with aticaprant.
  • a method of treating major depressive disorder in a human patient comprising administering a pharmaceutical composition comprising about 5 mg of aticaprant to the human patient, wherein the human patient had a previous inadequate response to other antidepressant therapy and wherein the human patient has a weight less than about 55 kg.
  • Aspect 2 The method of Aspect 1 , wherein the pharmaceutical composition is a tablet.
  • Aspect 3 The method of Aspect 1 or 2, wherein the human patient has an age under 18 years old.
  • Aspect 4 The method of any one of the preceding Aspects, wherein the pharmaceutical composition is administered to the human patient once daily.
  • Aspect 5. The method of any one of the preceding Aspects, wherein the other antidepressant therapy comprised one or more antidepressants.
  • Aspect 6 The method of Aspect 5, wherein the one or more antidepressants of the other antidepressant therapy comprised a SSRI, SNRI, or a combination thereof.
  • Aspect 7 The method of any one of the preceding Aspects, wherein the aticaprant is S-aticaprant.
  • Aspect 8 The method of any one of the preceding Aspects, wherein the aticaprant is crystalline aticaprant.
  • Aspect 9 The method of any one of the preceding Aspects, further comprising treatment with an effective amount of one or more antidepressants.
  • Aspect 10 The method of Aspect 9, wherein the one or more antidepressants is a SSRI, SNRI, or combination thereof.
  • Aspect 11 The method of any one of the preceding Aspects, wherein the patient has anhedonia.
  • Aspect 12 The method of any one of the preceding Aspects, wherein the pharmaceutical composition further comprises one or more of: a filler, a disintegrant, a glidant, a lubricant, a binder, and a coloring agent.
  • Aspect 13 The method of Aspect 12, wherein the filler is: microcrystalline cellulose, lactose monohydrate, or silicified microcrystalline cellulose; the disintegrant is croscarmellose sodium; the glidant is silica, colloidal anhydrous; and the lubricant is magnesium stearate.
  • Aspect 14 The method of any one of the preceding Aspects, wherein the pharmaceutical composition comprises about 4% to about 6% aticaprant by weight.
  • Aspect 15 The method of any one of the preceding Aspects, wherein the pharmaceutical composition comprises about 5% aticaprant by weight.
  • Aspect 16 The method of any one of the preceding Aspects, wherein the pharmaceutical composition further comprises between about 10% and 99.9% filler by weight.
  • Aspect 17 The method of any one of the preceding Aspects, wherein the human patient has a weight of 52 kg or less.
  • XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu Ka radiation (40 kV, 40 mA) and a 0-20 goniometer fitted with a Ge monochromator.
  • the incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and knife edge.
  • the diffracted beam passes through an 8.0 mm receiving slit with 2.5° Soller slits followed by the Lynxeye Detector.
  • the software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA respectively.
  • Samples were run under ambient conditions as flat plate specimens using powder as received.
  • the sample was prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane.
  • XRPD diffractograms were collected on a PANalytical Empyrean diffractometer using Cu Ka radiation (45 kV, 40 mA) in transmission geometry.
  • a 0.5° slit, 4 mm mask and 0.04 rad Soller slits with a focusing mirror were used on the incident beam.
  • the software used for data collection was X’Pert Data Collector using X’Pert Operator Interface. The data were analyzed and presented using Diffrac Plus EVA or HighScore Plus.
  • Samples were prepared and analyzed in either a metal or Millipore 96 wellplate in transmission mode. X-ray transparent film was used between the metalsheets on the metal well-plate and powders (approximately 1-2 mg) were used as received. The Millipore plate was used to isolate and analyze solids from suspensions by adding a small amount of suspension directly to the plate before filtration under a light vacuum.
  • the software used for data collection was X’Pert Data Collector and the data analyzed and presented using Diffrac Plus EVA.
  • DSC data were collected on a TA Instruments Q2000 equipped with a 50 position auto-sampler. Typically, 0.5-3 mg of each sample, in a pin-holed aluminum pan, was heated at 10 °C/min from 25 °C to 275 °C. A purge of dry nitrogen at 50 mL/min was maintained over the sample.
  • Modulated temperature DSC was carried out using an underlying heating rate of 2 °C/min and temperature modulation parameters of ⁇ 0.636 °C (amplitude) every 60 seconds.
  • the instrument control software was Advantage for Q Series and Thermal Advantage and the data were analyzed using Universal Analysis or TRIOS.
  • DSC data were collected on a TA Instruments Discovery DSC equipped with a 50 position auto-sampler. Typically, 0.5-3 mg of each sample, in a pin-holed aluminum pan, was heated at 10 °C/min from 25 °C to 275 °C. A purge of dry nitrogen at 50 mL/min was maintained over the sample. [00159] The instrument control software was TRIOS and the data were analyzed using TRIOS or Universal Analysis.
  • Form III of aticaprant was found to be crystalline by XRPD. showed that the material was consistent with the proposed structure, with the presence of residual ethyl acetate. Ion chromatography showed that there were no cations/anions present, and HPLC showed 99.8% purity.
  • the DSC (heating from 20 to 131 °C at 10°C/min) showed a peak temperature at 121 °C.
  • FIG. 1 containing the components in Table 10.
  • a “aticaprant microfine” is milled aticaprant (physically proceed in milling equipment).
  • b From animal origin.
  • c From vegetable source.
  • d Removed during processing.
  • the adult population pharmacokinetic model was developed using aticaprant plasma concentrations from 4 clinical studies [I2Z-MC-LAFA (single-ascending dose study), I2Z-MC-LAFB (multiple-ascending dose study), I2Z-MC-LAFC (PET receptor occupancy study), and MDD2001 (efficacy, safety, and pharmacokinetics study in subjects with adjunctive MDD (aMDD))], using nonlinear mixed-effects modeling (NONMEM 7.4.1; Beal SL, Sheiner LB, Boeckmann AJ, et al. NONMEM 7.1.0 users guides. Ellicott City: Icon Development Solutions; 1989-2009). See, FIG. 2. Covariates were evaluated in the popPK model. Exploratory analysis, diagnostic graphics, and post-processing of NONMEM analysis results were carried out using R. Model evaluation was based on acceptable parameter precision, goodness-of-fit and visual predictive checks.
  • Model-based simulations were performed to predict aticaprant exposure metrics (i.e., steady-state AUCo-24h and trough concentration (Ctrou h)) for each adult subject among 10,000 virtual adult patient population, using the aticaprant dose of 10 mg QD and adolescent populations under different dosing scenarios (Scenario 1 and 4: flat dose of 10 and 5 mg QD, respectively; Scenario 2, 3, and 5: switch the dose of 10 mg QD to 5 mg QD with body weight below 40, 50, and 45 kg, respectively).
  • the median value and 5th and 95th percentiles of the simulated aticaprant exposures in the full virtual adult patient population were summarized and served as reference for comparison with adolescent simulations.
  • the steady-state C concentration was defined at day 29 predose (23.99h).
  • the aticaprant exposure in the adolescent subjects were simulated using the same approach as in the adult population and investigated by body weight or age category.
  • age category a total of 60,000 virtual adolescent subjects (12 to ⁇ 18 years) were sampled from the virtual adolescent subject database.
  • body weight category a total of 710,000 virtual adolescent subjects (30 to 100 kg) were sampled.
  • the race distribution of adolescent population was sampled from the adult study MDD2001.
  • the dose selected for the planned studies in adolescent subjects was determined by selecting the dose among the scenarios tested in Table 11 predicting that > 80% of the adolescent subjects would have aticaprant exposures (i.e., AUCo-24h and Ctrou h at steady state) within the 5th and 95th percentiles of the corresponding adult exposure after 10 mg QD dose. If multiple dose scenarios reached the 80% criteria, the dose leading to the highest proportion of adolescent matching adult exposures would be selected
  • the popPK model in adults was based on 2,258 aticaprant plasma concentrations from 151 healthy subjects and patients. Observed data were well described by an open two-compartment model with first-order absorption (K a ) and linear clearance (CL). Body weight was a covariate, with the allometric scaling exponent of 0.75 for CL and Q, and 1 for V2 and V3. Race (Black and Hispanic) was a covariate on relative bioavailability FL shown in Table 11. The interindividual variability in CL, V2, Fl (relative bioavailability factor), and K a was assumed to be log normally distributed. The residual error was described by a proportional error model. The parameter estimates of the final model were provided in Table 11.
  • Scenario 2 predicted the proportion of aticaprant exposures below 80% in the body weight range of 40-45kg and did not reach the cri eria for the adolescen within the body weight ranges. The result was consistent with the result by investigating across age category in FIG. 4.
  • both the weight cut-off of 50 and 45 kg could provide adequate AUCo-24h and Ctrough in adolescents, matching target adult exposure.
  • the dose change at the body weight cut-off of 45 kg might be preferable.
  • the 45 kg cut- off -73% adolescents can benefit from the adult dose, and less adults would fall in the 5 mg QD dose (FIG. 5), and hence this body weight cut-off of may be recommended in adolescents.
  • Results show that a dose of 5 mg QD (half the adult dose) is recommended for adolescents with a body weight ⁇ 45 kg and a dose of 10 mg QD (adult dose) is recommended for adolescents with a body weight > 45 kg.
  • This dose regimen is expected to achieve systemic aticaprant exposures in adolescents comparable to those in adults at the proposed clinical dose of lOmg QD.

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Abstract

The present disclosure relates to a method of treating major depressive disorder in a human patient where that human patient had a previous inadequate response to other antidepressant therapy and has a weight less than about 55 kg. Such methods involve the administration about 5 mg of aticaprant to the human, including oral compositions in the form of tablets.

Description

COMPOSITIONS COMPRISING ATICAPRANT FOR USE IN TREATING MAJOR DEPRESSIVE DISORDER
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of the priority of U.S. Provisional Patent Application No. 63/580,940, filed September 6, 2023, the disclosure of which is incorporated by reference herein.
TECHNICAL FIELD
[0002] The present disclosure relates to methods of treating major depressive disorder in certain patient populations by administration of aticaprant, including oral compositions of aticaprant in the form of tablets.
BACKGROUND
[0003] Kappa opioid receptors (KOR) and their native ligand dynorphin are localized in areas of the brain that effect reward and stress and may play a key role in mood, stress, and addictive disorders. Chronic stress, substance abuse, and acute withdrawal lead to increased dynorphin expression, activating KORs and subsequent downstream signaling pathways to inhibit mesolimbic dopamine surge, contributing to negative affective states. The behavioral pharmacology of KOR antagonism has been tested in animal models of anhedonia, depression, and anxiety and found to have meaningful effects that may translate to therapeutic benefit in humans. KOR antagonists may be effective for the treatment of patients with mood disorders, perhaps by modulating the negative affective state associated with stress response.
[0004] Only about 50% of patients with MDD show a meaningful response (>50% improvement to a first line antidepressant treatment), leaving many patients with substantial persistent impairment. Therapeutic strategies such as switching antidepressants and using adjuvant drug treatments can improve response, however almost 40% of patients remain symptomatic and fail to achieve full remission. Moreover certain patient populations, including adolescent patient populations, are in need of treatment options that differ from adult populations. Whereas an aticaprant dose of 10 mg QD has been selected in adult patients for certain studies based on safety and efficacy data, there is a need for an appropriate dose in adolescents (e.g. patients from 12 years old to less than 18 years old) and/or patients below a certain weight that result in systemic exposures comparable to those achieved by adults at the proposed adult dosing regimen.
SUMMARY
[0005] In some aspects, the disclosure provides methods of treating major depressive disorder in a human patient, comprising administering a pharmaceutical composition comprising about 5 mg of aticaprant to the human patient, wherein the human patient had a previous inadequate response to other antidepressant therapy and wherein the human patient has a weight less than about 55 kg. Such patient populations typically comprise adolescents, including those from 12 years old to less than 18 years old.
[0006] In other aspects, the disclosure provides oral tablets comprising about 5 mg aticaprant, wherein the oral tablet comprises a core tablet of about 100 mg, wherein the core tablet comprises an intragranular and extragranular phase, wherein the intragranular phase comprises about 30 mg microcrystalline cellulose, about 30 mg lactose monohydrate, about 2.5 mg croscarmellose sodium, and about 0.5 mg silica, colloidal anhydrous; and wherein the extragranular phase comprises about 28.5 mg silicified microcrystalline cellulose, about 2.5 mg croscarmellose sodium, about 0.5 mg silica, colloidal anhydrous, and about 0.5 mg magnesium stearate.
[0007] In further aspects, the disclosure provides methods of treating major depressive disorder (MDD) in a human patient comprising administering to the patient the pharmaceutical composition, oral tablet, or solid pharmaceutical composition described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 is the flow chart for the process for preparing tablets containing aticaprant. In this figure, a refers to microfine, i.e., milled aticaprant.
[0009] FIG. 2 is a schematic for the adult population pharmacokinetic model development.
[0010] FIG. 3 is a schematic of the workflow for the simulation of aticaprant exposures in adult and adolescent populations.
[0011] Fig. 4 are graphs showing the matching aticaprant exposures in adolescent and adult populations. In the left figures: 90% prediction interval of simulated aticaprant steady-state AUC(0-24h) in adolescents (shaded areas) as function of body weight (upper left) and age (lower left), compared to the adult simulated median exposure value (dashed line) and 5th and 95th percentiles (dotted lines) for Scenario 5 (aticaprant 5 mg QD for <45 kg and 10 mg QD for >45 kg). In the right figures: Proportion of adolescents within the 5th and 95th simulated percentiles of steady-state AUC(0-24h) in adults as function of body weight (upper right) and age (lower right), for the five different dosing regimens scenarios.
[0012] FIG. 5 is a graph showing the body weight distributions in adolescents and the proportion P of adolescents 12 to <18 years below 45 (green) and 50 (red) kg, respectively.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0013] All individual features (e.g., particular embodiments or specific preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including particular embodiment or preferred feature) mentioned herein; hence, preferred features may be taken in conjunction with other preferred features, or independently of them (and likewise with particular embodiments).
[0014] The disclosure provides compositions comprising pure crystalline Form of III aticaprant that are anhydrous and stable in the solid form.
[0015] The term “crystalline” refers to a solid form of a chemical moiety that contains a highly ordered intermolecular structure.
[0016] The term “polymorph” refers to a crystalline form of a molecule having one specific crystal structure. A crystalline compound may have one crystal form or may have two or more crystal forms, i.e., polymorphs. As is understood to those skilled in the art, polymorphs of a chemical compound may distinguished from each other by compared physicochemical properties such as solubility, dissolution rate, stability, bioavailability, among others. Polymorphs also may have different spectra selected from, without limitation, x-ray powder diffraction (XRPD), single crystal x-ray diffraction, thermogravimetric analysis (TGA), infrared spectroscopy, Raman spectroscopy, solid state nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), polarized light microscopy (PLM), hot stage microscopy, or dynamic solvent sorption.
[0017] The term “crystalline” refers to solid state form of a chemical moiety wherein the atoms, molecules, or ions are assembled in a highly ordered structure that extends in all directions. Thus, “crystalline” includes all crystalline forms of Compound I, including salts thereof. Characterization of crystalline forms may be performed by those skilled in the art including, without limitation, XRPD or DSC. Typically, the XRPD pattern contains sharp intensity peaks. This contrasts to the XRPD pattern of an amorphous form that often contains a broad, peak, without no identifying peaks. A crystalline form may be completely crystalline or partially crystalline. In some aspects, a crystalline sample may be 100% w/w crystalline. A crystalline sample may also contain solids that are amorphous. In certain aspects, a crystalline form may contain solids such that the sample is at least about 99% w/w crystalline, at least about 95% w/w amorphous, at least about 90% w/w crystalline, at least about 85% w/w crystalline, at least about 80% w/w crystalline, or the like.
[0018] The term “anhydrous” or “anhydrate” as used herein refers to a crystalline as described herein that substantially lacks water. In some aspects, an anhydrous form contains less than about 1% w/w of water. In other aspects, an anhydrous form contains less than about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1% w/w of water.
[0019] As provided herein, all temperature values may vary. Such variations may depend on instrument type, instrument parameters, laboratory techniques, and/or laboratory conditions. Unless otherwise defined, a recited temperature may vary. In some aspects, the temperatures noted herein vary by about 0.1°, about 0.5°, about 1°, about 2°, about 3°, about 4°, or about 5°.
[0020] Similarly, 20 values obtained from the XRPD patterns also may vary. Such variations may depend on instrument type, instrument parameters, laboratory techniques, sample (including particle size, impurities, etc.), and/or laboratory conditions. Unless otherwise defined, the XRPD patterns and/or the 20 peak values may vary. In certain aspects, the 20 peak values vary (higher or lower) by about 0.05°, about 0.1°, about 0.15°, or about 0.2°. In other aspects, one or more of the 20 peak values are higher by about 0.05°, about 0.1°, about 0.15°, or about 0.2°. In further aspects, one or more of the 20 peak values are lower by about 0.05°, about 0.1°, about 0.15°, or about 0.2°.
[0021] As used herein, the term “corresponds to” may be used in reference to certain spectra. Thus, “corresponds to” includes a spectrum that is identical or substantially similar to another spectrum. One skilled in the art would be able to compare such spectra and determine if a spectrum corresponds to another. Thus, the term “corresponds to” is used herein to compare XRPD patterns, DSC thermograms, among others. In some aspects, one XRPD pattern corresponds to another XRPD pattern when their 20 values are within the margin of error as described above. In other aspects, one XRPD pattern corresponds to another XRPD pattern when the peaks have the same 20 peak value, but one or more peaks have a different height (intensity). In further aspects, one XRPD pattern corresponds to another XRPD pattern when the peaks have the same 20 peak value, but one or more peaks have a different peak area. In yet other aspects, one XRPD pattern corresponds to another XRPD pattern when the peaks have the same 20 peak value, but one or more peak is obscured. Such obscured peaks may be due to impurities, excipients, or the like. Such obscured peaks typically do not prevent characterization of the crystalline form.
[0022] As used herein, unless otherwise noted, the term “aticaprant” refers to 3- fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-l-yl-methylphenoxybenzamide, i.e. , the following compound:
Figure imgf000007_0001
and is also known as JNJ-67953964, 67953964- AAA, CERC-501, and LY-2456302. In some embodiments, “aticaprant” refers to the (S)-enantiomer of aticaprant, i.e., the following
Figure imgf000007_0002
also known as (S)-aticaprant or (S)-3-fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-l-yl- methylphenoxybenzamide. In other embodiments, the aticaprant used in the methods described herein is substantially free of the (R)-enantiomer, i.e., (R)-aticaprant or (R)-3- fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-l-yl-methylphenoxybenzamide having the following structure:
Figure imgf000008_0001
[0023] In other embodiments, the aticaprant contains less than about 10% by weight, based on the weight of aticaprant, of the (R)-enantiomer of aticaprant. In further embodiments, aticaprant contains less than about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, about 1, about 0.5, about 0.1, about 0.005, or about 0.001% by weight, based on the weight of aticaprant, of the (R)-enantiomer of aticaprant. In yet other embodiments, the aticaprant contains about 0.001 to about 10% by weight, based on the weight of aticaprant, of the (R)-enantiomer of aticaprant. In still further embodiments, the aticaprant contains about 0.001 to about 10%, about 0.001 to about 5%, about 0.001 to about 1%, about 0.001 to about 0.5%, about 0.001 to about 0.1%, about 0.1 to about 5%, about 0.1 to about 1%, about 0.1 to about 5%, or about 0.5 to about 5% by weight, based on the weight of aticaprant.
[0024] Pharmaceutically acceptable salts of aticaprant are also contemplated by the present invention, which may be readily selected by those skilled in the art. A “pharmaceutically acceptable salt” refers a salt of aticaprant that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, G.S. Paulekuhn, “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665-72, S.M. Berge, “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for administration to patients without undue toxicity, irritation, or allergic response.
[0025] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, bromides (such as hydrobromides), iodides (such as hydroiodides), acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4-dioates, hexyne- 1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, and mandelates.
[0026] In some embodiments, the aticaprant is crystalline Form III of aticaprant. Crystalline Form III of aticaprant may be characterized by a number of techniques including, without limitation, x-ray diffraction and differential scanning calorimetry. In some embodiments, crystalline Form III of aticaprant is characterized by x-ray diffraction. In other embodiments, crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 20 (± 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4°. In further embodiments, crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 20 (± 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° and one or more additional peaks at 16.4°, 20.1°, 20.3°, 24.1°, and 25.7°. In yet other embodiments, crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 20 (± 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° and one or more additional peaks at 15.1°, 16.4°, 20.0°, 20.1°, 20.3°, 24.1°, 25.0°, 25.7°, 26.2°, and 28.8°. In still further embodiments, crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 20 (± 0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° and one or more additional peaks at 8.2°, 9.7°, 12.0°, 13.5°, 15.1°, 16.4°, 19.4°, 28.4°, 20.0°, 20.1°, 20.3°, 24.1°, 25.0°, 25.7°, 26.2°, 28.8°, and 30.0°. In other embodiments, crystalline Form III of aticaprant is characterized by four or more x-ray diffraction pattern peaks at 20 (± 0.2) of
Figure imgf000009_0001
In still other embodiments, crystalline Form III of aticaprant is characterized the x-ray diffraction pattern peaks in Table 2.
Figure imgf000010_0003
,
Table 3 Table 3
Position (20) Position (20)
. 25.7. . 324.
26.3 33.0
26.4 33.2
. 27. 1. .33.6.
28.4 33.9
28.6 34.4
28.8
Figure imgf000010_0001
35.4
30.0 36.0
. 30.2. .36.4.
30.5 37.0
31 2 38.2
31.8 38.5
Figure imgf000010_0004
32.2
Figure imgf000010_0002
39.5
[0027] Crystalline Form III of aticaprant may also be characterized by differential scanning calorimetry. In some embodiments, the differential scanning calorimetry thermogram comprises a peak temperature (Tm) at about 121 °C.
Pharmaceutical Compositions
[0028] The disclosure also contemplates pharmaceutical composition comprising aticaprant and one or more pharmaceutically acceptable excipient. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. The preferred pharmaceutical composition contains crystalline Form III of aticaprant as the active ingredient intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
[0029] The amount of aticaprant present in the compositions is about 5 mg, and, in particular embodiments, the amount is 5 mg. In some embodiments, the composition contains about 4.9 mg to about 5.1 mg of aticaprant. In other embodiments, the composition contains about 4.9, about 5, or about 5.1 mg of aticaprant. The composition contains about 4.9% to about 5.1% by weight of aticaprant, based on a 100 mg core tablet. In some embodiments, the composition contains about 4.9, about 5, or about 5.1% by weight, based on the weight of the composition, of aticaprant. In other embodiments, the composition contains about 4.9 to about 5.1, about 4.9 to about 5, or about 5 to about 5.1% by weight, based on the weight of the composition, of aticaprant. In further embodiments, the composition contains about 5% by weight of aticaprant. In yet other embodiments, the composition contains about 4.9% by weight of aticaprant. In still further embodiments, the composition contains about 5.1% by weight of aticaprant. The amount of aticaprant for administration according to the methods described herein may be determined by one skill in the art and, unless otherwise noted, are set forth on an aticaprant free base basis. That is, the amounts indicate that amount of the aticaprant molecule administered, exclusive of, for example, solvent (such as in solvates) or counterions (such as in pharmaceutically acceptable salts).
[0030] In some embodiments, the pharmaceutical compositions have a particular pharmacokinetic (PK) profile at a specific dose. In further embodiments, the pharmaceutical compositions have a PK profile that is dose-proportional. In other embodiments, the pharmaceutical compositions have a PK profile comprising parameters, e.g., exposure parameters such as Cmax or AUC, that are dose-proportional. In further embodiments, the pharmaceutical compositions have a PK profile or PK parameter that is dose -proportional to about 5 mg aticaprant, about 4.9 mg aticaprant, or about 5.1 mg aticaprant.
[0031] Some embodiments include pharmaceutical compositions comprising aticaprant that are bioequivalent to any one of the pharmaceutical compositions described herein. Bioequivalence may be demonstrated by any method known to one skilled in the art, for example, as described in Chow, Bioavailability and Bioequivalence in Drug Development, Wiley interdisciplinary reviews, Computational statistics, 6, 4 (2014): 304-
312. doi: 10.1002/wics,1310.
[0032] In some embodiments, the pharmaceutical composition comprises about 5 mg aticaprant, wherein when the pharmaceutical composition is compared to a reference composition, the 90% confidence interval of the ratio of geometric means of one or more PK parameters of the pharmaceutical composition and reference composition is within the bioequivalence limits of 80% and 125%.
[0033] In some embodiments, the PK profile is based on administration of the composition, containing about 5 mg aticaprant, to a human after at least a 10-hour fast. In other embodiments, the PK profile is based on administration of the composition, containing about 5 mg aticaprant, to a human about 30 minutes after the start of a high-fat meal following at least a 10-hour fast. In further embodiments, the PK profile is based on administration of the composition, containing about 5 mg aticaprant, to a human after at least a 10-hour fast. In yet other embodiments, the PK profile is based on administration of a composition containing about 5 mg aticaprant to a human. In still further embodiments the PK profile is based on administration of a composition containing 4.9 to about 5.1, about 4.9 to about 5, or about 5 to about 5.1 mg of aticaprant to a human.
[0034] In certain aspects, the PK profile is determined after an at least 10-hour food fast. In some embodiments, the food fast is at least about 1, about 2, about 4, about 5, about 10, about 12, about 15, about 18, about 20, about 22, about 24, about 28, or about 32 hours.
[0035] As noted, the compositions contain a pharmaceutically acceptable excipient, one of which may be a filler. In some embodiments, the filler is the filler is microcrystalline cellulose, lactose monohydrate, or silicified microcrystalline cellulose, or a combination thereof. In other embodiments, the filler is microcrystalline cellulose. In further embodiments, the filler is lactose monohydrate. In yet other embodiments, the filler is silicified microcrystalline cellulose. The composition comprises between about 10% to about 99.9% filler by weight, based on the weight of the composition. In some embodiments, the composition contains about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, or about 99.9% by weight, based on the weight of the composition, of a filler In other embodiments, the composition comprises about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 99.9, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 99.9, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 40 to about 99.9, about 40 to about 90, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 50 to about 99.9, about 50 to about 90, about 50 to about 80, about 50 to about 70, about 50 to about 60, about 60 to about 99.9, about 60 to about 90, about 60 to about 80, about 60 to about 70, about 70 to about 99.9, about 70 to about 90, about 70 to about 80, about 80 to about 99.9, about 80 to about 90, or about 90 to about
99.9% by weight, based on the weight of the composition, of a filler. In further embodiments, the composition comprises about 90% by weight, based on the weight of the composition, of the filler. In other embodiments, the composition comprises about 88.5% by weight, based on the weight of the composition, of the filler.
[0036] The aticaprant to filler ratio is between about 0.005 and about 9 by weight.
In some embodiments, the aticaprant to filler ratio is about 0.008 and 0.8 about by weight. In other embodiments, the aticaprant to filler ratio is about 0.005 to about 8, about 0.005 to about 7, about 0.005 to about 6, about 0.005 to about 5, about 0.005 to about 4, about 0.005 to about 3, about 0.005 to about 2, about 0.005 to about 1, about 0.005 to about 0.5, about 0.005 to about 0.1, about 0.005 to about 0.05, about 0.005 to about 0.01, about 0.01 to about 9, about 0.01 to about 8, about 0.01 to about 7, about 0.01 to about 6, about 0.01 to about 5, about 0.01 to about 4, about 0.01 to about 3, about 0.01 to about 2, about 0.01 to about 1, about 0.01 to about 0.5, about 0.01 to about 0.1, about 0.01 to about 0.05, about 0.05 to about 9, about 0.05 to about 8, about 0.05 to about 7, about 0.05 to about 6, about 0.05 to about 5, about 0.05 to about 4, about 0.05 to about 3, about 0.05 to about 2, about 0.05 to about 1, about 0.05 to about 0.5, about 0.05 to about 0.1, about 0.1 to about 9, about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 1 to about 9, about 1 to about 8, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 4, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 9, about 7 to about 8, or about 8 to about 9 by weight. In further embodiments, the aticaprant to filler ratio is about 0.056 by weight.
[0037] The composition may further comprise one or more of a filler, disintegrant, glidant, lubricant, solvent, coloring agent, binder buffers, preservatives, penetration agents, wetting agents, surfactants, solubilizing agents, thickening agents, colorants, antioxidants, emulsifying agents, isotonizing agents, suspending agents, and/or viscosity increasing agents.
[0038] In some embodiments, the composition further comprises one or more of a disintegrant. Examples of disintegrants useful in the compositions include, e.g., the disintegrant is croscarmellose sodium. The composition comprises between about 0.5% to about 50% by weight, based on the weight of the composition, of the disintegrant. In some embodiments, the composition comprises about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50% by weight, based on the weight of the composition, of the disintegrant. In other embodiments, the composition comprises about 0.5 to about 40%, about 0.5 to about 30%, about 0.5 to about 20%, about 0.5 to about 10%, about 0.5 to about 5%, about 0.5 to about 4%, about 0.5 to about 3%, about 0.5 to about 2%, about 0.5 to about 1%, about 5 to about 50%, about 5 to about 40%, about 5 to about 30%, about 5 to about 20%, about 5 to about 10%, about 10 to about 50%, about 10 to about 40%, about 10 to about 30%, about 10 to about 20%, about 20 to about 50%, about 20 to about 40%, about 20 to about 30%, about 30 to about 50%, about 30 to about 40%, or about 40 to about 50% by weight, based on the weight of the composition of the disintegrant. In further embodiments, the composition comprises about 5% by weight, based on the weight of the composition, of the disintegrant. The aticaprant to disintegrant ratio is between about 0.1 and 10 by weight. In some embodiments, the aticaprant to disintegrant ratio is about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 by weight. In other embodiments, the aticaprant to disintegrant ratio is about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 10, about 0.5 to about 9, about 0.5 to about 8, about 0.5 to about 7, about 0.5 to about 6, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 10, about 8 to about 9, about 9 to about 10 by weight. In further embodiments, the aticaprant to disintegrant ratio is about 5 by weight. In other embodiments, the aticaprant to disintegrant ratio is about 1 by weight.
[0039] In other embodiments, the composition further comprises one or more of a glidant. Examples of glidants useful in the compositions include, e.g., silica, colloidal anhydrous. The composition comprises between about 0.1% to about 10% glidant by weight, based on the weight of the composition. In some embodiment, the composition contains about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10% by weight, based on the weight of the composition, of the glidant. In other embodiments, the composition contains about 0.1 to about 9, about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about
10, about 0.5 to about 9, about 0.5 to about 8, about 0.5 to about 7, about 0.5 to about 6, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about
1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 10, about 8 to about 9, or about 9 to about 10% by weight, based on the weight of the composition, of the glidant. In further embodiments, the composition contains about 1 % by weight, based on the weight of the composition, of the glidant. The aticaprant to glidant ratio is between 0.5 and 50 by weight. In some embodiments, the aticaprant to glidant ratio is about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 by weight. In other embodiments, the aticaprant to glidant ratio is about 0.5 to about 50, about 0.5 to about 45, about 0.5 to about 40, about 0.5 to about 35, about 0.5 to about 30, about 0.5 to about 25, about 0.5 to about 20, about 0.5 to about 15, about 0.5 to about 10, about 0.5 to about 5, about 0.5 to about 1, about 1 to about 50, about 1 to about 45, about 1 to about 40, about 1 to about 35, about 1 to about 30, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 5, about 5 to about 50, about 5 to about 45, about 5 to about 40, about 5 to about 35, about 5 to about 30, about 5 to about 25, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 50, about 10 to about 45, about 10 to about 40, about 10 to about 35, about 10 to about 30, about 10 to about 25, about 10 to about 20, about 10 to about 15, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 50, about 23 to about 40, about 40 to about 50, or about 45 to about 50 by weight. In further embodiments, the aticaprant to glidant ratio is about 5 by weight.
[0040] In further embodiments, the composition further comprises one or more of a lubricant. Examples of lubricants useful in the compositions include, e.g., the lubricant is magnesium stearate. The composition comprises between about 0.05% to about 5% lubricant by weight, based on the weight of the composition. In some embodiments, the composition comprises about 0.05, about 0.1, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5 or about 5% by weight, based on the weight of the composition, of lubricant. In other embodiments, the composition comprises about 0.05 to about 4.5, about 0.05 to about 4, about 0.05 to about 3, about 0.05 to about 2, about 0.05 to about 1, about 0.05 to about 0.5, about 0.05 to about 0.1, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5% by weight, based on the weight of the composition, of lubricant. In further embodiments, the composition comprises about 0.5% by weight, based on the weight of the composition, of the lubricant. The aticaprant to lubricant ratio is between about 1 and about 100 by weight. In some embodiments, the aticaprant to lubricant ratio is about 1, about 5, 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100 by weight. In other embodiments, the aticaprant to lubricant ratio is 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 5 to about 100, about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 5 to about 100, about 5 to about 90, about 5 to about 80, about 5 to about 70, about 5 to about 60, about 5 to about 50, about 5 to about 40, about 5 to about 30, about 5 to about 20, about 5 to about 10, about 10 to about 100, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 100, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 100, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 40, to about 100, about 40 to about 90, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 50 to about 100, about 50 to about 90, about 50 to about 80, about 50 to about 70, about 50 to about 60, about 60 to about 100, about 60 to about 90, about 60 to about 80, about 60 to about 70, about 70 to about 100, about 70 to about 90, about 70 to about 80, about 80 to about 100, about 80 to about 90, or about 90 to about 100 by weight. In further embodiments, the aticaprant to lubricant ratio is about 10 by weight.
[0041] In some aspects, the composition comprises one or more of an aticaprant to filler ratio between 0.005 and 9 by weight; an aticaprant to disintegrant ratio between 0.1 and 10 by weight; an aticaprant to glidant ratio between 0.5 and 50 by weight; and an aticaprant to lubricant ratio between 1 and 100 by weight. In other aspects, the composition comprises one or more of an aticaprant to filler ratio of about 0.06 by weight; an aticaprant to disintegrant ratio of about 1 by weight; an aticaprant to glidant ratio of about 5 by weight; and an aticaprant to lubricant ratio of about 10 by weight. In further aspects, the composition comprises about 5% by weight of aticaprant, about 88.5% by weight of filler, about 5% by weight of disintegrant by weight, about 1% by weight of glidant, and about 0.5% by weight of lubricant, based on the weight of the composition.
[0042] In certain aspects, the pharmaceutical composition comprises one or more of a filler, disintegrant, glidant, lubricant, binder, and/or coloring agent. In some embodiments, the filler is microcrystalline cellulose, lactose monohydrate, or silicified microcrystalline cellulose; the disintegrant is croscarmellose sodium; the glidant is silica, colloidal anhydrous; and the lubricant is magnesium stearate. [0043] Desirably, the composition is formulated as a solid composition. In some embodiments, the solid composition is a tablet, capsule, or caplet. In other embodiments, the solid composition is a tablet such as an oral tablet. In further embodiments, the solid composition is a capsule such as an oral capsule. In yet other embodiments, the solid composition is a caplet such as an oral caplet. Optionally, the solid compositions are coated. For example, the coating is an enteric coating. By doing so, the coating provides a film coat on the solid composition. In some embodiments, the film coat comprises a coating powder. In other embodiments, the film coat comprises Opadry II Orange. In further embodiments, the coating powder is Opadry II Orange. Exemplary aticaprant tablet and capsule formulations, including excipients, are disclosed in U.S. Patent Application No. 18/179,093, filed March 6, 2023, the disclosure of which is incorporated by reference herein.
[0044] The tablet may comprise one or more layers. In some embodiments, the tablet comprises a core tablet and a film coat to provide a film coated tablet. The ratio of the film coat to core tablet is between about 0.03 to 10 by weight. In some embodiments, the ratio of the film coat to core tablet is about 0.03, 0.05, 0.08, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 by weight, based on the weight of the composition. In other embodiments, the ratio of the film coat to core tablet is about 0.03 to about 9, about 0.03 to about 8, about 0.03 to about 7, about 0.03 to about 6, about 0.03 to about 6, about 0.03 to about 5, about 0.03 to about 4, about 0.03 to about 3, about 0.03 to about 2, about 0.03 to about 1, about 0.03 to about 0.5, about 0.03 to about 0.1, about 0.05 to about 10, 0.05 to about 9, about 0.05 to about 8, about 0.05 to about 7, about 0.05 to about 6, about 0.05 to about 6, about 0.05 to about 5, about 0.05 to about 4, about 0.05 to about 3, about 0.05 to about 2, about 0.05 to about 1, about 0.05 to about 0.5, about 0.05 to about 0.1, about 0.1 to about 10, 0.1 to about 9, about 0.1 to about 8, about 0.1 to about 7, about 0.1 to about 6, about 0.1 to about 6, about 0.1 to about 5, about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, 0.5 to about 9, about 0.5 to about 8, about 0.5 to about 7, about 0.5 to about 6, about 0.5 to about 6, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 10, 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 10, about 8 to about 9, or about 9 to about 10.
[0045] The core tablet may contain one or more phases. In some embodiments, the core tablet comprises a first phase such as an intragranular phase. In other embodiments, the core tablet comprises a second phase such as an extragranular phase. In further embodiments, the core tablet comprises intragranular and extragranular phases.
[0046] The ratio of the intragranular phase to extragranular phase in the core tablet is between about 1.5 and about 3 by weight. In some embodiments, the ratio of the intragranular phase to extragranular phase in the core tablet is about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, or about 3 by weight. In other embodiments, the ratio of the intragranular phase to extragranular phase in the core tablet is about 1.5 to about 2.8, about 1.5 to about 2.5, about 1.5 to about 2.3, about 1.5 to about 2, about 1.5 to about 1.8, about 1.8 to about 3, about 1.8 to about 2.8, about 1.8 to about 2.5, about 1.8 to about 2.3, about 2 to about 3, about 2 to about 2.8, about 2 to about 2.5, about 2 to about 2.3, about 2 to about 2.1, about 2.1 to about 3, about 2.1 to about 2.8, about 2.1 to about 2.5, about 2.1 to about 2.3, about 2.3 to about 3, about 2.3 to about 2.8, about 2.3 to about 2.5 to about 2.5 to about 3, about 2.5 to about 2.8, and about 2.8 to about 3 by weight. In further embodiments, the ratio of the intragranular phase to extragranular phase in the core tablet is about 2.1 by weight.
[0047] As for the composition, the solid composition contains aticaprant and one or more pharmaceutically acceptable excipients. In some aspects, the intragranular phase comprises aticaprant, a filler, a disintegrant, and a glidant. In other aspects, the intragranular phase comprises one filler. In further aspects, the intragranular phase comprises two fillers.
[0048] The intragranular phase comprises about 10 to about 120 mg of the filler. In some embodiments, the intragranular phase comprises about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, or about 120 mg of the filler. In other embodiments, the intragranular phase comprises about 10 to about 110, about 10 to about 100, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 120, about 20 to about 110, about 20 to about 100, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 120, about 30 to about 110, about 30 to about 100, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 40 to about 120, about 40 to about 110, about 40 to about 100, about 40 to about 90, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 50 to about 120, about 50 to about 110, about 50 to about 100, about 50 to about 90, about 50 to about 80, about 50 to about 70, about 50 to about 60, about 60 to about 120, about 60 to about 110, about 60 to about 100, about 60 to about 90, about 60 to about 80, about 60 to about 70, about 70 to about 120, about 70 to about 110, about 70 to about 100, about 70 to about 90, about 70 to about 80, about 80 to about 120, about 80 to about 110, about 80 to about 100, about 80 to about 90, about 90 to about 120, about 90 to about 110, about 90 to about 100, about 100 to about 120, about 100 to about 110, or about 110 to about 120. In further embodiments, the intragranular phase contains about 60 mg of filler. In yet other embodiments, the intragranular phase contains about 30 mg of microcrystalline cellulose. In still further embodiments, the intragranular phase contains about 30 mg of lactose monohydrate. In other embodiments, the intragranular phase contains about 60 mg of microcrystalline cellulose. In further embodiments, the intragranular phase contains about 60 mg of lactose monohydrate.
[0049] The intragranular phase comprises an aticaprant to filler ratio of between about 0.008 and 0.8 by weight. In some embodiments, the intragranular phase contains an aticaprant to filler ratio of about 0.008, about 0.005, about 0.001, about 0.01, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, or about 0.8 by weight. In other embodiments, the intragranular phase comprises an aticaprant to filler ratio of about 0.008 to about 0.7, about 0.008 to about 0.6, about 0.008 to about 0.5, about 0.008 to about 0.6, about 0.008 to about 0.5, about 0.008 to about 0.4, about 0.008 to about 0.3, about 0.008 to about 0.2, about 0.008 to about 0.1, about 0.008 to about 0.05, about 0.008 to about 0.01, about 0.01 to about 0.8, about 0.01 to about 0.7, 0.01 to about 0.6, about 0.01 to about 0.5, about 0.01 to about 0.4, about 0.01 to about 0.5, about 0.01 to about 0.4, about 0.01 to about 0.3, about 0.01 to about 0.2, about 0.01 to about 0.1, about 0.01 to about 0.05, about 0.05 to about 0.8, about 0.05 to about 0.9, about 0.05 to about 0.8, about 0.05 to about 0.7, about 0.05 to about 0.6, about 0.05 to about 0.6, about 0.05 to about 0.5, about 0.05 to about 0.4, about 0.05 to about 0.3, about 0.05 to about 0.2, about 0.05 to about 0.1, about 0.1 to about 0.8, about 0.1 to about 0.7, about 0.1 to about 0.6, about 0.1 to about 0.5, about 0.1 to about 0.4, about 0.1 to about 0.3, about 0.1 to about 0.2, about 0.2 to about 0.8, about 0.2 to about 0.7, about 0.2 to about 0.6, about 0.2 to about 0.5, about 0.2 to about 0.4, about 0.2 to about 0.3, about 0.3 to about 0.8, about 0.3 to about 0.7, about 0.3 to about 0.6, about 0.3 to about 0.5, about 0.3 to about 0.4, about 0.4 to about 0.8, about 0.4 to about 0.7, about 0.4 to about 0.6, about 0.4 to about 0.5, about 0.5 to about 0.8, about 0.5 to about 0.7, about 0.5 to about 0.6, about 0.6 to about 0.8, about 0.6 to about 0.7, or about 0.7 to about 0.8 by weight.
In further embodiments, the intragranular phase comprises an aticaprant to filler ratio of about 0.08 by weight.
[0050] The intragranular phase also may contain a disintegrant. In some embodiments, the intragranular phase contains about 1 to about 10 mg of the disintegrant. In other embodiments, the intragranular phase contains about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, 7, about 7.5, about 8, about 8.5, about 9, about 9.5 or about 10 mg of the disintegrant. In further embodiments, the intragranular phase contains about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 2.5 to about 10, about 2.5 to about 9, about 2.5 to about 8, about 2.5 to about 7, about 2.5 to about 6, about 2.5 to about 5, about 2.5 to about 4, about 2.5 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 10, about 8 to about 9, or about 0 to about 10. In yet other embodiments, the intragranular phase contains about 2.5 mg of the disintegrant. In still further embodiments, the intragranular phase contains about 5 mg of the disintegrant. In other embodiments, the intragranular phase contains about 2.5 mg of croscarmellose sodium. In further embodiments, the intragranular phase contains about 5 mg of croscarmellose sodium.
[0051] The intragranular phase may further contain a glidant. In some embodiments, the intragranular phase contains about 0.1 to about 5 mg of a glidant. In other embodiments, the intragranular phase contains about 0.1, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5 mg of a glidant. In further embodiments, the intragranular phase contains about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5 mg of a glidant. In yet other embodiments, the intragranular phase contains about 0.5 mg of the glidant. In still further embodiments, the intragranular phase contains about 1 mg of the glidant. In other embodiments, the intragranular phase contains about 0.5 mg of silica, colloidal anhydrous. In further embodiments, the intragranular phase contains about 1 mg of silica, colloidal anhydrous.
[0052] The intragranular phase has an aticaprant to disintegrant ratio of between about 0.2 and 20 by weight; In some embodiments, the intragranular phase has an aticaprant to disintegrant ratio of about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 by weight. In other embodiments, the intragranular phase comprises an aticaprant to disintegrant ratio of about 0.2 to about 18, about 0.2 to about 16, about 0.2 to about 14, about 0.2 to about 12, about 0.2 to about 10, about 0.2 to about 8, about 0.2 to about 6, about 0.2 to about 4, about 0.2 to about 3, about 0.2 to about 2, about 0.2 to about 1, about 0.2 to about 0.5, about 0.5 to about 20, about 0.5 to about 18, about 0.5 to about 16, about 0.5 to about 14, about 0.5 to about 12, about 0.5 to about 10, about 0.5 to about 8, about 0.5 to about 6, about 0.5 to about 4, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 20, about 1 to about 18, about 1 to about 16, about 1 to about 14, about 1 to about 12, about 1 to about 10, about 1 to about 8, about 1 to about 6, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 1 to about 1.5, about 2 to about 20, about 2 to about 18, about 2 to about 16, about 2 to about 14, about 2 to about 12, about 2 to about 10, about 2 to about 8, about 2 to about 6, about 2 to about 4, about 4 to about 20, about 4 to about 18, about 4 to about 16, about 4 to about 14, about 4 to about 12, about 4 to about 10, about 4 to about 6, about 4 to about 8, about 4 to about 6, about 5 to about 20, about 6 to about 18, about 6 to about 16, about 6 to about 14, about 6 to about 12, about 6 to about 10, about 6 to about 8, about 8 to about 20, about 8 to about 18, about 8 to about 16, about 8 to about 14, about 8 to about 12, about 8 to about 10, about 10 to about 20, about 10 to about 18, about 10 to about 16, about 10 to about 14, about 10 to about 12, about 12 to about 20, about 12 to about 18, about 12 to about 16, about 12 to about 14, about 14 to about 20, about 14 to about 18, about 14 to about 16, about 16 to about 20, about 16 to about 18, or about 18 to about 20 by weight. In further embodiments, the intragranular phase comprises an aticaprant to disintegrant ratio of about 2 by weight. [0053] The intragranular phase comprises an aticaprant to glidant ratio of between about 1 and 100 by weight. In some embodiments, the intragranular phase comprises an aticaprant to glidant ratio of about 1, about 5, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 by weight. In other embodiments, the intragranular phase comprises an aticaprant to glidant ratio of about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 5, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 15, about 2 to about 10, about 2 to about 5, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 80, about 40 to about 60, or about 60 to about 80 by weight. In further embodiments, the intragranular phase comprises an aticaprant to glidant ratio of 10 by weight.
[0054] The extragranular phase comprises one or more of a filler, a disintegrant, a glidant, and a lubricant. In some embodiments, the extragranular phase comprises a filler. In other embodiments, the extragranular phase comprises a disintegrant. In further embodiments, the extragranular phase comprises a glidant. In yet other embodiments, the extragranular phase comprises a lubricant.
[0055] The extragranular phase may comprise a filler. In some embodiments, the extragranular phase contains one filler. In other embodiment, the extragranular phase contains about 10 to about 80 mg of a filler. In further embodiments, the extragranular phase contains about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 70, or about 80 mg of a filler. In still other embodiments, the extragranular phase contains about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 10 to about 15, about 15 to about 80, about 15 to about 70, about 15 to about 60, about 15 to about 50, about 15 to about 40, about 15 to about 30, about 15 to about 20, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 25 to about 80, about 25 to about 70, about 25 to about 60, about 25 to about 50, about 25 to about 40, about 25 to about 30, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 35 to about 80, about 35 to about 70, about 35 to about 60, about 35 to about 50, about 35 to about 40, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 40 to about 80, about 40 to about 70, about 45 to about 80, about 45 to about 70, about 45 to about 60, about 45 to about 50, about 50 to about 80, about 50 to about 70, about 50 to about 60, about 50 to about 55, about 55 to about 80, about 55 to about 70, about 55 to about 60, about 60 to about 80, about 60 to about 70, about 65 to about 80, about 65 to about 80, about 70 to about 80, or about 75 to about 80 mg of a filler. In yet further embodiments, the extragranular phase contains about 28.5 mg of the filler. In other embodiments, the extragranular phase contains about 28.5 of silicified microcrystalline cellulose. In further embodiments, the extragranular phase contains about 57 mg of the filler. In still other embodiments, the extragranular phase contains about 57 mg of silicified microcrystalline cellulose.
[0056] The extragranular phase may additionally contain a disintegrant. In some embodiments, the disintegrant is croscarmellose sodium. In other embodiments, the extragranular phase contains about 1 to about 10 mg of a disintegrant. In further embodiments, the extragranular phase contains about 1, about 2, about 2.5, about 3, about 4, about 5, about 6, about 7, about 7.5, about 8, about 9, or about 10 mg of a disintegrant. In yet other embodiments, the extragranular phase contains about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 2.5 to about 10, about 2.5 to about 9, about 2.5 to about 8, about 2.5 to about 7, about 2.5 to about 6, about 2.5 to about 5, about 2.5 to about 4, about 2.5 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 7.5 to about 10, about 7.5 to about 9, about 7.5 to about 8, about 8 to about 10, about 8 to about 9, or about 9 to about 10 mg of a disintegrant. In still further embodiments, the extragranular phase contains about 2.5 mg of a disintegrant. In other embodiments, the extragranular phase contains about 5 mg of a disintegrant. In further embodiments, the extragranular phase contains about 2.5 mg of croscarmellose sodium. In still other embodiments, the extragranular phase contains about 5 mg of croscarmellose sodium.
[0057] The extragranular phase comprises a filler to disintegrant ratio of between about 1 and 100 by weight. In some embodiments, the extragranular phase comprises a filler to disintegrant ratio of 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 by weight. In further embodiments, the extragranular phase comprises a filler to disintegrant ratio of about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 5 to about 100, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 10 to about 15, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 by weight. In yet other embodiments, the extragranular phase comprises a filler to disintegrant ratio of about 11.4.
[0058] The extragranular phase further may contain a glidant. In some embodiments, the glidant is silica, colloidal anhydrous. In other embodiments, the extragranular phase contains about 0.1 to about 5 mg of the glidant. In further embodiments, the extragranular phase contains about 0.1, about 0.25, about 0.5, about 0.75, about 1, about
2, about 3, about 4, or about 5 mg of a glidant. In yet other embodiments, the extragranular phase contains about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about
3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5 mg of a glidant. In still further embodiments, the extragranular phase contains about 0.5 mg of a glidant. In other embodiments, the extragranular phase contains about 1 mg of a glidant. In further embodiments, the extragranular phase contains about 0.5 mg of silica, colloidal anhydrous.
In yet other embodiments, the extragranular phase contains about 1 mg of silica, colloidal anhydrous.
[0059] The extragranular phase comprises a filler to glidant ratio of between about 5 and 500 by weight. In other embodiments, the extragranular phase comprises a filler to glidant ratio of about 5, about 10, about 25, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500. In further embodiments, the extragranular phase comprises a filler to glidant ratio of about 5 to about 400, about 5 to about 300, about 5 to about 200, about 5 to about 100, about 5 to about 75, about 5 to about 50, about 10 to about 500, about 10 to about 400, about 10 to about 300, about 10 to about 200, about 10 to about 100, about 10 to about 50, about 25 to about 500, about 25 to about 400, about 25 to about 300, about 25 to about 200, about 25 to about 100, about 25 to about 75, about 25 to about 50, about 50 to about 500, about 50 to about 400, about 50 to about 300, about 50 to about 200, about 50 to about 100, about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200 to about 500, about 200 to about 400, about 200 to about 300, about 300 to about 500, about 300 to about 400, or about 400 to about 500 by weight. In still further embodiments, the extragranular phase comprises a filler to glidant ratio of about 57.
[0060] The extragranular phase may also contain a lubricant. In some embodiments, the lubricant is magnesium stearate. In other embodiments, the extragranular phase contains about 0.1 to about 5 mg of the lubricant. In further embodiments, the extragranular phase contains about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 2, about 3, about 4, or about 5 mg of a lubricant. In yet other embodiments, the extragranular phase contains about 0.1 to about 4, about 0.1 to about 3, about 0.1 to about 2, about 0.1 to about 1, about 0.1 to about 0.5, about 0.5 to about 5, about 0.5 to about 4, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5 mg of a lubricant. In still further embodiments, the extragranular phase contains about 0.5 mg of a lubricant. In other embodiments, the extragranular phase contains about 1 mg of a lubricant. In further embodiments, the extragranular phase contains about 0.5 mg of magnesium stearate. In yet other embodiments, the extragranular phase contains about 1 mg of magnesium stearate.
[0061] The extragranular phase comprises a filler to lubricant ratio of between about 5 and 500 by weight. In other embodiments, the extragranular phase comprises a filler to lubricant ratio of about 5, about 10, about 25, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500. In further embodiments, the extragranular phase comprises a filler to lubricant ratio of about 5 to about 400, about 5 to about 300, about 5 to about 200, about 5 to about 100, about 5 to about 75, about 5 to about 50, about 10 to about 500, about 10 to about 400, about 10 to about 300, about 10 to about 200, about 10 to about 100, about 10 to about 50, about 25 to about 500, about 25 to about 400, about 25 to about 300, about 25 to about 200, about 25 to about 100, about 25 to about 75, about 25 to about 50, about 50 to about 500, about 50 to about 400, about 50 to about 300, about 50 to about 200, about 50 to about 100, about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200 to about 500, about 200 to about 400, about 200 to about 300, about 300 to about 500, about 300 to about 400, or about 400 to about 500 by weight. In still further embodiments, the extragranular phase comprises a filler to lubricant ratio of about 57.
[0062] In some embodiments, the intragranular phase comprises one or more of: an aticaprant to filler ratio of between about 0.008 and 0.8 by weight; an aticaprant to disintegrant ratio of between about 0.2 and 20 by weight; and an aticaprant to glidant ratio of between about 1 and 100 by weight.
[0063] In some embodiments, the extragranular phase comprises one or more of: a filler to disintegrant ratio of between about 1 and 100 by weight; a filler to glidant ratio of between about 5 and 500 by weight; and a filler to lubricant ratio of between about 5 and 500 by weight. In other embodiments, the extragranular phase comprises a filler to disintegrant ratio of about 11.4 by weight. In further embodiments, the extragranular phase comprises a filler to glidant ratio of about 57 by weight. In yet other embodiments, the extragranular phase comprises a filler to lubricant ratio of about 57 by weight.
[0064] In other aspects, the core tablet comprises about 5% aticaprant by weight, about 88.5% filler by weight, about 5% disintegrant by weight, about 1% glidant by weight, and about 0.5% lubricant by weight.
[0065] The oral tablet may be of weight that is suitable for administration by a patient. In some embodiments, the oral tablet has a core tablet of about 10 to about 1000 mg. In other embodiments, the core tablet is about 10, about 25, about 50, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, or about 1000 mg. In further embodiments, the core tablet is about 10 to about 900, about 10 to about 800, about 10 to about 700, about 10 to about 600, about 10 to about 500, about 10 to about 400, about 10 to about 300, about 10 to about 200, about 10 to about 100, about 10 to about 50, about 25 to about 1000, about 25 to about 900, about 25 to about 800, about 25 to about 700, about 25 to about 600, about 25 to about 500, about 25 to about 400, about 25 to about 300, about 25 to about 200, about 25 to about 100, about 25 to about 75, about 50 to about 1000, about 50 to about 900, about 50 to about 800, about 50 to about 700, about 50 to about 600, about 50 to about 500, about 50 to about 400, about 50 to about 300, about 50 to about 200, about 50 to about 100, about 100 to about 1000, about 100 to about 900, about 100 to about 800, about 100 to about 700, about 100 to about 600, about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200 to about 1000, about 200 to about 900, about 200 to about 800, about 200 to about 700, about 200 to about 600, about 200 to about 500, about 200 to about 400, about 200 to about 300, about 500 to about 1000, about 500 to about 800, about 500 to about 600, about 800 to about 1000, or about 800 to about 900 mg. In yet other embodiments, the core tablet is about 100 mg. In still further embodiments, the oral tablet comprises a core tablet of about 200 mg.
[0066] In some aspects, the core tablet contains a disintegrant. For example, the core tablet contains about 5 to about 100 mg of a disintegrant. In some embodiments, the core tablet contains about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg of a disintegrant. In other embodiments, the core tablet contains about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 mg of a disintegrant. In further embodiments, the core tablet contains about 5 mg of the disintegrant. In yet other embodiments, the core tablet contains about 10 mg of the disintegrant.
[0067] In other aspects, the core tablet contains a glidant. For example, the core tablet contains about 1 to about 100 mg of a glidant. In some embodiments, the core tablet contains about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg of a glidant. In other embodiments, the core tablet contains about 1 to about 100, about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 2 to about 100, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 10, about 2 to about 5, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 mg of a glidant. In further embodiments, the core tablet contains about 1 mg of the glidant. In yet other embodiments, the core tablet contains about 2 mg of the glidant.
[0068] In further aspects, the core tablet contains a lubricant. For example, the core tablet contains about 0.5 to about 100 mg of a lubricant. In some embodiments, the core tablet contains about 0.5, about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg of a lubricant. In other embodiments, the core tablet contains about 0.5 to about 80, about 0.5 to about 60, about 0.5 to about 40, about 0.5 to about 20, about 0.5 to about 10, about 0.5 to about 5, about 0.5 to about 1, about 1 to about 100, about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 2 to about 100, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 10, about 2 to about 5, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 100, about 60 to about 80, or about 80 to about 100 mg of a lubricant. In further embodiments, the core tablet contains about 0.5 mg of the lubricant. In yet other embodiments, the core tablet contains about 1 mg of the lubricant.
[0069] In further aspects, the core tablet contains a filler. For example, the core tablet contains about 1 to about 200 mg of a filler. In some embodiments, the core tablet contains about 1, about 2, about 3, about 4, about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, or about 200 mg of a filler. In other embodiments, the core tablet contains about 1 to about 180, about 1 to about 160, about 1 to about 140, about 1 to about 120, 1 to about 100, about 1 to about 80, about 1 to about 60, about 1 to about 40, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 2 to about 200, about 2 to about 180, about 2 to about 160, about 2 to about 140, about 2 to about 120, about 2 to about 100, about 2 to about 80, about 2 to about 60, about 2 to about 40, about 2 to about 20, about 2 to about 10, about 2 to about 5, about 5 to about 200m, about 5 to about 180, about 5 to about 160, about 5 to about 140, about 5 to about 120, about 5 to about 100, about 5 to about 80, about 5 to about 60, about 5 to about 40, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 200, about 10 to about 180, about 10 to about 160, about 10 to about 140, about 10 to about 120, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 10 to about 20, about 20 to about 200, about 20 to about 180, about 20 to about 160, about 20 to about 140, about 20 to about 120, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 40 to about 200, about 40 to about 180, about 40 to about 160, about 40 to about 140, about 40 to about 120, bout 40 to about 100, about 40 to about 80, about 40 to about 60, about 60 to about 200, about 60 to about 180, about 60 to about 160, about 60 to about 140, about 60 to about 120, about 60 to about 100, about 60 to about 200, about 60 to about 180, about 60 to about 160, about 60 to about 140, about 60 to about 120, about 60 to about 100, about 60 to about 80, about 80 to about 200, about 80 to about 180, about 80 to about 160, about 80 to about 140, about 80 to about 120, about 80 to about 100 mg, about 100 to about 200, about 100 to about 180, about 100 to about 160, about 100 to about 140, about 100 to about 120, about 120 to about 200, about 120 to about 180, about 120 to about 160, about 120 to about 140, about 140 to about 200, about 140 to about 180, about 140 to about 160, about 160 to about 200, about 160 to about 180, or about 180 to about 200 mg of a filler. In further embodiments, the core tablet contains about 88.5 mg of the filler. In yet other embodiments, the core tablet contains about 177 mg of the filler.
[0070] In some preferred embodiments, the oral tablet comprises a core tablet of about 100 mg and comprising about 5 mg aticaprant, about 5 mg disintegrant, about 88.5 mg filler, about 1 mg glidant, and about 0.5 mg lubricant.
[0071] As noted above, the core tablet may be coated with a film coat. In some embodiments, the oral tablet comprises about 3 mg of film coat.
[0072] In some aspects, the film coated oral tablet comprises about 80 to about 99.9% by weight of the core tablet and about 0.1 to about 20% by weight, based on the weight of the film coated oral tablet, of the core tablet. In some embodiments, the film coated oral tablet comprises about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, or 99.9% by weight, based on the weight of the film coated oral tablet. In other embodiments, the film coated oral tablet comprises about 80 to about 99, about 80 to about 96, about 80 to about 94, about 80 to about 92, about 80 to about 90, about 80 to about 88, about 80 to about 86, about 80 to about 84, about 80 to about 82, about 82 to about 99, about 82 to about 96, about 82 to about 94, about 82 to about 92, about 82 to about 90, about 82 to about 88, about 82 to about 86, about 82 to about 84, about 84 to about 99, about 84 to about 99, about 84 to about 96, about 84 to about 94, about 84 to about 92, about 84 to about 90, about 84 to about 88, about 84 to about 86, about 86 to about 99, about 86 to about 96, about 86 to about 94, about 86 to about 92, about 86 to about 90, about 86 to about 88, about 88 to about 99, about 88 to about 96, about 88 to about 94, about 88 to about 92, about 88 to about 90, about 90 to about 99, about 90 to about 96, about 90 to about 94, about 90 to about 92, about 92 to about 99, about 92 to about 96, about 92 to about 94, about 94 to about 99, about 94 to about 96, about 96 to about 99, or about 98 to about 99% by weight, based on the weight of the film coated oral tablet, of the core tablet. In further embodiments, the film coated oral tablet comprises about 97% core tablet by weight, based on the weight of the film coated oral tablet. In yet other embodiments, the film coated oral tablet comprises about 0.1 to about 20% by weight, based on the weight of the film coated oral tablet, of film coat. In still further embodiments, film coated oral tablet comprises about 0.1, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20% by weight, based on the weight of the film coated oral tablet, of the film coat. In other embodiments, the film coated oral tablet comprises about 0.1 to about 18, about 0.1 to about 16, about 0.1 to about 14, about 0.1 to about 12, about 0.1 to about 10, about 0.1 to about 8, about 0.1 to about 6, about 0.1 to about 4, about 0.1 to about 2, about 0.1 to about 1, about 0.5 to about 20, about 0.5 to about 18, about 0.5 to about 16, about 0.5 to about 14, about 0.5 to about 12, about 0.5 to about 10, about 0.5 to about 8, about 0.5 to about 6, about 0.5 to about 4, about 0.5 to about 2, about 1 to about 20, about 1 to about 18, about 1 to about 16, about 1 to about 14, about 1 to about 12, about 1 to about 10, about 1 to about 8, about 1 to about 6, about 1 to about 4, about 1 to about 2, about 2 to about 20, about 2 to about 18, about 2 to about 16, about 2 to about 14, about 2 to about 12, about 2 to about 10, about 2 to about 8, about 2 to about 8, about 2 to about 6, about 2 to about 4, about 4 to about 20, about 4 to about 18, about 4 to about 16, about 4 to about 12, about 4 to about 10, about 4 to about 8, about 4 to about 6, about 6 to about 20, about 6 to about 18, about 6 to about 16, about 6 to about 14, about 6 to about 12, about 6 to about 10, about 6 to about 8, about 8 to about 20, about 8 to about 18, about 8 to about 16, about 8 to about 14, about 8 to about 12, about 8 to about 10, about 10 to about 20, about 10 to about 18, about 10 to about 16, about 10 to about 14, about 10 to about 12, about 12 to about 20, about 12 to about 18, about 12 to about 16, about 12 to about 14, about 14 to about 20, about 14 to about 18, about 14 to about 16, about 16 to about 20, about 16 to about 18, or about 18 to about 20% by weight, based on the weight of the film coated oral tablet, of the film coat. In further embodiments, the film coated oral tablet comprises about 3% by weight, based on the weight of the film coated oral tablet, of the film coat. In yet other embodiments, the film coated oral tablet comprises about 97% core tablet by weight and about 3% film coat by weight, based on the weight of the film coated oral tablet.
[0073] In some embodiments, the disclosure provides oral tablets comprising about 5 mg aticaprant, wherein the oral tablet comprises a core tablet of about 100 mg, wherein the core tablet comprises an intragranular and extragranular phase, wherein the intragranular phase comprises about 30 mg microcrystalline cellulose, about 30 mg lactose monohydrate, about 2.5 mg croscarmellose sodium, and about 0.5 mg silica, colloidal anhydrous; and wherein the extragranular phase comprises about 28.5 mg silicified microcrystalline cellulose, about 2.5 mg croscarmellose sodium, about 0.5 mg silica, colloidal anhydrous, and about 0.5 mg magnesium stearate.
[0074] In other embodiments, the disclosure provides oral tablets comprising about 10 mg aticaprant, wherein the oral tablet comprises a core tablet of about 200 mg, wherein the core tablet comprises an intragranular and extragranular phase, wherein the intragranular phase comprises about 60 mg microcrystalline cellulose, about 60 mg lactose monohydrate, about 5 mg croscarmellose sodium, and about 1 mg silica, colloidal anhydrous; and wherein the extragranular phase comprises about 57 mg silicified microcrystalline cellulose, about 5 mg croscarmellose sodium, about 1 mg silica, colloidal anhydrous, and about 1 mg magnesium stearate.
[0075] The solid compositions may also have a desirable dissolution profile that provide the desired release of aticaprant. In some embodiments, the solid composition contains about 5 mg of aticaprant and has a dissolution profile comprising a Q value of between about 60% and 90% at 45 minutes, under the dissolution operating conditions of (i) apparatus: Paddle (USP Type 2, Ph. Eur., JP), (ii) dissolution medium: 0.01 M hydrochloric acid, (iii) volume: 900 mL, (iv) temperature: 37 ± 0.5 ° C, (v) rotation speed: 50 rpm, and (vi) analytical finish: UHPLC with UV detection at 247 nm. In some embodiments, the Q value is about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, or about 95% at 45 minutes. In other embodiments, the Q value is about 60 to about 85, about
60 to about 80, about 60 to about 75, about 60 to about 70, about 70 to about 90, about 70 to about 85, about 70 to about 80, about 70 to about 75, about 75 to about 90, about 75 to about 85, about 75 to about 80, about 80 to about 90, about 80 to about 85, or about 85 to about 90% at 45 minutes. In further embodiments, the Q value is between about 70% and 80% at 45 minutes. In other aspects, the Q value is about 75% at 45 minutes.
[0076] Advantageously, aticaprant may be administered once daily, or the total daily dosage may be administered in divided doses of two, three or four times daily. In some embodiments, the composition containing aticaprant is administered once daily. In other embodiments, the oral tablet containing aticaprant is administered once daily. In further embodiments, the solid pharmaceutical composition containing aticaprant is administered once daily. [0077] As described herein, in particular, the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaprant. Thus, in a particular embodiment, the disclosure relates to aticaprant, for use as described herein, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaprant. In a further particular embodiment, the disclosure also relates to the use of aticaprant in the manufacture of a medicament, as described herein, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with of aticaprant. In a further particular embodiment, the disclosure further relates to a package or pharmaceutical product as described herein, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaprant. Such antidepressant therapy can be in particular selected from a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.
[0078] As described herein, aticaprant may be used as adjunctive treatment, or in other words, in conjunction, as an add-on, or in combination with one or more antidepressants, for example, the patient may be already, or also, administered one or more antidepressants. Thus, in a further particular embodiment, the disclosure relates to aticaprant, for use as described herein, comprising administration of aticaprant, as adjunctive treatment with an effective amount of one or more antidepressants. In a further particular embodiment, the disclosure relates to aticaprant, for use as described herein, comprising administration of aticaprant, in conjunction with an effective amount of one or more antidepressants. In a further particular embodiment, the disclosure relates to aticaprant, for use as described herein, comprising administration of aticaprant, in combination with an effective amount of one or more antidepressants. In a further particular embodiment, the disclosure also relates to the use of aticaprant, in the manufacture of a medicament, as described herein, wherein the treatment comprises administration of an effective amount of aticaprant, as adjunctive treatment with an effective amount of one or more antidepressants. In a further particular embodiment, the disclosure also relates to the use of aticaprant, as described herein, wherein the treatment comprises administration of an effective amount of aticaprant, in conjunction with an effective amount of one or more antidepressants. In a further particular embodiment, the disclosure also relates to the use of aticaprant, as described herein, wherein the treatment comprises administration of an effective amount of aticaprant, in combination with an effective amount of one or more antidepressants. In a further particular embodiment, the disclosure further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct the administration of an effective amount of aticaprant, as adjunctive treatment with an effective amount of one or more antidepressants. In a further particular embodiment, the disclosure further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct the administration of an effective amount of aticaprant, in conjunction with an effective amount of one or more antidepressants. In a further particular embodiment, the disclosure further relates to a package or pharmaceutical as described herein, wherein the instructions for treatment direct administration of an effective amount of aticaprant, in combination with an effective amount of one or more antidepressants. Such one or more antidepressants can be selected from a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.
[0079] As already described, the disclosure relates to aticaprant, for use as described herein. In a particular embodiment, aticaprant is S-aticaprant. In a further embodiment of the disclosure, aticaprant, in particular S-aticaprant, for use as described herein, is to be administered in an amount of about 5 mg. In a yet further embodiment, aticaprant, in particular S-aticaprant, for use as described herein, is administered orally. Furthermore, in a further particular embodiment, the disclosure relates to aticaprant, in particular S-aticaprant, for use as described herein, administered once daily. The disclosure also relates to the use of aticaprant, in the manufacture of a medicament, as described herein. In a particular embodiment, aticaprant is S-aticaprant. In a further embodiment of the use as described herein, about 5 mg. In a yet further embodiment of the use, aticaprant is to be administered orally. Furthermore, in a further particular embodiment of the use aticaprant in particular S- aticaprant, is to be administered once daily. In a further particular embodiment, the disclosure further relates to a package or pharmaceutical product as described herein, wherein aticaprant is in particular S-aticaprant. In a further embodiment of the package or pharmaceutical product as described herein, the instructions for treatment direct administration of about 5 mg. In a yet further embodiment of the package or pharmaceutical product as described herein, the instructions for treatment direct aticaprant, in particular S- aticaprant, is for oral administration. Furthermore, in a further particular embodiment of the package or pharmaceutical product, as described herein, the instructions for treatment direct aticaprant, in particular S-aticaprant, is for once daily administration.
[0080] Advantageously, administration of aticaprant, does not result in weight gain during treatment, including clinically relevant weight gain. Thus, in a further particular embodiment, the disclosure relates to aticaprant, for use as described herein, wherein the patient does not experience weight gain during the treatment with aticaprant. In a further particular embodiment, the disclosure relates to a use as defined herein, wherein the patient does not experience weight gain during the treatment with aticaprant. In a further particular embodiment, the disclosure further relates to a package or pharmaceutical product as described herein, wherein the patient does not experience weight gain during the treatment with aticaprant. The body weight of the patient can in particular be assessed at the time of the initial administration of aticaprant.
[0081] As already described, the patient may have anhedonia. In certain aspects, the anhedonia is moderate. In other aspects, the anhedonia is severe. Anhedonia can be measured, through an anhedonia scale, for example, the Snaith Hamilton Pleasure Scale (SHAPS). Thus, in a particular embodiment, the disclosure relates to aticaprant, for use as described herein, wherein the anhedonia of the patient is reduced by at least 40%, as measured by the change from baseline in total score in an anhedonia scale following 6 weeks of the treatment with aticaprant, more in particular, the anhedonia of the patient is reduced within about 3 weeks to about 6 weeks as measured by the change from baseline in total score in an anhedonia scale. In a further particular embodiment, the anhedonia scale is the Snaith Hamilton Pleasure Scale (SHAPS). Thus, in a particular embodiment, the disclosure relates to the use as described herein, wherein the anhedonia of the patient is reduced by at least 40%, as measured by the change from baseline in total score in an anhedonia scale following 6 weeks of the treatment with aticaprant, more in particular, the anhedonia of the patient is reduced within about 3 weeks to about 6 weeks as measured by the change from baseline in total score in an anhedonia scale. In a further particular embodiment, the anhedonia scale is the Snaith Hamilton Pleasure Scale (SHAPS). In a further particular embodiment, the disclosure relates to the package or pharmaceutical product as described herein, wherein the anhedonia of the patient is reduced by at least 40%, as measured by the change from baseline in total score in an anhedonia scale following 6 weeks of the treatment with aticaprant, more in particular, the anhedonia of the patient is reduced within about 3 weeks to about 6 weeks as measured by the change from baseline in total score in an anhedonia scale. In a further particular embodiment, the anhedonia scale is the Snaith Hamilton Pleasure Scale (SHAPS).
Treatment Methods
[0082] In one aspect of the present invention, methods are provided for treating patients having a more severe type of depression, i.e.. major depressive disorder, using the compounds, compositions, e.g., solid compositions, and tablets, e.g., oral tablets, described herein. The patient also may be experiencing anhedonia. Because MDD alone is difficult to treat, treatment patients having anhedonia are even more problematic since their ability to gauge pleasure is impaired. Thus, such patients often receive inadequate treatment due to ineffective medications, repeated and unnecessary medical appointments, lack of patient compliance, overall patient frustration, among others. Further, antidepressants are known to have a variety of side effects such as weight gain, metabolic side effects, extrapyramidal symptoms, akathisia, cognitive impairment, among others. Thus, patients may choose to refrain from or stop taking antidepressants to avoid or prevent any side-effects.
[0083] The methods described herein are effective in managing the patient’s depression and/or anhedonia using aticaprant. In some embodiments, the methods successfully permit the patient to manage their depression while simultaneously reducing anhedonia. In particular embodiments, the patients treated according to the described methods have moderate to severe anhedonia. The term “anhedonia” as used herein refers to the lack of or decreased ability to experience pleasure in daily activities. The term anhedonia includes loss of pleasure in sensory experiences (z.e., touch, taste, smell), as well as social interactions. In some embodiments, anhedonia and depressed mood are diagnostic criteria for a major depressive episode as part of MDD. Anhedonia also describes deficits in one or more components of reward-related behavior, also known as the pleasure cycle, such as wanting, liking, and learning. The pleasure cycle can be divided into three phases: the appetitive phase (dominated by wanting), the consummatory phase (dominated by liking), and the satiety phase (dominated by learning). The appetitive phase is characterized by the initial energy expenditure to attain a reward; the consummatory phase is enjoyment of the reward; and the satiety phase is characterized by learning and feedback integration.
[0084] To assess a potential effect on anhedonia, an anhedonia scale may be used. For example, the Snaith-Hamilton Pleasure Scale (SHAPS) analysis is a validated scale for the measurement of anhedonia. The SHAPS is a subject completed scale in which subjects score whether or not they experience pleasure in performing a list of activities or experiences. The SHAPS is a self-reported 14-item instrument, developed for the assessment of hedonic capacity. Subjects score whether they experience pleasure in performing a list of activities or experiences. Subjects can rate the answers as 1-4 where 1 indicates “Definitely agree”, 2 indicates “Agree”, 3 indicates “Disagree” and 4 indicates “Definitely disagree”. The subject's item responses are summed to provide a total score ranging from 14 to 56. A higher total SHAPS score indicates higher levels of current anhedonia. Physician/clinical judgment can be used to assess anhedonia separately or in conjunction with an anhedonia scale. [0085] In some embodiments, the patient has moderate anhedonia. In other embodiments, the patient has severe anhedonia. An assessment of moderate or severe anhedonia is typically determined physician/clinical judgment and/or by one or more tests that provide insight into whether a patient has anhedonia. For example, the severity of the anhedonia may be determined using the SHAPS method. In some embodiments, a patient with moderate or severe anhedonia is considered to have a high level of anhedonia. For example, a patient with a SHAPS score of 38 or greater is considered to have moderate to severe anhedonia that can be considered a high level of anhedonia. In some embodiments, a high level of anhedonia is reflected by a SHAPS score of at least about 40, about 42, about 44, about 46, about 48, about 50, about 52, about 54, about 56, about 58, or higher. A patient with mild or no anhedonia would be considered to have a low level of anhedonia that is assessed by physician/clinical judgment and/or one or more tests. For example, a patient with a SHAPS score of less than 38 is considered to have low anhedonia. In certain embodiments, a patient with mild anhedonia may have a SHAPS score of 20 to less than 38, for example, a SHAPS score of 20 to about 36, about 22 to about 36, about 24 to about 36, about 26 to about 36, about 26 to about 34, about 26 to about 32, about 26 to about 30, about 26 to about 28, about 28 to about 36, about 28 to about 36, about 30, to about 36, about 32 to about 36, about 34 to about 36, about 20 to about 34, about 22 to about 34, about 24 to about 34, about 26 to about 32, about 26 to about 30, about 26 to about 28, about 28 to about 36, about 28 to about 34, about 28 to about 32, about 28 to about 30, about 30 to about 36, about 30 to about 34, about 30 to about 32, about 32 to about 36, about 32 to about 34, or about 34 to about 36. Typically, a SHAPS score of less than 20 can be considered to correspond to normal hedonic functioning, and for purposes of this disclosure, would fall into the low category of anhedonia, e.g., a SHAPS score of less than 38.
[0086] In some embodiments, the patient’s anhedonia is reduced from a high level of anhedonia to a low level of anhedonia. In yet other embodiments, the patient’s anhedonia is reduced by at least about 40%, as measured by the change from baseline in total score in an anhedonia scale following treatment with aticaprant. In yet other embodiments, the patient’s anhedonia is reduced by at least about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%, as measured by the change from baseline in total score in an anhedonia scale following treatment with aticaprant. In still further embodiments, In yet other embodiments, the patient’s anhedonia is reduced by about 40 to about 90%, about 50 to about 90%, about 60 to about 90%, about 70 to about 90%, about 80 to about 90%, about 40 toa bout 80%, about 50 to about 80%, about 60 to about 80%, about 70 to about 80%, about 40 to about 70%, about 50 to about 70%, about 60 to about 70%, about 40 to about 60%, about 50 to about 60%, or about 50 to about 60%, as measured by the change from baseline in total score in an anhedonia scale following treatment with aticaprant. In other embodiments, the patient’s anhedonia is ameliorated, i.e., reduced by 100%, as measured by the change from baseline in total score in an anhedonia scale following treatment with aticaprant.
[0087] Reduction of anhedonia after initiating treatment with aticaprant may be measured relative to the anhedonia of the patient as measured before treatment with aticaprant, i.e., a baseline anhedonia measurement. In doing so, the treating clinician is able to calculate the change of anhedonia from the baseline to the real time anhedonia measurement at any point after treatment with aticaprant. Thus, standard methods for measuring anhedonia may be used, such as an anhedonia scale, e.g., SHAPS.
[0088] Desirably, a baseline anhedonia measurement is obtained no more than about 1 week before initiating treatment with aticaprant. In some embodiments, a baseline anhedonia measurement is obtained about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day before treatment with aticaprant. In further embodiments, a baseline anhedonia measurement is obtained about 24 hours, about 18 hours, about 12 hours, about 8 hours, about 4 hours, about 2 hours, about 1 hours, about 30 minutes, or about 15 minutes before initiating treatment with aticaprant.
[0089] The patient’s change of anhedonia will depend on several factors including, without limitation, anhedonia severity, patient’ s sensitivity to aticaprant, other pharmaceutical agents being administered, among others. In some embodiments, the patient’s anhedonia is reduced after about 3 weeks of treatment with aticaprant. In other embodiments, the patient’s anhedonia is reduced after about 3 weeks of treatment with aticaprant. In further embodiments, the patient’s anhedonia is reduced after about 3 weeks to about 6 weeks, and, in certain embodiments, through week 6, of treatment with aticaprant. In certain embodiments, the patient’s anhedonia is reduced by at least about 40%, as measured by the change from baseline in total score in an anhedonia scale following about 6 weeks of the treatment with aticaprant. In further embodiments, the anhedonia of the patient is reduced within about 3 weeks, and in some embodiments within about 3 weeks to about 6 weeks, as measured by the change from baseline in total score in an anhedonia scale and/or by physician/clinical judgement.
[0090] The methods described herein were found to not only improve the patient’s depression and/or anhedonia symptoms, but resulted in fewer antidepressant side effects. Doing so resulted in less absenteeism (i.e., more visits or interactions with physicians), greater cognitive functioning, improvements in health-related quality of life, more interest and engagement in everyday activities, improvement in family and inter-personal relationships, ability to function in the workplace, fewer hospitalizations, among others.
[0091] In some embodiments, the disclosure provides methods for treating MDD in a human patient by administering to the patient a pharmaceutical composition comprising about 5 mg aticaprant, wherein the patient had an inadequate response to other antidepressant therapy prior to treatment with aticaprant. In some embodiments, administration of the pharmaceutical composition to the patient achieves a pharmacokinetic (PK) profile comprising one or more of the PK parameters noted above after administration of the composition to a human after at least a 10-hour fast.
[0092] As used herein, unless otherwise noted, the terms “subject” and “patient” refer to a human having a weight of less than about 55 kg, who has been the object of treatment, observation or experiment. Preferably, the patient has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the patient is an adult. As used herein, the term “adult” as used herein refers to a human that is 18 years of age or older. In other embodiments, the patient is an elderly adult, i.e., greater than or equal to 65 years of age. In further embodiments, the patient is a child. As used herein, the term “child” as used herein refers to a human that has an age under 18 years. Thus, the term “child” includes adolescents. In some embodiments, the patients is 6 to 17 years old. In other embodiments, the patient is 12 years old to less than 18 years old.
[0093] As noted above, the methods of treatment and compositions disclosed herein are particularly suited for patients having a weight of less than about 55 kg. In some embodiments, the patient has a weight less than about 50, about 45, about 40, about 35, about 30, about 25, about 20, about 15, or about 10 kg. In certain embodiments, the patient has a weight of 52 kg or less, and, more particularly, a weight of less than 50 kg, or a weight of less than 45 kg. In other embodiments, the patient has a weight of about 20 to about 52, about 20 to about 50, about 20 to about 45, about 20 to about 40, about 20 to about 35, about 20 to about 30, about 20 to about 25, about 25 to about 52, about 25 to about 50, about 25 to about 45, about 25 to about 40, about 25 to about 35, about 25 to about 30, about 30 to about 52, about 30 to about 50, about 30 to about 45, about 30 to about 40, about 30 to about 35, about 35 to about 52, about 35 to about 50, about 35 to about 45, about 35 to about 40, about 40 to about 52, about 40 to about 50, about 40 to about 45, about 45 to about 52, or about 45 to about 50 kg.
[0094] As used herein, unless otherwise noted, the terms “treating”, “treatment” and the like, shall include the management and care of a subject or patient (preferably mammal, more preferably human) for the purpose of combating a disease, condition, or disorder and includes the administration of a compound described herein to prevent the onset of the symptoms or complications, alleviate one or more of the symptoms or complications, or eliminate the disease, condition, or disorder.
[0095] As used herein, the term “depression” (also referred to as depressive disorder) includes major depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholic, mid-life depression, late-life depression, bipolar depression, depression due to identifiable stressors, treatment resistant depression, or combinations thereof. In certain embodiments, the depression is major depressive disorder. In other embodiments, the major depressive disorder is with melancholic features or anxious distress. In further embodiments, the depression is treatment-resistant depression. In other embodiments, the depression is major depressive disorder with suicidal ideation.
[0096] As known in the art, a patient is considered to have major depressive disorder if exhibiting five or more symptoms during the same two week period that are a change from previous functioning; depressed mood and/or loss of interest/pleasure must be present; excluding symptoms clearly attributable to another medical condition. See, e.g., Table 4.
. Table 4.
1. Depressed mood: Most of the day, nearly every day; may be subjective (e.g., feels sad, empty, hopeless) or observed by others (e.g., appears tearful); in children and adolescents, can be irritable mood
2. Loss of interest/pleasure: Markedly diminished interest/pleasure in all (or almost all) activities most of the day, nearly every day; may be subjective or observed by others
3. Weight loss or gain: Significant weight loss (without dieting) or gain (change of >5% body weight in a month), or decrease or increase in appetite nearly every day; in children, may be failure to gain weight as expected
4. Insomnia or hypersomnia: Nearly every day 5. Psychomotor agitation or retardation: Nearly every day and observable by others (not merely subjectively restless or slow)
6. Fatigue: Or loss of energy, nearly every day
7. Feeling worthless or excessive/inappropriate guilt: Nearly every day; guilt may be delusional; not merely self-reproach or guilt about being sick
8. Decreased concentration: Nearly every day; may be indecisiveness; may be subjective or observed by others
9. Thoughts of death/suicide” Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without specific plan, or suicide attempt, or a specific plan for suicide
[0097] In some embodiments, to be diagnosed with MDD, the following criteria also are met:
1. Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
2. Episode not attributable to physiological effects of a substance or another medical condition
3. Episode not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders
4. No history of manic or hypomanic episode
[0098] Major depressive disorder may be categorized as mild, moderate, or severe. In some embodiments, the MDD is mild. In other embodiments, the MDD is moderate. In further embodiments, the MDD is severe. As used herein, “mild MDD” applies to a patient having few, if any, symptoms in excess of those required to make the diagnosis, the intensity of the symptoms is distressing but manageable, and the symptoms result in minor impairment in social or occupational functioning. The mild MDD may be a single episode (ICD-10 F32.0) or a recurrent episode (ICD-10 F33.0). “Moderate MDD” applies to a patient having a number of symptoms, intensity of symptoms, and/or functional impairment are between those specified for “mild” and “severe.” The moderate MDD may be a single episode (ICD-10 F32.1) or a recurrent episode (ICD-10 F33.1). “Severe MDD” applies to a patient where the number of symptoms is substantially in excess of that required to make the diagnosis, the intensity of symptoms is seriously distressing and unmanageable, and the symptoms markedly interfere with social and occupational functioning, and urgent symptom control is necessary. In some embodiments, the severe MDD may be a single episode (ICD-10 F32.2) or a recurrent episode (ICD-10 F33.2). In other embodiments, MDD is classified according to the DSM-5 definition of Table 5. fable 5: DSM-5 Criteria for MDD
1. Depressed Mood At least 1
2. Loss of interest/pleasure (anhedonia)
1. Weight loss or gain At least 5
2. Sleep problems
3. Psychomotor agitation or retardation
4. Guilt or worthlessness
5. Decreased concentration
6. Suicidality
7. Fatigue
1. Symptoms cause significant distress or impairment Must have all 4
2. Not attributable to medical condition
3. Exclude schizophrenia disorders
4. No hx of mania or hypomania
[0099] Several scales are known in the art that may be utilized to diagnose or monitor patients with MDD. Examples of these scales include, without limitation, the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression - Severity (CGI-S) scale, Symptoms of Major Depressive Disorder Scale (SMDDS), Self- Assessment of Treatment Experience (SATE) scale, and Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ), i.e., MGH-ATRQ.
[00100] In some embodiments, MADRS is utilized to diagnose and/or monitor the patient. MADRS is a 10-item rating scale that is used in antidepressant studies. It is clinician-administered and designed to be used in subjects with MDD to measure the overall severity of depressive symptoms. The MADRS scale is validated, reliable, and acceptable to regulatory health authorities as a primary scale to determine efficacy in major depression. In some embodiments, MADRS is administered using the Structured Interview Guide for the MADRS (SIGMA). The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), summed for a total possible score of 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts.
[00101] In other embodiments, CGI-S is utilized to diagnose and/or monitor the patient’s depression. CGI-S is a scale that rates the severity of the subject’s illness at the time of assessment, relative to the clinician’s past experience with subjects who have the same diagnosis and improvement with treatment. CGI-S provides an overall clinician-determined summary measure of severity of subject’s illness that considers all available information, including knowledge of subject’s history, psychosocial circumstances, symptoms, behavior, and impact of symptoms on subject’s ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Subject is assessed on severity of mental illness at time of rating according to: 0=not assessed; 1 =normal (not at all ill); 2=bordcrlinc mentally ill; 3=mildly ill; 4=modcratcly ill; 5=markcdly ill; 6=scvcrcly ill; 7=among most extremely ill patients.
[00102] In further embodiments, SMDDS is utilized to diagnose and/or monitor the patient’s depression. SMDDS is a subjective rating of the patient. The SMDDS is a 16-item PRO measure. Each item is rated by the subject according to a 5-point Likert scale. Subjects respond to each question using a rating scale between 0 (“Not at all” or “Never”) to 4 (“Extremely” or “Always”). The total score ranges from 0 to 60. The SMDDS uses a 7-day recall period and verbal rating scales. Higher score indicates more severe depressive symptomatology.
[00103] In yet other embodiments, SATE is utilized to diagnose and/or monitor the patient’s depression. SATE is a one to three questionnaire administered when the subject is unable to complete other evaluations, i.e., away from the clinical setting such as at home. SATE is useful to evaluate improvement or deterioration of depressive symptoms of the subjects over a short period of time. For rating overall depression, subject selected one option out of Improved, not changed or got worse; for depression improvement, subject selected one option out of slightly improved, much improved, very much improved and for depression worsen subject selected slightly worse, much worse, very much worse. See, Table 6.
Table 6: SATE Questionnaire
Question 1: Since starting this study medication, overall would you say your depression is: o Improved o Got worse o Not changed
If the subject selects answer 1 (Improved), following question is asked: Question 2: How much did your depression improve? o Slightly improved o Much improved o Very much improved
If the subject selects answer 3 (Got worse), following question is asked: Question 3:How much did your depression worsen? o Slightly worse o Much worse o Very much worse
[00104] The MGH-ATRQ is a self-rated scale used to determine treatment resistance in patient’s having MDD. This questionnaire examines the antidepressant treatment history, using specific anchor points to define the adequacy of both dose and duration of each antidepressant trial, and the degree of symptomatic improvement. The MGH-ATRQ permits determining treatment resistance in depression and is known to those skilled in the art.
[00105] In certain embodiments, the patient had an inadequate response to other antidepressant therapy. “Inadequate response” as used herein refers to a patient experiencing a less than about 50% reduction in depressive symptom severity from the start of initiating treatment. Typically, the inadequate response is during a current/active episode of the depression. In some embodiments, an inadequate response refers to a patient experiencing about 26 to less than about 50% reduction in depressive symptom severity from the start of initiating treatment. In other embodiments, an inadequate response refers to a patient experiencing about 26 to about 49, about 26 to about 45, about 26 to about 40, about 26 to about 35, about 26 to about 30, about 30 to about 49, about 30 to about 45, about 30 to about 40, about 30 to about 35, about 35 to about 49, about 35 to about 45, about 35 to about 40, about 40 to about 49, or about 40 to about 45% reduction in depressive symptom severity from the start of initiating treatment. A patient’s response may be measured by one or more scales described herein and/or by physician/clinical judgment. In some embodiments, an inadequate response is measured by MGH-ATRQ, MADRS, or SHAPS. In further embodiments, an inadequate response is measured by MGH-ATRQ. [00106] To the extent a patient is said to have a partial response to treatment, this refers to some minor to moderate symptomatic improvement since the initiation of treatment, but some of the initial symptoms are still present and troubling to the patient and these persistent symptoms still affect behavior and function. For instance, the patient’s motivation, productivity, and interest in his or her usual activities may still be impaired.
[00107] The term “other antidepressant therapy” as used herein refers to an antidepressant medication or non-pharmacological treatment that is used to treat patients having depression. In some aspects, the other antidepressant therapy is an antidepressant medication. In other aspects, the other antidepressant therapy is a non-pharmacological treatment. In further aspects, the other antidepressant therapy is an antidepressant medication other than aticaprant.
[00108] The antidepressant medication is any pharmaceutical agent which can be used to treat depression. Suitable examples include, without limitation, mono-amine oxidase inhibitors, tricyclics, tetracyclics, non-cyclics, triazolopyridines, selective serotonin reuptake inhibitors (SSRI), serotonin receptor antagonists, serotonin noradrenergic reuptake inhibitors (SNRI), noradrenergic and specific serotonergic agents, noradrenaline reuptake inhibitors, or antipsychotics (typical or atypical antipsychotics). Examples of mono-amine oxidase inhibitors include phenelzine, tranylcypromine, moclobemide, and the like. Examples of tricyclics include imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, and the like. Examples of tetracyclics includes maprotiline, and the like. Examples of non-cyclics include nomifensine, and the like. Examples of triazolopyridines include trazodone, and the like. Examples of SSRIs include fluoxetine, sertraline, paroxetine, citalopram, citalopram, escitalopram, fluvoxamine, and the like. Examples of serotonin receptor antagonists include nefazadone, and the like. Examples of SNRIs include venlafaxine, milnacipran, desvenlafaxine, duloxetine, levomilnacipran and the like. Examples of noradrenergic and specific serotonergic agents include mirtazapine, and the like. Examples of noradrenaline reuptake inhibitors include reboxetine, edivoxetine and the like. Examples of typical antipsychotics include phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazin), thioxanthenes e.g., thiothixene, flupentixol), butyrophenones e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), substituted benzamides (e.g., sulpride, amisulpride), and the like. Examples of atypical antipsychotics include paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sertindole, ORG-5222, sonepiprazole, aripiprazole, nemonapride, SR-31742, CX-516, SC-111, NE-100, divalproate (mood stabilizer) and the like. In further embodiments, the antidepressant medication includes natural products such as Kava-Kava, St. John's Wort, and the like or dietary supplements such as s-adenosylmethionine, and the like. In yet other embodiments, the other antidepressant includes neuropeptides such as thyrotropin-releasing hormone and the like or compounds targeting neuropeptide receptors such as neurokinin receptor antagonists and the like. In still further embodiments, the other antidepressant is a hormone such as triiodothyronine, and the like. In other embodiments, the other medication is SSRI, SNRI, or a combination thereof. Preferably, the other antidepressant is a SSRI that is escitalopram, sertraline, paroxetine, fluoxetine or citalopram. In other embodiments, the other antidepressant is a SNRI that is venlafaxine, duloxetine, vortioxeine or desvenlafaxine.
[00109] The non-pharmacologic treatment for use herein may be selected by one skilled in the art. In some embodiments, the non-pharmacologic treatment is psychotherapy, transcranial magnetic stimulation, or the like.
[00110] Therapeutically effective amounts/dosage levels and dosage regimens for the other antidepressant therapy may be readily determined by one of ordinary skill in the art. For example, therapeutic dosage amounts and regimens for pharmaceutical agents approved for sale are publicly available, for example as listed on packaging labels, in standard dosage guidelines, in standard dosage references such as the Physician’s Desk Reference (Medical Economics Company or online at http:///www.pdrel.com) or other sources.
[00111] In some embodiments, other antidepressant therapy may include one antidepressant medication. In other embodiments, other antidepressant therapy includes two or more antidepressant medications. In further embodiments, other antidepressant therapy includes two antidepressant medications. In yet other embodiments, other antidepressant therapy includes three antidepressant medications. The attending physician would be able to select suitable antidepressant therapies for use as described herein.
[00112] In certain embodiments, the patient was receiving treatment with other antidepressant therapy prior to receiving aticaprant. In some embodiments, the patient was receiving treatment with other antidepressant therapy that comprised a SSRI, SNRI, or a combination thereof. In other embodiments, the patient stopped treatment with other antidepressant therapy before initiating treatment with aticaprant.
[00113] Also encompassed by the methods described herein include adjunctive treatment with an effective amount of one or more antidepressants. As used herein, the term “adjunctive treatment” and “adjunctive therapy” shall mean treatment of a patient in need thereof by administering aticaprant in combination with one or more antidepressant(s), wherein aticaprant and the antidepressant(s) are administered by any suitable means, simultaneously, sequentially, separately, or in a single pharmaceutical formulation.
[00114] In some aspects, aticaprant is administered adjunctively with other antidepressant(s) currently being administered to the patient, including current antidepressant(s) to which the patient had an inadequate response, i.e., the antidepressant failed to treat the patient’s depression. In other embodiments, aticaprant is administered adjunctively with an antidepressant(s) not previously administered to the patient, i.e., a new antidepressant. In still other embodiments, aticaprant is administered in a regimen with an antidepressant(s) previously administered to the patient.
[00115] Where aticaprant and other antidepressant(s) are administered in separate dosage forms, the number of dosages administered per day for each active compound may be the same or different and more typically different. The antidepressant may be dosed as prescribed by the attending physician and/or by its label and aticaprant is dosed as described herein. Thus, the “effective amount” of the antidepressant(s) may be determined by one skilled in the art. Typically, a patient is under concurrent treatment with both an antidepressant and aticaprant, where both are administered by their prescribed dosing regimens. The aticaprant and antidepressant(s) may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms.
[00116] Aticaprant and the antidepressant(s) may be administered via the same or different routes of administration. Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intranasal (in) intramuscular (im), subcutaneous (sc), transdermal, buccal, or rectal. In some embodiments, aticaprant is administered orally.
[00117] Treatment with aticaprant as described herein has several advantages over the treatments in the art. In some embodiments, the patient does not experience many of the side effects that are associated with other antidepressants, i.e., antidepressants other than aticaprant. In certain aspects, the patient does not experience weight gain during the treatment with aticaprant. As used herein, the term “weight gain” refers to an increase in the weight of patient, relative to the weight of the patient before taking aticaprant or the weight of the patient that is assessed at the time of the initial administration of aticaprant. In certain embodiments, the patient may actually see a decrease in overall weight, relative to the weight of the patient before taking aticaprant. In further embodiments, the patient’s weight is stable, i.e., does not increase or decrease. In certain embodiments, the patient does not experience a clinically relevant weight gain which is characterized as a weight increase of > 7%.
[00118] This is contrary to many other antidepressants where weight gain, including clinically relevant weight gain, is a common, but unfortunate, side-effect.
[00119] Other scales may be utilized to determine the effectiveness of the methods used herein to treat the patient. Examples include the Cognitive and Physical Functioning Questionnaire (CPFQ), Karolinska Sleepiness Scale (KSS), and Temporal Experience of Pleasure Scale (TEPS). The CPFQ is a brief self-report scale that provides additional information regarding the impact of adjunctive treatment on aspects of cognitive and executive function including attention, memory and mental acuity. Subjects with MDD are often reported to have difficulties with functioning in this area. The KSS is a subject-reported assessment used to rate sleepiness on a scale of 1 to 9, ranging from “extremely alert” (1) to “very sleepy, great effort to keep awake, fighting sleep” (9). The TEPS includes 18 items, 2 subscales designed to distinguish between anticipatory and consummatory pleasure.
[00120] The methods described herein include administering an effective amount of aticaprant to the patient. The term “effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a human that is being sought by a researcher, medical doctor or other clinician, which includes alleviation of one or more of the symptoms of the disease or disorder being treated. In some embodiments, aticaprant is utilized in an effective amount as determined by the attending physician. In other embodiments, other antidepressant(s) is utilized in an effective amount either separately or in combination with aticaprant.
Aspects
[00121] Aspect 1. A method of treating major depressive disorder in a human patient, comprising administering a pharmaceutical composition comprising about 5 mg of aticaprant to the human patient, wherein the human patient had a previous inadequate response to other antidepressant therapy and wherein the human patient has a weight less than about 55 kg.
[00122] Aspect 2. The method of Aspect 1 , wherein the pharmaceutical composition is a tablet.
[00123] Aspect 3. The method of Aspect 1 or 2, wherein the human patient has an age under 18 years old.
[00124] Aspect 4. The method of any one of the preceding Aspects, wherein the pharmaceutical composition is administered to the human patient once daily. [00125] Aspect 5. The method of any one of the preceding Aspects, wherein the other antidepressant therapy comprised one or more antidepressants.
[00126] Aspect 6. The method of Aspect 5, wherein the one or more antidepressants of the other antidepressant therapy comprised a SSRI, SNRI, or a combination thereof.
[00127] Aspect 7. The method of any one of the preceding Aspects, wherein the aticaprant is S-aticaprant.
[00128] Aspect 8. The method of any one of the preceding Aspects, wherein the aticaprant is crystalline aticaprant.
[00129] Aspect 9. The method of any one of the preceding Aspects, further comprising treatment with an effective amount of one or more antidepressants.
[00130] Aspect 10. The method of Aspect 9, wherein the one or more antidepressants is a SSRI, SNRI, or combination thereof.
[00131] Aspect 11. The method of any one of the preceding Aspects, wherein the patient has anhedonia.
[00132] Aspect 12. The method of any one of the preceding Aspects, wherein the pharmaceutical composition further comprises one or more of: a filler, a disintegrant, a glidant, a lubricant, a binder, and a coloring agent.
[00133] Aspect 13. The method of Aspect 12, wherein the filler is: microcrystalline cellulose, lactose monohydrate, or silicified microcrystalline cellulose; the disintegrant is croscarmellose sodium; the glidant is silica, colloidal anhydrous; and the lubricant is magnesium stearate.
[00134] Aspect 14. The method of any one of the preceding Aspects, wherein the pharmaceutical composition comprises about 4% to about 6% aticaprant by weight.
[00135] Aspect 15. The method of any one of the preceding Aspects, wherein the pharmaceutical composition comprises about 5% aticaprant by weight.
[00136] Aspect 16. The method of any one of the preceding Aspects, wherein the pharmaceutical composition further comprises between about 10% and 99.9% filler by weight.
[00137] Aspect 17. The method of any one of the preceding Aspects, wherein the human patient has a weight of 52 kg or less.
[00138] Aspect 18. The method of any one of the preceding Aspects, wherein the human patient has a weight of less than 45 kg. [00139] The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.
Abbreviations
AE Adverse Event
ATRQ Antidepressant Treatment History Questionnaire
CGI-S Clinical Global Impression - Severity
CPFQ Cognitive and Physical Functioning Questionnaire
C-SSRS Columbia Suicide Severity Rating Scale
DSC Differential Scanning Calorimetry
DSM Diagnostic and Statistical Manual of Mental Disorders
HAM-A 1 Hamilton Depression Rating Scale
HDRS-17
HAM-A6 6 Item Subscale from HAM-A
KOR Kappa Opioid Receptor
KSS Karolinska Sleepiness Scale
LC-MS/MS Liquid Chromatography/Mass Spectrometry/Mass Spectrometry
MADRS Montgomery Asberg Depression Rating Scale
MDD Major Depressive Disorder
MedDRA Medical Dictionary for Regulatory Activities
MINI Mini International Neuropsychiatric Interview
MMRM Mixed-effects Model for Repeated Measures
PK Pharmacokinetic
QD Once Daily
RH Relative Humidity
RT Room Temperature
SATE Self- Assessment of Treatment Experience
SHAPS Snaith-Hamilton Pleasure Scale
SIGH-A Structured Interview Guide for the Hamilton Anxiety scale
SIGMA The Structured Interview Guide for the MADRS
SMDDS Symptoms of Major Depressive Disorder Scale
SNRI Serotonin-Norepinephrine Reuptake Inhibitor SSRI Selective Serotonin Reuptake Inhibitor
THF Tetrahydrofuran
USP United States Pharmacopeia
XRPD X-ray Powder Diffraction
Example 1 - Instrument and Methodology Details
[00140] A. X-ray Powder Diffraction (XRPD)
[00141] Bruker AXS D8 Advance
[00142] XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu Ka radiation (40 kV, 40 mA) and a 0-20 goniometer fitted with a Ge monochromator. The incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and knife edge. The diffracted beam passes through an 8.0 mm receiving slit with 2.5° Soller slits followed by the Lynxeye Detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA respectively.
[00143] Samples were run under ambient conditions as flat plate specimens using powder as received. The sample was prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane.
[00144] The details of the standard Pharmorphix data collection method are:
• Angular range: 2 to 42° 20
• Step size: 0.05° 20
• Collection time: 0.5 s/step (total collection time: 6.40 min)
[00145] When required other methods for data collection are used with details as shown in Table 7.
; Table 7: Additional D8 XRPD methods i
4 Minute Method
: Angular Range : 2 to 31 ° 20
: Step Size § 0.06 ° 20
: Time per Step : 0.5 s/step
Figure imgf000051_0001
[00146] PANalytical Empyrean
[00147] XRPD diffractograms were collected on a PANalytical Empyrean diffractometer using Cu Ka radiation (45 kV, 40 mA) in transmission geometry. A 0.5° slit, 4 mm mask and 0.04 rad Soller slits with a focusing mirror were used on the incident beam. A PIXcel3D detector, placed on the diffracted beam, was fitted with a receiving slit and 0.04 rad Soller slits. The software used for data collection was X’Pert Data Collector using X’Pert Operator Interface. The data were analyzed and presented using Diffrac Plus EVA or HighScore Plus.
[00148] Samples were prepared and analyzed in either a metal or Millipore 96 wellplate in transmission mode. X-ray transparent film was used between the metalsheets on the metal well-plate and powders (approximately 1-2 mg) were used as received. The Millipore plate was used to isolate and analyze solids from suspensions by adding a small amount of suspension directly to the plate before filtration under a light vacuum.
[00149] The scan mode for the metal plate used the gonio scan axis, whereas a 20 scan was utilized for the Millipore plate.
[00150] The details of the standard screening data collection method are:
• Angular range: 2.5 to 32.0° 20
• Step size: 0.0130° 20
• Collection time: 12.75 s/step (total collection time of 2.07 min)
[00151] The software used for data collection was X’Pert Data Collector and the data analyzed and presented using Diffrac Plus EVA.
[00152] B. Differential Scanning Calorimetry ( DSC )
[00153] TA Instruments 02000
[00154] DSC data were collected on a TA Instruments Q2000 equipped with a 50 position auto-sampler. Typically, 0.5-3 mg of each sample, in a pin-holed aluminum pan, was heated at 10 °C/min from 25 °C to 275 °C. A purge of dry nitrogen at 50 mL/min was maintained over the sample.
[00155] Modulated temperature DSC was carried out using an underlying heating rate of 2 °C/min and temperature modulation parameters of ±0.636 °C (amplitude) every 60 seconds.
[00156] The instrument control software was Advantage for Q Series and Thermal Advantage and the data were analyzed using Universal Analysis or TRIOS.
[00157] TA Instruments Discovery DSC
[00158] DSC data were collected on a TA Instruments Discovery DSC equipped with a 50 position auto-sampler. Typically, 0.5-3 mg of each sample, in a pin-holed aluminum pan, was heated at 10 °C/min from 25 °C to 275 °C. A purge of dry nitrogen at 50 mL/min was maintained over the sample. [00159] The instrument control software was TRIOS and the data were analyzed using TRIOS or Universal Analysis.
[00160] C. Chemical Purity Determination by HPLC
[00161] Purity analysis was performed on an Agilent HP 1100/Infinity II 1260 series system equipped with a diode array detector and using OpenLAB software . The full method details are provided in Table 8.
Figure imgf000053_0002
Example 2 - Preparation of the Aticaprant THF Solvate
Figure imgf000053_0001
[00162] Aqueous sodium hydroxide was added to compound 1 in 2- methyltetrahydrofuran. After phase separation, compound 2, i.e., the free base of compound 1, in 2-MeTHF was solvent switched to tetrahydrofuran (THF). Reductive amination of compound 3 using compound 2 was carried out by adding sodium triacetoxyborohydride and THF. Upon reaction completion, the reaction mixture was washed with saturated sodium bicarbonate and sodium chloride. The organic phase containing crude compound 4 was concentrated and ethanol and water were added. The product was crystallized using THF, ethanol, and water to produce compound 4 as a solid. [00163] Charge 7.3 L/kg water into a reactor. Charge 6.6 L/kg 2-MeTHF into the reactor. Charge 1.15 mol/mol of compound 1 into the reactor. Dose 2.3 mol/mol 50% aq. NaOH into the reactor over a minimum 20 minutes at 22°C while stirring. Rinse with 1.0 L/kg water into the reactor. Stir for minimum 30 minutes at 22°C. Settle for minimum 30 minutes. Separate and discard the lower aqueous layer. Concentrate under vacuum to minimal volume at maximum 45°C. Charge portions of THF to the reactor and distill back to minimal volume to complete the solvent switch. Adjust the reactor to 20°C. Charge 5.0 L/kg THF into the reactor. Charge 1.00 mole compound 3 into the reactor. Charge 10.0 L/kg THF into the reactor. Adjust R1 to 32°C and stir for minimum 1 hour. Adjust the reactor to 15°C. Charge 1.50 mole/mole NaBH(OAc)3 in portions into the reactor at 15°C. Stir for minimum 1 hour at 15°C. Dose 5.0 L/kg water at 15°C to the reactor. Dose 3.05 mole/mole 50% aq. NaOH at 15°C to the reactor and stir for minimum 2 hours. Rinse with 0.5 L/kg water. Settle for minimum 30 minutes. Separate and discard the lower aqueous layer. Charge 6.2 L/kg 20% aq. NaCl at 15°C to the reactor and stir for minimum 30 minutes. Settle for minimum 30 minutes. Separate and discard the lower aqueous layer. Concentrate under vacuum to 8.0 L/kg at maximum 45°C. Adjust the reactor to 25°C. Charge 8.0 L/kg EtOH (2% MeOH) and 8.0 L/kg water at 25°C to the reactor. Dose 2.0 L/kg water at 25 °C over minimum 2.5 hours. Charge 0.03 kg/kg of crude compound 4 seeds to the reactor at 25 °C. Stir for minimum 2 hours at 25°C. Charge 6.0 L/kg water at 25°C to the reactor over minimum 7.5 hours. Cool to 2.5°C over minimum 7 hours. Stir for minimum 6 hours at 2.5°C. Isolate the product and wash with THF/EtOH/water 1:1:2 (volume ratio). Dry the product at 25 °C.
Example 3 - Preparation of Pure Aticaprant
Figure imgf000054_0001
[00164] Charge 1.0 mol of crude compound 4 into a dissolution reactor. Add 1.91 L/mol of 2-MeTHF. Add 2.39 L/mole n heptane. Stir the contents of the reactor. Adjust temperature to 42 °C and stir for minimum 10 minutes until full dissolution. Filter the solution over a polish filter into a crystallization reactor to remove insoluble matter that might be present. Rinse the polish filter. Stir for minimum 10 minutes at 40 °C. Cool to 20 °C over minimum 1 hour. Stir for minimum 10 minutes at 20 °C. Dose 1.23 L/mol n-heptane over a minimum 30 minutes at 20 °C. Stir for a minimum 10 minutes at 20°C. Seed with 0.02 mole/mole JNJ 67953964 AAA at 20 °C. Stir for a minimum 8 hours at 20 °C. Dose 3.68 L/mol of n-heptane over a minimum 12 hours at 20 °C. Stir for a minimum 2 hours at 20 °C.
Cool to 10 °C over a minimum 3 hours. Stir for a minimum 4 hours at 10 °C. Isolate compound 5. Wash the wet cake with 2-MeTHF/n-heptane (25/75 w/w%). Dry compound 5 at 50 °C.
[00165] Characterization was performed on compound 5 and the results are shown in Table 9.
Figure imgf000055_0002
[00166] Form III of aticaprant was found to be crystalline by XRPD.
Figure imgf000055_0001
showed that the material was consistent with the proposed structure, with the presence of residual ethyl acetate. Ion chromatography showed that there were no cations/anions present, and HPLC showed 99.8% purity. The DSC (heating from 20 to 131 °C at 10°C/min) showed a peak temperature at 121 °C.
Example 4 - Tablets Containing Aticaprant
[00167] Tablets containing aticaprant were prepared according to the scheme in
FIG. 1 containing the components in Table 10.
Figure imgf000055_0003
Figure imgf000056_0001
a “aticaprant microfine” is milled aticaprant (physically proceed in milling equipment). b From animal origin. c From vegetable source. d Removed during processing.
[00168] Tablets were prepared according to the following:
[00169] 1. Mix the following, screened components in a blend using a suitable blender:
[00170] a. Aticaprant or aticaprant microfine
[00171] b. Microcrystalline cellulose
[00172] c. Silica, colloidal anhydrous
[00173] d. Lactose monohydrate
[00174] 2. Screen the blend using a suitable screen.
[00175] 3. Add the following screened components to the blend. Mix further using a suitable blender:
[00176] a. Microcrystalline cellulose
[00177] b. Lactose monohydrate
[00178] 4. Screen the blend using a suitable screen.
[00179] 5. Add the following screened components to the blend. Mix further using a suitable blender
[00180] a. Microcrystalline cellulose
[00181] b. Lactose monohydrate
[00182] 6. Screen the blend using a suitable screen.
[00183] 7. Add the following screened components to the blend. Mix further using a suitable blender:
[00184] Microcrystalline cellulose
[00185] Lactose monohydrate
[00186] Croscarmellose sodium
[00187] 8. Make a dry granulate by using a suitable compaction technique.
[00188] 9. Add the following screened components to the dry granulate and mix using a suitable blender:
[00189] a. Silicified microcrystalline cellulose
[00190] b. Croscarmellose sodium
[00191] c. Silica, colloidal anhydrous [00192] 10. Add the following screened component to the blend and mix using a suitable blender
[00193] a. Magnesium stearate
[00194] 11. Compress the blend into core tablets using a suitable tablet press.
[00195] 12. Suspend the coating powder in purified water using a suitable vessel.
[00196] 13. Spray the coating suspension on the core tablets using a suitable coater. [00197] 14. Collect the film-coated tablets and package them in a suitable container.
Example 5
[00198] This example was performed to determine appropriate aticaprant dose in adolescents (12 to <18 years).
[00199] The adult population pharmacokinetic model was developed using aticaprant plasma concentrations from 4 clinical studies [I2Z-MC-LAFA (single-ascending dose study), I2Z-MC-LAFB (multiple-ascending dose study), I2Z-MC-LAFC (PET receptor occupancy study), and MDD2001 (efficacy, safety, and pharmacokinetics study in subjects with adjunctive MDD (aMDD))], using nonlinear mixed-effects modeling (NONMEM 7.4.1; Beal SL, Sheiner LB, Boeckmann AJ, et al. NONMEM 7.1.0 users guides. Ellicott City: Icon Development Solutions; 1989-2009). See, FIG. 2. Covariates were evaluated in the popPK model. Exploratory analysis, diagnostic graphics, and post-processing of NONMEM analysis results were carried out using R. Model evaluation was based on acceptable parameter precision, goodness-of-fit and visual predictive checks.
[00200] For adults, a dataset containing 10,000 virtual adults was generated by sampling the demographic distribution (i.e., body weight and race) from the adult study MDD2001. For adolescents, a dataset of 96,000 virtual adolescents (12 to <18 years) was generated uniformly across age and gender with body weight simulated for each year in age group and gender based on CDC growth charts weight-for-age statistical tables, e.g., 8000 subjects per gender and per age year. See, National Center for Health Statistics (Center for Disease Control and Prevention). Percentile data files with LMS values. WTAGE. https://www.cdc.gov/growthcharts/percentile_data_files.htm.
[00201] Model-based simulations were performed to predict aticaprant exposure metrics (i.e., steady-state AUCo-24h and trough concentration (Ctrou h)) for each adult subject among 10,000 virtual adult patient population, using the aticaprant dose of 10 mg QD and adolescent populations under different dosing scenarios (Scenario 1 and 4: flat dose of 10 and 5 mg QD, respectively; Scenario 2, 3, and 5: switch the dose of 10 mg QD to 5 mg QD with body weight below 40, 50, and 45 kg, respectively). The median value and 5th and 95th percentiles of the simulated aticaprant exposures in the full virtual adult patient population were summarized and served as reference for comparison with adolescent simulations.
[00202] The steady-state AUCo-24h was calculated with the equation (AUCo-24h =Fl*Dose/CL) by sampling random effects on parameters (i.e., Fl and CL) from a lognormal distribution using model parameter point estimates and omega matrix estimates. The steady-state C concentration was defined at day 29 predose (23.99h).
[00203] The aticaprant exposure in the adolescent subjects were simulated using the same approach as in the adult population and investigated by body weight or age category. For age category, a total of 60,000 virtual adolescent subjects (12 to <18 years) were sampled from the virtual adolescent subject database. For body weight category, a total of 710,000 virtual adolescent subjects (30 to 100 kg) were sampled. The race distribution of adolescent population was sampled from the adult study MDD2001.
[00204] To select the most appropriate dose(s) for the adolescent population, the aticaprant exposures in adolescents were simulated following the administration of 2 different dose strengths of 5 and 10 mg. The investigated dosing scenarios are presented in FIG. 3.
[00205] The dose selected for the planned studies in adolescent subjects was determined by selecting the dose among the scenarios tested in Table 11 predicting that > 80% of the adolescent subjects would have aticaprant exposures (i.e., AUCo-24h and Ctrou h at steady state) within the 5th and 95th percentiles of the corresponding adult exposure after 10 mg QD dose. If multiple dose scenarios reached the 80% criteria, the dose leading to the highest proportion of adolescent matching adult exposures would be selected
[00206] The popPK model in adults was based on 2,258 aticaprant plasma concentrations from 151 healthy subjects and patients. Observed data were well described by an open two-compartment model with first-order absorption (Ka) and linear clearance (CL). Body weight was a covariate, with the allometric scaling exponent of 0.75 for CL and Q, and 1 for V2 and V3. Race (Black and Hispanic) was a covariate on relative bioavailability FL shown in Table 11. The interindividual variability in CL, V2, Fl (relative bioavailability factor), and Ka was assumed to be log normally distributed. The residual error was described by a proportional error model. The parameter estimates of the final model were provided in Table 11.
Figure imgf000058_0001
Figure imgf000059_0002
Figure imgf000059_0001
[00207] The model-based simulations in the 10,000 virtual adults receiving aticaprant 10 mg QD, resulted in median (5th and 95th percentiles) steady-state AUCo-24 and Ctrough of 312.7 (141.1-685.1) ng*h/ml and 7.6 (3.0-17.7) ng/ml, respectively, which served as reference for comparison with adolescent simulations.
[00208] The model-based simulations in virtual adolescents across body weight (30- 100 kg) categories demonstrated that the scenarios 3 and 5 resulted in > 80% of the adolescents have aticaprant exposures within the adult reference exposure for both steadystate AUCo-24h and Ctrough- See, FIG. 4. Scenario 1 (Flat 10 mg QD for all adolescents) did not pass the criteria for the adolescent below 45 kg due to over-exposure and Scenario 4 (Flat 5 mg QD for all adolescents) did not reach the criteria for the adolescent above 52 kg due to under-exposure. Scenario 2 predicted the proportion of aticaprant exposures below 80% in the body weight range of 40-45kg and did not reach the cri eria for the adolescen within the body weight ranges. The result was consistent with the result by investigating across age category in FIG. 4.
[00209] Both the weight cut-off of 50 and 45 kg could provide adequate AUCo-24h and Ctrough in adolescents, matching target adult exposure. Considering the simulated adolescent weight distribution, the dose change at the body weight cut-off of 45 kg might be preferable. With the 45 kg cut- off, -73% adolescents can benefit from the adult dose, and less adults would fall in the 5 mg QD dose (FIG. 5), and hence this body weight cut-off of may be recommended in adolescents.
[00210] Results show that a dose of 5 mg QD (half the adult dose) is recommended for adolescents with a body weight < 45 kg and a dose of 10 mg QD (adult dose) is recommended for adolescents with a body weight > 45 kg. This dose regimen is expected to achieve systemic aticaprant exposures in adolescents comparable to those in adults at the proposed clinical dose of lOmg QD.

Claims

What is Claimed Is:
1. A method of treating major depressive disorder in a human patient, comprising administering a pharmaceutical composition comprising about 5 mg of aticaprant to the human patient, wherein the human patient had a previous inadequate response to other antidepressant therapy and wherein the human patient has a weight less than about 55 kg.
2. The method of claim 1, wherein the pharmaceutical composition is a tablet.
3. The method of claim 1 or 2, wherein the human patient has an age under 18 years old.
4. The method of any one of the preceding claims, wherein the pharmaceutical composition is administered to the human patient once daily.
5. The method of any one of the preceding claims, wherein the other antidepressant therapy comprised one or more antidepressants.
6. The method of claim 5, wherein the one or more antidepressants of the other antidepressant therapy comprised a SSRI, SNRI, or a combination thereof.
7. The method of any one of the preceding claims, wherein the aticaprant is S-aticaprant.
8. The method of any one of the preceding claims, wherein the aticaprant is crystalline aticaprant.
9. The method of any one of the preceding claims, further comprising treatment with an effective amount of one or more antidepressants.
10. The method of claim 9, wherein the one or more antidepressants is a SSRI, SNRI, or combination thereof.
11. The method of any one of the preceding claims, wherein the patient has anhedonia.
12. The method of any one of the preceding claims, wherein the pharmaceutical composition further comprises one or more of: a filler, a disintegrant, a glidant, a lubricant, a binder, and a coloring agent.
13. The method of claim 12, wherein the filler is: microcrystalline cellulose, lactose monohydrate, or silicified microcrystalline cellulose; the disintegrant is croscarmellose sodium; the glidant is silica, colloidal anhydrous; and the lubricant is magnesium stearate.
14. The method of any one of the preceding claims, wherein the pharmaceutical composition comprises about 4% to about 6% aticaprant by weight.
15. The method of any one of the preceding claims, wherein the pharmaceutical composition comprises about 5% aticaprant by weight.
16. The method of any one of the preceding claims, wherein the pharmaceutical composition further comprises between about 10% and 99.9% filler by weight.
17. The method of any one of the preceding claims, wherein the human patient has a weight of 52 kg or less.
18. The method of any one of the preceding claims, wherein the human patient has a weight of less than 45 kg.
19. A pharmaceutical composition for use in treating major depressive disorder, wherein the pharmaceutical composition comprises about 5 mg of aticaprant and is formulated for administration to a human patient, wherein the human patient had a previous inadequate response to other antidepressant therapy and wherein the human patient has a weight less than about 55 kg.
20. The pharmaceutical composition of claim 19, that is a tablet.
21. The pharmaceutical composition of claim 19 or 20, wherein the human patient has an age under 18 years old.
22. The pharmaceutical composition of any one of claims 19-21, that is formulated for administration once daily.
23. The pharmaceutical composition of any one of claims 19-22, wherein the other antidepressant therapy comprised one or more antidepressants.
24. The pharmaceutical composition of claim 23, wherein the one or more antidepressants of the other antidepressant therapy comprised a SSRI, SNRI, or a combination thereof.
25. The pharmaceutical composition of any one of claims 19-24, wherein the aticaprant is S-aticaprant.
26. The pharmaceutical composition of any one of claims 19-25, wherein the aticaprant is crystalline aticaprant.
27. The pharmaceutical composition of any one of claims 19-26, that is formulated for administration with an effective amount of one or more antidepressants.
28. The pharmaceutical composition of claim 27, wherein the one or more antidepressants is a SSRI, SNRI, or combination thereof.
29. The pharmaceutical composition of any one of claims 19-28, wherein the human patient has anhedonia.
30. The pharmaceutical composition of any one of claims 19-29, that further comprises one or more of: a filler, a disintegrant, a glidant, a lubricant, a binder, and a coloring agent.
31. The pharmaceutical composition of claim 30, wherein the filler is: microcrystalline cellulose, lactose monohydrate, or silicified microcrystalline cellulose; the disintegrant is croscarmellose sodium; the glidant is silica, colloidal anhydrous; and the lubricant is magnesium stearate.
32. The pharmaceutical composition of any one of claims 19-31, that comprises about 4% to about 6% aticaprant by weight.
33. The pharmaceutical composition of any one of claims 19-32, that comprises about 5% aticaprant by weight.
34. The pharmaceutical composition of any one of claims 19-33, that further comprises between about 10% and 99.9% filler by weight.
35. The pharmaceutical composition of any one of claims 19-34, wherein the human patient has a weight of 52 kg or less.
36. The pharmaceutical composition of any one of claims 19-35, wherein the human patient has a weight of less than 45 kg.
PCT/IB2024/058663 2023-09-06 2024-09-05 Compositions comprising aticaprant for use in treating major depressive disorder Pending WO2025052301A1 (en)

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Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2023131920A1 (en) * 2022-01-10 2023-07-13 Janssen Pharmaceuticals, Inc. Compositions and methods for the treatment of depression

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WO2023131920A1 (en) * 2022-01-10 2023-07-13 Janssen Pharmaceuticals, Inc. Compositions and methods for the treatment of depression

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