WO2023150500A1 - Inhibiteurs peptidiques du récepteur de l'interleukine-23 et compositions pharmaceutiques associées - Google Patents

Inhibiteurs peptidiques du récepteur de l'interleukine-23 et compositions pharmaceutiques associées Download PDF

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WO2023150500A1
WO2023150500A1 PCT/US2023/061651 US2023061651W WO2023150500A1 WO 2023150500 A1 WO2023150500 A1 WO 2023150500A1 US 2023061651 W US2023061651 W US 2023061651W WO 2023150500 A1 WO2023150500 A1 WO 2023150500A1
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composition
compound
formula
amount
solvate
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PCT/US2023/061651
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English (en)
Inventor
Geraldine BROECKX
David T. Breslin
Clara Anduix CANTO
Christopher Paul DE DOBBELAERE
Gildas DENIAU
Giustino Di Pretoro
Philippe Fernandes
Ruzica KOLAKOVIC
Nathalie MERTENS
Betty Lomstein PEDERSEN
Gopal Rajan
Dajun SUN
Sejal PATAL
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Janssen Pharmaceutica Nv
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to peptide inhibitor of the interleukin-23 receptor (IL- 23R) or salt, solvates or forms thereof, corresponding pharmaceutical compositions, methods and/or uses for treatment of autoimmune inflammation diseases and related disorders.
  • IL- 23R interleukin-23 receptor
  • cytokine has been implicated as playing a crucial role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel diseases (IBDs), e.g., ulcerative colitis and Crohn’s disease.
  • IL-23R is expressed on various adaptive and innate immune cells including Th17 cells, ⁇ T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are found abundantly in the intestine.
  • NK natural killer
  • IL-23R mediates this effect by promoting the development of a pathogenic CD4 + T cell population that produces IL-6, IL-17, and tumor necrosis factor (TNF).
  • IL-23 is enriched in the intestine, where it is believed to play a key role in regulating the balance between tolerance and immunity through T-cell-dependent and T-cell- independent pathways of intestinal inflammation through effects on T-helper 1 (Th1) and Th17- associated cytokines, as well as restraining regulatory T cell responses in the gut, favoring inflammation.
  • Th1 T-helper 1
  • Th17- associated cytokines T-helper 1
  • IL-23R polymorphisms in the IL-23 receptor
  • IBDs inflammatory bowel diseases
  • Psoriasis a chronic skin disease affecting about 2%-3% of the general population has been shown to be mediated by the body’s T cell inflammatory response mechanisms.
  • IL-23 has one of several interleukins implicated as a key player in the pathogenesis of psoriasis, purportedly by maintaining chronic autoimmune inflammation via the induction of interleukin-17, regulation of T memory cells, and activation of macrophages.
  • Expression of IL- 23 and IL-23R has been shown to be increased in tissues of patients with psoriasis, and antibodies that neutralize IL-23 showed IL-23-dependent inhibition of psoriasis development in animal models of psoriasis.
  • IL-23 is a heterodimer composed of a unique p19 subunit and the p40 subunit shared with IL-12, which is a cytokine involved in the development of interferon- ⁇ (IFN- ⁇ )-producing T helper 1 (TH1) cells.
  • IFN- ⁇ interferon- ⁇
  • IL-23 and IL-12 both contain the p40 subunit, they have different phenotypic properties.
  • animals deficient in IL-12 are susceptible to inflammatory autoimmune diseases, whereas IL-23 deficient animals are resistant, presumably due to a reduced number of CD4 + T cells producing IL-6, IL-17, and TNF in the CNS of IL-23- deficient animals.
  • IL-23 binds to IL-23R, which is a heterodimeric receptor composed of IL- 12R ⁇ 1 and IL-23R subunits. Binding of IL-23 to IL-23R activates the Jak-stat signaling molecules, Jak2, Tyk2, and Stat1, Stat 3, Stat 4, and Stat 5, although Stat4 activation is substantially weaker and different DNA-binding Stat complexes form in response to IL-23 as compared with IL-12. IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with Stat3. In contrast to IL-12, which acts mainly on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells.
  • Efforts have been made to identify therapeutic moieties that inhibit the IL-23 pathway, for use in treating IL-23-related diseases and disorders.
  • a number of antibodies that bind to IL-23 or IL-23R have been identified, including ustekinumab, an antibody that binds the p40 subunit of IL-23, which has been approved for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, moderately to severely active Crohn’s disease and moderately to severely active ulcerative colitis.
  • polypeptide inhibitors that bind to IL-23R and inhibit the binding of IL-23 to IL-23R have been identified (see, e.g., US Patent Application Publication No.
  • compositions of peptide inhibitors or pharmaceutically acceptable salt or solvate forms thereof that: bind IL-23R to inhibit IL-23 binding, IL-23 signaling through IL-23 receptor and/or IL-23 Pathway, for treatment of inflammatory diseases or disorders (i.e., e.g., which may include, but is not limited to psoriasis, psoriatic arthritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease and the like), which include, but not limited to aforementioned diseases or disorders that may be moderate to severe in degree and suitable for oral administration.
  • inflammatory diseases or disorders i.e., e.g., which may include, but is not limited to psoriasis, psoriatic arthritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease and the like
  • inflammatory diseases or disorders i.e., e.g., which may include, but is not limited to psoriasis, psoriatic arthritis,
  • compositions and corresponding methods and/or uses for specific targeting of IL-23R from the luminal side of the gut can provide therapeutic benefit to IBD patients suffering from local inflammation of the intestinal tissue.
  • BRIEF SUMMARY [0012] Provided herein are crystalline forms of a peptide inhibitor of the interleukin-23 receptor (IL-23R) as well as pharmaceutical compositions, methods and/or uses for treatment of autoimmune inflammation diseases and related disorders. Crystalline forms have advantageous properties such as ease of isolation, enhanced purity, and greater physical and chemical stability compared to analogous amorphous forms. These attributes can be particularly important for pharmaceutical agents where large-scale production, reproducibility, and compound purity are required.
  • the present invention relates to peptide inhibitor of the interleukin-23 receptor (IL-23R) or hydrochloride salt, solvates or forms thereof, corresponding pharmaceutical compositions, methods and/or uses for treatment of autoimmune inflammation diseases and related disorders.
  • the present invention relates to pharmaceutical compositions of peptide inhibitors of the interleukin-23 receptor (IL-23R) or hydrochloride salt, solvates or forms thereof, corresponding methods and/or uses for treatment of autoimmune inflammation and related diseases and disorders.
  • the present invention relates to pharmaceutical compositions of peptide inhibitors of the interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salt, solvates or forms thereof, corresponding methods and/or uses for treatment of autoimmune inflammation and related diseases and disorders.
  • IL-23R interleukin-23 receptor
  • the present invention relates to pharmaceutical compositions as described herein, which comprises a crystalline form of the peptide of SEQ ID NO: 1: Ac-[Pen]*-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]*-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3- Pal]-Sarc-NH2 (in which [Pen]*-[Pen]* form a disulfide bond); or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing, having the structure of Formula (I)::): [0017]
  • the present invention provides a crystalline hydrochloride salt form of a compound of Formula (I) that has the structure:
  • the present invention also provides a crystalline form of a peptide of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing.
  • the pharmaceutically acceptable salts of a peptide of SEQ ID NO: 1 provided herein include hydrochloride salts, bis-hydrochloride salts, acetate salts, fumarate salts, glutarate salts, glycolate salts, mesylate salts, sulfate salts, and citrate salts.
  • the present invention also provides a crystalline form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing.
  • the pharmaceutically acceptable salts of the compound of Formula (I) provided herein include hydrochloride salt, bis-hydrochloride salt, acetate salt, fumarate salt, glutarate salt, glycolate salt, mesylate salt, sulfate salt, and citrate salt.
  • a crystalline form of a free base of a peptide of a compound of Formula (I), or a solvate thereof is a crystalline form of a free base of a compound of Formula (I) or a solvate thereof.
  • the present invention further provides pharmaceutical compositions that include the hydrochloride salt form of the peptide of a compound of Formula (I), or solvate thereof, wherein the hydrochloride salt form of peptide of SEQ ID NO: 1 is characterized by an XRPD pattern substantially as set forth in FIG.1. .
  • the present invention further provides pharmaceutical compositions that include the hydrochloride salt form of the compound of Formula (I) or solvate thereof, and a pharmaceutically acceptable excipient, characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG.1.
  • the present invention further provides pharmaceutical compositions that include the hydrochloride salt form of the peptide of SEQ ID NO: 1 or solvate thereof, and one or more pharmaceutically acceptable excipients, wherein the hydrochloride salt form of peptide of SEQ ID NO: 1 is characterized by an XRPD pattern substantially as set forth in FIG.2.
  • the present invention further provides pharmaceutical compositions that include the hydrochloride salt form of the peptide of SEQ ID NO: 1 or solvate thereof, and one or more pharmaceutically acceptable excipients, wherein the hydrochloride salt form of peptide of SEQ ID NO: 1 is characterized by an XRPD pattern substantially as set forth in FIG.3.
  • the present invention further provides pharmaceutical compositions that include the acetate salt form of the peptide of SEQ ID NO: 1 or solvate thereof, and one or more pharmaceutically acceptable excipients, wherein the acetate salt form of the peptide of SEQ ID NO: 1 is characterized by an XRPD pattern substantially as set forth in FIG.7.
  • the present invention further provides pharmaceutical compositions that include the fumarate salt form of the peptide of SEQ ID NO: 1 or solvate thereof, and one or more pharmaceutically acceptable excipients, wherein the fumarate salt form of the peptide of SEQ ID NO: 1 is characterized by an XRPD pattern substantially as set forth in FIG.15.
  • the present invention further provides pharmaceutical compositions that include the glutarate salt form of the peptide of SEQ ID NO: 1 or solvate thereof, and one or more pharmaceutically acceptable excipients, wherein the glutarate salt form of the peptide of SEQ ID NO: 1 is characterized by an XRPD pattern substantially as set forth in FIG.18.
  • the present invention further provides pharmaceutical compositions that include the glycolate salt form of the peptide of SEQ ID NO: 1 or solvate thereof, and one or more pharmaceutically acceptable excipients, wherein the glycolate salt form of the peptide of SEQ ID NO: 1 is characterized by an XRPD pattern substantially as set forth in FIG.21.
  • the present invention further provides pharmaceutical compositions that include the mesylate salt form of the peptide of SEQ ID NO: 1 or solvate thereof, and one or more pharmaceutically acceptable excipients, wherein the mesylate salt form of the peptide of SEQ ID NO: 1 is characterized by an XRPD pattern substantially as set forth in FIG.24.
  • the present invention further provides pharmaceutical compositions that include the sulfate salt form of the peptide of SEQ ID NO: 1 or solvate thereof, and one or more pharmaceutically acceptable excipients, wherein the sulfate salt form of the peptide of SEQ ID NO: 1 is characterized by an XRPD pattern substantially as set forth in FIG.26.
  • the present invention further provides pharmaceutical compositions that include the citrate salt form of the peptide of SEQ ID NO: 1 or solvate thereof, and one or more pharmaceutically acceptable excipients, wherein the citrate salt form of the peptide of SEQ ID NO: 1 is characterized by an XRPD pattern substantially as set forth in FIG.28.
  • the present invention further provides pharmaceutical compositions that include the bis-hydrochloride salt form of the peptide of SEQ ID NO: 1 or solvate thereof, and one or morepharmaceutically acceptable excipients, wherein the bis-hydrochloride salt form of the peptide of SEQ ID NO: 1 is characterized by an XRPD pattern substantially as set forth in FIG. 29.
  • the present invention further provides pharmaceutical compositions that include the free base form of the peptide of SEQ ID NO: 1 or solvate thereof, and one or more pharmaceutically acceptable excipients, wherein the free base form of the peptide of SEQ ID NO: 1 is characterized by an XRPD pattern substantially as set forth in FIG.11.
  • the present invention further provides pharmaceutical compositions that include the hydrochloride salt form of the compound of Formula (I) or solvate thereof, and a pharmaceutically acceptable excipient, wherein the hydrochloride salt form of the compound of Formula (I) is characterized by an XRPD pattern substantially as set forth in FIG.3.
  • the present invention further provides pharmaceutical compositions that include the acetate salt form of the compound of Formula (I) or solvate thereof, and a pharmaceutically acceptable excipient, wherein the acetate salt form of the compound of Formula (I) is characterized by an XRPD pattern substantially as set forth in FIG.7.
  • the present invention further provides pharmaceutical compositions that include the fumarate salt form of the compound of Formula (I) or solvate thereof, and a pharmaceutically acceptable excipient, wherein the fumarate salt form of the compound of Formula (I) is characterized by an XRPD pattern substantially as set forth in FIG.15.
  • the present invention further provides pharmaceutical compositions that include the glutarate salt form of the compound of Formula (I) or solvate thereof, and a pharmaceutically acceptable excipient, wherein the glutarate salt form of the compound of Formula (I) is characterized by an XRPD pattern substantially as set forth in FIG.18.
  • the present invention further provides pharmaceutical compositions that include the glycolate salt form of the compound of Formula (I) or solvate thereof, and a pharmaceutically acceptable excipient, wherein the glycolate salt form of the compound of Formula (I) is characterized by an XRPD pattern substantially as set forth in FIG.21.
  • the present invention further provides pharmaceutical compositions that include the mesylate salt form of the compound of Formula (I) or solvate thereof, and a pharmaceutically acceptable excipient, wherein the mesylate salt form of the compound of Formula (I) is characterized by an XRPD pattern substantially as set forth in FIG.24.
  • the present invention further provides pharmaceutical compositions that include the sulfate salt form of the compound of Formula (I) or solvate thereof, and a pharmaceutically acceptable excipient, wherein the sulfate salt form of the compound of Formula (I) is characterized by an XRPD pattern substantially as set forth in FIG.26.
  • the present invention further provides pharmaceutical compositions that include the citrate salt form of the compound of Formula (I) or solvate thereof, and a pharmaceutically acceptable excipient, wherein the citrate salt form of the compound of Formula (I) is characterized by an XRPD pattern substantially as set forth in FIG.28.
  • the present invention further provides pharmaceutical compositions that include the bis-hydrochloride salt form of the compound of Formula (I) or solvate thereof, and a pharmaceutically acceptable excipient, wherein the bis-hydrochloride salt form of the compound of Formula (I) is characterized by an XRPD pattern substantially as set forth in FIG.28.
  • the present invention further provides pharmaceutical compositions that include the glycolate salt form of the compound of Formula (I) or solvate thereof, and a pharmaceutically acceptable excipient, wherein the glycolate salt form of the compound of Formula (I) is characterized by an XRPD pattern substantially as set forth in FIG.21.
  • the present invention further provides pharmaceutical compositions that include the free base form of the compound of Formula (I) or solvate thereof, and a pharmaceutically acceptable excipient, wherein the free base form of the compound of Formula (I) is characterized by an XRPD pattern substantially as set forth in FIG.11.
  • composition comprising a hydrochloride salt form of a peptide of the compound of Formula (I) , or a solvate thereof, in an amount of from about 0.1% to about 15% (w/w) of the composition; and one or more pharmaceutically acceptable excipients.
  • composition comprising a crystalline form of a peptide of the compound of Formula (I) , or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing, in an amount of from about 0.1% to about 60% (w/w) of the composition; and one or more pharmaceutically acceptable excipients.
  • composition comprising a hydrochloride salt form of a peptide of the compound of Formula (I) , or a solvate thereof, in an amount of from about 0.1% to about 15% (w/w) of the composition; an absorption enhancer in an amount of from about 5% to about 50% (w/w) of the composition; and one or more pharmaceutically acceptable excipients.
  • composition comprising a crystalline form of a peptide of the compound of Formula (I) , or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing, in an amount of from about 0.1% to 60% (w/w), of the composition; an absorption enhancer in an amount of from about 5% to about 65% (w/w) of the composition; and one or more pharmaceutically acceptable excipients.
  • a method including: forming a mixture comprising a hydrochloride salt form of a peptide of the compound of Formula (I) , or a solvate thereof, a silicified microcrystalline cellulose, sorbitol, crospovidone, and a silica (e.g., Aerosil 200); adding magnesium stearate to the mixture; compressing the mixture; and applying a subcoating to the mixture, to form a tablet.
  • a hydrochloride salt form of a peptide of the compound of Formula (I) or a solvate thereof, a silicified microcrystalline cellulose, sorbitol, crospovidone, and a silica (e.g., Aerosil 200)
  • a method including: forming a mixture comprising a hydrochloride salt form of a peptide of the compound of Formula (I) , or a solvate thereof, sodium caprate, a microcrystalline cellulose, sorbitol, a silica (e.g., Aerosil 200), a silicified microcrystalline cellulose and crospovidone to form a core tablet; applying a subcoating over the core tablet; and applying an enteric coating over the subcoating to form a tablet.
  • a hydrochloride salt form of a peptide of the compound of Formula (I) or a solvate thereof, sodium caprate, a microcrystalline cellulose, sorbitol, a silica (e.g., Aerosil 200), a silicified microcrystalline cellulose and crospovidone to form a core tablet
  • a subcoating e.g., Aerosil 200
  • an enteric coating over the subcoating to form a tablet.
  • the present invention provides a method of treating inflammatory disease, which comprises administering to the subject a therapeutically effective amount of a composition of the present invention to a subject or patient in need thereof as described herein.
  • the present invention provides a method of treating inflammatory bowel diseases (IBD), which comprises administering a therapeutically effective amount of a composition of the present invention to a subject or patient in need thereof.
  • IBD inflammatory bowel diseases
  • the present invention provides use of the compositions of the present invention in the manufacture of a medicament for treating an inflammatory bowel disease (IBD).
  • the present invention provides a method of treating psoriasis or psoriatic arthritis in a subject that includes administering to the subject a therapeutically effective amount of a composition of the present invention described herein.
  • the present invention provides use of the compositions of the present invention, in the manufacture of a medicament for treating psoriasis or psoriatic arthritis.
  • FIG.1 shows an X-ray powder diffraction (XRPD) pattern of a crystalline form of a hydrochloride salt of a compound of Formula (I) .
  • FIG.2 shows an XRPD pattern of a crystalline form of a hydrochloride salt of a compound of Formula (I) .
  • FIG.3 shows an XRPD pattern of a crystalline form of a hydrochloride salt of a compound of Formula (I) .
  • FIG.4 shows a thermogravimetric analysis (TGA) graph of a crystalline form of a hydrochloride salt of a compound of Formula (I) .
  • FIG.5 shows a differential scanning calorimetry (DSC) graph of a crystalline form of a hydrochloride salt of a peptide of a compound of Formula (I) .
  • FIG.6 shows a dynamic vapor sorption (DVS) curve of a crystalline form of a hydrochloride salt of a peptide of a compound of Formula (I) .
  • FIG.7 shows an XRPD pattern of a crystalline form of an acetate salt of a peptide of a compound of Formula (I) .
  • FIG.8 shows a TGA graph of a crystalline form of an acetate salt of a compound of Formula (I) .
  • FIG.9 shows a DSC graph of a crystalline form of an acetate salt of a compound of Formula (I) .
  • FIG.10 shows a DVS curve of a crystalline form of an acetate salt of a compound of Formula (I) .
  • FIG.11 shows an XRPD pattern of a crystalline form of a free base of a compound of Formula (I) .
  • FIG.12 shows a TGA graph of a crystalline form of a free base of a compound of Formula (I) .
  • FIG.13 shows a DSC graph of a crystalline form of a free base of a compound of Formula (I) .
  • FIG.14 shows a DVS curve of a crystalline form of a free base of a compound of Formula (I) .
  • FIG.15 shows an XRPD pattern of a crystalline form of a fumarate salt of a mesylate peptide of SEQ ID NO: 1.
  • FIG.16 shows a TGA graph of a crystalline form of a fumarate salt of a compound of Formula (I) .
  • FIG.17 shows a DSC graph of a crystalline form of a fumarate salt of a compound of Formula (I) .
  • FIG.18 shows an XRPD pattern of a crystalline form of a glutarate salt of a compound of Formula (I) .
  • FIG.19 shows a simultaneous thermal analysis (SDT) thermogram of a crystalline form of a glutarate salt of a compound of Formula (I) .
  • FIG.20 shows a DVS curve of a crystalline form of a glutarate salt of a compound of Formula (I) .
  • FIG.21 shows an XRPD pattern of a crystalline form of a glycolate salt of a compound of Formula (I) .
  • FIG.22 shows a simultaneous thermal analysis (SDT) thermogram of a crystalline form of a glycolate salt of a compound of Formula (I) .
  • FIG.23 shows a DVS curve of a crystalline form of a glycolate salt of a compound of Formula (I) .
  • FIG.24 shows an XRPD pattern of a crystalline form of a mesylate salt of a compound of Formula (I) .
  • FIG.25 shows a simultaneous thermal analysis (SDT) thermogram of a crystalline form of a mesylate salt of a compound of Formula (I) .
  • FIG.26 shows an XRPD pattern of a crystalline form of a sulfate salt of a compound of Formula (I) .
  • FIG.27 shows a simultaneous thermal analysis (SDT) thermogram of a crystalline form of a sulfate salt of a compound of Formula (I) .
  • FIG.28 shows an XRPD pattern of a crystalline form of a citrate salt of a compound of Formula (I) .
  • FIG.29 shows an XRPD pattern of a crystalline form of a bis-hydrochloride salt of a compound of Formula (I) .
  • FIG.30 shows a TGA graph of a crystalline form of a bis-hydrochloride salt of a compound of Formula (I) .
  • FIG.31 shows a DSC graph of a crystalline form of a bis-hydrochloride salt of a compound of Formula (I) .
  • FIG.32 shows a DVS curve of a crystalline form of a bis-hydrochloride salt of a compound of Formula (I) .
  • DETAILED DESCRIPTION I. GENERAL [0090] The present invention relates to peptide inhibitors of the interleukin-23 receptor (IL- 23R) or pharmaceutically acceptable salts thereof, or solvates of thereof, corresponding pharmaceutical compositions, methods and/or uses for treatment of autoimmune inflammation and related diseases and disorders.
  • IL- 23R interleukin-23 receptor
  • the present invention relates to crystalline forms of a peptide inhibitor of IL-234R and pharmaceutically acceptable compositions thereof.
  • the present invention relates to hydrochloride salt compositions of peptide inhibitors of the interleukin-23 receptor (IL-23R) or solvates thereof, corresponding pharmaceutical compositions, methods and/or uses for treatment of autoimmune inflammation and related diseases and disorders.
  • IL-23R interleukin-23 receptor
  • solvates thereof corresponding pharmaceutical compositions, methods and/or uses for treatment of autoimmune inflammation and related diseases and disorders.
  • about 50% includes a range of from 45% to 55%
  • about 20 molar equivalents includes a range of from 18 to 22 molar equivalents.
  • “about” refers to each of the stated values +/- 10% of the stated value of each end of the range.
  • a ratio of from about 1 to about 3 (weight/weight) includes a range of from 0.9 to 3.3.
  • reference to about a value or parameter includes a description of that value or parameter per se.
  • reference to about 20 molar equivalents includes and describes 20 molar equivalents per se.
  • Absorption enhancer refers to a component that improves or facilitates the mucosal absorption of a drug in the gastrointestinal tract, such as a permeation enhancer or intestinal permeation enhancer.
  • permeation enhancers are agents aimed to improve oral delivery of therapeutic drugs with poor bioavailability. PEs are capable of increasing the paracellular and/or transcellular passage of drugs.
  • Pharmaceutical excipients that can increase permeation have been termed ‘absorption modifying excipients' (AMEs). AMEs may be used in oral compositions, for example, as wetting agents (sodium dodecyl sulfate), antioxidants (e.g.
  • IPE Intestinal permeation enhancer
  • Suitable representative IPEs for use in the present invention include, but are not limited to, various surfactants, fatty acids, medium chain glycerides, steroidal detergents, acyl carnitine and alkanoylcholines, N-acetylated alpha-amino acids and N- acetylated non-alpha-amino acids, and chitosans, other mucoadhesive polymers and the like.
  • a suitable IPE for use in the present invention may be sodium caprate.
  • administering refers to administration of the composition of the present invention to a subject.
  • composition or “Pharmaceutical Composition” as used herein is intended to encompass an invention or product comprising the specified active product ingredient (API), which may include pharmaceutically acceptable excipients, carriers or diluents as described herein, such as in specified amounts defined throughout the originally filed disclosure, which results from combination of specific components, such as specified ingredients in the specified amounts as described herein.
  • API active product ingredient
  • Gramulated mixture refers to a mixture of two or more agents made by mixing the two or more agents and granulating them together in a particulate form. Such a mixture provides particulate material that is composed of two or more agents.
  • the compositions may include, but are not limited to granulated mixtures of a hydrochloride salt form of the peptide of SEQ ID NO: 1 or solvate thereof and absorption or permeation enhancer, such as sodium caprate.
  • a granulated mixture is formed into a particle or tablet forms, which contain a hydrochloride salt form of a compound of Formula (I) or solvate thereof and sodium caprate.
  • the compositions may include granulated mixtures comprising sodium caprate.
  • “Disintegrant” refers to a pharmaceutical excipient that is incorporated into a composition to promote their disintegration when they come into contact with a liquid.
  • a disintegrant is a pharmaceutically acceptable agent, used in preparation of tablets, which causes tablets to disintegrate and release medicinal substances on contact with moisture.
  • disintegrants include, without limitation, crosslinked polymers, including crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), and modified starch sodium starch glycolate and the like.
  • disintegrants for use in the present invention may include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums (like gellan), low- substituted hydroxypropyl cellulose, or mixtures thereof and the like.
  • disintegrants for use in the present invention may include, but are not limited to croscarmellose sodium.
  • Additional representative disintegrants for use in the present invention may include, but are not limited to microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginate, crospovidone, cellulose, agar and related gums, sodium starch glycolate, corn starch, potato starch, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum combinations thereof, and the like.
  • Representative disintegrants for use in the present invention include, but are not limited to, starches, clays, celluloses, alginates and gums and crosslinked starches, celluloses and polymers, combinations thereof and the like.
  • enteric coating refers to any of the commonly applied polymeric coatings employed for delayed release of active ingredients.
  • an enteric coating generally is a polymer barrier applied to oral medication that prevents its dissolution or disintegration in the gastric environment. This helps by either protecting drugs from the acidity of the stomach, the stomach from the detrimental effects of the drug, or to release the drug after the stomach (usually in the upper tract of the intestine). Some drugs are unstable at the pH of gastric acid and need to be protected from degradation.
  • An enteric coating is also an effective method to obtain drug targeting (such as gastro-resistant drugs). Such delayed release is typically pH dependent and allows for release of the active ingredient further in the intestinal tract where the pH differs from that in the stomach.
  • suitable materials used for enteric coatings may include, but is not limited to fatty acids, waxes, shellac, plastics, and plant fibers, where such enteric materials, may include, but is not limited to cellulose acetate phthalate, polyvinylalcohol phthalate, shellac, zein, hydroxypropylmethyl cellulose phthalate, cellulose acetate trimaleate, film resins, etc and the like.
  • enteric coating for use in the present invention, may include, without limitation, those based on esters of aleurtic acid, cellulose acetate phthalate (CAP), poly(methacrylic acid-co-methyl methacrylate), poly(vinyl acetate phthalate) (PVAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP) and the like.
  • CAP cellulose acetate phthalate
  • PVAP poly(methacrylic acid-co-methyl methacrylate
  • PVAP poly(vinyl acetate phthalate)
  • CAT cellulose acetate trimellitate
  • HPPMCP hydroxypropyl methylcellulose phthalate
  • enteric coatings may also include, but is not limited to methacrylic acid copolymers, poly(methacrylic acid ethyl acrylate) 1:1, poly(methacrylic acid methyl methacrylate) 1:2, poly(methacrylic acid ethyl acrylate) (L100D-55), combinations of methyl acrylate, methyl methacrylate, hydroxypropyl methylcellulose (HPMC), methacrylic acid (FS30D), Eudragit®, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), and Type L, M or H of HPMC-AS.
  • the enteric coating is disposed over a subcoating.
  • “Glidant” refers to a substance that is added to a powder to improve its flowability and/or lubricity. Examples of glidants, may include, but is not limited to, magnesium stearate, fumed silica, starch, talc and the like.
  • “Silica” refers to a pharmaceutical excipient that can be employed as flow agent (anti-caking), adsorbent and desiccant in solid product forms. It can also be used to increase the mechanical stability and the disintegration rate of the compositions. The silica can be fumed, i.e., referring to its production through a pyrogenic process to generate fine particles of silica.
  • Particles of fumed silica can vary in size such as from 5 nm to 100 nm, or from 5 to 50 nm.
  • the particles can be non porous and have a surface area from 50 1,000 m /g or from 50 600 m /g.
  • Examples of silicas include Aerosil 200, having a specific surface area of about 200 m 2 /g.
  • the silica can be hydrophilic.
  • suitable silica materials include, but are not limited to SiO2, colloidal silicon dioxide, aerosol, colloidal silica, fumed silica, silicon dioxide fumed, colloidal anhydrous silica, colloidal silicon dioxide, and the like.
  • “Lubricant” refers to a substance added to a formulation to reduce friction.
  • MCC microcrystalline cellulose
  • SMCC silicified microcrystalline cellulose
  • “Patient” or “subject” refers to a living organism, which includes, but is not limited to a human subject suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Further non-limiting examples may include, but is not limited to humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, horse, and other mammalian animals and the like. In some aspects, the patient is human.
  • compositions of the present invention i.e., that which is useful, safe, non-toxic acceptable for pharmaceutical use.
  • pharmaceutically acceptable means approved or approvable as is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • Hemi hydrochloride salts refer to salts having a substoichiometric amount of hydrochloride.
  • a hemi hydrochloride salt can have from about 0.1 to about 0.9 molar equivalents of hydrogen chloride associated with the peptide of SEQ ID NO: 1.
  • Representative, non-limiting hemi hydrochloride salts include, but are not limited to 0.2, 0.3, 0.4, 0.50.6 and 0.7 equivalents HCl associated with peptide of SEQ ID NO: 1.
  • the terms “hemi” hydrochloride salt shall be indistinguishable from the term “partial” hydrochloride.
  • “hemi” refers to other pharmaceutically acceptable salt forms of the peptide of SEQ ID NO: 1, such as an acetate salt of the peptide of SEQ ID NO: 1, a fumarate salt of the peptide of SEQ ID NO: 1, a glutarate salt of the peptide of SEQ ID NO: 1, a glycolate salt of the peptide of SEQ ID NO: 1, a mesylate salt of the peptide of SEQ ID NO: 1, a bis hydrochloride salt of the peptide of SEQ ID NO: 1, a citrate salt of the peptide of SEQ ID NO: 1, or a sulfate salt of the peptide of SEQ ID NO: 1.
  • Free base refers to the peptide of SEQ ID NO: 1 with the following structure: in a salt-free form.
  • “Crystalline salt” refers to a crystalline form of a pharmaceutically acceptable salt of a compound of Formula (I) , which may include, but is not limited to a crystalline acetate salt of a compound of Formula (I) , a crystalline hydrochloride salt of a compound of Formula (I) , a crystalline fumarate salt of a compound of Formula (I) , a crystalline glutarate salt of a compound of Formula (I) , a crystalline glycolate salt of a compound of Formula (I) , a crystalline mesylate salt of the compound of Formula (I), a crystalline citrate salt of a compound of Formula (I) , a crystalline bis-hydrochloride salt of a compound of Formula (I) , or a crystalline sulfate salt of a compound of Formula (I) .
  • compositions or pharmaceutical compositions of the present invention may be in different pharmaceutically acceptable forms, which may include, but are not limited to a liquid composition, a tablet or matrix composition, a capsule composition, etc. and the like.
  • the composition is a tablet composition
  • the tablet may include, but is not limited to different layers.
  • the tablet composition can also include, but is not limited to one or more coatings.
  • “Silicified microcrystalline cellulose,” or “SMCC,” refers to a particulate agglomerate of coprocessed microcrystalline cellulose and silicon dioxide.
  • SMCC may include, but is not limited to amounts from about 0.1% to about 20% silicon dioxide, by weight of the microcrystalline cellulose, where the silicon dioxide can have a particle size from about 1 nanometer (nm) to about 100 microns ( ⁇ m), based on average primary particle size.
  • the silicon dioxide can contain from about 0.5% to about 10% of the silicified microcrystalline cellulose, or from about 1.25% to about 5% by weight relative to the microcrystalline cellulose.
  • the silicon dioxide can have a particle size from about 5 nm to about 40 ⁇ m, or from about 5 nm to about 50 ⁇ m.
  • the silicon dioxide can have a surface area from about 10 m 2 /g to about 500 m 2 /g, or from about 50 m 2 /g to about 500 m 2 /g, or from about 175 m 2 /g to about 350 m 2 /g.
  • Silicified microcrystalline cellulose is commercially available from a number of suppliers known to one of skill in the art, Including Penwest Pharmaceuticals, Inc., under the trademark PROSOLV ® .
  • PROSOLV ® is available in a number of grades, including, for example, PROSOLV ® SMCC 50, PROSOLV ® SMCC 90, and PROSOLV ® HD.
  • Other products include, without limitation, SMCC 50LD, SMCC HD90 and SMCC 90LM and the like.
  • Sodium caprate or “NaC10” refers to the IUPAC compound sodium decanoate having molecular formula C 10 H 19 NaO 2 and the structural formula: .
  • sodium caprate functions as either an absorption enhancer or an excipient in tablet formulation.
  • Sodium caprate is approved by the European Union and Food and Drug Administration (FDA) as a direct food additive for human consumption.
  • Solvate as used herein, means a physical association of the peptide of SEQ ID NO: 1 of the present invention with one or more solvent molecules. This physical association involves varying degrees bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation.
  • solvate is intended to encompass both solution-phase and isolatable solvates.
  • suitable solvates include hydrates.
  • “Sorbitol” refers to the sugar alcohol D-glucitol and which may serve as a binder promoting adhesion of ingredients in tablet compositions.
  • “Sugar alcohol” as used herein refers to compounds derived from sugars and containing one or more hydroxyl groups. Sugar alcohol may contain multiple –OH groups and be classified as polyols. Examples of sugar alcohol include but not limited to sorbitol, mannitol, xylitol.
  • Subcoating refers to any number of film layers disposed over the core tablet that can provide one or more benefits such as, providing a smooth tablet surface to ease swallowing of compositions, accommodate pigmentation to aid in pill identification, provide a moisture barrier, and provide a high tensile strength outer layer of the tablet.
  • Such subcoatings can comprise, but is not limited to graft co-polymers of polyvinyl alcohol (PVA) and polyethylene glycol (PEG).
  • PVA polyvinyl alcohol
  • PEG polyethylene glycol
  • Commercial products that provide subcoatings include the line of products under the trade names OPADRY ® , OPAGLOS ® , and the like.
  • a subcoating may be further covered by one or more additional coatings.
  • the subcoating refers to any number of film layers disposed over the core tablet.
  • suitable materials for cosmetic subcoatings include a polyvinyl alcohol—polyethylene glycol (PVA-PEG) graft co-polymer (e.g., OPADRY ® QX).
  • PVA-PEG polyvinyl alcohol—polyethylene glycol
  • Other coatings include, without limitation, HPMC, HPC, PVA, Eudragit E based coatings and the like.
  • a subcoating may be further covered by one or more additional coatings, such as an enteric coating or a functional coating.
  • a subcoating comprises one or more of a plasticizer, anti-tacking agent, coloring agent, HPMC, HPC, PVA, and Eudragit E based coatings.
  • a subcoating is covered with one or more additional coatings.
  • the one or more additional coatings over the subcoating is an enteric coating.
  • the one or more additional coatings over the subcoating is a functional coating.
  • a subcoating is not covered by one or more additional coatings and is referred to as a cosmetic subcoating.
  • a core tablet is covered by a cosmetic coating and the cosmetic coating is not further covered with an enteric coating or a functional coating.
  • a cosmetic coating can serve as a smooth surface to aid in swallowing the tablet.
  • a cosmetic coating can provide a vehicle for pigmentation for tablet identification. serve as a smooth surface to aid in swallowing the tablet.
  • “Core tablet” refers to a mixture of the components of the core tablet.
  • the components are one or more of a crystalline form of the peptide of SEQ ID NO: 1, a pharmaceutically acceptable salt thereof, or a solvate of the foregoing, and suitable excipients.
  • the suitable excipient is one or more of the following, but not limited to, a filler, a disintegrant, a glidant, a lubricant, and an absorption enhancer.
  • a subcoating, a cosmetic coating, an enteric coating, or any combination thereof may be disposed over the core tablet.
  • “Therapeutically effective amount” refers to an amount of a compound (i.e., a peptide of SEQ ID NO: 1) or of a pharmaceutical composition useful for treating or ameliorating an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. "Therapeutically effective amount” further includes within its meaning a non-toxic but sufficient amount of the particular drug to which it is referring to provide the desired therapeutic effect.
  • Treatment refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.
  • (V/V) refers to the phrase “volume for volume”, i.e., the proportion of a particular substance within a mixture, as measured by volume or a volume amount of a component of the composition disclosed herein relative to the total volume amount of the composition. Accordingly, the quantity is unit less and represents a volume percentage amount of a component relative to the total volume of the composition.
  • a 2% (V/V) solvent mixture can indicate 2 mL of one solvent is present in 100 mL of the solvent mixture.
  • (w/w) refers to the phrase “weight for weight”, i.e., the proportion of a particular substance within a mixture, as measured by weight or mass or a weight amount of a component of the composition disclosed herein relative to the total weight amount of the composition. Accordingly, the quantity is unit less and represents a weight percentage amount of a component relative to the total weight of the composition. For example, a 2% (w/w) solution can indicate 2 grams of solute is dissolved in 100 grams of solution.
  • Systemic routes of administration refer to or are defined as a route of administration of drug, a pharmaceutical composition or formulation, or other substance into the circulatory system so that various body tissues and organs are exposed to the drug, formulation or other substance.
  • administration can take place orally (where drug or oral preparations are taken by mouth, and absorbed via the gastrointestinal tract), via enteral administration (absorption of the drug also occurs through the gastrointestinal tract) or parenteral administration (generally injection, infusion, or implantation, etc.
  • Systemically active peptide drug therapy as it relates to the present invention generally refers to treatment by means of a pharmaceutical composition comprising a peptide active ingredient, wherein said peptide resists immediate metabolism and/or excretion resulting in its exposure in various body tissues and organs, such as the cardiovascular, respiratory, gastrointestinal, nervous or immune systems.
  • Systemic drug activity in the present invention also refers to treatment using substances that travel through the bloodstream, reaching and affecting cells in various body tissues and organs. Systemic active drugs are transported to their site of action and work throughout the body to attack the physiological processes that cause inflammatory diseases.
  • Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. Bioavailability of a drug is impacted by the properties of the dosage form, which depend partly on its design and manufacture.
  • “Digestive tract tissue” as used herein refers to all the tissues that comprise the organs of the alimentary canal. For example only, and without limitation, “digestive tract tissue” includes tissues of the mouth, esophagus, stomach, small intestine, large intestine, and anus. III.
  • CRYSTALLINE FORMS [0132] Provided herein are crystalline forms of a peptide inhibitor of the interleukin-23 receptor (IL-23R). Crystalline forms of a compound of Formula (I) were unexpectedly obtained and isolated. Crystalline forms of pharmaceutically acceptable salts of a compound of Formula (I) were prepared, isolated, and found suitable for use in pharmaceutical formulations. As such, crystalline forms of peptides may be uniquely advantageous as the corresponding amorphous forms are often unsuitable for formulating, such as tableting. [0133] In one aspect, the present invention relates to a pharmaceutical composition of a crystalline salt of a compound of Formula (I) : , or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing.
  • the present invention relates to a crystalline free base form of a compound of Formula (I) .
  • the present invention relates to a pharmaceutical composition of a hydrochloride salt of a peptide of SEQ ID NO: 1.
  • the present invention relates to a pharmaceutical composition of a hydrochloride salt of a compound of Formula (I).
  • the present invention relates to a pharmaceutical composition of a crystalline form of the hydrochloride salt of a peptide of SEQ ID NO: 1.
  • the present invention relates to a pharmaceutical composition of a crystalline form of a pharmaceutically acceptable salt of a peptide of SEQ ID NO: 1.
  • the crystalline form of a pharmaceutically acceptable salt of a peptide of SEQ ID NO: 1 may be a crystalline hydrochloride salt, a crystalline acetate salt, a crystalline fumarate salt, a crystalline glycolate salt, a crystalline glutarate salt, a crystalline mesylate salt, a crystalline sulfate salt, a crystalline bis-hydrochloride salt, and a crystalline citrate salt of a peptide of SEQ ID NO: 1.
  • the present invention relates to a pharmaceutical composition of a crystalline form of the hydrochloride salt of a compound of Formula (I). [0140] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of a pharmaceutically acceptable salt of a compound of Formula (I).
  • the crystalline form of a pharmaceutically acceptable salt of a compound of Formula (I) may be a crystalline hydrochloride salt, a crystalline acetate salt, a crystalline fumarate salt, a crystalline glycolate salt, a crystalline glutarate salt, a crystalline mesylate salt, a crystalline sulfate salt, a crystalline bis-hydrochloride salt, and a crystalline citrate salt of a compound of Formula (I).
  • the crystalline hydrochloride salt form of a compound of Formula (I) has the structure: , or a solvate thereof.
  • the crystalline hydrochloride salt form of a compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG.1.
  • the crystalline hydrochloride salt form or solvate thereof is a hemi hydrochloride salt.
  • the crystalline hydrochloride salt form of a compound of Formula (I) is characterized by an XRPD pattern substantially as set forth in FIG.1 or FIG. 2.
  • the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of a crystalline hydrochloride salt or solvate thereof described herein and one or more pharmaceutically acceptable excipients.
  • the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of a crystalline salt or solvate thereof described herein and one or more pharmaceutically acceptable excipients.
  • Free Base Form [0145] In some embodiments, the compound of Formula (I) is a free base of the compound of Formula (I). In some embodiments, the free base of the compound of Formula (I) is crystalline. In some embodiments, the free base of the compound of Formula (I) is in the form of a solvate.
  • the solvate of the free base of the compound of Formula (I) is a hydrate. In some other embodiments, the free base of the compound of Formula (I) is crystalline and in the form of a solvate. [0146] In some embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 7.7, 9.1, 9.6, and 13.3 +/- 0.2 degrees two theta.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 7.7, 9.1, 9.6, and 13.3 +/- 0.3 degrees two theta.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 7.7, 9.1, 9.6, and 13.3 +/- 0.4 degrees two theta.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 +/- 0.2 degrees two theta.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 +/- 0.3 degrees two theta.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 +/- 0.4 degrees two theta.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 +/- 0.2 degrees two theta.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 +/- 0.3 degrees two theta.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 +/- 0.4 degrees two theta.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 +/- 0.2 degrees two theta.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 +/- 0.3 degrees two theta.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 +/- 0.4 degrees two theta.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 +/- 0.2 degrees two theta.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 +/- 0.3 degrees two theta.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 +/- 0.4 degrees two theta.
  • the crystalline free base salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.11.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having endotherm peaks at about 71.0 °C and/or about 130.2 °C, as determined by DSC. In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having substantially a DSC curve as shown in FIG.13. [0152] In some embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having a weight loss of about 3.7% from about 26.5 °C to about 70.0 °C and a weight loss of about 2.7% from 70.0 °C to about 170.0 °C, as determined by TGA.
  • the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having a TGA graph substantially as shown in FIG.12.
  • the crystalline bis hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having a DVS graph substantially as shown in FIG.14.
  • the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline free base of the compound of Formula (I) or solvate thereof described herein and one or more pharmaceutically acceptable excipients.
  • Salt Ratios [0154]
  • the compound of Formula (I) is in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt of the compound of Formula (I) is crystalline.
  • a crystalline pharmaceutically acceptable salt of a compound of Formula (I) comprises a cationic form of the compound of Formula (I) and a pharmaceutically acceptable anion.
  • a crystalline hydrochloride salt of a compound of Formula (I) comprises the compound of Formula (I) in its cationic form and a chloride anion.
  • the salt compositions described herein include a salt of a compound of Formula (I) wherein the salt is a pharmaceutically acceptable salt chosen from an acetate salt, a fumarate salt, a glycolate salt, a glutarate salt, a mesylate salt, a sulfate salt, a citrate salt, a bis-hydrochloride salt, and the like.
  • the pharmaceutically acceptable salt of a compound of Formula (I) is a hydrochloride salt and the anion is chloride.
  • the salt of a compound of Formula (I) is an acetate salt and the anion is acetate.
  • the salt of a compound of Formula (I) is a fumarate salt and the anion is fumarate.
  • the salt of a compound of Formula (I) is a glutarate salt and the anion is glutarate.
  • the salt of a compound of Formula (I) is a glycolate salt and the anion is glycolate.
  • the salt of a compound of Formula (I) is a mesylate salt and the anion is mesylate.
  • the salt of a compound of Formula (I) is a sulfate salt and the anion is sulfate.
  • the salt of a compound of Formula (I) is a citrate salt and the anion is citrate. In some embodiments, the salt of a compound of Formula (I) is a bis-hydrochloride salt and the anion is chloride. [0156] In some embodiments, the molar equivalents of an anion of a crystalline salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0.
  • the molar equivalents of an anion of a salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is 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 1.0, 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, or about 2.0, including any amount in between and fractions thereof.
  • the molar equivalents of a chloride anion of a crystalline hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0.
  • the molar equivalents of a chloride anion of a crystalline hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.4 to about 1.5. In other embodiments, the molar equivalents of a chloride anion of a crystalline hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.5 to about 1.0. In certain embodiments, the molar equivalents of a chloride anion of a crystalline hydrochloride salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.6 to about 0.7.
  • the molar equivalents of an acetate anion of a crystalline acetate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0. In some embodiments, the molar equivalents of an acetate anion of a crystalline acetate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.4 to about 1.5. In other embodiments, the molar equivalents of an acetate anion of a crystalline acetate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.5 to about 1.0.
  • the molar equivalents of an acetate of a crystalline acetate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.6 to about 0.7. In certain embodiments, the molar equivalents of an acetate of a crystalline acetate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is about 0.65. [0159] In some embodiments, the molar equivalents of a fumarate anion of a crystalline fumarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0.
  • the molar equivalents of a fumarate anion of a crystalline fumarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.4 to about 1.5. In other embodiments, the molar equivalents of a fumarate anion of a crystalline fumarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.5 to about 1.0. In other embodiments, the molar equivalents of a fumarate anion of a crystalline fumarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.0 to about 1.5.
  • the molar equivalents of a fumarate anion of a crystalline fumarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.5 to about 2.0.
  • the molar equivalents of a glutarate anion of a crystalline glutarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0.
  • the molar equivalents of a glutarate anion of a crystalline glutarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 1.0.
  • the molar equivalents of a glutarate anion of a crystalline glutarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.3 to about 0.6. In certain embodiments, the molar equivalents of a glutarate anion of a crystalline glutarate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is about 0.5. [0161] In some embodiments, the molar equivalents of a glycolate anion of a crystalline glycolate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0.
  • the molar equivalents of a glycolate anion of a crystalline glycolate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 1.0. In other embodiments, the molar equivalents of a glycolate anion of a crystalline glycolate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.3 to about 0.6. In certain embodiments, the molar equivalents of a glycolate anion of a crystalline glycolate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is about 0.5.
  • the molar equivalents of a mesylate anion of a crystalline mesylate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0. In some embodiments, the molar equivalents of a mesylate anion of a crystalline mesylate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.0 to about 2.0. In other embodiments, the molar equivalents of a mesylate anion of a crystalline mesylate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.5 to about 2.0.
  • the molar equivalents of a mesylate anion of a crystalline mesylate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.8 to about 1.9. In certain embodiments, the molar equivalents of a mesylate anion of a crystalline mesylate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is about 1.8. [0163] In some embodiments, the molar equivalents of a sulfate anion of a crystalline sulfate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0.
  • the molar equivalents of a sulfate anion of a crystalline sulfate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.0 to about 2.0. In other embodiments, the molar equivalents of a sulfate anion of a crystalline sulfate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.5 to about 2.0. In other embodiments, the molar equivalents of a sulfate anion of a crystalline sulfate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.5 to about 1.7.
  • the molar equivalents of a sulfate anion of a crystalline sulfate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is about 1.6.
  • the molar equivalents of a citrate anion of a crystalline citrate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0.
  • the molar equivalents of a citrate anion of a crystalline citrate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.4 to about 1.5.
  • the molar equivalents of a citrate anion of a crystalline citrate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.5 to about 1.0. In other embodiments, the molar equivalents of a citrate anion of a crystalline citrate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.0 to about 1.5. In other embodiments, the molar equivalents of a citrate anion of a crystalline citrate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.5 to about 2.0.
  • the molar equivalents of a chloride anion of a crystalline bis- hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0. In some embodiments, the molar equivalents of a chloride anion of a crystalline bis-hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.0 to about 2.0. In other embodiments, the molar equivalents of a chloride anion of a crystalline bis-hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.5 to about 2.0.
  • the molar equivalents of a chloride anion of a crystalline hydrochloride salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.9 to about 2.0. In certain embodiments, the molar equivalents of a chloride anion of a crystalline bis-hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is about 2.0. Salt Forms Hydrochloride Salt [0166] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a hydrochloride salt. In some embodiments, a hydrochloride salt of the compound of Formula (I) is crystalline.
  • the hydrochloride salt of the compound of Formula (I) is in the form of a solvate.
  • the solvate of the hydrochloride salt of the compound of Formula (I) is a hydrate.
  • the hydrochloride salt of the compound of Formula (I) is crystalline and in the form of a solvate.
  • a pharmaceutically acceptable salt of a compound of Formula (I) is a hydrochloride salt.
  • a hydrochloride salt of the compound of Formula (I) is crystalline.
  • the hydrochloride salt of the compound of Formula (I) is in the form of a solvate.
  • the solvate of the hydrochloride salt of the compound of Formula (I) is a hydrate. In some other embodiments, the hydrochloride salt of the compound of Formula (I) is crystalline and in the form of a solvate. [0168] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.2 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.3 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.4 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 13.9, 15.7, or 17.1 +/- 0.2 degrees two theta.
  • the crystalline hydrochloride salt of the compound of SEQ ID NO: 1 or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 13.9, 15.8, or 17.1 +/- 0.3 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.3 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.4 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 +/- 0.2 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 +/- 0.3 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 +/- 0.4 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 +/- 0.2 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 +/- 0.3 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 +/- 0.4 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.1.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.2. [0172] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 +/- 0.2 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.6, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 +/- 0.3 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 +/- 0.4 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 +/- 0.2 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 +/- 0.3 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 +/- 0.4 degrees two theta.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.3.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.1, FIG.2, or FIG.3. [0175] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having endotherm peaks at about 81.4 °C, as determined by differential scanning calorimetry (DSC). In certain embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having a DSC curve substantially as set forth in FIG.5.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having a weight loss of about 5.6% from about 26.5 °C to about 160.0 °C, as determined by thermogravimetric analysis (TGA).
  • TGA thermogravimetric analysis
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having a TGA graph substantially as set forth in FIG.4.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having a DVS graph substantially as shown in FIG.6.
  • the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof described herein and one or more pharmaceutically acceptable excipients.
  • Acetate Salt [0178]
  • a pharmaceutically acceptable salt of a compound of Formula (I) is an acetate salt.
  • the acetate salt of the compound of Formula (I) is crystalline.
  • the acetate salt of the compound of Formula (I) is in the form of a solvate.
  • the solvate of the acetate salt of the compound of Formula (I) is a hydrate.
  • the acetate salt of the compound of Formula (I) is crystalline and in the form of a solvate.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.2 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.3 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.4 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.2 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.3 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.4 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/ 0.2 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.3 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.4 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 +/- 0.2 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 +/- 0.3 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 +/- 0.4 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least three diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 +/- 0.2 degrees two theta.
  • the crystalline acetate salt of the peptide of SEQ ID NO: 1 or solvate thereof is characterized as having an XRPD pattern having at least three diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 +/- 0.3 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least three diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 +/- 0.4 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1. +/- 0.2 degrees two theta.
  • the crystalline acetate salt of the peptide of compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 +/- 0.3 degrees two theta.
  • the crystalline acetate salt of compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 +/- 0.4 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least three diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1. +/- 0.2 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at three theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 +/- 0.3 degrees two theta.
  • the crystalline acetate salt of the peptide of SEQ ID NO: 1 or solvate thereof is characterized as having an XRPD pattern having at least three diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 +/- 0.4 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 +/- 0.2 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 +/- 0.3 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 +/- 0.4 degrees two theta.
  • the crystalline acetate salt of the peptide of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 +/- 0.2 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4 and 20.1 +/- 0.3 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 +/- 0.4 degrees two theta.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.7.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having endotherm peaks at about 80.7 °C and/or about 240.7 °C, as determined by DSC. In certain embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having a DSC curve substantially as set forth in FIG.9. [0189] In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having a weight loss of about 5.8% from about 26.5 °C to about 150.0 °C, as determined by TGA.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having a TGA graph substantially as set forth in FIG.8. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having a DVS graph substantially as shown in FIG.10. [0190] In some aspects, the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline acetate salt of the compound of Formula (I) or solvate thereof described herein and a pharmaceutically acceptable excipient. Fumarate Salt [0191] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a fumarate salt.
  • the fumarate salt of the compound of Formula (I) is crystalline. In some embodiments, the fumarate salt of the compound of Formula (I) is in the form of a solvate. In certain embodiments, the solvate of the fumarate salt of the compound of Formula (I) is a hydrate. In some other embodiments, the fumarate salt of the compound of Formula (I) is crystalline and in the form of a solvate.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.2 degrees two theta.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.3 degrees two theta.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.4 degrees two theta.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.2 degrees two theta.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.3 degrees two theta.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.4 degrees two theta.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.2 degrees two theta.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.3 degrees two theta.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.4 degrees two theta.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7,17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 +/- 0.2 degrees two theta.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7,17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 +/- 0.3 degrees two theta.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7,17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 +/- 0.4 degrees two theta.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7,17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 +/- 0.2 degrees two theta.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7,17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 +/- 0.3 degrees two theta.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7,17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 +/- 0.4 degrees two theta.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.15.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an endotherm peak at about 65.3 °C, as determined by DSC.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having a DSC curve substantially as set forth in FIG.17.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having a weight loss of about 4.4% from about 26.5 °C to about 110.0 °C, as determined by TGA.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having a TGA graph substantially as set forth in FIG.16.
  • the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline fumarate salt of the compound of Formula (I) or solvate thereof described herein and a pharmaceutically acceptable excipient.
  • Glutarate Salt [0199]
  • a pharmaceutically acceptable salt of a compound of Formula (I) is a glutarate salt.
  • the glutarate salt of the compound of Formula (I) is crystalline.
  • the glutarate salt of the compound of Formula (I) is in the form of a solvate.
  • the solvate of the glutarate salt of the compound of Formula (I) is a hydrate. In some other embodiments, the glutarate salt of the compound of Formula (I) is crystalline and in the form of a solvate. [0200] In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.2 degrees two theta.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.3 degrees two theta.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.4 degrees two theta.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.2 degrees two theta.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.3 degrees two theta.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.4 degrees two theta.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.2 degrees two theta.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.3 degrees two theta.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.4 degrees two theta.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 +/- 0.2 degrees two theta.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles of selected from 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 +/- 0.3 degrees two theta.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 +/- 0.4 degrees two theta.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 +/- 0.2 degrees two theta.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 +/- 0.3 degrees two theta.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 +/- 0.4 degrees two theta.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.18.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an endotherm peak at about 224.0 °C, as determined by simultaneous thermal analysis (SDT).
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an SDT thermogram substantially as set forth in FIG.19.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having a weight loss of about 6.4% from about 26.5 °C to about 125.0 °C, as determined by SDT..
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having a DVS graph substantially as shown in FIG.20.
  • the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline glutarate salt of the compound of Formula (I) or solvate thereof described herein and a pharmaceutically acceptable excipient.
  • Glycolate Salt of a Peptide of SEQ ID NO: 1 [0207]
  • a pharmaceutically acceptable salt of a compound of Formula (I) is a glycolate salt.
  • the glycolate salt of the compound of Formula (I) is crystalline.
  • the glycolate salt of the compound of Formula (I) is in the form of a solvate.
  • the solvate of the glycolate salt of the compound of Formula (I) is a hydrate.
  • the glycolate salt of the compound of Formula (I) is crystalline and in the form of a solvate.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.2 degrees two theta.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.3 degrees two theta. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.4 degrees two theta.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.2 degrees two theta.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.3 degrees two theta.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.4 degrees two theta.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.2 degrees two theta.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.3 degrees two theta.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.4 degrees two theta.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0,13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 +/- 0.2 degrees two theta.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0,13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 +/- 0.3 degrees two theta.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0,13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 +/- 0.4 degrees two theta.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0,13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 +/- 0.2 degrees two theta.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0,13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 +/ 0.3 degrees two theta.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0,13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 +/- 0.4 degrees two theta.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.21.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an endotherm peak at about 237.0 °C, as determined by SDT. In certain embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having and SDT thermogram substantially as set forth in FIG.22. [0214] In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having a weight loss of about 5.1% from about 26.5 °C to about 100.0 °C, as determined by SDT.
  • the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an SDT thermogram substantially as set forth in FIG.22. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having a DVS graph substantially as shown in FIG.23. [0215] In some aspects, the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline glycolate salt of the compound of Formula (I) or solvate thereof described herein and one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable salt of a compound of Formula (I) is a sulfate salt.
  • the sulfate salt of the compound of Formula (I) is crystalline.
  • the sulfate salt of the compound of Formula (I) is in the form of a solvate.
  • the solvate of the sulfate salt of the compound of Formula (I) is a hydrate.
  • the sulfate salt of the compound of Formula (I) is crystalline and in the form of a solvate.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.2 degrees two theta.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/ 0.3 degrees two theta.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.4 degrees two theta.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 +/- 0.2 degrees two theta.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 +/- 0.3 degrees two theta.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 +/- 0.4 degrees two theta.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 +/- 0.2 degrees two theta.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 +/- 0.3 degrees two theta.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 +/- 0.4 degrees two theta.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 +/- 0.2 degrees two theta.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 +/- 0.3 degrees two theta.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 +/- 0.4 degrees two theta.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.26.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an endotherm peak at about 255.0 °C, as determined by SDT. In certain embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an SDT thermogram substantially as set forth in FIG. 27. [0222] In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having a weight loss of about 4.4% from about 26.5 °C to about 80.0 °C, as determined by SDT.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an SDT thermogram substantially as set forth in FIG.27.
  • the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline sulfate salt of the compound of Formula (I) or solvate thereof described herein and a pharmaceutically acceptable excipient.
  • Mesylate Salt of a Peptide of SEQ ID NO: 1 [0224]
  • a pharmaceutically acceptable salt of a compound of Formula (I) is a mesylate salt.
  • the mesylate salt of the compound of Formula (I) is crystalline.
  • the mesylate salt of the compound of Formula (I) is in the form of a solvate.
  • the solvate of the mesylate salt of the compound of Formula (I) is a hydrate.
  • the mesylate salt of the compound of Formula (I) is crystalline and in the form of a solvate.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.2 degrees two theta.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.3 degrees two theta.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.4 degrees two theta.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 +/- 0.2 degrees two theta.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 +/- 0.3 degrees two theta.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 +/- 0.4 degrees two theta.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8 and 27.8 degrees two theta +/- 0.2 degrees two theta.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8 and 27.8 degrees two theta +/- 0.3 degrees two theta.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8 and 27.8 degrees two theta +/- 0.4 degrees two theta.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8 and 27.8 degrees two theta +/- 0.2 degrees two theta.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8 and 27.8 degrees two theta +/- 0.3 degrees two theta.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8 and 27.8 degrees two theta +/- 0.4 degrees two theta.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.24.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an endotherm peak at about 242.1 °C, as determined by SDT.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an SDT thermogram substantially as set forth in FIG. 25.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having a weight loss of about 5.4% from about 26.5 °C to about 80.0 °C, as determined by SDT.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an SDT thermogram substantially as set forth in FIG.25.
  • the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline mesylate salt of the compound of Formula (I) or solvate thereof described herein and a pharmaceutically acceptable excipient.
  • Citrate Salt of a Peptide of SEQ ID NO: 1 [0231]
  • a pharmaceutically acceptable salt of a compound of Formula (I) is a citrate salt.
  • the citrate salt of the compound of Formula (I) is crystalline.
  • the citrate salt of the compound of Formula (I) is in the form of a solvate.
  • the solvate of the citrate salt of the compound of Formula (I) is a hydrate.
  • the citrate salt of the compound of Formula (I) is crystalline and in the form of a solvate.
  • the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.2 degrees two theta.
  • the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.3 degrees two theta. In some embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.4 degrees two theta.
  • the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 +/- 0.2 degrees two theta.
  • the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 +/- 0.3 degrees two theta.
  • the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 +/- 0.4 degrees two theta.
  • the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1,13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 +/- 0.2 degrees two theta.
  • the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1,13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 +/- 0.3 degrees two theta.
  • the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1,13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 +/- 0.4 degrees two theta.
  • the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1,13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 +/- 0.2 degrees two theta.
  • the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1,13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 +/- 0.3 degrees two theta.
  • the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1,13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 +/- 0.4 degrees two theta.
  • the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.28.
  • the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline citrate salt of the compound of Formula (I) or solvate thereof described herein and a pharmaceutically acceptable excipient.
  • Bis-Hydrochloride Salt of a Peptide of SEQ ID NO: 1 [0237]
  • a pharmaceutically acceptable salt of a compound of Formula (I) is a bis-hydrochloride salt.
  • the bis-hydrochloride salt of the compound of Formula (I) is crystalline.
  • the bis-hydrochloride salt of the compound of Formula (I) is in the form of a solvate.
  • the solvate of the bis- hydrochloride salt of the compound of Formula (I) is a hydrate.
  • the bis-hydrochloride salt of the compound of Formula (I) is crystalline and in the form of a solvate.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.2 degrees two theta.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.3 degrees two theta.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 +/- 0.4 degrees two theta.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.2 degrees two theta.
  • the crystalline bis- hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.3 degrees two theta.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.4 degrees two theta.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.2 degrees two theta.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.3 degrees two theta.
  • the crystalline bis- hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 +/- 0.4 degrees two theta.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 +/- 0.2 degrees two theta.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 +/- 0.3 degrees two theta.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 +/- 0.4 degrees two theta.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 +/- 0.2 degrees two theta.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 +/- 0.3 degrees two theta.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 +/- 0.4 degrees two theta.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.29.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having endotherm peaks at about 79.5 °C and/or about 235.3 °C, as determined by DSC.
  • the crystalline bis- hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having a DSC curve as substantially set forth in FIG.31.
  • the crystalline bis hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having a weight loss of about 11.3% from about 26.5 °C to about 190.0 °C, as determined by TGA.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having a TGA graph substantially as set forth in FIG.30.
  • the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having a DVS graph substantially as shown in FIG.32.
  • the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof described herein and a pharmaceutically acceptable excipient.
  • the crystalline salt of the compound of Formula (I) or solvate thereof produced by the methods described herein has a purity level of at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least 98%, or at least about 99% as determined by ultra-performance liquid chromatography (UPLC), high-performance liquid chromatography (HPLC), or other appropriate methods.
  • UPLC ultra-performance liquid chromatography
  • HPLC high-performance liquid chromatography
  • the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of between about 90% and 100%.
  • the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of at least about 95.0%, about 96.0%, about 97.0%, about 98.0%, about 99.0%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or about 99.9%, including any amount in between and fractions thereof.
  • the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of between about 95.0% and 99.9%.
  • the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of at least 95%.
  • the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of at least 96%. In some embodiments, the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of at least 97%. In some embodiments, the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of at least 98%. In some embodiments, the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of at least 99%. In some embodiments, the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of at least 99.5%.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof has a purity level of at least about 95.0%, about 96.0%, about 97.0%, about 98.0%, about 99.0%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or about 99.9%, including any amount in between and fractions thereof.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof has a purity level of between about 99.0% and 99.5%.
  • the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof has a purity level of at least 99.0%.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof has a purity level of at least about 95.0%, about 96.0%, about 97.0%, about 98.0%, about 99.0%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or about 99.9%, including any amount in between and fractions thereof.
  • the crystalline acetate salt of the compound of Formula (I) or solvate thereof has a purity level of at least 99.0%. In other embodiments, the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of between about 99.0% and 99.5%. [0250] In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof has a purity level of at least 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%, or about 98%, or about 99%, including any amount in between and fractions thereof.
  • the crystalline fumarate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 86% and 90%. In other embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 86% and 87%. In certain embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof has a purity level of at least 86%.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof has a purity level of at least about 95.0%, about 96.0%, about 97.0%, about 98.0%, about 99.0%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or about 99.3%, including any amount in between and fractions thereof.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 85% and 90%.
  • the crystalline glutarate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 90% and 95%. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 95% and 99%. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 99.0% and 99.5%. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof has a purity level of at least 99.0%.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof has a purity level of at least 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%, or about 98%, or about 99%, including any amount in between and fractions thereof.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 90% and 95%.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 95% and 99%.
  • the crystalline mesylate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 90% and 92%. In certain embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof has a purity level of at least 90%. [0253] In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof has a purity level of at least 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%, or about 98%, or about 99%, including any amount in between and fractions thereof.
  • the crystalline sulfate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 90% and 95%. In other embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 95% and 99%. In other embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 90% and 92%. In certain embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof has a purity level of at least 91%.
  • the crystalline citrate salt of the compound of Formula (I) or solvate thereof has a purity level of at least about 95.0%, about 96.0%, about 97.0%, about 98.0%, about 99.0%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or about 99.9%, including any amount in between and fractions thereof.
  • the crystalline citrate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 99.0% and 99.9%.
  • the crystalline citrate salt of the compound of Formula (I) or solvate thereof has a purity level of at least 99.5%.
  • the crystalline free base of the compound of Formula (I) or solvate thereof has a purity level of at least about 95.0%, about 96.0%, about 97.0%, about 98.0%, about 99.0%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or about 99.3%, including any amount in between and fractions thereof.
  • the crystalline free base of the compound of Formula (I) or solvate thereof has a purity level of at least 97.0%.
  • the crystalline free base of the compound of Formula (I) or solvate thereof has a purity level of at least 98.0%. In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof has a purity level of at least 99.0%. In other embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof has a purity level of between about 97.0% and 98.0%. In other embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof has a purity level of between about 98.0%. In other embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof has a purity level of between about 99.0%. IV.
  • the present invention relates to pharmaceutical hydrochloride salt forms and compositions of peptide inhibitors of the interleukin-23 receptor (IL-23R) or solvates thereof, corresponding pharmaceutical compositions, methods and/or uses for treatment of autoimmune inflammation and related diseases and disorders as defined herein.
  • the present invention relates to pharmaceutical crystalline salt forms and compositions of peptide inhibitors of the interleukin-23 receptor (IL-23R) or solvates thereof, corresponding pharmaceutical compositions, methods and/or uses for treatment of autoimmune inflammation and related diseases and disorders as defined herein.
  • the present invention relates to a pharmaceutical composition of a hydrochloride salt of a compound of Formula (I): Ac-[Pen]*-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]*-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E- N-[3-Pal]-Sarc-NH 2 (in which ([Pen]*-[Pen]* form a disulfide bond); and having the chemical structure shown below:
  • the monocyclic peptide comprises an amino acid sequence of Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-(2-aminoethoxy))]-[2-Nal]-[THP]-E-N- [3Pal]-[Sarc]-NH2, wherein the monocyclic peptide is cyclized via a Pen-Pen disulfide bond; or a pharmaceutically acceptable salt thereof.
  • one or more amino acids is in the L configuration. In certain embodiments, all amino acids are in the L configuration.
  • the crystalline form of a compound of formula (I) or solvate thereof has a moisture content in the range of about 0.1% to about 20%, 0.5% to about 15%, about 1% to about 10%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 0.1% to about 5%, about 0.1% to about 4%, or about 0.1% to about 3% by weight.
  • the crystalline form of a compound of formula (I) or solvate thereof has a moisture content level of about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.7%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 7%, 8%m 9%, or 10% by weight.
  • the crystalline form of a compound of formula (I) or solvate thereof has a moisture content level of greater than about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.7%, 3%, 3.5%, 4%, 4.5%, 5%, or 5.5% by weight. In some embodiments, the crystalline form of a compound of formula (I) or solvate thereof has a moisture content level of lower than about 1%, 1.5%, 2%, 2.7%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 7%, 8%, 9%, or 10% by weight.
  • the amount of a crystalline form of a compound of formula (I) or solvate thereof in the composition is in the range of about 0.1% to about 65%, about 0.1% to about 60%, about 0.1% to about 55%, about 0.1% to about 50%, about 0.1% to about 45%, about 0.1% to about 40%, about 0.1% to about 35%, about 0.1% to about 30%, about 0.1% to about 25%, about 0.1% to about 20%, about 0.1% to about 15%, about 0.1% to about 10%, or about 0.1% to about 5% by weight.
  • the amount of a crystalline form of a compound of formula (I) or solvate thereof in the composition is in the range of about 1% to about 65%, about 1% to about 60%, about 1% to about 55%, 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%, or about 1% to about 5% by weight.
  • the amount of a crystalline form of a compound of formula (I) or solvate thereof in the composition is in the range of about 2% to about 65%, about 2% to about 60%, about 2% to about 55%, about 2% to about 50%, about 2% to about 45%, about 2% to about 40%, about 2% to about 35%, about 2% to about 30%, about 2% to about 25%, about 2% to about 20%, about 2% to about 15%, about 2% to about 10%, or about 2% to about 5% by weight.
  • the amount of a crystalline form of a compound of formula (I) or solvate thereof in the composition is in the range of about 5% to about 65%, about 5% to about 60%, about 5% to about 55%, 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%, or about 5% to about 10% by weight.
  • the amount of a crystalline form of a compound of formula (I) or solvate thereof in the composition is in the range of about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65% by weight.
  • the hydrochloride salt of a compound of Formula (I) or corresponding solvate thereof may be present in any form, such as a hydrate or other solvate.
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof may be provided in crystalline form, in an amorphous form, or a semi-crystalline form.
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof is a crystalline form. In some aspects, the hydrochloride salt of a compound of Formula (I) or solvate thereof is an amorphous form. In some aspects, the hydrochloride salt of a compound of Formula (I) or solvate thereof is a semi-crystalline form. [0263] In one aspect, the composition of a hydrochloride salt of a compound of Formula (I) or solvate thereof is a hemi hydrochloride salt.
  • the hemi hydrochloride salt has from about 0.1 to about 0.9, such as from about 0.2 to about 0.8 or from about 0.3 to about 0.7, molar equivalents of hydrogen chloride compared to the compound of Formula (I). In some aspects, the hemi hydrochloride salt has about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or about 0.9 molar equivalents of hydrogen chloride compared to the compound of Formula (I). In some aspects, the hemi hydrochloride salt has about 0.5 molar equivalents of hydrogen chloride compared to the compound of Formula (I).
  • the hydrochloride salt form of a compound of Formula (I) or solvate thereof may be a hydrate.
  • the hydrate of the hydrochloride salt of a compound of Formula (I) has from about 0.2 to about 100 molar equivalents of water compared to the compound of Formula (I).
  • the hydrate may be present in a range of about 2% w/w to about 10% w/w water compared to the hydrochloride salt of the compound of Formula (I).
  • the present invention relates to hydrochloride salt compositions of the present invention, which may be in a liquid or a solid composition.
  • the hydrochloride salt form of a compound of formula (I) or solvate thereof has a moisture content in the range of about 0.1% to about 20%, 0.5% to about 15%, about 1% to about 10%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 0.1% to about 5%, about 0.1% to about 4%, or about 0.1% to about 3% by weight.
  • the hydrochloride salt form of a compound of formula (I) or solvate thereof has a moisture content level of about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.7%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 7%, 8%m 9%, or 10% by weight. In some embodiments, the hydrochloride salt form of a compound of formula (I) or solvate thereof has a moisture content level of greater than about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.7%, 3%, 3.5%, 4%, 4.5%, 5%, or 5.5% by weight.
  • the hydrochloride salt form of a compound of formula (I) or solvate thereof has a moisture content level of lower than about 1%, 1.5%, 2%, 2.7%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 7%, 8%, 9%, or 10% by weight.
  • the hydrochloride salt compositions of the present invention can be administered to a subject or patient by any means in accordance with therapeutic administration, which accomplishes intended purpose or pharmaceutical efficacy. Examples include administration by oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal or ocular routes.
  • the administration of the hydrochloride salt composition of the present invention is adapted for oral administration.
  • the present invention provides a composition which comprises a hydrochloride salt of a compound of Formula (I) or solvate thereof in an amount of from about 0.1% to about 15% (w/w) of the composition and one or more pharmaceutically acceptable excipients.
  • the present invention provides a composition, which comprises: a hydrochloride salt of a compound of Formula (I) or solvate thereof; and about 50 mM pH 7.4 phosphate buffered aqueous solution.
  • the present invention relates to a composition, which comprises a hydrochloride salt of a compound of Formula (I) or solvate thereof in an amount of from about 0.1% to about 15% (w/w) of the composition; an absorption enhancer in an amount from about 10% to about 60% (w/w); and one or more pharmaceutically acceptable excipients.
  • the amount of hydrochloride salt of a compound of formula (I) or solvate thereof in the composition is in the range of about 0.1% to about 65%, about 0.1% to about 60%, about 0.1% to about 55%, about 0.1% to about 50%, about 0.1% to about 45%, about 0.1% to about 40%, about 0.1% to about 35%, about 0.1% to about 30%, about 0.1% to about 25%, about 0.1% to about 20%, about 0.1% to about 15%, about 0.1% to about 10%, or about 0.1% to about 5% by weight.
  • the amount of hydrochloride salt of a compound of formula (I) or solvate thereof in the composition is in the range of about 1% to about 65%, about 1% to about 60%, about 1% to about 55%, 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%, or about 1% to about 5% by weight.
  • the amount of hydrochloride salt of a compound of formula (I) or solvate thereof in the composition is in the range of about 2% to about 65%, about 2% to about 60%, about 2% to about 55%, about 2% to about 50%, about 2% to about 45%, about 2% to about 40%, about 2% to about 35%, about 2% to about 30%, about 2% to about 25%, about 2% to about 20%, about 2% to about 15%, about 2% to about 10%, or about 2% to about 5% by weight.
  • the amount of hydrochloride salt of a compound of formula (I) or solvate thereof in the composition is in the range of about 5% to about 65%, about 5% to about 60%, about 5% to about 55%, 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%, or about 5% to about 10% by weight.
  • the amount of hydrochloride salt of a compound of formula (I) or solvate thereof in the composition is in the range of about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65% by weight.
  • the present invention provides a composition which comprises a hydrochloride salt of a compound of Formula (I) or solvate thereof in an amount of from about 0.1% to about 15% (w/w) of the composition, sodium caprate in an amount of from about 20% to about 45% (w/w) of the composition, and a microcrystalline cellulose.
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in any amount from about 0.1% to about 15% (w/w) of the composition.
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in an amount of from about 0.5% to about 15% (w/w), or from about 1% to about 10%, or from about 0.5% to about 5%, or from about 0.5% to about 3%, or from about 1% to about 3%, or from about 1.5% to about 2.5%, or from about 1.5% to about 2.0% (w/w) of the composition.
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof is present in an amount of from about 1% to about 5% (w/w).
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in an amount of from about 1 to about 5% (w/w).
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in amounts including about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or about 15% (w/w) of the composition, and any fractional amount in between.
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof maybe present in an amount of about 1.8% (w/w).
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in any amount, such as an amount of from about 1 mg to about 1000 mg, or from about 1 mg to about 500 mg, from about 1 mg to about 100 mg, from about 10 mg to about 50 mg, from about 20 mg to about 40 mg, or from about 20 mg to about 30 mg.
  • the amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be from about 1 mg to about 1000 mg.
  • the amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be from about 5 mg to about 300 mg. In another aspect, the amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof is from about 25 mg to about 150 mg. In another aspect, the amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be from about 25 mg to about 100 mg. In another aspect, the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in an amount of from about 1 mg to about 100 mg.
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in an amount of from about 20 mg to about 40 mg. In another aspect, the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in an amount of from about 20 mg to about 30 mg. [0275] In yet another aspect, the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in an amount of about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, or about 150 mg, including any amount in between and fractions thereof. In another aspect, an amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 5 mg.
  • an amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 10 mg. In another aspect, an amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 25 mg. In another aspect, an amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 50 mg. In another aspect, an amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 75 mg. In another aspect, an amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 100 mg.
  • an amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 150 mg.
  • the amount of the crystalline form of a pharmaceutically acceptable salt of a compound of Formula (I) or solvate thereof may be present in an amount of about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, or about 1400 mg, including any amount in between and fractions thereof [0277]
  • pharmaceutical compositions of the present invention may be formed into different dosage forms prepared using conventional materials and techniques known in the pharmaceutical and formulary arts, which may include, but is not limited to techniques, such as mixing, blending and the like and as set forth throughout the instant disclosure.
  • composition used to form dosage forms may also include, but are not limited to, suitable adjuvants, carriers, excipients, or stabilizers, etc. and can be in solid or liquid form such as, solid or liquid dosage forms, which may include, but are not limited to tablets, capsules, powders, solutions, suspensions, or emulsions and the like, etc.
  • solid unit dosage forms may be other conventional types known in the art.
  • Suitable compositions of the present invention may be in different forms, including, but are not limited to a liquid, a tablet, a capsule, etc. and the like. In some aspects, the composition may be a tablet composition or a capsule composition.
  • solutions which may, but are not limited to, such as in water, saline, aqueous dextrose and related sugar solutions, and glycols such as, propylene glycol or polyethylene glycol, buffered solutions and the like, etc., are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • compositions of the present invention may include a variety of other pharmaceutically acceptable components or excipients, such as, including, but is not limited to, a glidant, a lubricant, a disintegrant, a binder, a desiccant, a filler, and other components or excipients and the like. These components are described within.
  • compositions as described herein may include at least one filler.
  • a composition of the present invention may comprise a filler including, but is not limited to, one or more of alpha cellulose, beta cellulose, gamma cellulose, starch, modified starch, sorbitol, mannitol, lactose, dextrose, sucrose, dibasic calcium phosphate, tribasic calcium phosphate, or calcium carbonate and the like.
  • a composition of the present invention may include mannitol.
  • a composition of the present invention may include sorbitol.
  • Representative fillers for use in the compositions of the present invention may include, but are not limited to, starch, lactitol, lactose, an inorganic calcium salt, microcrystalline cellulose, sucrose, combinations thereof and the like.
  • Additional fillers or diluents for use in the compositions of the present invention may include, but are not limited to fillers or diluents conventionally known in the art, i.e., which are typically used in formulation of pharmaceutical compounds.
  • fillers or diluents for use in accordance with the present invention may include, but are not limited to sugars such as lactose, dextrose, glucose, sucrose, cellulose, starches and carbohydrate derivatives, polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, calcium carbonates, magnesium carbonates, microcrystalline cellulose, combinations thereof, and the like.
  • such fillers or diluents suitable for use in the present invention may include, but are not limited to lactose, microcrystalline cellulose, combinations thereof and the like.
  • a filler for use in the present invention may be present in an amount of from about 1% to about 99% (w/w) of the composition, or from about 1% to about 50%, or from about 1% to about 25%, or from about 1% to about 20%, or from about 1% to about 10%, or from about 2% to about 8%, or from about 3% to about 5% (w/w) of a composition as defined in the instant specification.
  • such a filler may also be present in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w/w) of the composition, which may include any fractional amount in between those as defined.
  • the filler is present in an amount from about 10% to about 95% (w/w) of the composition as defined in the instant specification. In some embodiments, the filler is present in an amount from about 25% to about 95% (w/w) of the composition as defined in the instant specification. In some embodiments, the filler is present in an amount from about 30% to about 90% (w/w) of the composition as defined in the instant specification. In some embodiments, the filler is present in an amount from about 10% to about 50% (w/w) of the composition as defined in the instant specification. In some embodiments, the filler is present in an amount from about 10% to about 40% (w/w) of the composition as defined in the instant specification.
  • the filler is present in an amount from about 10% to about 30% (w/w) of the composition as defined in the instant specification. In some embodiments, the filler is present in an amount from about 10% to about 20% (w/w) of the composition as defined in the instant specification. In certain embodiments, the filler is present in an amount from about 10% to about 15% (w/w). In certain embodiments, the filler is present in an amount of about 12% (w/w). [0285] In some aspects, the composition further can include microcrystalline cellulose.
  • microcrystalline cellulose may be selected from, but is not limited to MICROCEL® or AVICEL®types: PH101, PH102, PH103, PH105, PH 112, PH113, PH200, PH301, and the like and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose.
  • a composition for use in the present invention may include microcrystalline cellulose (AVICEL PH102).
  • a composition suitable for use in the present invention may include microcrystalline cellulose (AVICEL PH101).
  • a microcrystalline cellulose may be present in an amount of from about 1% to about 99% (w/w) of the composition, or from about 1% to about 50%, or from about 1% to about 25%, or from about 1% to about 20%, or from about 1% to about 10%, or from about 2% to about 8%, or from about 3% to about 5% (w/w) of a composition as defined in the instant specification.
  • a microcrystalline cellulose may also be present in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w/w) of the composition, which may include any fractional amount in between those as defined.
  • a microcrystalline cellulose may also be present in an amount of from about 3% to about 5% (w/w) of a composition.
  • the composition further can include a silicified microcrystalline cellulose.
  • silicified microcrystalline cellulose may be, but is not limited to SMCC 50, SMCC 50LD, SMCC 90, SMCC HD90 or SMCC 90LM and the like.
  • silicified microcrystalline cellulose may be SMCC 50, SMCC 50LD, SMCC 90, SMCC HD90 or SMCC 90LM. Without being bound by theory, the silicified microcrystalline cellulose is understood to protect an enteric coating from premature erosion by sodium caprate present in the composition.
  • the silicified microcrystalline cellulose may be present in any suitable amount for use in the present invention.
  • the SMCC can be present in an amount of from about 1% to about 99% (w/w) of the composition, or from about 10% to about 50%, or from about 20% to about 50%, or from about 25% to about 45%, or from about 30% to about 40%, or from about 35% to about 37% (w/w) of the composition.
  • the amount of the silicified microcrystalline cellulose is from about 30% to about 70% (w/w) of the composition.
  • the amount of the silicified microcrystalline cellulose is from about 65% to about 85% (w/w) of the composition.
  • the amount of the silicified microcrystalline cellulose is from about 66.5% to about 81.3% (w/w) of the composition. In some aspects, the amount of the silicified microcrystalline cellulose is about 31.3%, about 36.6%, about 37.7%, about 50.9%, about 52%, about 65.2%, about 71.5%, about 79%, or about 80.5% of the composition.
  • the SMCC can be present in an amount of about 30% (w/w) of the composition, or about 31%, 32%, 33%, 34%, 35%, 36%, 36.1%, 36.2%, 36.3%, 36.4%, 36.5%, 36.6%, 36.7%, 36.8%, 36.9%, 37%, 38%, 39%, or about 40% (w/w) of the composition.
  • SMCC is present in an amount of from about 20% to about 90% (w/w), which includes, but is not limited to any fractional amount in between.
  • SMCC is present in an amount of from about 25% to about 85% (w/w), which includes, but is not limited to any fractional amount in between.
  • SMCC is present in an amount of from about 25% to about 45% (w/w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 30% to about 40% (w/w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 65% to about 90% (w/w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 70% to about 85% (w/w), which includes, but is not limited to any fractional amount in between.
  • SMCC is present in an amount of from about 70% to about 75% (w/w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 80% to about 85% (w/w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 30%. In some embodiments, SMCC is present in an amount of about 40%, which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 50%, which includes, but is not limited to any fractional amount in between.
  • SMCC is present in an amount of about 60%, which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 70%, which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 80%, which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 90%, which includes, but is not limited to any fractional amount in between. [0289] In some embodiments, SMCC is a mixture of microcrystalline cellulose and colloidal silicon dioxide.
  • the composition further can include one or more of alpha cellulose, beta cellulose, gamma cellulose, starch, modified-starch, sorbitol, mannitol, lactose, dextrose, sucrose, dibasic calcium phosphate, tribasic calcium phosphate, or calcium carbonate.
  • the composition further can include mannitol.
  • a composition of the present invention may include sorbitol.
  • sorbitol may be present in an amount of from about 1% to about 99% (w/w) of the composition, or from about 1% to about 50%, or from about 1% to about 25%, or from about 5% to about 25%, or from about 5% to about 20%, or from about 5 to about 15%, or from about 8 to about 12% (w/w) of the composition.
  • sorbitol can be present in an amount of about 5% (w/w) of the composition, or about 6%, 7%, 8%, 9%, 10%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 11%, 12%, 13%, 14%, or about 15% (w/w) of the composition.
  • the composition also includes sorbitol in an amount of from about 5% to about 15% (w/w) of the composition.
  • the amount of the sorbitol is from about 10% to about 15% (w/w) of the composition.
  • the composition includes sorbitol in an amount of about 10.7% (w/w) of the composition.
  • a composition of the present invention may include mannitol.
  • mannitol may be present in an amount of from about 1% to about 99% (w/w) of the composition, or from about 1% to about 50%, or from about 1% to about 25%, or from about 5% to about 25%, or from about 5% to about 20%, or from about 5 to about 15%, or from about 8 to about 12% (w/w) of the composition.
  • mannitol can be present in an amount of about 5% (w/w) of the composition, or about 6%, 7%, 8%, 9%, 10%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 11%, 12%, 13%, 14%, or about 15% (w/w) of the composition, which includes, but is not limited to any fractional amount in between.
  • the composition also includes mannitol in an amount of from about 5% to about 15% (w/w) of the composition.
  • the amount of the mannitol is from about 10% to about 15% (w/w) of the composition.
  • the composition includes mannitol in an amount of about 10.7% (w/w) of the composition.
  • the amount of the sugar alcohol can be present in range from about 1% to about 50% (w/w) of the composition, or from about 5% to about 50%, or from about 5% to about 30%, or from about 10% to about 30% (w/w) of the composition.
  • the amount of the sugar alcohol can be present in an amount of about 1%, 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, or about 20% (w/w) of the composition.
  • the amount of the sugar alcohol can be present in an amount higher than about 1%, 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, or about 20% (w/w) of the composition. In some aspects, the amount of the sugar alcohol can be present in an amount lower than about 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, or about 20% (w/w) of the composition.
  • the pharmaceutical composition described herein does not include an sugar alcohol. In some embodiments, the pharmaceutical composition described herein does not include sorbitol. In some embodiments, the pharmaceutical composition described herein does not include mannitol.
  • composition of the invention may include, but is not limited to at least one disintegrant in an effective therapeutic amount for use as determined in accordance with the present invention.
  • Representative disintegrants for use in the present invention include, but are not limited to, starches, clays, celluloses, alginates and gums and crosslinked starches, celluloses and polymers, combinations thereof and the like.
  • Additional representative disintegrants for use in the present invention may include, but are not limited to microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginate, crospovidone, cellulose, agar and related gums, sodium starch glycolate, corn starch, potato starch, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum combinations thereof, and the like.
  • the disintegrant is a cross-linked carboxymethyl cellulose (croscarmellose), a starch glycolate, a polyvinyl pyrrolidone, a sago starch, psyllium husk, a silicate, or a soy polysaccharide.
  • the disintegrant is croscarmellose sodium or crospovidone.
  • disintegrants for use in the present invention may include, but are not limited to croscarmellose sodium.
  • a disintegrant for use in the present invention can include crospovidone.
  • a disintegrant may be present in an amount of from about 1% to about 99% (w/w) of a composition of the present invention, or from about 1% to about 50%, or from about 1% to about 25%, or from about 1% to about 20%, or from about 1% to about 10%, or from about 2% to about 8%, or from about 4% to about 6% (w/w) of the composition.
  • Disintegrants for use in the present invention may also be present in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, or about 12% (w/w) of the composition, which include, but is not limited to any fractional amount in between.
  • an amount of the disintegrant may be present in from about 1% to about 10% (w/w) of a composition of the present invention. In some aspects, an amount of the disintegrant may be present in from about 8% to about 12% (w/w) of a composition of the present invention. In some aspects, an amount of the disintegrant may be present in from about 3% to about 8% (w/w) of a composition of the present invention.
  • a composition of the present invention may also include, but is not limited to silica in any amount for purposes of the present invention. In particular, silica is exemplified by Aerosil 200, having a specific surface area of about 200 m 2 /g.
  • silica may include, but are not limited to talc, sodium ferrocyanide, potassium ferrocyanide, calcium carbonate, magnesium carbonate, silicon dioxide, precipitated silica, sodium aluminosilicate, combinations thereof and the like.
  • a composition of the present invention may further comprise a silica.
  • silica may be present in compositions of the present invention in an amount of from about 0.1% to about 10% (w/w) of the composition, or from about 0.1% to about 5%, or from about 0.1% to about 2%, or from about 0.1% to about 1.5%, or from about 0.1% to about 1.25%, or from about 0.5% to about 1.5%, or from about 1.0% to about 1.25%, or from about 0.1% to about 1%, or from about 0.3% to about 0.7% (w/w) of the composition of the present invention.
  • silica as used in the present invention may be present in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4% or about 1.5% (w/w) of the composition, including any fraction amount in between as defined.
  • a composition of the present invention may further include an amount of silica in from about 0.1% to about 1.5% (w/w) of the composition.
  • a composition of the present invention may further include an amount of silica in from about 0.5% to about 2% (w/w) of the composition.
  • a composition of the present invention may further include an amount of silica in from about 0.3% to about 0.7% (w/w) of the composition. In further aspects, a composition of the present invention may further include an amount of silica in about 0.5% (w/w) of the composition. In some aspects, the composition further may comprise silica in an amount of about 1% (w/w) of the composition.
  • suitable silica materials include, but are not limited to colloidal silicon dioxide, aerosol, colloidal silica, fumed silica, silicon dioxide fumed, colloidal anhydrous silica, colloidal silicon dioxide, and the like. In some embodiments, the silica is colloidal silica.
  • the composition can also include a binder.
  • Binders for use in the compositions of the present invention include binders commonly used in the formulation of pharmaceuticals.
  • binders for use in the present invention include but are not limited to cellulose derivatives (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, and sodium carboxymethyl cellulose), glycol, sucrose, dextrose, corn syrup, polysaccharides (including acacia, targacanth, guar, alginates and starch), corn starch, pregelatinized starch, modified corn starch, gelatin, polyvinylpyrrolidone, polyethylene, polyethylene glycol, combinations thereof and the like.
  • the binder is hydroxypropyl methylcellulose (HPMC).
  • HPMC hydroxypropyl methylcellulose
  • binders for use in the present invention may also be present in an amount of about 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, or about 12% (w/w) of the composition, which include, but is not limited to any fractional amount in between.
  • the composition may include a lubricant in any suitable amount for use as described herein.
  • suitable lubricants for use in the present invention may include, but are not limited to magnesium carbonate, magnesium lauryl sulphate, calcium silicate, talc, fumed silicon dioxide, combinations thereof, and the like.
  • Other useful suitable lubricants may include, but are not limited to magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, sodium benzoate, colloidal silicon dioxide, magnesium oxide, microcrystalline cellulose, starches, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium acetate, sodium chloride, combinations thereof, and the like.
  • lubricant may include, but is not limited to magnesium stearate.
  • an amount of the lubricant can be present in from about 0.1% to about 10% (w/w) of the composition, or from about 0.1% to about 5%, or from about 0.1% to about 2.5%, or from about 0.1% to about 1%, or from about 0.1% to about 0.5% (w/w) of the composition.
  • an amount of the lubricant can be present in from about 0.5% to about 2.5% or about 0.5% to about 2.0% (w/w) of the composition.
  • an amount of the lubricant can be present in from about 0.1% to about 0.5% (w/w) of the composition.
  • the amount of the lubricant is from about 0.3% to about 0.7% (w/w) of the composition. In some aspects, the amount of the lubricant is about 0.5% (w/w) of the composition.
  • the lubricant can also be present in an amount of about 0.10% (w/w) of the composition, or about 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, or about 0.30% (w/w) of the composition.
  • the lubricant can also be present in an amount of about 0.5% (w/w) of the composition, or about 0.75%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, or about 2.5% (w/w) of the composition. In some aspects, the lubricant may be present in an amount of about 0.25% (w/w).
  • the composition includes: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of from about 0.2% to about 15% (w/w) of the composition; (ii) a silicified microcrystalline cellulose in an amount of from about 66.5% to about 81.3% (w/w) of the composition; (iii) sorbitol in an amount of about 12.5% (w/w) of the composition; (iv) a disintegrant in an amount of about 5% (w/w) of the composition; (v) a silica in an amount of about 0.5% (w/w) of the composition; and (vi) a lubricant in an amount of about 0.5% (w/w) of the composition.
  • the pharmaceutical composition includes: (i) the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof, in an amount of from about 0.1% to about 60 % (w/w) of the composition; (ii) a silicified microcrystalline cellulose in an amount of from about 40% to about 85% (w/w) of the composition; (iii) a disintegrant in an amount of about 5% to about 10% (w/w) of the composition; (iv) a silica in an amount of about 0.1% to about 1.0% (w/w) of the composition; and (v) a lubricant in an amount of about 0.5 % to about 1.5% (w/w) of the composition.
  • the pharmaceutical composition includes: (i) the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof, in an amount of from about 10% to about 20% (w/w) of the composition; (ii) the silicified microcrystalline cellulose in an amount of about 85% (w/w) of the composition; (iii) crospovidone in an amount of about 5% (w/w) of the composition; (iv) the silica in an amount of about 0.2% (w/w) of the composition; and (v) magnesium stearate in an amount of about 0.5% of the composition.
  • the pharmaceutical composition includes: (i) an absorption enhancer in an amount of from about 5% to about 65% (w/w) of the composition; (ii) the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof, in an amount of from about 0.1% to about 15% (w/w) of the composition, and (iii) a silicified microcrystalline cellulose in an amount of from about 10% to about 50% (w/w) of the composition.
  • the pharmaceutical composition includes: (i) an absorption enhancer in an amount of from about 30% to about 45% (w/w) of the composition; (ii) a disintegrant in an amount of from about 5% to 10% (w/w) of the composition; and (iii) the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof, in an amount of from about 0.5% to about 15% (w/w) of the composition; (iv) a silicified microcrystalline cellulose in an amount of from about 30% to about 40% (w/w) of the composition; (v) a silica in an amount of about 0.2% to about 1.5% (w/w) of the composition; (vi) a disintegrant in an amount of about 5% to about 10% (w/w) of the composition; (vii) a filler in an amount of about 7.5% to about 15% (w/w) of the composition; and (viii) a lubricant in an amount of about 0.2 %
  • the pharmaceutical composition includes: (i) a crystalline form of a pharmaceutically acceptable salt of a compound of Formula (I), or a solvate thereof, in an amount of from about 10% to about 20% (w/w) of the composition; (ii) an absorption enhancer in an amount of from about 30% to about 45% (w/w) of the composition; (iii) a disintegrant in an amount of from about 0.5% to about 1.0% (w/w) of the composition; (iv) crospovidone in an amount of about 5% (w/w) of the composition; (vi) a microcrystalline cellulose in an amount of about 1.3% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of from about 34.8% to about 39.7% (w/w) of the composition; (viii) mannitol in an amount of about 10.7% (w/w) of the composition; (ix) crospovidone in an amount of about 5% (w/w)
  • the pharmaceutical composition includes: (i) sodium caprate in an amount of about 38.5% (w/w) of the composition; (ii) hydroxypropyl methylcellulose in an amount of about 0.8% (w/w) of the composition; (iii) the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof, in an amount of from about 3.9% (w/w) of the composition; (iv) a silicified microcrystalline cellulose in an amount of about 39.7% (w/w) of the composition; (v) mannitol in an amount of about 10.7% (w/w) of the composition; (vi) crospovidone in an amount of about 5% to about 7.5% (w/w) of the composition; (vii) a silica in an amount of from about 0.5% to about 1.0% (w/w) of the composition; and (viii) magnesium stearate in an amount of about 0.5% (w/w) of the composition.
  • the pharmaceutical composition includes: (i) a crystalline form of a pharmaceutically acceptable salt of a compound of Formula (I), or a solvate thereof, in an amount of from about 10% to about 20% (w/w) of the composition; (ii) an absorption enhancer in an amount of from about 30% to about 45% (w/w) of the composition; (iii) a disintegrant in an amount of from about 0.5% to about 1.0% (w/w) of the composition; (iv) crospovidone in an amount of about 5% (w/w) of the composition; (v) a microcrystalline cellulose in an amount of about 1.3% (w/w) of the composition; (vi) a silicified microcrystalline cellulose in an amount of from about 34.8% to about 39.7% (w/w) of the composition; (vii) mannitol in an amount of about 10.7% (w/w) of the composition; (viii) crospovidone in an amount of about 5% (w/w)
  • the composition includes: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 1% (w/w) of the composition; (ii) a silicified microcrystalline cellulose in an amount of about 80.5% (w/w) of the composition; (iii) sorbitol in an amount of about 12.5% (w/w) of the composition; (iv) crospovidone in an amount of about 5% (w/w) of the composition; (v) a silica in an amount of about 0.5% (w/w) of the composition; and (vi) magnesium stearate in an amount of about 0.5% (w/w) of the composition.
  • the composition includes: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 2.5% (w/w) of the composition; (ii) a silicified microcrystalline cellulose in an amount of about 79% (w/w) of the composition; (iii) sorbitol in an amount of about 12.5% (w/w) of the composition; (iv) crospovidone in an amount of about 5% (w/w) of the composition; (v) a silica in an amount of about 0.5% (w/w) of the composition; and (vi) magnesium stearate in an amount of about 0.5% (w/w) of the composition.
  • the composition includes: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 10% (w/w) of the composition; (ii) a silicified microcrystalline cellulose in an amount of about 71.5% (w/w) of the composition; (iii) sorbitol in an amount of about 12.5% (w/w) of the composition; (iv) crospovidone in an amount of about 5% (w/w) of the composition; (v) a silica in an amount of about 0.5% (w/w) of the composition; and (vi) magnesium stearate in an amount of about 0.5% (w/w) of the composition.
  • the tablet composition can also include one or more coatings.
  • composition described herein may include a variety of other pharmaceutically acceptable components or excipients, such as, including, but is not limited to, a glidant, a lubricant, a disintegrant, a binder, a desiccant, a filler, and other components or excipients and the like.
  • composition described herein can include at least one disintegrant in any suitable amount in accordance with the present invention.
  • disintegrants for use in the present invention may include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums (like gellan), low-substituted hydroxypropyl cellulose, or mixtures thereof and the like.
  • the disintegrant may include croscarmellose sodium.
  • the disintegrant may include crospovidone.
  • suitable disintegrant may be, but is not limited to being present in an amount of about 1% (w/w), 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w/w) of the composition, including any fractional amount in between as defined in the present invention.
  • disintegrant may be, but is not limited to being present in an amount of about 1 to 10% (w/w) of the composition.
  • the disintegrant may be present in an amount of about 5.0% (w/w) of the composition.
  • the microcrystalline cellulose can be present in an amount of from about 1% to about 10% (w/w) of the composition.
  • the microcrystalline cellulose can be present in an amount of about 3.9% (w/w) of the composition.
  • the composition further may comprise silica.
  • the composition further may comprise silica in an amount of from about 0.1% to about 1.5% (w/w) of the composition.
  • the silica can be present in an amount of about 0.1%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.75%, 0.8%, 0.9%, 1.0%, or about 1.5% (w/w) of the composition, including any fraction amount in between as defined herein.
  • the composition further may comprise silica in an amount of from about 0.3% to about 0.7% (w/w) of the composition.
  • the composition further may comprise silica in an amount of from about 0.5% to about 2% (w/w) of the composition. In some aspects, the composition further may comprise silica in an amount of about 0.5% (w/w) of the composition.
  • the composition of the present invention may further comprise at least one of: a disintegrant in an amount from about 1% to about 10% (w/w) of the composition, a microcrystalline cellulose in an amount from about 1% to about 10% (w/w) of the composition, a silica in an amount from about 0.1% to about 1.5% (w/w) of the composition, or sorbitol in an amount from about 5% to about 15% (w/w) of the composition.
  • the composition further may comprise: a disintegrant in an amount from about 1% to about 10% (w/w) of the composition; a microcrystalline cellulose in an amount from about 1% to about 10% (w/w) of the composition; a silica in an amount from about 0.1% to about 1.5% (w/w) of the composition; and sorbitol in an amount from about 5% to about 15% (w/w) of the composition.
  • a disintegrant in an amount from about 1% to about 10% (w/w) of the composition
  • a microcrystalline cellulose in an amount from about 1% to about 10% (w/w) of the composition
  • a silica in an amount from about 0.1% to about 1.5% (w/w) of the composition
  • sorbitol in an amount from about 5% to about 15% (w/w) of the composition.
  • compositions of the present invention further may comprise at least one of: a microcrystalline cellulose in an amount of about 3.9% (w/w); sorbitol in an amount of about 10.7% (w/w); a disintegrant in an amount of about 5.0% (w/w); and a silica in an amount of about 0.5% (w/w).
  • the compositions further may comprise: a microcrystalline cellulose in an amount of about 3.9% (w/w); sorbitol in an amount of about 10.7% (w/w); a disintegrant in an amount of about 5.0% (w/w); and a silica in an amount of about 0.5% (w/w).
  • compositions further may comprise: Avicel PH101 in an amount of about 3.9% (w/w); sorbitol in an amount of about 10.7% (w/w); croscarmellose sodium in an amount of about 5.0% (w/w); and Aerosil 200 in an amount of about 0.5% (w/w).
  • the microcrystalline cellulose can include any microcrystalline cellulose known in the art.
  • the microcrystalline cellulose may comprise a silicified microcrystalline cellulose (SMCC).
  • SMCC silicified microcrystalline cellulose
  • microcrystalline cellulose may be a silicified microcrystalline cellulose (SMCC) and may have any particle size.
  • the composition includes silicified microcrystalline cellulose in an amount of from about 25% to about 45% (w/w) of the composition. In some aspects, the composition includes silicified microcrystalline cellulose in an amount of about 36.6% (w/w) of the composition. [0325]
  • the composition can include at least one disintegrant in any suitable amount in accordance with the present invention.
  • disintegrants for use in the present invention may include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums (like gellan), low-substituted hydroxypropyl cellulose, or mixtures thereof and the like.
  • the disintegrant may include croscarmellose sodium.
  • the disintegrant may include crospovidone.
  • the disintegrant for use in the present invention may be, but is not limited to being present in an amount of from about 1% to about 99% (w/w) of the composition, or from about 1% to about 50%, or from about 1% to about 25%, or from about 1% to 20%, or from about 1% to about 10%, or from about 2% to about 8%, or from about 4% to about 6% (w/w) of the composition.
  • suitable disintegrant may be, but is not limited to being present in an amount of about 1% (w/w), 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w/w) of the composition, including any fractional amount in between as defined in the present invention.
  • disintegrant may be, but is not limited to being present in an amount of about 1% to about 10% (w/w) of the composition. In other aspects, the disintegrant may be present in an amount of about 5.0% (w/w) of the composition.
  • the composition may also include silica in any amount in accordance with the present invention. Silica is exemplified by Aerosil 200, having a specific surface area of about 200 m 2 /g. Alternatives to silica include, without limitation, talc, sodium ferrocyanide, potassium ferrocyanide, calcium carbonate, magnesium carbonate, silicon dioxide, precipitated silica, sodium aluminosilicate, and combinations thereof and the like.
  • Silica e.g., Aerosil 200
  • the compositions may be present in the compositions in an amount of from about 0.1 to 10% (w/w) of the composition, or from about 0.1 to 5%, or from about 0.1 to 2%, or from about 0.1 to 1.5%, or from about 0.1 to 1%, or from about 0.3 to 0.7% (w/w) of the composition.
  • the Aerosil 200 silica can be present in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, or 1.5% (w/w) of the composition, including any fraction amount in between.
  • the composition further may comprise silica (e.g., Aerosil 200).
  • the composition further may comprise silica (e.g., Aerosil 200) in in an amount of from about 0.1% to about 1.5% (w/w) of the composition.
  • silica e.g., Aerosil 200
  • the silica can be present in an amount of about 0.1%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.75%, 0.8%, 0.9%, 1.0%, or about 1.5% (w/w) of the composition, including any fraction amount in between as defined herein.
  • the composition further may comprise silica (e.g., Aerosil 200) in an amount of from about 0.3% to about 0.7% (w/w) of the composition.
  • the composition further may comprise silica (e.g., Aerosil 200) in an amount of from about 0.5% to about 2% (w/w) of the composition. In some aspects, the composition further may comprise silica in an amount of about 0.5% (w/w) of the composition. In some aspects, the composition further may comprise silica (e.g., Aerosil 200) in an amount of about 1% (w/w) of the composition.
  • the composition described herein can include a variety of other pharmaceutically excipients or components, which may include, but is not limited to a lubricant, a disintegrant, a binder, a desiccant, a filler, and other components and the like.
  • a disintegrant may be present in the compositions in an amount of from about 0.1% to about 10% (w/w) of the composition, or from about 0.1% to about 5%, or from about 0.1% to about 2%, or from about 0.1% to about 1.5%, or from about 0.1% to about 1%, or from about 0.1% to about 0.4% (w/w) of the composition.
  • the composition further may comprise a disintegrant.
  • the composition further may comprise silica (e.g., Aerosil 200) in an amount of from about 0.1% to about 1.5% (w/w) of the composition.
  • the composition further may comprise a disintegrant in an amount of about 0.25% (w/w) of the composition.
  • compositions disclosed herein can further comprise at least one of: a lubricant in an amount from about 0.1% to about 0.5% by weight of the composition, a disintegrant in an amount from about 1% to about 10% by weight of the composition, or a silica (e.g., Aerosil 200) in an amount from about 0.1% to about 1.5% by weight of the composition.
  • a lubricant in an amount from about 0.1% to about 0.5% by weight of the composition
  • a disintegrant in an amount from about 1% to about 10% by weight of the composition
  • silica e.g., Aerosil 200
  • the compositions further can include: a lubricant in an amount from about 0.1% to about 0.5% by weight of the composition; a disintegrant in an amount from about 1% to about 10% by weight of the composition; and a silica (e.g., Aerosil 200) in an amount from about 0.1% to about 1.5% by weight of the composition.
  • a disintegrant in an amount of about 5.0% (w/w); a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w); and a lubricant in an amount of about 0.25% (w/w).
  • the compositions comprises: a silicified microcrystalline cellulose in an amount of about 36.6% (w/w); a disintegrant in an amount of about 5.0% (w/w); a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w); and a lubricant in an amount of about 0.25% (w/w).
  • the compositions can include: SMCC HD90 in an amount of about 36.6% (w/w); croscarmellose sodium in an amount of about 5.0% (w/w); Aerosil 200 in an amount of about 0.5% (w/w); and magnesium stearate in an amount of about 0.25% (w/w).
  • compositions of the present invention may not include or may exclude use of an absorption enhancer depending on the intended delivery or use thereof and/or for treatment of specific indications as defined in the present invention.
  • the absorption enhancer is excluded.
  • the absorption enhancer is included.
  • suitable compositions of the present invention may exhibit improved bioavailability when administered in conjunction with an absorption enhancer.
  • compositions of the present invention may include an absorption enhancer.
  • the absorption enhancer may be zwitterionic, cationic, anionic or non- ionic.
  • the absorption enhancer is an intestinal permeation enhancer.
  • the absorption enhancer may be selected from, but is not limited to medium-chain saturated fatty acids, such as a caprate, a caprylate, a myristate, a palmitate, or a stearate, including salt forms, such as sodium caprate, sodium caprylate, sodium myristate, sodium palmitate, or sodium stearate) and the like.
  • absorption enhancers may include, but is not limited to a citric acid or citrate salt, such as sodium citrate, tartaric acid or tartrate salt, a salicylic acid or a derivative thereof, or a salicylate salt, a fatty acid acylated amino acid, an alkylsaccharide, a C8-o- alkylpolysaccharide, n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D-maltoside, n-tetradecyl- beta-D-maltoside, tridecylbeta-D-maltoside, sucrose laurate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose monotetradecanoate, a coco-glucoside, a cyclodextrins, alkanoyl carn
  • the absorption enhancer may include, but is not limited to sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium salcaprozate (SNAC), a polyethylene glycol (PEG)-modified medium chain fatty acid triglyceride of capric and caprylic acid (such as LABRASOL®, available from Gattefosse, USA), sucrose laurate, or lauroyl-L-carnitine (LC, such as PEPTELLIGENCE®, available from Enteris BioPharma, NJ, USA) and the like.
  • PEG polyethylene glycol
  • LABRASOL® available from Gattefosse, USA
  • sucrose laurate or lauroyl-L-carnitine
  • LC lauroyl-L-carnitine
  • the absorption enhancer is sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium salcaprozate (SNAC), a polyethylene glycol (PEG)-modified medium chain fatty acid triglyceride of capric and caprylic acid, sucrose laurate, or lauroyl-L-carnitine (LC).
  • the absorption enhancer can be present in a composition in an amount of from about 1% to about 99% (w/w) of the composition, or from about 5% to about 50% (w/w), or from about 10% to about 50% (w/w), or from about 20% to about 50% (w/w), or from about 30% to about 50% (w/w), or from about 30% to about 40% (w/w), or from about 32% to about 38% (w/w), or from about 35% to about 36% (w/w) of the composition.
  • an amount of the absorption enhancer is present in from about 5% to about 50% (w/w).
  • an amount of the absorption enhancer is present in from about 5% to about 40% (w/w).
  • an amount of the absorption enhancer is present in from about 30% to about 40% (w/w).
  • absorption enhancer can be present in an amount of about 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or about 40% (w/w) of the composition, including any fractional amounts in between.
  • the absorption enhancer is present in an amount of from about 30% to about 40% (w/w).
  • the absorption enhancer can be present in an amount from about 32% to about 38% (w/w). In some aspects, the absorption enhancer can be present in an amount of about 35.7% (w/w).
  • the absorption enhancer used in a composition of the present invention may be sodium caprate.
  • the sodium caprate can be present in a composition in an amount of from about 1% to about 99% (w/w) of the composition, or from about 5% to about 50% (w/w), or from about 10% to about 50% (w/w), or from about 20% to about 50% (w/w), or from about 30% to about 50% (w/w), or from about 30% to about 40% (w/w), or from about 32% to about 38% (w/w), or from about 35% to about 36% (w/w) of the composition.
  • the sodium caprate is present in an amount of from about 5% to about 50% (w/w).
  • the sodium caprate is present in an amount of from about 5% to about 40% (w/w). In some aspects, the sodium caprate is present in an amount of from about 30% to about 40% (w/w). For example, sodium caprate can be present in an amount of about 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or about 40% (w/w) of the composition, including any fractional amounts in between. In some aspects, the sodium caprate is present in an amount of from about 30% to about 40% (w/w). In some aspects, the sodium caprate can be present in an amount from about 32% to about 38% (w/w). In some aspects, the sodium caprate can be present in an amount of about 35.7% (w/w).
  • sodium caprate may have a purity of at least about 98%, 98.2%, 98.4%.98.6%, 98.8%, 99.0%, 99.5%, or at least about 99.9%. Without being bound by any theory, the higher degree of purity of the sodium caprate can provide improved bioavailability compared to lower technical grade sodium caprate, such about 90% or about 95% pure sodium caprate. In some aspects, sodium caprate for use in the present invention has a purity of at least about 98% for use in the present invention. [0343] In another aspect, for use in the present invention, sodium caprate may have an average particle size of from about 10 nm to about 150 microns and sodium caprate may be in various particle sizes.
  • sodium caprate particles suitable for use in the present invention may have an average diameter from about 1 micron to about 150 microns. In some aspects, such sodium caprate particles may have an average diameter from about 50 microns to about 150 microns. In other aspects, the sodium caprate particles may have an average diameter of from about 10 nm to about 5 microns. In some aspects, the sodium caprate particles may have an average diameter of from about 50 nm to about 1 micron. In some aspects, the sodium caprate particles may have an average diameter of from about 100 nm to about 800 nm. [0344] In another aspect, sodium caprate may be present in crystalline form, amorphous form, or semi-crystalline form.
  • the use of crystalline sodium caprate may enhance bioavailability of the hydrochloride salt of a compound of Formula (I) or solvate thereof.
  • the use of amorphous sodium caprate may enhance bioavailability of the hydrochloride salt of a compound of Formula (I) or solvate thereof.
  • the use of semi-crystalline sodium caprate may enhance bioavailability of the hydrochloride salt of a compound of Formula (I) or solvate thereof.
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof and the sodium caprate may form a mixture or a granulated mixture.
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof and the sodium caprate form a mixture.
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof and the sodium caprate form a granulated mixture.
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof and the sodium caprate can be mixed to form a granulated mixture.
  • the granulated mixture may be formed of particles having any average diameter suitable for use in compositions of the present invention.
  • the particles of the granulated mixture can have an average diameter of from about 100 nm to about 5 microns.
  • the particles can also have an average diameter from about 1 micron to about 150 microns. In some aspects, the particles of the granulated mixture of the composition of the present invention may have an average diameter of from about 200 nanometers to about 1 micron.
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof and the sodium caprate form a mixture or a granulated mixture.
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof and the sodium caprate form a mixture. In some aspects, the hydrochloride salt of a compound of Formula (I) or solvate thereof and the sodium caprate form a granulated mixture.
  • the absorption enhancer used may be sodium salcaprozate.
  • the absorption enhancer used may include, but is not limited to a polyethylene glycol (PEG)-modified medium chain fatty acid triglyceride of capric and caprylic acid and the like.
  • the composition can include a hydrochloride salt of a compound of Formula (I) or solvate thereof in an amount of from about 0.1% to about 15% (w/w) of the composition; an absorption enhancer in an amount from about 5% to about 50% (w/w); and one or more pharmaceutically acceptable excipients.
  • the composition further can include microcrystalline cellulose.
  • the composition can include a hydrochloride salt of a compound of Formula (I) or solvate thereof in an amount of from about 0.1% to about 15% (w/w) of the composition; sodium caprate in an amount from about 5% to about 50% (w/w); and one or more pharmaceutically acceptable excipients.
  • the composition further can include microcrystalline cellulose.
  • the composition described herein can include: the hydrochloride salt of a compound of Formula (I) or solvate thereof in an amount of about 1.8% (w/w); and sodium caprate in an amount of about 35.7% (w/w).
  • the present invention provides a composition which comprises a hydrochloride salt of a compound of Formula (I) or solvate thereof: in an amount of from about 0.1% to about 10% (w/w) of the composition, and an absorption enhancer in an amount of from about 20% to about 45% (w/w) of the composition.
  • the present invention provides a composition which comprises includes a hydrochloride salt of a compound of Formula (I) or solvate thereof: in an amount of from about 0.1% to about 15% (w/w) of the composition, and the absorption enhancer sodium caprate in an amount of from about 5% to about 40% (w/w) of the composition, and a silicified microcrystalline cellulose.
  • the present invention provides a composition which comprises a hydrochloride salt of a compound of Formula (I) or solvate thereof: in an amount of from about 0.1% to about 10% (w/w) of the composition, and sodium caprate in an amount of from about 20% to about 45% (w/w) of the composition, and a microcrystalline cellulose.
  • the present invention provides a composition includes: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of from about 0.5% to about 10% (w/w) of the composition; (ii) the absorption enhancer sodium caprate in an amount of about 5% to about 40% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) a disintegrant in an amount of about 5% (w/w) of the composition; and (vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of from about 30% to about 70% (w/w) of the composition; (viii) a disintegrant in an amount of about 5% (w/w) of
  • the present invention provides a composition includes: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 0.7% (w/w) of the composition; (ii) the absorption enhancer sodium caprate in an amount of about 35.7% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) crospovidone in an amount of about 5% (w/w) of the composition; and (vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of about 37.7% (w/w) of the composition; (viii) crospovidone in an amount of about 5% (w/w) of the composition; (ix) a
  • the present invention provides a composition includes: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 1.8% (w/w) of the composition; (ii) the absorption enhancer sodium caprate in an amount of about 35.7% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) crospovidone in an amount of about 5% (w/w) of the composition; and (vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of about 36.6% (w/w) of the composition; (viii) crospovidone in an amount of about 5% (w/w) of the composition; (ix) a
  • the present invention provides a composition includes: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 0.7% (w/w) of the composition; (ii) the absorption enhancer sodium caprate in an amount of about 21.4% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) crospovidone in an amount of about 5% (w/w) of the composition; and (vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of about 52% (w/w) of the composition; (viii) crospovidone in an amount of about 5% (w/w) of the composition; (ix) a silica (e.g.
  • the present invention provides a composition includes: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 1.8% (w/w) of the composition; (ii) the absorption enhancer sodium caprate in an amount of about 21.4% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) crospovidone in an amount of about 5% (w/w) of the composition; and (vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of about 50.9% (w/w) of the composition; (viii) crospovidone in an amount of about 5% (w/w) of the composition; (ix) a
  • the present invention provides a composition wherein: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 7.1% (w/w) of the composition; (ii) the absorption enhancer sodium caprate in an amount of about 35.7% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) crospovidone in an amount of about 5% (w/w) of the composition; and (vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of about 31.3% (w/w) of the composition; (viii) crospovidone in an amount of about 5% (w/w) of the composition; (ix)
  • the present invention provides a composition includes: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 1.8% (w/w) of the composition; (ii) the absorption enhancer sodium caprate in an amount of about 7.1% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) crospovidone in an amount of about 5% (w/w) of the composition; and (vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of about 65.2% (w/w) of the composition; (viii) crospovidone in an amount of about 5% (w/w) of the composition; (ix) a silica (e.g.
  • the present invention provides a composition includes: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 1.8% (w/w) of the composition, (ii) the absorption enhancer sodium caprate in an amount of about 35.7% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) crospovidone in an amount of about 5% (w/w) of the composition; and (vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of about 36.6% (w/w) of the composition; (viii) crospovidone in an amount of about 5% (w/w) of the composition; (ix) a
  • a composition of the present invention may be in a dosage form, which may be, but is not limited to a tablet or capsule dosage form.
  • the composition may be a tablet or capsule composition.
  • the composition can be a tablet composition.
  • such as tablet composition may comprise a unit dose size in amounts which may include, but is not limited to amounts from about 25 mg to about 2000 mg, from about 500 mg to about 2000 mg.
  • compositions of the present invention may be of any suitable size in accordance with the present invention, such as, but not limited tablets or capsules in doses or amounts of 25, 50, 75, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950 or 2000 milligrams (mg) and the like.
  • tablets or capsules in doses or amounts of 25, 50, 75, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1050, 1100, 1150,
  • a composition of the present invention may be as a 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, or 1400 mg tablet, respectively, which may be administered, but is not limited to once or twice daily or as determined by medical necessity.
  • the composition may be a unit dose size of from about 500 mg to about 2000 mg.
  • the composition may be a unit dose size of about 1400 mg.
  • the composition may be a unit dose size of about 1000 mg. [0365]
  • such as tablet composition may comprise a unit dose size from 500 mg to about 2000 mg.
  • the tablet compositions may be of any suitable size in accordance with the present invention, such as, but not limited to 25, 50, 75, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950 or 2000 mg tablets.
  • the composition is a 1400 mg tablet.
  • compositions of the present invention may be administered in single or multiple administrations depending on dosing and frequency as required and tolerated by the patient, where such tablets contain a sufficient quantity or amount of active agent to effectively treat specific disease state.
  • the present invention relates to a composition for oral administration of the hydrochloride salt of a compound of Formula (I) or solvate thereof, which may be taken in a daily amount of from about 0.05 to about 30 mg per kg of body weight per day.
  • dosages can be from about 0.1 mg to about 20 mg per kg of body weight per day.
  • dosages can be from about 0.1 mg to about 5 mg per kg of body weight per day.
  • dosages can be from about 0.1 mg to about 1 mg per kg of body weight per day.
  • Coatings Cosmetic Subcoating [0367]
  • the composition can further include a subcoating.
  • the subcoating is a cosmetic subcoating.
  • the cosmetic subcoating can also serve as a physical barrier.
  • Cosmetic coatings can include polyethylene glycol-polyvinyl alcohol (PEG-PVA) graft copolymer, polyvinyl alcohol (PVA), hypromellose (HPMC), and hydroxypropyl cellulose (HPC).
  • the weight of the cosmetic subcoating is compared weight/weight to the weight of the composition prior to coating.
  • the cosmetic subcoating can be present in an amount from about 1% to about 10% (w/w). In some embodiments, the cosmetic subcoating is present in an amount from about 1% to about 5% (w/w). For example, the cosmetic subcoating can be present in amounts including about 1%, 1.5%, 2.0%, 2.5%, and about 3%, including any fractional amounts in between and ranges thereof, such as between about 2.0% and 3.0%. In some embodiments, the cosmetic subcoating is present in an amount of about 3% (w/w). In some embodiments, the weight of the cosmetic subcoating is compared weight/weight to the weight of the composition, or to the weight of the core tablet, prior to coating.
  • the cosmetic subcoating level is indicated in terms of weight (mg) of the cosmetic subcoating per the surface area of the core tablet.
  • the surface area is the surface area of the outer most layer of a coating covering the core tablet.
  • the surface area for calculating the cosmetic subcoating level is the surface area of the core tablet.
  • the surface area is the surface area of the cosmetic subcoating, subcoating, or enteric coating disposed over the core tablet.
  • more than one coating is disposed over the core tablet and the surface area refers to the surface area of the outermost coating.
  • the cosmetic subcoating level is from about 6 mg/cm 2 to about 30 mg/cm 2 . In some emobidments, the cosmetic subcoating level is from about 9 mg/cm 2 to about 30 mg/cm 2 . In other emobidments, the cosmetic subcoating level is from about 12 mg/cm 2 to about 30 mg/cm 2 . In some embodiments, the cosmetic subcoating level is from about 17 mg/cm 2 to about 30 mg/cm 2 . In some embodiments, the cosmetic subcoating level is from about 20 mg/cm 2 to about 30 mg/cm 2 . In some embodiments, the cosmetic subcoating level is from about 25 mg/cm 2 to about 30 mg/cm 2 .
  • the cosmetic subcoating level is about 6 mg/cm 2 , 7 mg/cm 2 , 8 mg/cm 2 , 9 mg/cm 2 , 10 mg/cm 2 , 6 mg/cm 2 , 11 mg/cm 2 , 12 mg/cm 2 , 13 mg/cm 2 , 14 mg/cm 2 , 15 mg/cm 2 , 16 mg/cm 2 , 17 mg/cm 2 , 18 mg/cm 2 , 19 mg/cm 2 , 21 mg/cm 2 , 22 mg/cm 2 , 23 mg/cm 2 , 24 mg/cm 2 , 25 mg/cm 2 , 26 mg/cm 2 , 27 mg/cm 2 , 28 mg/cm 2 , 29 mg/cm 2 , or 30 mg/cm 2 .
  • the cosmetic subcoating level is about 6 mg/cm 2 . In some embodiments, the cosmetic subcoating level is about 7 mg/cm 2 . In some embodiments, the cosmetic subcoating level is about 8 mg/cm 2 . In some embodiments, the cosmetic subcoating level is about 9 mg/cm 2 . In some embodiments, the cosmetic subcoating level is about 10 mg/cm 2 . In some embodiments, the cosmetic subcoating level is about 11 mg/cm 2 . In some embodiments, the cosmetic subcoating level is about 6 mg/cm 2 . In some embodiments, the cosmetic subcoating level is about 12 mg/cm 2 . In some embodiments, the cosmetic subcoating level is about 13 mg/cm 2 .
  • the cosmetic subcoating level is about 14 mg/cm 2 . In some embodiments, the cosmetic subcoating level is about 15 mg/cm 2 . In some embodiments, the cosmetic subcoating level is about 16 mg/cm 2 . In some embodiments, the cosmetic subcoating level is about 17 mg/cm 2 . In some embodiments, the cosmetic subcoating level is about 18 mg/cm 2 .
  • the composition further can include a subcoating of a PVA-PEG graft co-polymer disposed over the composition. In some aspects, compositions can comprise a subcoating of a PVA-PEG graft co-polymer disposed over the core tablet.
  • This coating can serve as a smooth surface to aid in swallowing the tablet. It can also provide a platform for a further layer which can comprise an enteric coating disposed over the subcoating.
  • the subcoating can also provide a vehicle for pigmentation for tablet identification.
  • Other coatings include, without limitation, HPMC, HPC, PVA, Eudragit E based coatings and the like.
  • the composition further can include a subcoating. This coating can serve as a barrier between the components of the core tablet and the enteric coating or functional coating. Subcoatings can include the OPADRY® class of products and can be present in any desired amounts.
  • the weight of the subcoating is compared weight/weight to the weight of the composition prior to coating.
  • the subcoating can be present in an amount from about 1% to about 10% (w/w). In some aspects, the subcoating is present in an amount from about 1% to about 5% (w/w). In some aspects, the subcoating can be present in an amount from about 1% to about 3% (w/w) relative to the core tablet prior to coating. For example, the subcoating can be present in amounts including about 1%, 1.5%, 2.0%, 2.5%, and about 3%, including any fractional amounts in between. In some aspects, the subcoating is present in an amount of about 3% (w/w). In some aspects, the weight of the subcoating is compared weight/weight to the weight of the composition, or to the weight of the core tablet, prior to coating.
  • the subcoating level is measured in a coating weight gain (mg/cm 2 ). In some embodiments, the subcoating level is from about 6 mg/cm 2 to about 30 mg/cm 2 . In some emobidments, the subcoating level is from about 9 mg/cm 2 to about 30 mg/cm 2 . In other emobidments, the subcoating level is from about 12 mg/cm 2 to about 30 mg/cm 2 . In some embodiments, the subcoating level is from about 17 mg/cm 2 to about 30 mg/cm 2 . In some embodiments, the subcoating level is from about 20 mg/cm 2 to about 30 mg/cm 2 .
  • the subcoating level is from about 25 mg/cm 2 to about 30 mg/cm 2 .
  • the subcoating level is about 6 mg/cm 2 , 7 mg/cm 2 , 8 mg/cm 2 , 9 mg/cm 2 , 10 mg/cm 2 , 6 mg/cm 2 , 11 mg/cm 2 , 12 mg/cm 2 , 13 mg/cm 2 , 14 mg/cm 2 , 15 mg/cm 2 , 16 mg/cm 2 , 17 mg/cm 2 , 18 mg/cm 2 , 19 mg/cm 2 , 21 mg/cm 2 , 22 mg/cm 2 , 23 mg/cm 2 , 24 mg/cm 2 , 25 mg/cm 2 , 26 mg/cm 2 , 27 mg/cm 2 , 28 mg/cm 2 , 29 mg/cm 2 , or 30 mg/cm 2 .
  • the subcoating level is about 6 mg/cm 2 . In some embodiments, the subcoating level is about 7 mg/cm 2 . In some embodiments, the subcoating level is about 8 mg/cm 2 . In some embodiments, the subcoating level is about 9 mg/cm 2 . In some embodiments, the subcoating level is about 10 mg/cm 2 . In some embodiments, the subcoating level is about 11 mg/cm . In some embodiments, the subcoating level is about 6 mg/cm 2 . In some embodiments, the subcoating level is about 12 mg/cm 2 . In some embodiments, the subcoating level is about 13 mg/cm 2 .
  • the subcoating level is about 14 mg/cm 2 . In some embodiments, the subcoating level is about 15 mg/cm 2 . In some embodiments, the subcoating level is about 16 mg/cm 2 . In some embodiments, the subcoating level is about 17 mg/cm 2 . In some embodiments, the subcoating level is about 18 mg/cm 2 .
  • Enteric Coating [0372] In some aspects, the composition includes an enteric coating disposed over the subcoating. In some aspects, the enteric coating is selected to provide release of the tablet contents at a pH range from about 5 to about 8. In some aspects, the enteric coating is a pH 5.5 enteric coating.
  • Enteric coating can include, without limitation, those based on cellulose acetate phthalate (CAP), poly(methacrylic acid-co-methyl methacrylate), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP) or hydroxypropyl methylcellulose phthalate (HPMCP).
  • CAP cellulose acetate phthalate
  • CAT cellulose acetate trimellitate
  • PVAP poly(vinyl acetate phthalate)
  • HPPMCP hydroxypropyl methylcellulose phthalate
  • the enteric coating can be a methacrylic acid co-polymer.
  • the enteric coating can include, without limitation, poly(methacrylic acid ethyl acrylate) (L100D-55), a combination methyl acrylate, methyl methacrylate and methacrylic acid (FS30D), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), Type L HPMC-AS, or a co-polymer of ethyl methacrylate acrylate (e.g., Acryl- eze®).
  • the weight of the enteric coating is compared weight/weight to the weight of the composition prior to coating.
  • the enteric coating can be present in an amount from about 1% to about 15% (w/w).
  • the enteric coating can be present in an amount from about 2% to about 15% (w/w). In some aspects, the enteric coating can make up from about 5% to about 15% (w/w) relative to the core tablet of the compositions.
  • the amounts of enteric coating can be in an amount of about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or about 15% (w/w), including fractions thereof.
  • the enteric coating can be present in an amount of about 6% (w/w). In some aspects, the enteric coating can be present in an amount of about 7% (w/w). In some aspects, the enteric coating can be present in an amount of about 8% (w/w).
  • the weight of the enteric coating is compared weight/weight to the weight of the core tablet prior to coating.
  • the enteric coating level is measured in a coating weight gain (mg/cm 2 ). In some embodiments, the enteric coating level is from about 6 mg/cm 2 to about 30 mg/cm 2 . In some embodiments, the enteric coating level is from about 9 mg/cm 2 to about 30 mg/cm 2 . In other embodiments, the enteric coating level is from about 12 mg/cm 2 to about 30 mg/cm 2 . In some embodiments, the enteric coating level is from about 17 mg/cm to about 30 mg/cm 2 .
  • the enteric coating level is from about 20 mg/cm 2 to about 30 mg/cm 2 . In some embodiments, the enteric coating level is from about 25 mg/cm 2 to about 30 mg/cm 2 .
  • the enteric coating level is about 6 mg/cm 2 , 7 mg/cm 2 , 8 mg/cm 2 , 9 mg/cm 2 , 10 mg/cm 2 , 6 mg/cm 2 , 11 mg/cm 2 , 12 mg/cm 2 , 13 mg/cm 2 , 14 mg/cm 2 , 15 mg/cm 2 , 16 mg/cm 2 , 17 mg/cm 2 , 18 mg/cm 2 , 19 mg/cm 2 , 21 mg/cm 2 , 22 mg/cm 2 , 23 mg/cm 2 , 24 mg/cm 2 , 25 mg/cm 2 , 26 mg/cm 2 , 27 mg/cm 2 , 28 mg/cm 2 , 29 mg/
  • the enteric coating level is about 6 mg/cm 2 . In some embodiments, the enteric coating level is about 7 mg/cm 2 . In some embodiments, the enteric coating level is about 8 mg/cm 2 . In some embodiments, the enteric coating level is about 9 mg/cm 2 . In some embodiments, the enteric coating level is about 10 mg/cm 2 . In some embodiments, the enteric coating level is about 11 mg/cm 2 . In some embodiments, the enteric coating level is about 6 mg/cm 2 . In some embodiments, the enteric coating level is about 12 mg/cm 2 . In some embodiments, the enteric coating level is about 13 mg/cm 2 .
  • the enteric coating level is about 14 mg/cm 2 . In some embodiments, the enteric coating level is about 15 mg/cm 2 . In some embodiments, the enteric coating level is about 16 mg/cm 2 . In some embodiments, the enteric coating level is about 17 mg/cm 2 . In some embodiments, the enteric coating level is about 18 mg/cm 2 . [0376] In some aspects, the tablet compositions of the present invention may have a subcoating of OPADRY® QX yellow in an amount of about 3% (w/w) and an enteric coating of Acryl-eze® yellow of about 6% (w/w).
  • the tablet compositions of the present invention may have a subcoating of OPADRY® QX yellow in an amount of about 3% (w/w) and an enteric coating of Acryl-eze® yellow of about 7% (w/w).
  • the tablet compositions of the present invention may have a subcoating of OPADRY® QX yellow in an amount of about 3% (w/w) and an enteric coating of Acryl-eze® yellow of about 8% (w/w).
  • the core tablet is covered by one or more of a cosmetic coating, a subcoating, an enteric coating, or any combination thereof.
  • the core tablet is covered by a cosmetic subcoating.
  • the core tablet is covered by a cosmetic subcoating and then covered by an enteric coating.
  • the core tablet is covered by a cosmetic subcoating and then covered by a subcoating, In certain embodiments, the core tablet is covered by a cosmetic subcoating followed by a subcoating, and then followed by an enteric coating. In certain embodiments, the core tablet is covered by a cosmetic subcoating followed by an enteric coating, and then followed by a subcoating. [0381] In other embodiments, the core tablet is covered by a subcoating. In some embodiments, the core tablet is covered by a subcoating and then covered by an enteric coating. In some embodiments, the core tablet is covered by a subcoating and then covered by a cosmetic subcoating.
  • the core tablet is covered by a subcoating followed by an enteric coating and then covered by a cosmetic subcoating. In certain embodiments, the core tablet is covered by a subcoating followed by a cosmetic subcoating and then covered by an enteric coating. [0382] In other embodiments, the core tablet is covered by an enteric coating. In other embodiments, the core tablet is covered by an enteric coating and then covered by a subcoating. In certain embodiments, the core tablet is covered by an enteric coating and then covered by a cosmetic subcoating. In other embodiments, the core tablet is covered by an enteric coating followed by a subcoating and then covered by a cosmetic coating.
  • the core tablet is covered by an enteric coating followed by a cosmetic coating and then covered by a subcoating.
  • the tablet compositions of the present invention may have a bioavailability of from about 1% to about 10% (w/w). In some aspects, the tablet compositions of the present invention may have a bioavailability of from about 10% to about 50%. For example, bioavailability may be about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10%. Bioavailability can be measured using area under curve (AUC) for oral dosing versus AUC by intravenous dosing.
  • AUC area under curve
  • the tablet compositions of the present invention may have a bioavailability of from about 0.01% to about 10% (w/w). In some aspects, the tablet compositions of the present invention may have a bioavailability of from about 0.1% to about 1% (w/w). For example, bioavailability may be about 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10%. Bioavailability can be measured using area under curve (AUC) for oral dosing versus AUC by intravenous dosing. [0385] [0386] A dose of a composition described herein may be administered according to a method and/or use of the present invention herein.
  • AUC area under curve
  • a dose of a composition of the present invention can be administered once daily, twice daily, or three times daily. In some aspects, a dose of a composition of the present invention can be administered once daily. In some aspects, a dose of a composition of the present invention can be administered twice daily. In some aspects, a dose of a composition of the present invention can be administered three times daily. [0387] In some embodiments described herein, such as relating to pharmaceutical compositions, tablets, methods, processes, and the like, the acetate salt of a compound of Formula (I) is excluded. In some embodiments described herein, such as relating to compositions, tablets, methods, processes, and the like, the acetate salt of a compound of Formula (I) is included. V.
  • compositions are comprised of active principal ingredient (i.e., a hydrochloride salt of the compound of Formula (I) or solvate thereof) and at least one or more additional pharmaceutically acceptable ingredients (i.e., which may include, but is not limited to absorption enhancers) and adjuvants, carriers, excipients or stabilizers, etc., as defined throughout the instant disclosure.
  • active principal ingredient i.e., a hydrochloride salt of the compound of Formula (I) or solvate thereof
  • additional pharmaceutically acceptable ingredients i.e., which may include, but is not limited to absorption enhancers
  • adjuvants i.e., which may include, but is not limited to absorption enhancers
  • carriers, excipients or stabilizers, etc. as defined throughout the instant disclosure.
  • the active principal ingredient is a crystalline salt of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing, as described herein.
  • API active principal ingredient
  • compositions of the present invention which may of course, be varied as amount of active compound in such therapeutically useful compositions is such that a suitable dosage for administration in a subject or patient will be obtained. It will be appreciated that the actual preferred dosages of API being used in the compositions of this invention will vary according to the particular composition formulated, the mode of administration, the particular site of administration and the host being treated. The choice of initial dosage most appropriate for the particular patient is determined by the practitioner using well-known medical principles, including, but is not limited to, body weight.
  • an oral tablet dosage form of the present invention may have a surface layer is coated with an enteric coat, which may be, but is not limited to an enteric coating set forth in the Definition section of the instant specification.
  • an oral tablet dosage form may be formulated as with core components, separate sequential layers or combinations thereof, where tablet components, such as core, other layers, may have different release modifying component properties based upon gastrointestinal environment, pH or time.
  • an oral tablet dosage form of the present invention may also be coated with a pH sensitive polymer.
  • Tablets including the compositions of the present invention may be prepared using conventional tablet forming equipment as conventionally known in the art, which may use compaction, rollers and the like. In some embodiments, the tablet forming technique is roller compaction. VI.
  • the present invention relates to a method and/or use for treating inflammatory disease in a subject which comprises administering to the subject a therapeutically effective amount of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof disclosed herein.
  • the present invention provides a method of treating inflammatory disease in a subject which comprises administering to the subject a therapeutically effective amount of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof of the present invention.
  • Suitable inflammatory diseases for treatment with compositions of the present invention may include, but is not limited to inflammatory bowel disease (IBD), Crohn’s disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA) and the like.
  • the inflammatory disease is moderate to severe in degree.
  • any of the method of treatment and/or uses embodiments detailed herein it is understood that such methods and uses may comprise any of the crystalline forms of a compound of Formula (I) and the pharmaceutical compositions as described herein the same as if each and every combination were specifically and individually listed.
  • any of the methods of treatment and/or uses may in some embodiments comprise administering to the subject a therapeutically effective amount of a crystalline form of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a solvate of the foregoing.
  • the crystalline form is selected from a hydrochloride salt of a compound of Formula (I), an acetate salt of a compound of Formula (I), a fumarate salt of a compound of Formula (I), a glutarate salt of a compound of Formula (I), a glycolate salt of a compound of Formula (I), a mesylate salt of a compound of Formula (I), a bis-hydrochloride salt of a compound of Formula (I), a citrate salt of a compound of Formula (I), and a sulfate salt of a compound of Formula (I).
  • the present invention provides methods and/or uses for treating a subject afflicted with a condition or indication associated with IL-21 or IL-23R (e.g., activation of the IL 23/IL 23R signaling pathway), where the method and/or use comprises administering to the subject the crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof of the present invention.
  • a condition or indication associated with IL-21 or IL-23R e.g., activation of the IL 23/IL 23R signaling pathway
  • a method and/or use for treating a subject afflicted with a condition or indication characterized by inappropriate, deregulated, or increased IL-23 or IL-23R activity or signaling, which comprises administering to the individual a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof of the present invention in an amount sufficient to inhibit (partially or fully) binding of IL-23 to IL-23R in the subject.
  • methods and/or uses of the present invention can comprise administering a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof of the present invention to a subject in need thereof.
  • the subject in need thereof has been diagnosed with or has been determined to be at risk of developing a disease or disorder associated with IL-23/IL-23R.
  • the subject is a mammal. In some aspect, the subject is a human.
  • the disease or disorder is autoimmune inflammation and related diseases and disorders, such as, which may include, but are not limited to multiple sclerosis, asthma, rheumatoid arthritis, inflammation of the gut, inflammatory bowel diseases (IBDs), juvenile IBD, adolescent IBD, Crohn’s disease, ulcerative colitis, sarcoidosis, Systemic Lupus Erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriasis, or psoriatic arthritis.
  • the disease or disorder is an inflammatory bowel disease (IBD).
  • the disease or disorder is Crohn’s disease. In some aspects, the disease or disorder is ulcerative colitis. In some aspects, the disease or disorder is psoriasis. In some aspects, the disease or disorder is psoriatic arthritis. [0398] In some aspects, the disease or disorder is or may be selected from psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, Palmo-Plantar Pustulosis, psoriasis vulgaris, or erythrodermic psoriasis), atopic dermatitis, acne ectopica, ulcerative colitis, Crohn’s disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis/esophagitis, colitis associated with radio
  • the present invention relates to methods and/or uses for treatment of autoimmune inflammation and related diseases and disorders, which may include, but is/are not limited to inflammatory bowel disease (IBD), Crohn’s disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA) and the like.
  • the inflammatory disease is inflammatory bowel disease (IBD), Crohn’s disease, ulcerative colitis, psoriasis, or psoriatic arthritis.
  • the inflammatory disease is inflammatory bowel disease (IBD).
  • the inflammatory disease is Crohn’s disease.
  • the inflammatory disease is ulcerative colitis.
  • the inflammatory disease is psoriasis. In some aspects, the inflammatory disease is psoriatic arthritis.
  • the present invention relates to methods and/or uses for inhibiting IL-23 receptor for treatment of autoimmune inflammation and related diseases and disorders, that include administering a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof of to a subject in need thereof.
  • the IL-23 receptor is inhibited in blood, blood circulation, tissue, skin, or joints.
  • the IL-23 receptor is inhibited in a tissue selected from blood, skin, cartilage, or synovial membrane.
  • the IL-23 receptor is inhibited in blood.
  • the IL-23 receptor is inhibited in skin. In some aspects, the IL-23 receptor is inhibited in cartilage. In some aspects, the IL-23 receptor is inhibited in synovial membrane. [0401] In some aspects, the present invention relates to methods and/or uses for inhibiting IL-23 receptor in a digestive tract tissue for treatment of autoimmune inflammation and related diseases and disorders, that include administering a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof of to a subject in need thereof.
  • the digestive tract tissue is selected from mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus.
  • the digestive tract tissue is mouth.
  • the digestive tract tissue is esophagus.
  • the digestive tract tissue is stomach.
  • the digestive tract tissue is small intestine.
  • the digestive tract tissue is large intestine.
  • the digestive tract tissue is duodenum.
  • the digestive tract tissue is anus.
  • the present invention provides a method and/or use for treating an inflammatory bowel disease (IBD) in a subject in need thereof, which comprises administering to the subject a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof of the present invention.
  • the present invention provides a method of treating an inflammatory bowel disease (IBD) in a subject comprising administering to the subject a therapeutically effective amount of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof of the present invention.
  • the IBD is ulcerative colitis.
  • the IBD is Crohn’s disease.
  • the present invention provides methods or use of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof of the present invention in the manufacture of a medicament for treating an inflammatory bowel disease (IBD).
  • the present invention relates to a method of treating an inflammatory bowel disease (IBD) in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof disclosed herein.
  • the IBD is Crohn’s disease or ulcerative colitis.
  • the IBD is Crohn’s disease.
  • the IBD is ulcerative colitis.
  • the present invention provides for a use of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof disclosed herein in the manufacture of a medicament for treating an inflammatory bowel diseases (IBD).
  • IBD inflammatory bowel diseases
  • the present invention relates to a method of treating psoriasis or psoriatic arthritis in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof of the present invention.
  • the present invention relates to a method that includes treating psoriasis.
  • the present invention relates to a method that includes treating psoriatic arthritis.
  • the present invention provides for a use of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof disclosed herein, in the manufacture of a medicament for treating psoriasis or psoriatic arthritis.
  • the present invention provides for a use for treating psoriasis.
  • the present invention provides for a use for treating psoriatic arthritis.
  • the method and/or use includes orally administering the crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof of the present invention.
  • the present invention relates to methods and/or uses of treating inflammatory bowel diseases (IBD) in a subject, which comprises administering a therapeutically effective amount of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof disclosed herein.
  • IBD inflammatory bowel diseases
  • the IBD is Crohn s disease or ulcerative colitis.
  • the methods and/or uses of the present invention include administering a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof in tablet form once, twice, or three times daily orally in accordance with patient treatment.
  • the present invention relates to methods and/or uses of treating psoriasis or psoriatic arthritis in a subject, which comprises administering a therapeutically effective amount of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof disclosed herein.
  • the present invention relates to methods and/or uses of treating psoriasis.
  • the present invention relates to methods and/or uses of treating psoriatic arthritis.
  • the methods and/or uses of the present invention include administering a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof in tablet form once, twice, or three times daily orally in accordance with patient treatment.
  • the methods and/or uses of the present invention include administering a dose of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof.
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in any dose range, such as a dose range of from about 1 mg to about 1000 mg, or from about 1 mg to about 500 mg, from about 1 mg to about 100 mg, from about 10 mg to about 50 mg, from about 20 mg to about 40 mg, or from about 20 mg to about 30 mg.
  • the dose range of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be from about 1 mg to about 1000 mg.
  • the dose range of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be from about 5 mg to about 300 mg. In another aspect, the dose range of the hydrochloride salt of a compound of Formula (I) or solvate thereof is from about 25 mg to about 150 mg. In another aspect, the dose range of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be from about 25 mg to about 100 mg. In another aspect, the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in a dose range of from about 1 mg to about 100 mg.
  • the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in a dose range of from about 20 mg to about 40 mg. In another aspect, the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in a dose range of from about 20 mg to about 30 mg. [0413] In yet another aspect, the methods and/or uses of the present invention include administering a dose of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof in a dose of about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, or about 150 mg, including any amount in between and fractions thereof.
  • a dose of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 5 mg. In another aspect, a dose of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 10 mg. In another aspect, a dose of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 25 mg. In another aspect, a dose of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 50 mg. In another aspect, a dose of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 75 mg.
  • a dose of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 100 mg. In another aspect, a dose of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 150 mg.
  • the methods and/or uses of the present invention include administering a dose of about 10 mg, about 25 mg, or about 50 mg of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof once daily or twice daily. In some aspects, the methods and/or uses of the present invention include administering a dose of about 10 mg of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof twice daily.
  • the methods and/or uses of the present invention include administering a dose of about 25 mg of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof twice daily. In some aspects, the methods and/or uses of the present invention include administering a dose of about 50 mg of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof twice daily. In some aspects, the methods and/or uses of the present invention include administering a dose of about 10 mg of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof once daily.
  • the methods and/or uses of the present invention include administering a dose of about 25 mg of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof once daily. In some aspects, the methods and/or uses of the present invention include administering a dose of about 50 mg of a crystalline hydrochloride salt of the compound of Formula (I) or solvate or composition thereof once daily. [0415] In some embodiments described herein, such as relating to compositions, tablets, methods, processes, and the like, the acetate salt of a compound of Formula (I) is excluded.
  • the acetate salt of a compound of Formula (I) is included.
  • the acetate salt of a compound of Formula (I) is excluded.
  • the acetate salt of a compound of Formula (I) is included.
  • the peptide chain was built up from the C terminus to the N terminus by repeated cycles until the resin carried the complete amino acid sequence: (i) N- ⁇ -deprotection with 20 % (V/V) piperidine in DMF to enable the coupling reaction (10 mL/g), (ii) coupling of protected building block (protected amino acid derivative) in the presence of DIC and Oxyma as suitable activating reagent(s) (solvent: DMF, 10 mL/g) (Table 2), systematic acetylation (capping) of remaining free amino groups using acetic anhydride and pyridine (solvent: DMF, 10 mL/g; c: DMF / Ac2O / Pyridine 50:1:1).
  • Each step consisted of the following operations: (i) addition of solvents/reagents to the resin; (ii) agitating of the reaction mixture, and (iii) removal of solvents/reagents by filtration and washing (solvents: DMF and/or IPA, 10 mL/g).
  • solvents DMF and/or IPA, 10 mL/g.
  • the resulting peptide solution was treated with aqueous I 2 2/KI solution (52 mM I2, 154 mM KI) to build the disulfide bond between the penicillamine residues by oxidation of the SH moieties.
  • the reaction was quenched by addition of aqueous ascorbic acid solution (662 mM, 0.106 g ascorbic acid/ g crude, 1.35 equivalents).
  • the cyclized peptide was purified by preparative HPLC on a reversed-phase column with ACN gradient elution and UV detection at 300 nm.
  • a NH 4 4HCO 3 3 system was employed for elution (eluent NH 4 4HCO 3 3 A: 15% ACN in 30 mM NH 44 HCO 33 ; eluent NH 44 HCO 33 B: 50% ACN in 10 mM NH 44 HCO 33 ).
  • the collected fractions were analyzed by HPLC and pooled accordingly (Target: ⁇ 97.0%). The pH of the pooled main fractions was adjusted to 7.0 ⁇ 0.2 with aqueous hydrochloric acid (5.5 M).
  • the temperature of the concentrated turbid product solution was reduced to 23 °C.
  • the pH was adjusted to 5.1 with 2.0 L of 1 N HCl aq., 12.0 L of IPA were added, and the solution was stirred for 19 hr. at 6°C. Further precipitation occurred during stirring of the solution.
  • the suspension was transferred to the mobile filter dryer, allowed to sediment for 10 min, and filtered by applying overpressure (0.5 bar at the beginning, later increased up to 2 bar). A clear mother liquor was observed during filtration.
  • the isolated product was dried in vacuo at 40°C, first at 65 mbar until solvent distillation ceased. Then, after approx.8.5 hr. drying was continued at full vacuum, but the temperature was reduced to 25°C, as drying was performed over the weekend instead of overnight.
  • the product was unloaded from the filter dryer.
  • the product was sieved (1.5 mm mesh size) applying a sieving mill. In total, 5.24 kg were obtained after sieving.
  • a purity (HPLC) of 97.3% was determined with the QC HPLC release method. The chloride content was determined as 1.3% (theoretical chloride content of the mono hydrochloride salt is 1.9%.), and the isolated material was readily soluble in water (1 mg/mL) without any pH adjustment required.
  • Step 2 [0434] The product was sieved (1.5 mm mesh size) applying a sieving mill. In total, 2.43 kg of the compound of Formula (I) were obtained after sieving. The chloride content was determined as 0.5%.
  • Step 2 [0435] The hydrochloride salt of the compound of Formula (I), as prepared in the previous step (2.13 kg) was suspended in 43 L of deionized water. A pH of 4.1 was determined for the suspension. By addition of 1.77 L of 1 N HCl aq. the pH was adjusted to 2.90. The resulting clear, slightly yellow solution was stirred for 1 h. By addition of 1.65 L of 1 M NH4HCO3 aq. the pH of the solution was increased from initially pH 2.87 to 5.09.
  • the resin was treated with 20% piperidine in DMF (10 ml/g resin each) for 5 ⁇ 2 min and 10 ⁇ 2 min at 25 °C. Couplings were performed using the building blocks, coupling reagents and conditions depicted in Table 3 with DMF as solvent (10 ml/g resin).
  • DMF dimethyl methacrylate
  • For capping the resin was treated with acidic anhydride and pyridine in DMF (volumetric ratio DMF / Ac2O/pyridine 50:1:1; DMF: 10 ml/g resin) for 20 min. Diisopropyl carbonate (DIC) was added in two portions, with the second portion was added after about 20 to 30 minutes after the first portion.
  • DIC Diisopropyl carbonate
  • Example 3 Alternative Synthetic Procedure for a Crystalline Hydrochloride Form of a Peptide of SEQ ID NO: 1 SPPS
  • 18.9 kg Rink amide AM resin substitution: 0.95 mmol/g
  • Each SPPS cycle consists of Fmoc cleavage, coupling with the respective building block and obligatory capping.
  • Fmoc cleavage the resin was treated with 20% piperidine in DMF (10 ml/g resin each) for 5 ⁇ 2 min and 10 ⁇ 2 min at 25 °C. Couplings were performed using the building blocks, coupling reagents and conditions depicted in Table 5. with DMF as solvent (10 ml/g resin).
  • TFA cleavage [0449] [In a jacketed reactor 100 g of PN21235-Rink amide AM resin (# 1000037885; 147841/1) were added at 18 °C to 700 mL of the cleavage cocktail, consisting of 630 mL TFA, 35 mL TIS, 17.5 mL EDT, and 17.5 mL water. The temperature increased to 30 °C upon addition of the resin, and the mixture was stirred for further 35 min at 30 °C. The mixture was cooled to 20 °C, and the resin was filtered off and washed two times with 100 mL TFA each. The filtrates were combined and cooled to -15 °C.
  • Example 5 Synthetic Procedure for a Crystalline Hydrochloride Salt of a Peptide of SEQ ID NO: 1 [0458] Crystalline hydrochloride salt of the compound of Formula (I) (30 g) prepared according to Example 3 were dissolved in 120 mL of methanol and 51.4 mL of water.
  • the dissolution was carried out in an EasyMax 402, under stirring at 40 °C.57.1 mL of sodium chloride 1 M were dosed to the EasyMax reactor at over 1 h.
  • the solution was then seeded with 300 mg of seeds of the hydrochloride salt of the compound of Formula (I) prepared according to Example 4.
  • the slurry was then aged for 8 h under stirring at 40 °C.
  • the slurry was cooled to 5 °C at a cooling rate of 0.1K/min.
  • An extra 114.31 mL of sodium chloride 1 M were dosed to the EasyMax reactor over 4 h and the slurry was aged for extra 5 h.
  • the solid was isolated by vacuum filtration and washed twice with 30 mL of water and twice with 30 mL of isopropanol. The solid was dried atmospherically.
  • the isolated solid of the crystalline hydrochloride form of the compound of Formula (I) had a purity (UPLC) of 99.3 area% and a water content (KF) of 6.33 w/w%.
  • the chloride content of the isolated crystalline hydrochloride form of the compound of Formula (I) was assayed by ion chromatography and found to be 0.64 molar equivalents to the compound of Formula (I).
  • An XRPD pattern of the crystalline hydrochloride form of the compound of Formula (I) confirmed its crystallinity (FIG.3).
  • thermogravimetric analysis of the isolated crystalline hydrochloride form of the compound of Formula (I) shows a 5.6% weight loss when heated to about 160°C, which is attributed to loss of solvent, mainly water (FIG.4).
  • the first endothermic event in the differential scanning calorimetry (DSC) profile of the isolated crystalline hydrochloride form of the compound of Formula (I) showing a maximum at 81.4 °C corresponds to the loss of solvent from the crystalline lattice, while the later event after 225 °C is attributed to decomposition of the solid (FIG.5).
  • a dynamic vapor sorption curve (DVS) of the isolated crystalline hydrochloride of the compound of Formula (I) showed a water intake of about 8.7% at 80% RH, indicating a hygroscopic material. (FIG.6).
  • Crystalline hydrochloride salt of the compound of Formula (I) (30 g) prepared according to Example 3 was dissolved in 120 mL of water and 30 mL of acetic acid concentrated. The dissolution was carried out in an EasyMax 402, under stirring at 25 °C.150 mL of an ammonium acetate aqueous solution (2.4 M) were dosed to the EasyMax reactor over 2 h. The solution was then seeded with seeds of the acetate salt of the compound of Formula (I), prepared according to Example 6. The slurry was then aged for 12 h under stirring at 25 °C.
  • the acetate content of the isolated solid of the crystalline acetate form of the compound of Formula (I) was assayed by ion chromatography and found to be 0.61 molar equivalents to the compound of Formula (I).
  • An XRPD pattern of the crystalline acetate form of the compound of Formula (I) confirmed its crystallinity (FIG.7). The following two theta peaks were observed: 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 degrees two theta +/- 0.2 degrees two theta.
  • a TGA of the isolated crystalline acetate form of the compound of Formula (I) shows a 5.8% weight loss when heated to about 150 °C (FIG.8).
  • the first endothermic event in the DSC profile of the isolated crystalline acetate form of the compound of Formula (I) showing a maximum at 80.7 °C corresponds to the loss of solvent from the crystalline lattice, while the later event at 240.7 (228.2 °C (onset)) is attributed to melting/decomposition of the solid (FIG. 9).
  • a dynamic vapor sorption curve (DVS) of the isolated crystalline acetate of the compound of Formula (I) indicated a hygroscopic material. (FIG.10) Example 8.
  • the solid was isolated by vacuum filtration and placed in a clean EasyMax 402 reactor.400 mL of water were added to the reactor and the slurry was stirred at 25 °C for 24 h. The solid was isolated by vacuum filtration and washed twice with 30 mL of water. The solid was dried atmospherically.
  • the isolated solid of the crystalline free base of the compound of Formula (I) had a purity (UPLC) of 97.9% and a water content (KF) of 12.68 w/w%.
  • the ionic content of the isolated crystalline solid was assayed by ion chromatography and found to be ⁇ 0.02 w/w% chloride and ⁇ 0.05 w/w% sodium.
  • a TGA of the isolated crystalline free base of the compound of Formula (I) shows two step weight loss thermogram with the first one showing a 3.7% weight loss when heated to about 70°C and the second one showing a 2.7 % additional weight loss when heated to about to about 170°C, which is attributed to loss of solvent, mainly water (FIG.12).
  • Example 9 Synthetic Procedure for a Crystalline Fumarate Salt of a Peptide of SEQ ID NO: 1 [0468] Crystalline free base of the compound of Formula (I) (900 mg) prepared according to Example 8 was dissolved in MeOH (4.5 mL) to give a clear solution. This stock solution was partitioned into HPLC vials (150 ⁇ l per vial).2 Mol eq. of a fumarate counterion stock solution was added to the vials at 25 °C. The samples were cooled from 25 °C to 5 °C at 1 °C/min.
  • a TGA of the isolated crystalline fumarate salt of the compound of Formula (I) shows a 4.4% weight loss when heated to about 110°C, which is attributed to loss of solvent, mainly water (FIG.16).
  • the first endothermic event in the DSC profile of the isolated crystalline fumarate salt of the compound of Formula (I) showing a maximum at 66.9°C corresponds to the loss of solvent from the crystalline lattice, while at higher temperature the solid decomposes (FIG.17).
  • Example 10 The first endothermic event in the DSC profile of the isolated crystalline fumarate salt of the compound of Formula (I) showing a maximum at 66.9°C corresponds to the loss of solvent from the crystalline lattice, while at higher temperature the solid decomposes (FIG.17).
  • the glutarate content of the isolated solid of the crystalline glutarate salt of the compound of Formula (I) was assayed by CAD analysis and found to be 0.5 molar equivalents to the compound of Formula (I).
  • An XRPD pattern of the crystalline glutarate salt of the compound of Formula (I) confirmed its crystallinity (FIG.18). The following two theta peaks were observed: 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 degrees two theta +/- 0.2 degrees two theta.
  • a simultaneous thermal analysis (SDT) was used to obtain TGA and DSC data.
  • the SDT thermogram of the isolated crystalline glutarate salt of the compound of Formula (I) shows a 6.4% weight loss when heated to about 125°C, which is attributed to loss of solvent, mainly water (FIG.19).
  • the first endothermic event in the SDT thermogram of the isolated crystalline glutarate salt of the compound of Formula (I) is wide and relates to the loss of solvent and continues until a maximum at 224°C is reached, corresponding to decomposition of the solid (FIG.19).
  • a dynamic vapor sorption curve (DVS) of the isolated crystalline glutarate salt of the compound of Formula (I) indicated a hygroscopic material (FIG.20).
  • Example 11 Synthetic Procedure for a Crystalline Glycolate Salt of a Peptide of SEQ ID NO: 1 [0473] Crystalline free base of the compound of Formula (I) (200 mg) prepared according to Example 8 and 4.4 mol equivalents of glycolic acid were suspended in 1 mL of water and stirred at 40°C for ca.24 h until a clear solution was observed.15 mL of anti-solvent (acetonitrile) was added to the solution, and precipitation of white solids was observed. The solids were isolated by Buchner filtration and air-dried at ambient prior to characterization.
  • anti-solvent acetonitrile
  • the glycolate content of the isolated solid of the crystalline glycolate salt of the compound of Formula (I) was assayed by CAD analysis and found to be 0.48 molar equivalents to the compound of Formula (I).
  • An XRPD pattern of the crystalline glycolate salt of the compound of Formula (I) confirmed the crystallinity (FIG.21). The following two theta peaks were observed: 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0,13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 degrees two theta +/- 0.2 degrees two theta.
  • a simultaneous thermal analysis (SDT) was used to obtain TGA and DSC data.
  • the SDT thermogram of the isolated crystalline glycolate salt of the compound of Formula (I) shows a 5.1% weight loss when heated to about 100°C, which is attributed to loss of solvent, mainly water (FIG.22).
  • the first endothermic event in the SDT thermogram of the isolated crystalline glycolate salt of the compound of Formula (I) is wide and relates to the loss of solvent and continues until a maximum at 237°C is reached, corresponding to decomposition of the solid (FIG.22).
  • a dynamic vapor sorption curve (DVS) of the isolated crystalline glycolate form of the compound of Formula (I) indicated a hygroscopic material (FIG.23).
  • the resulting slurry was vacuum filtered using What Grade 1 paper ( ⁇ 42.5 mm).
  • the isolated solid was dried under reduced pressure at ambient (ca.20 °C) for ca.5 h.
  • the isolated solid of the crystalline mesylate salt of the compound of Formula (I) had a purity (UPLC) of 90.78 area%.
  • the mesylate content of the isolated crystalline mesylate salt of the compound of Formula (I) solid was assayed by charged aerosol detected (CAD) analysis and found to be 1.8 molar equivalents to the compound of Formula (I).
  • An XRPD pattern of the crystalline mesylate salt of the compound of Formula (I) confirmed the crystallinity (FIG.24).
  • the first endothermic event in the SDT thermogram of the isolated crystalline mesylate salt of the compound of Formula (I) is wide, relates to the loss of solvent and continues until a maximum at 242 °C is reached, corresponding to decomposition of the solid (FIG.25).
  • Example 13 Synthetic Procedure for a Crystalline Sulfate Salt of a Peptide of SEQ ID NO: 1 [0479] Crystalline free base of the compound of Formula (I) (100 mg) prepared according to Example 8 was added to a 20 mL scintillation vial.3 mol equivalents of 1 M sulfuric acid with appropriate volume of water were added to the vial. The experiment was stirred at 25 °C for ca. 1 h until a clear solution was observed post-addition.
  • the sulfate content of the isolated solid of the crystalline sulfate salt of the compound of Formula (I) was assayed by CAD analysis and found to be 1.6 molar equivalents to the compound of Formula (I).
  • An XRPD pattern of the crystalline sulfate salt of the compound of Formula (I) confirmed the crystallinity (FIG.26). The following two theta peaks were observed: 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 degrees two theta +/- 0.2 degrees two theta.
  • SDT simultaneous thermal analysis
  • the SDT thermogram of the isolated crystalline sulfate salt of the compound of Formula (I) shows a 4.4% weight loss when heated to about 80 °C, which is attributed to loss of solvent, mainly water (FIG.27).
  • the first endothermic event in the SDT thermogram of the crystalline sulfate salt of the compound of Formula (I) is wide, relates to the loss of solvent and continues until a maximum at 255 °C is reached, corresponding to decomposition of the solid (FIG.27).
  • the slurry was centrifuged (0.2 ⁇ m nylon filter) to isolate the solid.
  • the isolated solid of the crystalline citrate salt of the compound of Formula (I) had a purity (HPLC) of 99.59 area%.
  • An XRPD pattern of the crystalline citrate salt of the compound of Formula (I) confirmed the crystallinity (FIG.28).
  • Crystalline hydrochloride salt of the compound of Formula (I) (12 g) prepared according to Example 3 was dissolved in 50.5 mL of water and 9.5 mL of hydrochloric acid 1 M. The dissolution was carried out in an EasyMax 102, under stirring at 20 °C.60 mL of sodium chloride 0.6 M were dosed to the EasyMax reactor at 0.04 mL/min. The slurry was then aged for 2 h under stirring at 20 °C. The solid was isolated by vacuum filtration and washed twice with 3 mL of water. The solid was dried atmospherically.
  • the isolated solid had a purity of 99.7 area% measured by UPLC and a water content (KF) of 10.83 w/w%.
  • the chloride content of the isolated crystalline solid of the bis- hydrochloride salt of the compound of Formula (I) was assayed by ion chromatography and found to be 1.97 molar equivalents to the compound of Formula (I).
  • An XRPD pattern of the crystalline bis-hydrochloride salt of the compound of Formula (I) confirmed its crystallinity (FIG.29).
  • a TGA of the isolated crystalline bis-hydrochloride salt of the compound of Formula (I) shows a 11.3 % weight loss when heated to about 190°C, which is attributed to loss of solvent, mainly water (FIG.30).
  • the first endothermic event in the DSC profile of the isolated crystalline bis-hydrochloride salt of the compound of Formula (I) showing a maximum at 79.5 °C corresponds to the loss of solvent from the crystalline lattice, while the later event at 235.3 °C (228.9°C (onset)) is attributed to melting/decomposition of the solid (FIG.31).
  • Step 1 Milling & Sieving
  • Teflon (PTFE) solid blocks were used to manually sieve the compound of Formula (I) through a 600 ⁇ ⁇ m stainless-steel sieve.
  • the collected powder was then sieved via the same procedure through stainless-steel sieves at 400 ⁇ ⁇ m and 150 ⁇ ⁇ m mesh size, sequentially.
  • Step 2 Dry Granulation [0490]
  • the resulting powder from Step 1 and all intragranular excipients, including functional excipients, comprising sodium caprate, microcrystalline cellulose, sorbitol, crospovidone and anhydrous colloidal silica listed in Composition of tablet compositions 1-3 were screened through a 1000 ⁇ m stainless-steel sieve and mixed for 10 minutes in a high-speed blender (such as Turbula).
  • the blended dry powder was compacted into tablet-like solids through single-stage compression on a single-punch tablet press (such as Styl’One Evolution).
  • Teflon (PTFE) solid blocks were used to manually break the resulting compact (i.e., “slugs”) into granules which were screened through a 1000 ⁇ m stainless-steel sieve.
  • Step 3 Blending and Tableting [0491] The resulting granulated powder from Step 2 and all extragranular excipients comprising silicified microcrystalline cellulose, crospovidone and anhydrous colloidal silica as listed in Composition of Ex 1-3 were screened through a 1000 ⁇ m stainless-steel sieve and mixed for 10 minutes in a high-speed blender (such as Turbula).
  • a high-speed blender such as Turbula
  • extragranular magnesium stearate was screened through the same mesh, added to the above mixture, and further mixed for 5 minutes under the same conditions.
  • the final blend was compressed into tablets through a two-stage (i.e., pre- and main-) compression cycle on a single-punch tablet press (such as Styl’One Evolution).
  • the resulting core tablets were collected into appropriate containers (e.g., HDPE bottles) and packages (e.g., sealed in aluminum laminated bags) which were stored until the next step.
  • Step 4 Film Coating Subcoat: [0492] The coating suspension at approximately 30 wt% solid concentration was prepared by adding the coating powder of the subcoat (i.e., Opadry® QX 321A220063 Yellow) into the vortex of vigorously agitated purified water, which was stirred by an overhead stirrer. The suspension was further stirred for a sufficient time (e.g., at least 45 min) to achieve a homogenous dispersion without foam and remained stirred during the coating process. [0493] The core tablets manufactured from Steps 1-3 were transferred to the pan of a semi- perforated tablet coating system such as Lödige.
  • a semi- perforated tablet coating system such as Lödige.
  • the process parameters were commonly optimized in following target values and ranges [min-max] – tablet bed temperature (indicated by the exhaust air temperature) at 40 °C [35-45 °C], inlet air flow rate and pressure at 105 [80-120] m 3 /hr and an atomizing air and pressure of 0.9 [0.6-1.2] bar, a drum rotation speed at 23 [10-30] rpm, and a feeding rate of coating suspension at 6.5-7 g/min[5-8] g/min.
  • the coating pan continued to rotate at a reduced drum speed (e.g., 5 rpm) at approximately 45 °C to remove residual water of the coated tablets.
  • the resulting subcoated tablets were collected from the pan and cooled to room temperature under ambient conditions.
  • Functional coat [0494] The coating suspension at approximately 20 wt% solid concentration was prepared by subsequently adding triethyl citrate (plasticizer) and Acryl-Eze® 93A220037 Yellow (coating powder), sequentially in this order, into the vortex of vigorously agitated purified water, which was stirred by an overhead stirrer. The suspension was further stirred for a sufficient time (e.g., at least 5 minutes after adding the plasticizer, at least 45 min after adding the coating powder) to achieve a homogenous dispersion free of agglomeration and free of foam.
  • a sufficient time e.g., at least 5 minutes after adding the plasticizer, at least 45 min after adding the coating powder
  • the coating suspension was passed through a 250 ⁇ m stainless-steel sieve and remained stirred during spraying.
  • the subcoated tablets were coated with the functional coat using the above coating and drying processes with modified parameters.
  • the process parameters were commonly optimized in following target values and ranges [min-max] – the exhaust air temperature at 32 °C [28-38 °C], inlet air flow rate of 105 [80-120] m 3 /hr and an atomizing and pattern air pressure of 0.9 [0.6- 1.2] bar, a drum rotation speed at 23 [10-30] rpm, and a feeding rate of coating suspension at 6.5 [5-8] g/min.
  • the coating pan continued to rotate at a reduced drum speed (e.g., 5 rpm) at approximately 40-45 °C to remove residual water of the coated tablets.
  • the coated tablets were removed from the coating pan and cooled to room temperature under ambient conditions.
  • the film-coated tablets were finally collected into appropriate containers (e.g., HDPE bottles) and packages (e.g., sealed in aluminum laminated bags) and stored under appropriate conditions.
  • a typical coating suspension for subcoat contains approximately 30% wt% solids.
  • a typical coating suspension for the functional coat contains approximately 20% wt% solids without the plasticizer.
  • Table 11 shows properties of Tablet Compositions 13.
  • Table 11. Properties of Blends/Core/Coated Tablets – Tablet Compositions 1-3 [A] Representative compression and coating batches such as stability or clinical batches were selected. [B] Coating levels (wt%) of each coating layer were calculated based on the measured weight gain and core tablet weight of 50 tablets in the batch.
  • Tablet Compositions 4-6 [0497] Film-Coated Tablets with compositions of Tablet Compositions 1-3, which included 50 mg, 25 mg, and 10 mg (equivalent to free base), respectively, of the compound of Formula (I) hydrochloride (HCl) salt and 300 mg sodium caprate as an absorption enhancer, were prepared by following unit operations: milling & sieving, dry granulation, blending & compression, and film coating, described in Steps 1-4 in Tablet Compositions 1-3. The in-process control data of the core and coated tablets in representative stability or clinical batches were collected, as summarized in the tables below. Table 12.
  • Table 15 shows properties of Tablet Compositions 46.
  • Table 15 Properties of Blends/Core/Coated Tablets – Tablet Compositions 4-6
  • Tablet Compositions 7-9 [0499] Film-Coated Tablets with compositions of Examples 7-9 at the strength of 25 mg (equivalent to free base) of the compound of Formula (I) hydrochloride (HCl) salt, which included 500 mg, 300 mg and 100 mg sodium caprate, respectively, as an absorption enhancer, were prepared by following unit operations: milling & sieving, dry granulation, blending & compression, and film coating, described in Steps 1-4 in Tablet Compositions 1-3.
  • HCl hydrochloride
  • Tablet Compositions 7-9 included croscarmellose sodium as the disintegrant in the core tablets and Opadry® QX 321A240072-CN Pink and Acryl-Eze® 93A18597 White (11.8% wt:wt with core tablets) in the coating layers.
  • the in-process control data of the core and coated tablets in these batches were collected, as summarized in the tables below. Table 16.
  • the weight of this excipient was corrected based on the assay value of the API to maintain a fixed tablet weight.
  • the coating suspension for subcoat contains was prepared at a concentration of 20% wt% solids.
  • the solvent of coating suspensions is removed during the coating processing.
  • a typical coating suspension for the functional coat contains approximately 20% wt% solids.
  • Table 19 shows properties of Tablet Compositions 79.
  • Coating levels (wt%) of each coating layer were calculated based on the measured weight gain and core tablet weight of the target tablets (not including backfills).
  • Tablet Compositions 10 and 11 [0502] Film-Coated Tablets with compositions of Tablet Compositions 10 and 11 at the strengths of 100 mg and 25 mg (equivalent to free base) of the Peptide of SEQ ID NO: 1 hydrochloride (HCl) salt, respectively, were prepared by following unit operations: milling & sieving, blending & compression, and film coating, described in Steps 1-3 below.
  • Step 1 Milling & Sieving
  • Teflon (PTFE) solid blocks were used to manually sieve the Peptide of SEQ ID NO: 1 through a 600 mm stainless-steel sieve.
  • the collected powder was then sieved via the same procedure through stainless-steel sieves at 400 mm and 150 mm mesh size, sequentially.
  • Step 2 Blending and Tabletting
  • the resulting powder from Step 1 and all excipients comprising silicified microcrystalline cellulose, sorbitol, crospovidone, and anhydrous colloidal silica as listed in Tablet Compositions 10 and 11 were screened through a 1000 mm stainless-steel sieve and mixed for 10 minutes in a high-speed blender (such as Turbula). To this mixture, magnesium stearate was sieved through the same mesh, added to the above mixture, and further mixed for 5 minutes under the same conditions.
  • a high-speed blender such as Turbula
  • Step 3 Film Coating
  • the core tablets manufactured from Steps 1-2 were transferred to the pan of a semi- perforated tablet coating system (such as Lödige or Bohle), depending on the batch size.
  • the coated tablets remained in the slowly rotating pan (e.g., 2 rpm) with inlet cooling air for an additional cooling period until the exhaust air reached an adequate temperature (e.g., 38 °C) for collection.
  • the resulting coated tablets were collected from the pan and cooled to room temperature under ambient conditions, before storing them in appropriate containers and packages (e.g., sealed in aluminum laminated bags) under appropriate conditions.
  • Table 22 shows properties of Tablet Compositions 10-11. Table 22: Properties of Blends/Core/Coated Tablets Tablet Compositions 1011 [A] Representative compression and coating batches such as stability or clinical batches were selected. [B] Coating levels (wt%) of each coating layer were calculated based on the measured weight gain and core tablet weight of 50 tablets in the batch.
  • Tablet Compositions 12 and 13 [0508] Film-Coated Tablets with compositions of Tablet Compositions 12 and 13 at the strength of 10 mg and 5 mg (equivalent to free base) of the compound of Formula (I) hydrochloride (HCl) salt, respectively, were prepared by following unit operations: milling & sieving, blending & compression, and film coating, described in Steps 1-3 in Tablet Compositions 10-11. The in-process control data of the core and coated tablets of selected batches were collected and summarized in the table below. It is understood that other salts of the compound of Formula (I) can also be used in forming the tablet compositions described herein.
  • Table 23 Tablet Compositions 12 and 13 TC is Tablet Composition
  • the weight of this excipient was corrected based on the assay value of the API to maintain a fixed tablet weight.
  • a typical coating suspension contains approximately 30% wt% solids.
  • the solvent of coating suspensions is removed during the coating processing.
  • Table 24 shows properties of Tablet Compositions 12-13.
  • Tablets with compositions of Tablet Compositions 14 through 43 were prepared by blending together the components of the core tablet, such as a crystalline pharmaceutically acceptable salt of the compound of Formula (I), and various excipients, including on or more of a filler, a disintegrant, a glidant, and a lubricant.
  • a suitable granulation process For certain tablet compositions, one or more of the components of the core tablet underwent a suitable granulation process before the blending procedure. After the blending procedure, the blended components were compressed into a core tablet employing a suitable tablet machine.
  • a cosmetic subcoating was disposed over the core tablets of Compositions 17 through 28 and 30 through 43.
  • the peptide of SEQ ID NO: 1 used in the compositions 14-43 is the crystalline form of HCl salt of the compound of Formula (I), but other crystalline forms of the compound of Formula (I) can also be used in forming the tablet compositions described herein.
  • Table 27 Tablet Compositions 17 and 18
  • Table 28 Tablet Compositions 19 to 22
  • Table 29 Tablet Compositions 23 and 24
  • Table 30 Tablet Compositions 25 and 26
  • Tablets with compositions of Tablet Compositions 43 through 93 were prepared by blending together the components of the core tablet, such as a crystalline pharmaceutically acceptable salt of the compound of Formula (I), and various excipients, including on or more of a filler, a disintegrant, a glidant, and a lubricant.
  • a suitable granulation process before the blending procedure.
  • the blended components were compressed into a core tablet employing a suitable tablet machine.
  • compositions 43 through 55, 73, 74, 84 through 88, and 90 through 93 Two coatings, a subcoating followed by an enteric coating, were disposed over the core tablets in Compositions 43 through 55, 73, 74, 84 through 88, and 90 through 93.
  • the peptide of SEQ ID NO: 1 used in the compositions 43-93 is the crystalline form of HCl salt of the compound of Formula (I), but other crystalline forms of the compound of Formula (I) can also be used in forming the tablet compositions described herein.
  • Table 40 Tablet Compositions 53 to 55 Table 41: Tablet Composition 56 Table 42: Tablet Composition 57 Table 43: Tablet Composition 58
  • Table 44 Tablet Composition 59 Table 45: Tablet Composition 60 Table 46: Tablet Composition 61 Table 47: Tablet Composition 62 Table 48: Tablet Composition 63 Table 49: Tablet Composition 64 Table 50: Tablet Composition 65 Table 51: Tablet Composition 66 Table 52: Tablet Composition 67 Table 53: Tablet Composition 68 Table 54: Tablet Composition 69 Table 55: Tablet Composition 70 Table 56: Tablet Composition 71 Table 57: Tablet Composition 72
  • Table 58 Tablet Compositions 73 and 74 Table 59: Tablet Compositions 75 and 76 Table 60: Tablet Composition 77 Table 61: Tablet Composition 78 Table 62: Tablet Composition 79 Table 63: Tablet Composition 80 Table 64: Tablet Composition 81 Table 65: Tablet Composition 82 Table 66: Tablet Composition 83 Table 67: Tablet Compositions 84 and 85 Table 68: Tablet Compositions 86 to 88 Table 69: Tablet Composition 89 Table 70: Tablet Compositions 90 and 91
  • the present invention relates to a crystalline form of a hydrochloride salt of a compound of Formula (I): Ac-[Pen]*-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]*-Phe[4-(2- aminoethoxy)] [2 Nal] [THP] E N [3 Pal] Sarc NH 2 (in which [Pen] [Pen] form a disulfide bond), having the structure: , or a solvate thereof.
  • the crystalline hydrochloride salt is a hemi hydrochloride salt.
  • crystalline hydrochloride is further characterized by an X-ray powder diffraction pattern substantially as depicted in FIG.2.
  • the X-ray powder diffraction pattern displays at least three measured 2 theta peaks from: 4.2920, 6.9201, 7.6600, 8.5693, 9.2667, 9.9817, 10.7256, 11.5429, 11.9937, 13.0633, 13.3317, 13.9650, 14.7879, 15.8430, 17.1481, 17.6468, 18.1402, 18.6158, 19.3291, 20.4899, 20.7090, or 21.7813 +/- 0.2 degrees two theta.
  • the X-ray powder diffraction pattern displays at least four measured 2 theta peaks from: 4.2920, 6.9201, 7.6600, 8.5693, 9.2667, 9.9817, 10.7256, 11.5429, 11.9937, 13.0633, 13.3317, 13.9650, 14.7879, 15.8430, 17.1481, 17.6468, 18.1402, 18.6158, 19.3291, 20.4899, 20.7090, or 21.7813 +/- 0.2 degrees two theta.
  • the crystalline form produces an X-ray powder diffraction pattern which comprises peaks at 6.9, 7.7, and 9.3 degrees two theta +/- 0.2 degrees two theta.
  • the crystalline form produces an X-ray powder diffraction pattern which comprises peaks at 6.9, 7.7, 8.6, and 9.3 degrees two theta +/- 0.2 degrees two theta.
  • the present invention relates to a crystalline form of a compound of Formula (I), which is Ac-[Pen]*-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]*-Phe[4-(2-aminoethoxy)]-[2- Nal]-[THP]-E-N-[3-Pal]-Sarc-NH 2 (in which [Pen]*-[Pen]* form a disulfide bond), having the structure:
  • the crystalline form is a crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof.
  • the crystalline form is a crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof.
  • the crystalline form of the pharmaceutically acceptable salt, or a solvate thereof is characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at angles two of 4.2, 6.9, 7.6, and 9.2 degrees two theta +/- 0.2 degrees two theta.
  • XRPD X-ray powder diffraction
  • the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof is a crystalline acetate salt of the compound of Formula (I) or a solvate thereof.
  • the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof is a crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof.
  • the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof is a crystalline glutarate salt of the compound of Formula (I) or a solvate thereof.
  • the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof is a crystalline glycolate salt of the compound of Formula (I) or a solvate thereof.
  • the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof is [0519]
  • the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof is a crystalline bis-hydrochloride salt of the compound of Formula (I) or a solvate thereof.
  • the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof is a crystalline fumarate salt of the compound of Formula (I) or a solvate thereof.
  • the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof is a crystalline mesylate salt of the compound of Formula (I).
  • the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof is a crystalline sulfate salt of the compound of Formula (I) or a solvate thereof.
  • the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof is a crystalline citrate salt of the compound of Formula (I) or a solvate thereof.
  • the crystalline pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof is characterized as having a XRPD pattern substantially as shown in FIG.1, FIG.2, FIG.3, FIG.7. FIG.15, FIG.18, FIG.21, FIG.24, FIG.26, FIG.28, or FIG.29.
  • the crystalline pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof having a DSC graph or SDT thermogram substantially as shown in FIG.5, FIG.9, FIG.17, FIG.19, FIG.22, FIG.25, or FIG.27.
  • the crystalline pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof is characterized as having: (i) endotherm peaks at about 80.7 °C and/or about 240.7 °C, as determined by DSC; (ii) endotherm peaks at about 81.4 °C as determined by DSC; (iiii) endotherm peaks at about 79.5 °C and/or about 235.3 °C, as determined by DSC; (iv) an endotherm peak at about 65.3 °C, as determined by DSC; (v) an endotherm peak at about 224.1 °C, as determined by SDT; (vi) an endotherm peak at about 237.0 °C, as determined by SDT; (vii) an endotherm peak at about 242.0 °C, as determined by SDT; or (viii) an endotherm peak at about 255.0 °C, as determined by SDT.
  • the crystalline pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof is characterized as having a TGA graph or SDT thermogram substantially as shown in FIG.4, FIG.8, FIG.16, FIG.19, FIG.22, FIG.25, FIG. 27, or FIG.30.
  • the crystalline pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof is characterized as having: (i) a weight loss of about 5.8% from about 26.5 °C to about 150.0 °C, as determined by TGA; (ii) a weight loss of about 5.6% from about 26.5 °C to about 160.0 °C, as determined by TGA; (iii) a weight loss of about 11.3% from about 26.5 °C to about 190.0 °C, as determined by TGA; (iv) a weight loss of about 4.4% from about 26.5 °C to about 110.0 °C, as determined by TGA; (v) a weight loss of about 6.4% from about 26.5 °C to about 125.0 °C, as determined by SDT; (vi) a weight loss of about 5.1% from about 26.5 °C to about 100.0 °C, as determined by SDT; (vii) a weight loss of about 5.4% from about 26.5 C to about 80.0 C
  • the crystalline pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof, the crystalline form is characterized as having a DVS graph substantially as shown in FIG.6, FIG.10, FIG.20, FIG.23, or FIG.32.
  • the crystalline pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof comprises a cationic form of the compound of Formula (I) and a pharmaceutically acceptable anion, wherein the molar equivalents of the pharmaceutically acceptable anion relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0.
  • the crystalline pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof is a crystalline form of a free base of the compound of Formula (I).
  • the crystalline form of a free base of the compound of Formula (I) is characterized as having an XRPD pattern comprising peaks at angles two theta of 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 degrees two theta +/- 0.2 degrees two theta.
  • the crystalline form of a free base of the compound of Formula (I) is characterized as having an XRPD pattern substantially as shown in FIG.11. [0526] In some embodiments, the crystalline form of a free base of the compound of Formula (I) is characterized as having a DSC graph substantially as shown in FIG.13. [0527] In some embodiments, the crystalline form of a free base of the compound of Formula (I) is characterized as having endotherm peaks at about 71.0 °C and/or about 130.2 °C, as determined by DSC. In some embodiments, the crystalline form of a free base of the compound of Formula (I) is characterized as having a TGA graph substantially as shown in FIG. 12.
  • the crystalline form of a free base of the compound of Formula (I) is characterized as having a weight loss of about 3.7% from about 26.5 °C to about 70.0 °C and a weight loss of about 2.7% from 70.0 °C to about 170.0 °C, as determined by TGA.
  • the crystalline form of a free base of the compound of Formula (I) is characterized as having a DVS graph substantially as shown in FIG.14.
  • the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of a crystalline hydrochloride salt or solvate thereof and a pharmaceutically acceptable excipient.
  • the present invention relates to a pharmaceutical composition which comprises a hydrochloride salt of a compound of Formula (I) having the structure:
  • the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of from about 0.1% to about 15% (w/w) of the composition; and one or more pharmaceutically acceptable excipients.
  • the hydrochloride salt of the compound of Formula (I) or solvate thereof in the pharmaceutical composition: is a crystalline hydrochloride salt.
  • the dose range of the hydrochloride salt of the compound of Formula (I) or solvate thereof is from about 1 mg to about 1000 mg, where the amount of HCl salt is defined in terms of an equivalent amount of a free base form of the compound of Formula (I).
  • a dose range of the hydrochloride salt of the compound of Formula (I) or solvate thereof is from about 5 mg to about 300 mg, where the amount of HCl salt is defined in terms of an equivalent amount of a free base form of the compound of Formula (I).
  • the dose of the hydrochloride salt of the compound of Formula (I) or solvate thereof is about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, and the like.
  • the pharmaceutical composition further comprises a silicified microcrystalline cellulose.
  • the amount of the silicified microcrystalline cellulose is from about 65% to about 85% (w/w) of the composition.
  • the pharmaceutical composition further comprises one or more of alpha cellulose, beta cellulose, gamma cellulose, starch, modified- starch, sorbitol, mannitol, lactose, dextrose, sucrose, dibasic calcium phosphate, tribasic calcium phosphate, or calcium carbonate.
  • the pharmaceutical composition further comprises sorbitol, where: the amount of the sorbitol is from about 10% to about 15% (w/w) of the composition.
  • the pharmaceutical composition further comprises a disintegrant, where: the disintegrant is a cross- linked carboxymethyl cellulose (croscarmellose), a starch glycolate, a polyvinyl pyrrolidone, a sago starch, psyllium husk, croscarmellose sodium or crospovidone a silicate, or a soy polysaccharide; the amount of the disintegrant is from about 3% to about 8% (w/w) of the composition.
  • the disintegrant is a cross- linked carboxymethyl cellulose (croscarmellose), a starch glycolate, a polyvinyl pyrrolidone, a sago starch, psyllium husk, croscarmellose sodium or crospovidone a silicate, or a soy polysaccharide
  • the amount of the disintegrant is from about 3% to about 8% (w/w) of the composition.
  • the pharmaceutical composition further comprises a silica (e.g., Aerosil 200), where the amount of the silica (e.g., Aerosil 200) is from about 0.3% to about 0.7% (w/w) of the composition.
  • the pharmaceutical composition further comprises a lubricant, where the amount of the lubricant is from about 0.3% to about 0.7% (w/w) of the composition.
  • the composition is a tablet composition or a capsule composition.
  • the pharmaceutical composition comprises: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of from about 0.2% to about 15% (w/w) of the composition; (ii) a silicified microcrystalline cellulose in an amount of from about 66.5% to about 81.3% (w/w) of the composition; (iii) sorbitol in an amount of about 12.5% (w/w) of the composition; (iv) a disintegrant in an amount of about 5% (w/w) of the composition; (v) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; and (vi) a lubricant in an amount of about 0.5% (w/w) of the composition.
  • a silica e.g., Aerosil 200
  • the pharmaceutical composition comprises: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 1% (w/w) of the composition; (ii) a silicified microcrystalline cellulose in an amount of about 80.5% (w/w) of the composition; (iii) sorbitol in an amount of about 12.5% (w/w) of the composition; (iv) crospovidone in an amount of about 5% (w/w) of the composition; (v) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; and (vi) magnesium stearate in an amount of about 0.5% (w/w) of the composition.
  • a silica e.g., Aerosil 200
  • the pharmaceutical composition comprises: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 2.5% (w/w) of the composition; (ii) a silicified microcrystalline cellulose in an amount of about 79% (w/w) of the composition; (iii) sorbitol in an amount of about 12.5% (w/w) of the composition; (iv) crospovidone in an amount of about 5% (w/w) of the composition; (v) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; and (vi) magnesium stearate in an amount of about 0.5% (w/w) of the composition.
  • a silica e.g., Aerosil 200
  • the pharmaceutical composition comprises: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 10% (w/w) of the composition; (ii) a silicified microcrystalline cellulose in an amount of about 71.5% (w/w) of the composition; (iii) sorbitol in an amount of about 12.5% (w/w) of the composition; (iv) crospovidone in an amount of about 5% (w/w) of the composition; (v) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; and (vi) magnesium stearate in an amount of about 0.5% (w/w) of the composition.
  • a silica e.g., Aerosil 200
  • the pharmaceutical composition comprises: A subcoating of a PVA-PEG graft co-polymer disposed over the composition, where the subcoating is present in an amount from about 1% to about 5% (w/w);
  • the present invention relates to a tablet, capsule or dosage form which comprises: [1] a core or core tablet comprises: a hydrochloride salt form of a compound of Formula (I) having the structure: , or a solvate thereof; and pharmaceutically acceptable excipients; and [2] at least one overcoat over the core tablet formed from pharmaceutically acceptable excipients.
  • a tablet or dosage form comprises: [1] a core or core tablet comprises: a hydrochloride salt form of a compound of Formula (I) having the structure: , or a solvate thereof; and pharmaceutically acceptable excipients; and [2] at least one overcoat over the core tablet formed from pharmaceutically acceptable excipients.
  • the tablet or dosage form where: the hydrochloride salt of a compound of Formula (I) is a crystalline form; and pharmaceutically acceptable excipients are selected from disintegrants, glidants, lubricants, film coatings or any combination thereof.
  • the present invention relates to a process of making a tablet or dosage form, comprises steps of: [1] forming a core or core tablet by blending and compressing a pharmaceutical composition mixture comprises: a hydrochloride salt form of a compound of Formula (I) having the structure: , or a solvate thereof; and pharmaceutically acceptable excipients to form a tablet core composition; and [2] overcoating by applying at least one overcoat over the core tablet formed from pharmaceutically acceptable excipients.
  • the present invention relates to a tablet formed by the process of: forming a mixture which comprises a hydrochloride salt of a compound of Formula (I) having the structure: , or a solvate thereof, a silicified microcrystalline cellulose, sorbitol, crospovidone, and a silica (e.g., Aerosil 200); adding magnesium stearate to the mixture; compressing the mixture; and applying a subcoating to the mixture, to form the tablet.
  • a hydrochloride salt of a compound of Formula (I) having the structure: , or a solvate thereof, a silicified microcrystalline cellulose, sorbitol, crospovidone, and a silica (e.g., Aerosil 200) e.g., Aerosil 200
  • the present invention relates to a method which comprises: forming a mixture which comprises a hydrochloride salt of a compound of Formula (I) having the structure: , or a solvate thereof, a silicified microcrystalline cellulose, sorbitol, crospovidone, and a silica (e.g., Aerosil 200); adding magnesium stearate to the mixture; compressing the mixture; and applying a subcoating to the mixture, to form a tablet.
  • a hydrochloride salt of a compound of Formula (I) having the structure: , or a solvate thereof, a silicified microcrystalline cellulose, sorbitol, crospovidone, and a silica (e.g., Aerosil 200) e.g., Aerosil 200
  • the present invention relates to a pharmaceutical composition which comprises a hydrochloride salt of a compound of Formula (I) having the structure: , or a solvate thereof, in an amount of from about 0.1% to about 15% (w/w) of the composition; an absorption enhancer in an amount of from about 5% to about 50% (w/w) of the composition; and one or more pharmaceutically acceptable excipients.
  • the present invention relates to a pharmaceutical composition where: the hydrochloride salt of the compound of Formula (I) or solvate thereof is a crystalline hydrochloride salt.
  • the present invention relates to a pharmaceutical composition where: the amount of the hydrochloride salt of the compound of Formula (I) or solvate thereof is from about 1 mg to about 1000 mg, where the amount of HCl salt is defined in terms of an equivalent amount of a free base form of the compound of Formula (I). In another aspect, the present invention relates to a pharmaceutical composition where: the amount of the hydrochloride salt of the compound of Formula (I) or solvate thereof is about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg.
  • the present invention relates to a pharmaceutical composition where: absorption enhancer is sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium salcaprozate (SNAC), a polyethylene glycol (PEG)-modified medium chain fatty acid triglyceride of capric and caprylic acid, sucrose laurate, or lauroyl-L-carnitine (LC).
  • absorption enhancer is sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium salcaprozate (SNAC), a polyethylene glycol (PEG)-modified medium chain fatty acid triglyceride of capric and caprylic acid, sucrose laurate, or lauroyl-L-carnitine (LC).
  • the present invention relates to a pharmaceutical composition where: the amount of the absorption enhancer is from about 5% to about 40% (w/w) of the composition.
  • the present invention relates to a pharmaceutical
  • the present invention relates to a pharmaceutical composition where: the amount of the microcrystalline cellulose is from about 3% to about 5% (w/w) of the composition. In another aspect, the present invention relates to a pharmaceutical composition where the pharmaceutical composition further comprises sorbitol. In another aspect, the present invention relates to a pharmaceutical composition where: the amount of the sorbitol is from about 10% to about 15% (w/w) of the composition. In another aspect, the present invention relates to a pharmaceutical composition where the pharmaceutical composition further comprises a silicified microcrystalline cellulose. In another aspect, the present invention relates to a pharmaceutical composition where: the amount of the silicified microcrystalline cellulose is from about 30% to about 70% (w/w) of the composition.
  • the present invention relates to a pharmaceutical composition where the pharmaceutical composition further comprises a disintegrant, where the disintegrant is a cross-linked carboxymethyl cellulose (croscarmellose), a starch glycolate, a polyvinyl pyrrolidone, a sago starch, psyllium husk, croscarmellose sodium or crospovidone, a silicate, or a soy polysaccharide.
  • the present invention relates to a pharmaceutical composition where: the amount of the disintegrant is from about 8% to about 12% (w/w) of the composition.
  • the present invention relates to a pharmaceutical composition where: the amount of the disintegrant is from about 8% to about 15% (w/w) of the composition. In another aspect, the present invention relates to a pharmaceutical composition where: the amount of the disintegrant is about 8%, about 10%, about 12%, or about 15% (w/w) of the composition. In another aspect, the present invention relates to a pharmaceutical composition where: the composition further comprises a silica (e.g., Aerosil 200), where the amount of the silica (e.g., Aerosil 200) is from about 0.5% to about 2% (w/w) of the composition. In another aspect, the present invention relates to a pharmaceutical composition where: the composition further comprises a lubricant.
  • a silica e.g., Aerosil 200
  • the present invention relates to a pharmaceutical composition where: the amount of the lubricant is from about 0.1% to about 0.5% (w/w) of the composition.
  • the present invention relates to a pharmaceutical composition where: the composition is a tablet composition or a capsule composition.
  • the present invention relates to a pharmaceutical composition which comprises (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of from about 0.1% to about 15% (w/w) of the composition, and (ii) the absorption enhancer sodium caprate in an amount of from about 5% to about 40% (w/w) of the composition; and a silicified microcrystalline cellulose.
  • the present invention relates to the composition which comprises: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of from about 0.5% to about 10% (w/w) of the composition, (ii) the absorption enhancer sodium caprate in an amount of about 5% to about 40% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) a disintegrant in an amount of about 5% (w/w) of the composition; and (vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of from about 30% to about 70% (w/w) of the composition; (viii) a disintegrant in an amount of about 5% (w/w)
  • the present invention relates to the composition comprises: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 0.7% (w/w) of the composition; (ii) the absorption enhancer sodium caprate in an amount of about 35.7% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) crospovidone in an amount of about 5% (w/w) of the composition; and (vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of about 37.7% (w/w) of the composition; (viii) crospovidone in an amount of about 5% (w/w) of the composition; (ix) a
  • the present invention relates to the composition comprises: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 1.8% (w/w) of the composition; (ii) the absorption enhancer sodium caprate in an amount of about 35.7% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) crospovidone in an amount of about 5% (w/w) of the composition; and (vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of about 36.6% (w/w) of the composition; (viii) crospovidone in an amount of about 5% (w/w) of the composition; (ix) a
  • the present invention relates to the composition which comprises: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 0.7% (w/w) of the composition; (ii) the absorption enhancer sodium caprate in an amount of about 21.4% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) crospovidone in an amount of about 5% (w/w) of the composition; and (vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of about 52% (w/w) of the composition; (viii) crospovidone in an amount of about 5% (w/w) of the composition; (ix) a
  • the present invention relates to the composition which comprises: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 1.8% (w/w) of the composition; (ii) the absorption enhancer sodium caprate in an amount of about 21.4% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) crospovidone in an amount of about 5% (w/w) of the composition; and (vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of about 50.9% (w/w) of the composition; (viii) crospovidone in an amount of about 5% (w/w) of the composition; (ix)
  • the present invention relates to the composition which comprises: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 7.1% (w/w) of the composition; (ii) the absorption enhancer sodium caprate in an amount of about 35.7% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) crospovidone in an amount of about 5% (w/w) of the composition; and(vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of about 31.3% (w/w) of the composition; (viii) crospovidone in an amount of about 5% (w/w) of the composition; (ix)
  • the present invention relates to the composition which comprises: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 1.8% (w/w) of the composition; (ii) the absorption enhancer sodium caprate in an amount of about 7.1% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) crospovidone in an amount of about 5% (w/w) of the composition; and (vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of about 65.2% (w/w) of the composition; (viii) crospovidone in an amount of about 5% (w/w) of the composition; (ix) a
  • the present invention relates to the composition which comprises: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 1.8% (w/w) of the composition, (ii) the absorption enhancer sodium caprate in an amount of about 35.7% (w/w) of the composition; (iii) a microcrystalline cellulose in an amount of about 3.9% (w/w) of the composition; (iv) sorbitol in an amount of about 10.7% (w/w) of the composition; (v) crospovidone in an amount of about 5% (w/w) of the composition; and (vi) a silica (e.g., Aerosil 200) in an amount of about 0.5% (w/w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of about 36.6% (w/w) of the composition; (viii) crospovidone in an amount of about 5% (w/w) of the composition; (ix)
  • the present invention relates to a subcoating which comprises: PVA-PEG graft co-polymer disposed over the composition. In another aspect the invention, the subcoating is present in an amount from about 1% to about 5% (w/w). [0558] In another aspect the present invention relates to a subcoating which comprises: an enteric coating disposed over the subcoating. In another aspect of the invention, the enteric coating is a methacrylic acid co-polymer. In another aspect of the invention, the enteric coating is present in an amount from about 2% to about 15% (w/w).
  • a tablet, capsule or dosage form which comprises: [1] a core or core tablet which comprises: a granulated mixture formed from: (i) a hydrochloride salt form of a compound of Formula (I) having the structure:
  • absorption enhancer (ii) optionally pharmaceutically acceptable excipients; wherein the mixture is blended and then compressed together to form a Core or Core Tablet; and [2] at least one overcoat over the core tablet formed from pharmaceutically acceptable excipients.
  • a tablet or dosage form which comprises: [1]a core or core tablet comprises: (i) a granule composition formed from: a hydrochloride salt form of a compound of Formula (I) having the structure: , or a solvate thereof, (ii) absorption enhancer; and (iii) optionally pharmaceutically acceptable excipients; wherein the mixture is blended and then compressed together to form a Core or Core Tablet; and [2] at least one overcoat over the core tablet formed from pharmaceutically acceptable excipients.
  • a core or core tablet comprises: (i) a granule composition formed from: a hydrochloride salt form of a compound of Formula (I) having the structure: , or a solvate thereof, (ii) absorption enhancer; and (iii) optionally pharmaceutically acceptable excipients; wherein the mixture is blended and then compressed together to form a Core or Core Tablet; and [2] at least one overcoat over the core tablet formed from pharmaceutically acceptable excipients.
  • the present invention relates to tablet or dosage form where: the hydrochloride salt of a compound of Formula (I) is a crystalline form; the absorption enhancer is sodium caprate; the pharmaceutically acceptable excipients defined in 1[a] and 1[b], respectively are selected from disintegrants, glidants, lubricants, film coatings or any combination thereof.
  • the present invention relates to a tablet or dosage form where the at least one overcoat over the core tablet of [2] is comprised of: a sub coat over the core tablet to form a subcoated tablet; and an enteric coat is overcoated or coated over the subcoated tablet, where: each sub coat and function coat, respectively, are formed from pharmaceutically acceptable excipients.
  • the present invention relates to a process of making a tablet or dosage form, which comprises steps of forming a core or core tablet which comprises: (1) a hydrochloride salt form of a compound of Formula (I) having the structure: , or a solvate thereof, (2) absorption enhancer; and (3) optionally pharmaceutically acceptable excipients; compressing the tablet core composition of step [2] to form a core or core tablet; overcoating by spraying or applying a subcoat to the core or core tablet to form a subcoated tablet; and finally applying another coating or over coating the subcoated tablet with a enteric coat; where: each sub coat and function coat, respectively, are formed from pharmaceutically acceptable excipients.
  • sodium caprate sodium caprate
  • a microcrystalline cellulose sorbitol, crospovidone, and a silica (e.g., Aerosil 200), and a silicified microcrystalline cellulose and crospovidone to form a core tablet; applying a subcoating over the core tablet; and applying an enteric coating over the subcoating to form the tablet.
  • a silica e.g., Aerosil 200
  • the present invention relates to a method which comprises: forming a mixture which comprises a hydrochloride salt of a compound of Formula (I) having structure: , or a solvate thereof, sodium caprate, a microcrystalline cellulose, sorbitol, crospovidone, and a silica (e.g., Aerosil 200); a silicified microcrystalline cellulose and crospovidone to form a core tablet; applying a subcoating over the core tablet; and applying an enteric coating over the subcoating to form a tablet.
  • a hydrochloride salt of a compound of Formula (I) having structure: , or a solvate thereof, sodium caprate, a microcrystalline cellulose, sorbitol, crospovidone, and a silica e.g., Aerosil 200
  • a silica e.g., Aerosil 200

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Abstract

La présente invention concerne un inhibiteur peptidique du récepteur de l'interleukine-23 (IL-23R) ou des sels, des solvates ou des formes de celui-ci, des compositions pharmaceutiques correspondantes, des procédés et/ou des utilisations pour le traitement de maladies inflammatoires auto-immunes et de troubles associés.
PCT/US2023/061651 2022-02-01 2023-01-31 Inhibiteurs peptidiques du récepteur de l'interleukine-23 et compositions pharmaceutiques associées WO2023150500A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130029907A1 (en) 2011-06-14 2013-01-31 Medical Diagnostic Laboratories, Llc Novel Polypeptides That Bound to IL-23 Receptor and Inhibit Binding of IL-23 and Cell Signaling Thereof
WO2021146441A1 (fr) 2020-01-15 2021-07-22 Janssen Biotech, Inc. Inhibiteurs peptidiques du récepteur de l'interleukine-23 et leur utilisation pour traiter des maladies inflammatoires

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130029907A1 (en) 2011-06-14 2013-01-31 Medical Diagnostic Laboratories, Llc Novel Polypeptides That Bound to IL-23 Receptor and Inhibit Binding of IL-23 and Cell Signaling Thereof
WO2021146441A1 (fr) 2020-01-15 2021-07-22 Janssen Biotech, Inc. Inhibiteurs peptidiques du récepteur de l'interleukine-23 et leur utilisation pour traiter des maladies inflammatoires
US20210261622A1 (en) 2020-01-15 2021-08-26 Janssen Biotech, Inc. Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases

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Title
"Pharmaceutical Dosage Forms and Drug Delivery SECOND EDITION", 1 January 2012, CRC PRESS, article MAHATO RAM I. ET AL: "Chapter 17: Tablets", pages: 313 - 335, XP055982183 *
"Remington: The Science and Practice of Pharmacy", 2003, LIPPINCOTT, WILLIAMS & WILKINS
CAS , no. 61791-12-6
LIEBERMAN, PHARMACEUTICAL DOSAGE FORMS, vol. 1-3, 1992
LLOYD, THE ART, SCIENCE AND TECHNOLOGY OF PHARMACEUTICAL COMPOUNDING, 1999
PICKAR, DOSAGE CALCULATIONS, 1999

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