Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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• • A—HUMAN NECESSITIES
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  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
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  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F01—MACHINES OR ENGINES IN GENERAL; ENGINE PLANTS IN GENERAL; STEAM ENGINES
  • F01N—GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR MACHINES OR ENGINES IN GENERAL; GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR INTERNAL-COMBUSTION ENGINES
  • F01N13/00—Exhaust or silencing apparatus characterised by constructional features
  • F01N13/08—Other arrangements or adaptations of exhaust conduits
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F01—MACHINES OR ENGINES IN GENERAL; ENGINE PLANTS IN GENERAL; STEAM ENGINES
  • F01N—GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR MACHINES OR ENGINES IN GENERAL; GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR INTERNAL-COMBUSTION ENGINES
  • F01N13/00—Exhaust or silencing apparatus characterised by constructional features
  • F01N13/18—Construction facilitating manufacture, assembly, or disassembly
  • F01N13/1872—Construction facilitating manufacture, assembly, or disassembly the assembly using stamp-formed parts or otherwise deformed sheet-metal
  • F01N13/1877—Construction facilitating manufacture, assembly, or disassembly the assembly using stamp-formed parts or otherwise deformed sheet-metal the channels or tubes thereof being made integrally with the housing
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F01—MACHINES OR ENGINES IN GENERAL; ENGINE PLANTS IN GENERAL; STEAM ENGINES
  • F01N—GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR MACHINES OR ENGINES IN GENERAL; GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR INTERNAL-COMBUSTION ENGINES
  • F01N13/00—Exhaust or silencing apparatus characterised by constructional features
  • F01N13/18—Construction facilitating manufacture, assembly, or disassembly
  • F01N13/1888—Construction facilitating manufacture, assembly, or disassembly the housing of the assembly consisting of two or more parts, e.g. two half-shells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F01—MACHINES OR ENGINES IN GENERAL; ENGINE PLANTS IN GENERAL; STEAM ENGINES
  • F01N—GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR MACHINES OR ENGINES IN GENERAL; GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR INTERNAL-COMBUSTION ENGINES
  • F01N2470/00—Structure or shape of exhaust gas passages, pipes or tubes
  • F01N2470/06—Tubes being formed by assembly of stamped or otherwise deformed sheet-metal
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F01—MACHINES OR ENGINES IN GENERAL; ENGINE PLANTS IN GENERAL; STEAM ENGINES
  • F01N—GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR MACHINES OR ENGINES IN GENERAL; GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR INTERNAL-COMBUSTION ENGINES
  • F01N2470/00—Structure or shape of exhaust gas passages, pipes or tubes
  • F01N2470/14—Plurality of outlet tubes, e.g. in parallel or with different length
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F01—MACHINES OR ENGINES IN GENERAL; ENGINE PLANTS IN GENERAL; STEAM ENGINES
  • F01N—GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR MACHINES OR ENGINES IN GENERAL; GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR INTERNAL-COMBUSTION ENGINES
  • F01N2470/00—Structure or shape of exhaust gas passages, pipes or tubes
  • F01N2470/16—Plurality of inlet tubes, e.g. discharging into different chambers

Definitions

• compositions that include compounds, such as biologically active compounds, and methods of making such compositions.
• PCT Application Publication Number WO 2007/002325 discloses propane- 1 -sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-lH-pyrrolo[2,3-b]pyridinc-3-carbonylJ-2,4-difluoro-phenyl ⁇ -amide (see e.g.. page 80 and corresponding formula on page 82),
• compositions that include or relate to Compound I.
• Compound 1 as used herein means propane- 1 -sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-lH- pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl ⁇ -amide (the compound has also been referred to using the nomenclature "propane- 1 -sulfonic acid ⁇ 3-[5-(4-chlorophenyl)-l H-pyrrolo [2,3- b] pyridine-3-carbonyl-2,4-difluoro-phenyl]-amide ⁇ ”), salts of such compound (including pharmaceutically acceptable salts), conjugates of such compound, derivatives of such compound, forms of such compound , and prodrugs of such compound.
• solid dispersion means any solid composition having at least two components
• a solid dispersion as disclosed herein includes an active ingredient (for example Compound 1), preferably dispersed among at least one other component, for example a polymer
• a solid dispersion as disclosed herein is a pharmaceutical dispersion that includes at least one pharmaceutically or biologically active ingredient (for example Compound 1)
• a solid dispersion includes Compound I molecularly dispersed with a polymer
• MBP microprecipitated bulk powder
• molecularly dispersed refers to the random distribution of a compound (e g , Compound I) with a polymer
• the compound is present in the polymer in a final state of subdivision See, e.g , M G, Vachon et al., J Microencapsulation, 14 281-301 (1997) and Vandelli et al,. J Microencapsulation, 10- 55-65 (1993)
• a compound for example.
• Compound I) may be dispersed witmn a matrix formed by the polymer in its solid state such that the compound is immobilized m its amorphous form Whether a compound is molecularly dispersed in a polymer may be evidenced in a variety of ways, e g , by the resulting solid molecular complex having a single glass transition temperature
• solid molecular complex' as used hei ein means a solid dispersion that includes Compound I molecularly dispersed within a polymer matrix
• immobilize means that molecules of the compound interact with molecules of the polymer m such a way that the molecules of the compound are held in the aforementioned matrix and prevented from crystal nucleation due to lack of mobility
• the polymer may prevent mtcrmolecular hydrogen bonding or weak dispersion forces between two or more drug molecules of Compound I See, for example, Matsumoro and Zografi, Pharmaceutical Research, Vo 16. No 11, p 1722-1728, 1999
• a solid dispersion that includes Compound I and a polymer
• a solid molecular complex that includes Compound I and a polymer
• the polymer may be a non-ionic polymer or an ionic polymer
• the polymer is selected from the group consisting of hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose, methacrylic acid copolymers, and the like, as well as mixtures of any two or more thereof.
• the ratio of the amount by weight of Compound I within the solid dispersion or solid molecular complex to the amount by weight of the ionic polymer therein is from about 1 :9 to about 5:5, hi a preferred embodiment of the invention, the ratio of the amount by weight of Compound I within the solid dispersion or solid molecular complex to the amount by w eight of the ionic polymer therein is from about 2 8 to about 4.6. In various embodiments the ratio of Compound I to the polymer in the solid dispersion is not 1 : 1 ; for example the ratio may be about 2:8; or about 3:7; or about 4:6.
• the ratio of the amount by weight of Compound I within the solid dispersion or solid molecular complex to the amount by weight of the ionic polymer therein is about 3 "7
• Compound I may be present in the solid dispersion in an amount of from about 0.1 % to about 80%, by weight, of the solid dispersion; or in amount of from about 10% to about 70%, by weight, of the solid dispersion; or in an amount of from about 20% to about 60%, by weight, of the solid dispersion, or in an amount of from about 20% to about 40%, by weight, of the solid dispersion; or in an amount of about 30%, by weight, of the solid dispersion,
• the polymer may be present in the solid dispersion in an amount of not less than about 20%, by weight, of the solid dispersion; or in an amount of from about 20% to about 95% by weight of the solid dispersion; or in an amount of from about 20% to about 70% by weight of the solid disper
• Compound I is stable in the solid dispersion (or solid molecular complex) for at least 2 months at 25°C; or for at least 6 months at 25°C; or for at least 12 months at 25 0 C; or for at least 15 months at 25°C; or for at least 18 months at 25 0 C, or for at least 24 months at 25°C, or for at least 2 months at 4O 0 C and 75% relative humidity; or for at least 4 months at 40°C and 75% relative humidity, or for at least 5 months at 40 0 C and 75% relative humidity; or for at least 6 months at 40°C and 75% relative humidity hi certain preferred embodiments, Compound I is immobilized so that it is primarily in amoiphous form within the solid dispersion or solid molecular complex for at least three weeks of storage at 40 0 C and 75% relative humidity, or for at least one month of storage at 4O 0 C and 75% relative humidity; or for at least two months of storage at 4O 0 C and 75% relative
• Compound I is present in the complex as a tosylate salt; or as a mesylate salt.
• the complex may further include a pharmaceutically acceptable carrier.
• the term "primarily in amorphous form” means that greater than 50%; or greater than 55%; or greater than 60%; or greater than 65%; or greater than 70%; or greater than 75%; or greater than 80%; or greater than 85%; or greater than 90%; or greater than 95% of the compound present in a composition is in amorphous form.
• the term "about” used in the context of quantitative measurements means the indicated amount ⁇ 10%.
• “about 2:8” would mean 1.8-2.2 : 7.2-8.8.
• an active compound is “stable” if the activity at the end of the specified period is at least 50%; or at least 60%; or at least 70%; or at least 75%; or at least 80%; or at least 85%; or at least 90%; or at least 95%; or at least 98% of the activity of the compound at the beginning of the specified period.
• a compound in an amorphous form is stable if at least 50%; or at least 60%; or at least 70%; or at least 75%; or at least 80%; or at least 85%; or at least 90%; or at least 95%; or at least 98% of the compound remains in the amorphous form at the end of the specified period.
• an amorphous compound is stable if it does not form any detectable crystalline peaks in powder XRD profiles during the indicated period.
• methacrylic acid copolymers includes methacrylic acid copolymers, methacrylic acid - methacrylate copolymers, methacrylic acid - ethyl aery late copolymers, ammonium methacrylate copolymers, aminoalkyl methacrylate copolymers and the like.
• a “methacrylic acid copolymer” may be EUDR AGITCS I.
• EUDRAGIT® L 12,5 also referred to as, or conforms with: “Methacrylic Acid Copolymer, Type A;” “Methacrylic Acid - Methyl Methacrylate Copolymer (1 : 1);” “Methacrylic Acid Copolymer L;” “DMF 1242” or “PR-MF 6918”); EUDRAGIT® S 100 and EUDRAGIT® S 12,5 (also referred to as, or conforms with: “Methacrylic Acid Copolymer, Type B;” “Methacrylic Acid - Methyl Methacrylate Copolymer ( 1 2)," “Methacrylic Acid Copolymer S;” “DMF 1242” or “PR-MF 6918”); EUDRAGIT 8 L 100-55 (also referred to as, or conforms with: “Methacrylic Acid Copolymer, Type C;” “Methacrylic Acid - Ethyl Acrylate Copolymer (1 : 1) Type A;” "Dried Meth
• EUDRAGIT ® RL 12,5 also referred to as, or conforms with: polymer conforms to "Ammonio Methacrylate Copolymer, Type A;” “Ammonio Methacrylate Copolymer (Type ⁇ ):" “DMF 1242” or “PR-MF 6918”
• EUDRAGIT* RL 30 D also referred to as, or conforms with: “Ammonio Methacrylate Copolymer Dispersion, Type A;” “Ammonio Methacrylate Copolymer (Type A);” or “DMF 1242”
• EUDRAGIT ® RS 100 also referred to as, or conforms with: "Ammonio Methacrylate Copolymer.
• Type B Type B;" NF “Ammonio Methacrylate Copolymer (Type B);” “Aminoalkyl Melhacrylate Copolymer RS;” “DMF 1242” or “PR-MF 6918”); EUDRAGlT* RS PO (also referred to as, or conforms with: “Ammonio Methacrylate Copolymer, Type D;” “ ⁇ mmonio Methacrylate Copolymer (Type B);” “Aminoalkyl Methacrylate Copolymer RS;” or “DMF 1242”); EUDRAGIT 8 RS 12,5 (also referred to as, or conforms with; “Ammonio Methacrylate Copolymer, Type B;” NF polymer conforms to "Ammonio Methacrylate Copolymer (Type B);” “DMF 1242” or “PR-MF 6918”); EUDRAGIT* RS 30 D (also referred to as, or conforms with: "Ammonio Methacrylate Copolymer
• a second aspect provided are methods of making solid dispersions or solid molecular complexes as disclosed herein.
• the method may involve using Compound I in the form of a tosylate or mesylate salt.
• a crystalline polymorph Form 1 of Compound I exhibits a powder x-ray diffraction pattern having characteristic peak locations of approximately 4 7, 9 4, 11 0, 12.5, and 15 4 degrees 2 ⁇ : or having characteristic peak locations of approximately 4.7, 9,4, 10.0, 1 l.U, 12.5, 14.2, 15.4, 18.6, and 22.2 degrees 2 ⁇ ; or having characteristic peak locations of approximately 4.7, 9.4, 10.0, 1 1.0, 12.5, 14.2, 15,4, 16.1 , 18.6, 19.0. 22,2 and 26.8 degrees 20.
• the crystallme polymorph Form 1 of Compound I exhibits a powder x-ray diffraction pattern substantially the same as the powder x-ray diffraction pattern of FIG 1
• a crystalline polymorph Form 2 ot Compound I exhibits a powder x-ray diffraction pattern having characte ⁇ stic peak locations of approximately 8 8, 9 2, 13 5, 19 1 and 24 4 degrees 20, or having characte ⁇ stic peak locations of approximately 6 7, 8 8, 9 2, 13 5, 15 0, 17 7, 19 1, 19 7, 21 4 and 24 4 degrees 20, or having charactenstic peak locations of approximately 6 7, 8 8, 9 2, 13 5, 14 1 , 14 5, 15 0, 16 2, 17 0, 17 7, 19 1, 19 7, 21 4, 22 2, 24 1 , 24 4, and 28 1 degrees 2 ⁇
• the crystalline polymorph Form 2 of Compound I exhibits a powder x-ray diffraction pattern substantially the same as the powder x-ray diffraction pattern of FIG 2
• methods of prepa ⁇ ng solid dispersions and solid molecular complexes as desc ⁇ bed herein wherein the solid dispersion or solid mo
• solid form refers to a solid preparation (i e a preparation that is neither gas ⁇ UJ liquid) of a pharmaceutically active compound that is suitable for administration to an intended animal subject for therapeutic purposes
• the solid iorm includes any complex such as a salt, co-crystal or an amorphous complex, as well as any polymorph of the compound
• the solid fo ⁇ n may be substantially crystalline, semi-crystalline or substantially amorphous
• the solid form may be administered directly or used m the preparation of a suitable composition having improved pharmaceutical properties
• the solid form may be used in a formulation comprising at least one pharmaceutically acceptable carrier or excipient
• substantially crystalline material embraces material which has greater than about 90% crystalhnity
• crystalline " ' material embraces material which has greater than about 98% crystalhnity
• substantially amorphous material embraces material which has no more than about 10% crystall ⁇ nit>, and "amorphous ' mate ⁇ al embraces matenal which has no more than about 2% crystalhnity
• a mixture of solid forms of a compound may be prepared, for example, a mixture of amorphous and crystalline solid fo ⁇ ns, e g to provide a "semi-crystalhne" solid form
• a “semi-crystallme” solid form may be prepared by methods known in the art, for example by mixing an amorphous solid form with a crystalline solid form in the desired ratio
• a compound mixed with acid or base forms an amorphous complex
• a semi- crystallme solid can be prepared employing an amount of compound component in excess of the stoichiometry of the compound and acid
• the term "stoichiometry" refers to the molar ratio of two or more reactants that combine to form a complex for example, the molar ratio of acid or base to compound that form an amorphous complex
• a l l mixture of acid or base with compound (i e 1 mole acid or base per mole of compound) resulting in an amorphous solid form has a l l stoichiometry
• composition refers to a pharmaceutical preparation suitable for administration to an intended animal subject for therapeutic purposes that contains at least one pharmaceutically actrve compound, including any solid form thereof
• the composition may include at least one additional pharmaceutically acceptable component to pro ⁇ ide an improved formulation of the compound, such as a suitable carrier or excipient
• a “pharmaceutically acceptable” indicates that the indicated mate ⁇ al does not to d ⁇ oid administration ⁇ f the material to a patient, taking into consideiation the disease or conditions to be treated and the respective route of administration For example it is commonly required that such a mate ⁇ al be essentially sterile, e g , for injectibles
• the term “therapeutically effective” or “effectn e amount” indicates that the materials or amount of material is effectn e to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated
• a “therapeutically-effective amount" of Compound 1 refers to such dosages and/or administration for such periods of time necessary to inhibit human b-Raf containing the V600E mutation
• a therapeutically effective amount may be one in which the overall thcrapcutically-beneficial effects outweigh the toxic or undesirable side effects ⁇ therapeutically effective amount of Com
• the terms “synergistically effective” or “synergistic effect” indicate that two or more compounds that are therapeutically effective, when used in combination, provide improved therapeutic effects greater than the additive effect that would be expected based on the effect of each compound used by itself
• the term “modulating” or “modulate” refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as a protein kinase
• a biological activity associated with a particular biomolecule such as a protein kinase
• an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, e g . an enzyme, by either increasing (e g agonist, activator), or decreasing (e g antagonist, inhibitor) the activity of the biomolecule, such as an enzyme
• Such activity is typically indicated in terms of an inhibitory concentration (IC ⁇ n) or excitation concentration (ECs 0 ) of the compound for an inhibitor or activator, respectiv ely, w ith respect to, for example, an enzyme
• Figure 1 is a powder x-ray diffraction pattern for the crystalline polymorph f orm 1 of Compound 1
• Figure 2 is a powder x-ray diffraction pattern for the crystalline polymorph Form 2 of Compound I
• Figure 3 is a compa ⁇ son of powder x-ray diffraction pattern for the crystalline polymorph Form 2 and the mesylate salt of Compound I
• Figure 4 is a compa ⁇ son of powder x-ray diffraction pattern for the crystalline polymorph Form 2 and the tosylate salt ol Compound I
• FIG. 5 is a schematic drawing of an exemplary setup for manufacturing a solid dispersion (MBP) according to steps a) to d), more specifically according to Example 22 of the present invention
• Figure 6 is a detailed schematic drawing of the high shear mixing unit ((6) of Fig 5)
• Figures 7 A and 7B provide a compa ⁇ son of X-ray patterns obtained from two lots of solid dispersions (MBP's) containing HPMCAS and Compound I, manufactured via high shear mixer precipitation according to the method disclosed in Hxamplc 22 (see Figure 7A) and via conventional spray precipitation (see Figure 7B)
• Propane- 1 -sulfonic acid ⁇ 3-[5-(4-chloro-phcnyl)-lH-pyt ⁇ olo[2,3-b]py ⁇ dme-3-carbonyl]- 2,4-difluoro-phenylJ -amide, is a compound with the following structure:
• Compound I is a b-raf kinase inhibitoi
• Noimally functioning b- Raf is a kinase which is involved in the relay of signals from the cell membrane to the nucleus and is active only when it is needed to relay such signals.
• Mutant b-Raf is constantly active and thus plays a role in tumor development.
• Mutant b-Raf containing a V600E mutation has been implicated in various tumors, for example, colorectal cancer, melanoma, and thyroid cancer Propane- 1 -sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-l H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4- difluoro-phenyl ⁇ -amide specifically targets mutant b-Raf containing the V600E mutation. Accordingly, such an inhibitor is used in the inhibition of tumors, particularly solid tumors such as melanoma.
• Compound I will refer to propane- 1 - sulfonic acid ⁇ 3-[5-(4-chlorophenyl)-lH-pyrrolo [2,3-b] pyridine-3-carbonyl-2,4-difluoro-phenyl]- amide as well as any salt, conjugate, derivative, or prodrug thereof,
• Amorphous forms of Compound I have improved solubility in water as compaied to the crystalline form, but is unstable as it has a tendency to crystallize Thus it is desired to iormulate Compound I so that it may stably exist primarily in amorphous form
• compositions and methods for improving the solubility and/or bioavailability of Compound 1 are provided in certain embodiments, provided are compositions and methods involving Compound I in a composition, form, or formulation in which it has improved water solubility and/or bioavailability of as compared to Compound I in a crystalline form, or Compound I in a primarily crystalline form
• the amorphous form of Compound I may have improved solubility m water as compared to Compound I in a crystalline form
• formulations of Compound I in which Compound I exists stably in amorphous form may be accomplished, for example, by immobilizing the compound within a matrix formed by a polymer See, for example, U S Patent No 6,350,786
• solid dispersions and solid molecular complexes that include Compound I
• Compound I may be dispersed within a matrix formed by a polymer in its solid state such that it is immobilized in its amorphous iorm
• the polymer may prevent intramolecular hydrogen bonding or weak dispersion forces between two or more drug molecules of Compound I See, for example, Matsumoro and Zografi, Pharmaceutical Research, Vo 16, No 1 1 , p 1 ⁇ 22-172S, 1999
• the solid dispersion provides lor a large surface area, thus further allowing for improved dissolution and bioavailability of Compound I
• a solid dispersion or solid molecular complex includes a therapeutically-effective amount of Compound I
• Compound I is present in the solid dispersion in an amount of from about 1 % to about 50%, by weight; or from about 10% to about 40% by weight; or from about 20% to
• a polymer is present in the solid dispersion in an amount of from about 0% to about 50% by weight; or from about 5 % to about 60% by weight; or from 10% to about 70% by weight. In certain embodiments a polymer is present in the solid dispersion in an amount greater than about 10% by weight; or greater than about 20% by weight; or greater than about 30% by weight; or greater than about 40% by weight; or greater than about 50% by weight. In one preferred embodiment, the solid dispersion is about 30% by weight Compound I and about 70% by weight polymer.
• the solid dispersion may comprise Compound I dispersed in a non-ionic polymer. This may be accomplished by various means, including: (A) melting the polymer and dissolving the compound in the polymer and then cooling the mixture; and (B) dissolving both the compound of interest and the polymer in an organic solvent and evaporating the solvent in a rotary evaporator, for example.
• the resulting solid dispersion may comprise the compound dispersed in the polymer in amorphous form.
• a solid dispersion may be formed by dispersing Compound I in an ionic polymer. Such solid dispersion may result in increased stability of Compound I. This may be accomplished by various means, including the methods described above for use in forming a dispersion in a non-ionic polymer. Because ionic polymers have pH dependent solubility in aqueous systems, the resulting solid dispersion of the Compound I and the polymer may be stable at low pH in the stomach and release the Compound I in the intestine at higher pH which is the site of absorption. In preferred embodiments, Compound I in such solid dispersions with an ionic polymer may thus be less capable of separating from the polymer and may be immobilized by the polymer in its amorphous form.
• ionic polymer Any ionic polymer may be used in the practice of the present invention.
• ionic polymers include hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose phthalate (HPMCP), and methacrylic acid copolymers.
• a polymer which is capable of immobilizing Compound I so that it exists primarily in an amorphous form for an extended period of time is preferred.
• polymers such as HPMC-AS and EudragitS 1 L 100-55 (a methdcryhc acid copolymer) are capable of immobilizing Compound I so that it exists primarily in an amorphous form for at least four weeks while in storage at 40 0 C and 75% relative humidity
• HPMC-AS and Eudragit® L 100-55 are preferred polymers for use in certain embodiments of the present invention
• HPMC-AS (HPMCAS or AQOATTM, which is available from, for example, Shin-Etsu) is a particularly preferred polymer for use in the practice of certain embodiments of the present invention It is available in the following grades AS-LF, AS MF, AS- HF, AS-LG, AS-MG and AS- HG HPMC-AS is an anionic, relatively water insoluble, high molecular weight polymer with a pH dependent water solubility, leading to dissolution at pH 5 2 and above Said dissolution can be tailored between pll 5 2 and 6 5 according to the HPMC-AS grades used HPMC-AS may be relatively resistant to breakdown in the acidic environment of the stomach and under normal temperatures of storage At the same time, because HPMC-AS dissolves at pH 5 2 and above, it dissolves in the basic environment of the intestine, thus allowing for improved absorption of Compound I and further allowing for improved bioavailability of the Compound I Accordingly, in certain embodiments of the invention, Compound I is in a solid dispersion
• the ratio of the amount by weight of Compound I within the solid complex to the amount by weight of the ionic polymer therein is from about 1 9 to about 1 1 In a preferred embodiment of the invention, the ratio of the amount by weight of Compound I within the solid complex to the amount by w eight of the ionic polymer therein is from about 2 8 to about 4 6 In a preferred embodiment of the invention, the ratio of the amount by weight of Compound I within the solid complex to the amount by weight of the ionic polymer therein is about 3 7
• Compound I is immobilized so that it is primarily in amorphous form within the complex for up to three w eeks of storage at 40 0 C and 75% relative humidity
• Compound I is immobilized so that it is primarily m amorphous form within the complex for up to one month of storage at 4O 0 C and 75% relative humidity
• Compound I is immobilized so that it is primarily in amorphous form within the complex for up to two months of storage at 4O 0 C and 75% relative humidity
• Compound I is immobilized so that it is primarily in amorphous form within the complex for up to three months of storage at 4O 0 C and 75% relative humidity
• HPMC-AS is present in the solid dispersion in amount of from about 1% to about 50% by weight; or from about 5 % to about 60% by weight; or from 10% to about 70% by weight. In certain embodiments , HPMC-AS is present in the solid dispersion in an amount greater than about 10% by weight, or greater than about 20% by weight; oi greater than about 30% by weight, or greater than about 40% by weight, or greater than about 50% by weight
• the present inventions also relate to compositions comprising a solid dispersion or solid molecular complex as disclosed herein.
• the composition may, in addition to the solid dispersion or solid molecular complex, also comprise therapeutically inert, inorganic oi organic earners (for example, pharmaceutically-acceptable carriers or excipients).
• the pharmaceutical composition may also contain additional agents such as preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colonng agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents and antioxidants
• additional agents such as preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colonng agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents and antioxidants
• the composition may dlso contain additional therapeutically-active compounds or more than one therapeutically-active compound/polymer complex (e.g., a solid dispersion or solid molecular complex)
• the composition includes the solid dispersion or solid molecular complex suspended in an aqueous vehicle containing hydroxypropylcellulose (HPC)
• HPC hydroxypropylcellulose
• the vehicle contains about 2% by weight HPC.
• the composition includes colloidal silicon dioxide (silica).
• the addition of colloidal silicon dioxide may further improve the stability of the solid dispersion or solid molecular complex
• the composition includes at least about 0 5% by weight colloidal silicon dioxide
• compositions include Compound I (for example in a solid dispersion or solid molecular complex) and Crospovidone (or Polyplasdone XL; a disintegrating agent for the dosage form), magnesium stearate (a lubricant that may be used in tablet and capsulation operations), and/or croscarmellose sodium (AcDiSoI; a disintegrating agent),
• the composition comprises the solid dispersion or solid molecular complex suspended in an aqueous vehicle that is up to 2% by weight HPC and at least about 0.5% by weight colloidal silicon dioxide.
• Compound 1 may be microprecipitated with a polymer as disclosed herein (for example, HPMC-AS). Microprecipitation may be accomplished by any means known in the art, for example: spray drying or lyophilization; solvent-controlled precipitation; pH ⁇ controlled precipitation; hot melt extrusion; and supercritical fluid technology. Each of these methods is described in more detail below.
• the solid dispersion precipitates out of solution using the various methods, it can be recovered from the solution by procedures known to those skilled in the art, for example by filtration, centrifugation, washing, etc.
• the recovered solid molecular complex can then be dried (e.g., in air, an oven, or a vacuum) and the resulting solid can be milled, pulverized or micronized to a fine powder by means known in the art.
• the powder form of the solid dispersion can then be dispersed in a carrier to form a pharmaceutical composition.
• at least about 0.5% w/w colloidal silicon dioxide is added to the composition.
• Compound I and a polymer may be dissolved in a common solvent having a low boiling point, e.g., ethanol, methanol, acetone, etc.
• a common solvent having a low boiling point e.g., ethanol, methanol, acetone, etc.
• the solvent is evaporated by flash evaporation at a temperature close to the boiling point thereof, or under a high vacuum (low vapor pressure), leaving Compound I precipitated in a matrix formed by the polymer.
• Compound I is in a mesylate or tosylate salt form, and thus preferably has improved solubility.
• Compound 1 and a polymer may be dissolved in a common solvent, e.g., dimethylacetamide, dimethylformamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), etc.
• the Compound I / polymer solution is added to cold (0 to 7 0 C, preferably 2 to 5 0 C) water adjusted to an appropriate pH (for example in many embodiments an appropriate pH is a pll of 3 or less).
• This causes Compound 1 to microprecipitate in a matrix formed by the polymer (for example, HPMC- ⁇ S).
• the microprecipitate may be washed several times with aqueous medium until the residual solvent falls below an acceptable limit for that solvent.
• An "acceptable limit" for each solvent is determined pursuant to the International Conference on Harmonization (ICII) guidelines.
• a solution comprising Compound I, an organic solvent (such as dimethylformamide, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), and the like) and the ionic polymer is formed.
• the organic solvent is preferably DMA at 20 to 25 0 C.
• the solution may be formed by first dissolving Compound I into the organic solvent. Then, while stirring, the polymer is added. The mixture is then heated up to between about 50 to about H O 0 C, preferably to about 7O 0 C.
• a second solution that is 0.01 N HCl is also formed. This will herein be termed the "aqueous phase".
• the aqueous phase has a temperature between about 0 and about 6O 0 C, preferably between 5 and 15 0 C.
• the aqueous phase is then circulated through the mixing chamber of a high shear mixer while the organic phase is dosed into the chamber while the chamber is operating. Dosing may be accomplished with, for example, a gear pump, a hose pump, or a syringe pump. In a preferred embodiment, dosing is accomplished using a gear pump with an injector nozzle pointed into the mixing chamber.
• the mixing chamber preferably comprises a rotor and a stator.
• the rotor and the stator may, for example, each have either one or two rows of teeth. In a preferred embodiment, the rotor and the stator each have one row of teeth.
• the tip speed of the rotor is preferably set at between about 15 and about 25 m/sec.
• the above method includes the following steps,
• the present methods include the steps, wherein
• step (a) above is a 35 % solution of Compound I and HPMCAS in DMA, the ratio of Compound I to HPMCAS being 30% to 70% (w/w);
• step (b) above is achieved via an injector nozzle which is oriented at an angle between 40 and 50° to the longitudinal axis of the high shear mixer and has a distance of about 1 to about 10 mm from the rotor of said high shear mixer which is operating with a tip speed of about 15 to about 25 m/sec.
• the present methods include the step, wherein
• step (b) above is achieved via an injector nozzle which is oriented at an angle of about 45° to the longitudinal axis of the high shear mixer and has a distance of about 2 to about 4 mm from the rotor of said high shear mixer which is operating with a tip speed of about 25 m/sec.
• the present methods include the step, wherein
• step (g) above is achieved via fluidized bed drying.
• the dried precipitate obtained by the above method can be further processed into any type of solid pharmaceutical preparations or dosage forms, which are known to the person of skill in the art. Particularly preferred are oral dosage forms such as tablets, capsules, pills, powders, suspensions, and the like.
• Organic solvent means any organic solvent wherein both Compound I and HPMCAS are miscible.
• Preferred organic solvents are N- Methylpyrrolidone (NMP), Dimethylformamide (DMF), Dimethylsulfoxide (DMSO), Dimethylacetamide (DMA), and the like, with DMA being the most preferred.
• NMP N- Methylpyrrolidone
• DMF Dimethylformamide
• DMSO Dimethylsulfoxide
• DMA Dimethylacetamide
• the combined amount uf Compound I and HPMCAS together in the organic phase can be within the range of about 15 to 40 weight%, preferably about 25 to 40, most preferably about 35 weight% .
• the weight ratio of Compound I / HPMCAS in the organic solvent is about 30/70 weight%, respectively.
• the temperature of the organic solvent is adjusted between 50 and 1 10 0 C, preferably 60 and 90 0 C, most preferred at about 70 0 C prior to its addition to the mixing chamber as mentioned under step (b).
• the mixture of Compound I and HPMCAS in the organic solvent is also designated herein as the "organic phase” or "DMA phase”.
• aqueous phase preferably consists of acidic water
• the aqueous phase is kept at a temperature between about 0 and about 60 0 C, preferably between about 0 and 20 0 C, more preferred between about 5 and about 15 0 C, most preferably about 5 0 C .
• the aqueous phase circulates out of the bottom valve of its reservoir ((1) of Fig. 5) due to the stream created by the high shear mixer or with an auxiliary pump, preferably a rotary lobe pump, then passes through the high shear mixer, back into the reservoir.
• the outlet of the loop is placed under the fluid level maintained in the reservoir, in order to prevent foaming.
• step (b) The addition of the organic phase to the mixing chamber as mentioned in step (b) above is achieved via an injector nozzle which directly points into the aqueous phase.
• Any conventional nozzle known to the person of skill in the art can be used.
• Preferred injector nozzles show central or acentric geometry and have a diameter of about 1 to 10 mm.
• the acentric (not centered) geometry and a diameter of 5 mm are especially preferred.
• the injector nozzle may point to the rotor of the high shear mixing unit at an angle between 0 and 90°, preferably between 40 and 50°, most preferably at 45° (a, Fig. 6).
• the distance between the point of the injector nozzle and the tip of the rotor of the high shear mixing unit is about 1 to 10 mm, preferably about 2 to 4 mm and most preferably about 2.6 mm.
• the addition of the organic phase is preferably carried out at dosing rates of about 60/1 to about 300/1 (ratio of aqueous phase/organic phase during precipitation), preferably about 70/1 to about 120/1 and most preferably at about 100/1.
• Final ratio of aqueous phase/organic phase after precipitation is in the range of about 5/1 - 12/1 preferably 7/1 - 10/1 and most preferably at 8.5/1.
• the high shear mixing unit is operating Any conventional high shear mixing unit (rotor/stator unit) known to the person of skill in the art can be applied.
• the prctcrrcd rotor geometry according to the present invention uses a rotor/stator unit with a radial single teeth row or double teeth row or combination thereof
• the tip speed of the rotor is about 15 to about 25 m/sec , preferably 25 m/sec
• the obtained suspension is further circulated in the closed loop containing the high shear mixing unit Outside of the high shear mixing unit the circulation must be carried out with the aid of an auxiliary pump preferably a rotary lobe pump
• the suspension is passed through the high shear mixing unit several times, up to the moment where a desired particle size and'or particle size distribution is obtained Usually the suspension is passed through the high shear mixing unit about 1 to 60 times, most preferably 6 times
• the particle sue and 'or particle size distribution can be determined by standard techniques, well known to the person of skill in the art, such as for example dynamic light scattering
• Isolation of the solid dispersion (MBP) according to step (e) abo ⁇ e can be carried out by using conventional filter techniques or centrifuges Prior to isolation, the suspension is preferably adjusted to about 5 to 10 0 C Subsequently, the isolated solid dispersion is washed with acidic water, preferably 0 01 N HCl followed by further washing with pure water in order to substantially remove the organic solvent (step (f))
• the isolated (wet) solid dispersion (MBP) usually shows a water content between 60 and 70 % (w/w), which is prefeiably d ⁇ ed before any furfhei processing
• the drying can be carried out using any standard techniques known to the person of skill in the art, for example using a cabinet dryer at temperatures between 30 and 50 °C, preferably at about 40 C C and at reduced pressure, preferably below 20 mbar Several drying procedures can be combined or used sequentially, whereby the use of f ⁇ uidized bed drying is especially preferred as the final drvm
• Example 22 A specific method of making the (HPMCAS-Compound I) MBP according to steps a) to g) abo ⁇ e is desc ⁇ bed in Example 22, which forms a further preferred embodiment of the present mvention
• the stability of the solid dispersion (MBP) as obtained by the method of Example 22 was compared with the stability of an MBP obtained via conventional spray precipitation
• "Conventional spray precipitation * ' means that the organic phase was sprayed onto the aqueous phase via a nozzle which is placed outside the aqueous phase, above its surface like is the case for many conventional spray-precipitation techniques All further process parameters are the same for both methods
• the stability, thus the inhibition of re- crystallization of Compound I, is determined by x-ray diffraction measurements, using a conventional wide angle X-ray scattering setup as it is well known to the skilled artisan Sample preparation was identical for both MBP's The samples were treated in a climate chamber (50 0 C and 90 % humidity (RH))
• Figure 5 contemplates two reservoirs (v essels) with temperature contiol means, one foi providing the aqueous phase at a controlled temperature (1), the other for providing the organic phase at a controlled temperature (2) Both vessels are further equipped w ith automatic stirrers (3)
• the aqueous phase is circulated in a closed loop (4) using a pump (5), while passing through a high shear mixing unit (6)
• the organic phase is, added into the aqueous phase within the high shear mixing unit with the aid of a dosing pump (7) and via an injector nozzle which is shown in more detail in tig 6
• the nozzle (8) is placed w ithin the aqueous phase inside the high shear mixing unit
• the nozzle can be oriented within different angles ( ⁇ ) with respect to the rotor (9) of the high shear mixing unit, and within defined distances (d) of the rotor tip
• the solid dispersion in particular the MBP obtainable according to the methods provided can be used in a wide variety of forms for administration of drugs such as Compound I including drugs that are poorly water soluble, and in particular for oral dosage forms
• Exemplary dosage forms include powders or granules that can be taken orally either dry or reconstituted by addition of water to form a paste, slurry, suspension or solution, tablets, capsules, or pills
• Various additives can be mixed, ground or granulated with the solid dispersion as described herein to form a material suitable for the above dosage forms
• Potentially beneficial additiv es may fall generally into the following classes other matrix materials or diluents, surface active agents, drug complexing agents or solubihzers, fillers, dismtegrants, binders, lub ⁇ cants, and pH modifiers (e g , acids, bases, or buffers)
• Examples of other matrix materials, fillers, or diluents include lactose, manmtol,
• Additives may be incorporated into the solid amorphous dispersion during or after its formation
• any conv entional mate ⁇ als and procedures for formulation and preparation of oral dosage forms using the compositions disclosed herein known by those skilled in the art are potentially useful.
• a further embodiment includes a pharmaceutical preparation containing the solid dispersion as obtained by a method as described herein, in particular as obtained according to steps a) to g) as mentioned above, and more particularly as obtained according to the process described in Example 22.
• a solid dispersion as obtained according to the present process for use as a medicament in particular a solid dispersion comprising HPMCAS and Compound I, more particularly the solid dispersion as obtained according the steps a) to g) above or according to Example 22.
• solid dispersion obtainable by the present steps a) to g) or by the method of Example 22 in the manufacture of medicaments for the treatment of cancer, in particular solid tumors, and more particularly malignant (metastatic) melanomas.
• the process involves the microprecipitation of Compound I in an ionic polymer (for example, HPMC-AS).
• an ionic polymer for example, HPMC-AS.
• Compound I and the polymer are dissolved at a high pH and precipitated by lowering the pH of the solution or vice versa.
• the polymer is HPMC-AS which is insoluble at low pH.
• Compound I and HPMC-AS are dissolved in an organic solvent such as dimethylformamide, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), and the like
• the pH of the solution is then lowered, for example by adding an acid.
• Addition of the acid includes mixing of the Compound I and polymer solution and the acid, for example by adding acid to the Compound I and polymer solution, adding the Compound I and polymer solution to the acid, or mixmg the two simultaneously At the lowered pH, both Compound I and HPMC-AS simultaneously precipitate out, resulting in a solid molecular complex containing Compound I embedded in a matrix formed by HPMC- ⁇ S The resulting solid molecular complex may then be washed with water to remove the organic solvent
• Microprecipitation of the Compound I in a polymer can be achieved in certain embodiments by a hot melt extrusion process
• Compound I and the polymer are mixed and then fed continuously to a temperature-controlled extruder causing the Compound I to be molecularly dispersed in the molten polymer
• the resulting extrudate is cooled to room temperature and milled into a fine powder
• the resulting solid molecular complex prepared by any method may be further processed to provide suitable bioavailability
• the solid molecular complex may be processed by roller compaction, for example the complex and other powders may be blended and roller compacted to form a ribbon or sheet that is then milled, mixed with other excipients and encapsulated into 2-pc hard gelatin capsule shells at the desired strength
• Whether Compound I has been successfully immobilized in amorphous form can be determined by various means, including powder X-ray diffraction
• the glass transition temperature of the complex can be measured using modulated DSC and this can also provide information whether the dispersion is a multiphase or umphase A uniphase is indicatn e of such immobilization
• Crystalline polymorphs of pi opane-1 -sulfonic acid ⁇ 3-[5-(4-chloro-phenyI)- l H- pyrrolo[2,3-b]py ⁇ dme-3-carbon>l]-2,4-difluoro-phenyl ⁇ -amidc (Compound I) arc provided
• crystalline polymorph Form 1 is provided, wherein the polymorph exhibits a powder x- ray diffraction pattern having characte ⁇ stic peak locations of approximately 4 7, 9 4, 1 1 0, 12 5, and 15 4 degrees 2 ⁇
• polymorph Form 1 exhibits a powder x-ray diffraction pattern having characte ⁇ stic peak locations of approximately 4 7, 9 4, 10 0, 11 0, 12 5, 14 2, 15 4, 18 6, and 22 2 degrees 2 ⁇
• polymorph Form 1 exhibits a powder x-ray diffraction pattern having characte ⁇ stic peak locations of approximately 4 7, 9 4, 10 0, 1 1 0, 12 5, 14
• 4-difluoro-phenyl ⁇ -dmide may be retry stalhzed from acetone absolute ethanol in a ratio of from 1 1 to 5 1, preferably 2 1 by ⁇ olume (B) Crystalline Polymorph Form 2
• Crystalline polymorph Form 2 of propane- 1 -sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-lII- pyrrolo[2,3-b]pyndinc-3-carbonvl]-2,4-difluoro-phenyl ⁇ -amide is provided wherein the polymorph exhibits a powder x ray diffraction pattern having characteristic peak locations of approximately 8 8, 9 2, 13 5, 19 1 and 24 4 degrees 2 ⁇
• polymorph Form 2 exhibits, a powder x-ray diffraction pattern having characteristic peak locations of approximately 6 7, 8 8, 9 2, 13 5, 15 0, 17 7, 19 1 , 19 7, 21 4 and 24 4 degrees 2 ⁇
• polymorph Form 2 exhibits a powder x ray diffraction pattern having characteristic peak locations of approximately 6 7, 8 8, 9 2, 13 5, 14 1 , 14 5, 15 0, 16 2, 17 0, 17 7, 19 1, 19 7, 21 4, 22 2, 24 1 , 24 4, and 28 1 degrees 2 ⁇
• crystalline polymorph Form 2 of propane- 1 -s
• ⁇ mesylate salt form of propane-1 -sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)- lII-pyrrolo[2,3- b]py ⁇ dme 3 carbonyl] 2,4 difhioro phenyl ⁇ amide is provided in one embodiment, a mesylate salt form of propane- 1 -sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-lH-pyrrolo[2,3-b]py ⁇ dine-3-carbonyl]-2,4- difluoro-pheny] ⁇ -amide is provided
• the mesylate salt form is substantially crystalline
• the mesylate salt fo ⁇ n is partially amoiphous
• the mesylate salt fo ⁇ n is substantially amorphous
• the mesylate salt is used in a microprecipitated bulk process to formulate the salt in an amorphous form In
• a tosylate salt of propane- 1 -sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-lH-pyrrolo[2,3- b]py ⁇ d ⁇ ne-3-carbonyl]-2,4-diflu ⁇ ro-phenyl ⁇ -amide is provided in one embodiment, the tosylate salt form is substantially crystalline In one embodiment, the tosylate salt form is partially amorphous In one embodiment, the tosylate salt form is substantially amorphous In one embodiment, the tosylate salt is used in a microprecipitated bulk process to formulate the salt in an amorphous form In one embodiment, the tosylate salt is generated in situ in a microprecipitated bulk process to formulate the salt in an amorphous form In one embodiment, a composition is provided comprising the tosylate salt
• Protein kinases play key roles in propagating biochemical signals in diverse biological pathways More than 500 kinases have been desc ⁇ bed, and specific kinases have been implicated in a wide range of diseases or conditions (i e , indications), including for example without limitation, cancer, cardiovascular disease, inflammatory disease, neurological disease, and other diseases ⁇ s such, kinases represent important control pomts for small molecule therapeutic intervention Description of specific target protein kinases contemplated by the present invention follow
• A-Raf Target kinase A-Raf (i e , ⁇ -raf murine sarcoma 361 1 viral oncogene homolog 1) is a 67 6 kDa serine threonine kinase encoded by chromosome XpI 1 4-pl 1 2 (symbol ⁇ RAF)
• the mature protein comprises RBD (i e , Ras binding domain) and phorbol-ester/D ⁇ G-type zinc finger domain and is involved in the transduction of mitogemc signals from the cell membrane to the nucleus
• A-Raf inhibitors may be useful in treating neurologic diseases such as multi-mfarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e g colorectal, lung, breast, pancreatic, thyroid, renal, ovarian),
• Distal and Congenital Muscular Dystrophies include motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies due to endocrine abnormalities (including, but not limited to, hypothyroid myopathy and hypothyroid myopathy) diseases of peripheral nerve (including, but not limited to, Charcot-Ma ⁇ e-1 ooth disease, D ejenne- Sottas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, paramyotonia congen
• B-Raf Target kinase B-Raf (i e , v-raf murine sarcoma viral oncogene homolog B l) is a 84 4 kDa sc ⁇ nc'threonme kinase encoded by chromosome 7q34 (symbol BRAF)
• the mature protein comprises RBD (i.e , Ras binding domain), C l (i e., protein kinase C conserved region 1) and STK (i e . se ⁇ ne/threonme kinase) domains
• B-Raf is involved in the transduction of mucigenic signals from the cell membrane to the nucleus and may play a role in the postsynaptic responses of hippocampal neurons
• genes of the RAF family encode kinases that are regulated by Ras and mediate cellular responses to growth signals
• B-Raf kinase is a key component of the RAS->Raf->MEK- >ERKVM ⁇ P kinase signaling pathway, which plays a fundamental role in the regulation of cell growth, division and proliferation, and, when constitutively activated, causes tumori genesis.
• the B-typc, or B-Raf is the strongest activator of the downstream MAP kinase signaling.
• the BRAF gene is frequently mutated in a variety of human tumors, especially in malignant melanoma and colon carcinoma.
• the most common reported mutation was a missense thymine (T) to adenine (A) transversion at nucleotide 1796 (T 1796 A: amino acid change in the B- Raf protein is Val ⁇ 600> to Glu ⁇ 600> ) observed in 80% of malignant melanoma tumors.
• T 1796 A amino acid change in the B- Raf protein is Val ⁇ 600> to Glu ⁇ 600>
• Functional analysis reveals that this transversion is the only detected mutation that causes constitutive activation of B-Raf kinase activity, independent of RAS activation, by converting B-Raf into a dominant transforming protein.
• Niihori et al. report that in 43 individuals with cardio-facio-cutaneous (CFC) syndrome, they identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders (Niihori ct al., Nat Genet. 2006, 38(3):294-6).
• c-Raf-1 Target kinase c-Raf- 1 (i.e., v-raf murine sarcoma viral oncogene homolog 1 ) is a 73.0 kDa STK encoded by chromosome 3p25 (symbol: RAFl).
• c-Raf- 1 can be targeted to to the mitochondria by BCL2 (i.e., oncogene B-cell leukemia 2) which is a regulator of apoptotic cell death.
• BCL2 i.e., oncogene B-cell leukemia 2
• Active c-Raf- 1 improves BCL2-mcdiated resistance to apoptosis, and c-Raf- 1 phosphorylates BAD (i.e..
• c-Raf-1 is implicated in carcinomas, including colorectal, ovarian, lung and renal cell carcinoma. C-Raf- 1 is also implicated as an important mediator of tumor angiogenesis (Hood, ID. et al., 2002, Science 296, 2404). C-Raf-1 inhibitors may also be useful for the treatment of acute myeloid leukemia and myelodysplastic syndromes (Cramp, Curr Pharm Des 2002, 8(25):2243-8).
• Raf-1 activators may be useful as treatment for neuroendocrine tumors, such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma (Kunnimalaiyaan et al., Anticancer Drugs 2006, 17(2): 139-42).
• A-Raf, B-Raf and'or C-Raf inhibitors may be useful in treating A-Raf-medialed, B- Raf-mediated or c-Raf- 1 -mediated disease or condition selected from the group consisting oi neurologic diseases, including, but not limited to, multi-infarct dementia, head injury, spinal cord injury.
• Alzheimer's disease AD
• Parkinson's disease seizures and epilepsy
• neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e g gastrointestinal, Iner, bile duct (cholangiocarcinoma), colorectal, lung, breast, pancreatic, thyroid renal, ovarian, piostate), lymphoma (e g histiocytic lymphoma) neurofibromatosis, acute myeloid leukemia, myclodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocnne tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer, Kaposi's sarcoma, and pheochromocytoma, pam of neuropathic or inflammatory o ⁇ gm, including, but not limited to, acute pam, chrome pain, cancer-related pam, and migraine, cardiovascular diseases including, but not limited to, heart failure, ischemic stroke,
• diabetic nephropathy polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, polycystic liver disease, tuberous sclerosis, Von Hippel Lindau disease, medullary cystic kidney disease, nephronophthisis, and cystic fibrosis, metabolic disorders, including, but not limited to, obesity, infection, including, but not limited to Helicobacter pylon, Hepatitis and Influenza viruses, fever, HIV and sepsis, pulmonary diseases including, but not limited to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS), genetic developmental diseases, including, but not limited to, Noonan's syndrome, Costello syndrome, (faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-facio-cutaneous syndrome (CFC), and neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skm, hair and endoc ⁇ ne diseases, and diseases associated with muscle regeneration or degeneration, including, but
• Prodrugs are compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound.
• Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates ⁇ f the active compound.
• the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/ or metabolic properties.
• Prodrugs may include variants wherein an -NH group of the compound has undergone acylation, such as the 1-position of the pyrrolo[2,3-b]pyridine ring or the nitrogen of the sulfonamide group of Compound I or a pharmaceutically acceptable salt thereof where cleavage of the acyl group provides the free -NH group of the active drug
• Some prodrugs are activated enzymatically to yield the active compound, or a compound may undergo further chemical reaction to yield the active compound
• Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have actmt> or may be inactive
• bioprecursor prodrugs can be conceptually divided into two nonexclusive categories, bioprecursor prodrugs and carrier prodrugs
• bioprecursor prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protectrv e groups and are converted to an active form by metabolism or solvolysis Both the active drug form and any released metabolic products should have acceptably low toxicity
• the formation of active drug compound involves a metabolic process or reaction that is one of the following types
• Oxidative reactions are exemplified without limitation by reactions such as oxidation of alcohol, carbonyl, and acid functionalities, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon- carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-dcalkylation, oxidative O- and S-dealkylation, oxidative deamination, as well as other oxidative reactions
• Reductiv e reactions are exemplified without limitation by reactions such as reduction of carbonyl functionalities, reduction of alcohol functionalities and carbon-carbon double bonds, reduction of nitrogen-containing functional groups, and other reduction reactions
• Reactions without change m the oxidation state Reactions without change in the state of oxidation are exemplified without limitation to reactions such as hydrolysis of esters and ethers hydiolytic cleavage of carbon-nitrogen single bonds, hydrolyuc cleavage of non-aromatic hctcrocycles, hydration and dehydration at multiple bonds, new atomic linkages resulting from dehydration reactions, hydrolytic dehalogenation, removal of hydrogen hahde molecule, and other such reactions [0115]
• Carrier prodrugs are drug compounds that contain a transport moiety, e.g., thai improves uptake and/or localized delivery to a site(s) of action.
• the linkage between the drug moiety and the transport moiety is a covalent bond
• the prodrug is inactive or less active than the drug compound
• the prodrug and any release transport moiety are acceptably non-toxic.
• the release of the transport moiety should be rapid. Tn other cases, it is desirable to utilize a moiety that provides slow release, e.g., certain polymers or other moieties, such as cyclodextrins. (See, e.g., Cheng et al., U.S. Patent Publ. No. 20040077595, App. No.
• carrier prodrugs are often advantageous for orally administered drugs.
• the transport moiety provides targeted delivery of the drug, for example the drug may be conjugated to an antibody or antibody fragment.
• Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property).
• lipophilicity can be increased by esterification of hydroxyl groups with lipophilic carboxylic acids, or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols. Wermuth, supra.
• Metabolites e.g., active metabolites
• prodrugs as described above, e.g., bioprecursor prodrugs.
• metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic processes in the body of a subject.
• active metabolites are such pharmacologically active derivative compounds.
• the prodrug compound is generally inactive or of lower activity than the metabolic product.
• the parent compound may be cither an active compound or may be an inactive prodrug.
• one or more alkoxy groups can be metabolized to hydroxyl groups while retaining pharmacologic activity and/or carboxyl groups can be esterified, e.g., glucuronidation,
• carboxyl groups can be esterified, e.g., glucuronidation
• there can be more than one metabolite where an intermediate metabolite(s) is further metabolized to provide an active metabolite.
• a derivative compound resulting from metabolic glucuronidation may be inactive or of low activity, and can be further metabolized to provide an active metabolite.
• Metabolites of a compound may be identified using routine techniques known in the art, and their activities determined using tests such as those described herein See, e g , Bertolini et al , 1997, J Med Chan , 40 201 1-2016, Shan et al , 1997, J P harm Sci 86(7) 756-757, Bagshawc, 1995, Drug De ⁇ Res , 34 220-230, Wermuth, supra
• composition of such compound can be in the form of pharmaceutically acceptable salts, or can be formulated as pharmaceutically acceptable salts
• Contemplated pharmaceutically acceptable salt forms include, without limitation, mono, bis, t ⁇ s, tetrakis, and so on
• Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered The preparation of such salts can facilitate the pharmacological use by altering the physical characte ⁇ stics of a compound without preventing it from exerting its physiological effect
• Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate admimste ⁇ ng higher concentrations of the drug
• Compound I possesses a sufficiently acidic and a sufficiently basic functional group, and accordingly can react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt
• Pharmaceutically acceptable salts include acid addition salts such as those containing chloride, bromide, iodide, hydrochloride, acetate, dichloroacetate phenylacetate, acrylate, ascorbate, aspartate, benzoate, 2-phenox ⁇ benzoate, 2-acetoxybenzoate dinitrobenzoate, hydroxybenzoate methoxybenzoate, methylbenzoate, bicarbonate, butyne- 1 ,4 dioatc, hcxync-l,6-dioate, caproate, caprylate, chlorobenzoate, cinnamate, citrate, decanoate, formate, fumarate, glycolate gluconate, glucarate, glucuronate, glucose-6-phosphate, glutamate, heptanoale, hexanoate, iscthionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate, lactate,
• pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, ethanolamine, diethanolamine, triethanolamine, t-butylamine, dicyclohexylamine, ethylenediamine, N,N'-dibenzylethylenediamine, meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazi ⁇ e, procaine, aluminum, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, ammonium, and mono-, di-, or tri- alkylamines (e.g.
• diethylamine or salts derived from amino acids such as L-histidine, L-glycine, L-lysine, and L-arginine.
• L-histidine amino acids
• L-glycine amino acids
• L-lysine amino acids
• L-arginine amino acids
• salts can be prepared by standard techniques.
• the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution.
• a salt can be prepared by reacting the free base and acid in an organic solvent. If the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an appropriate inorganic or organic base.
• suitable solvent such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution.
• a salt can be prepared by reacting the free base and acid in an organic solvent. If the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an appropriate inorganic or organic base.
• the compounds and salts may exist in different crystal or polymorphic forms, or may be formulated as co-crystals, or may be in an amorphous form, or may be any combination thereof (e.g. partially crystalline, partially amorphous, or mixtures of polymorphs) all of which are intended to be within the scope of the present invention and specified formulae Whereas salts are formed by acid/base addition, i.e.
• co-crystals are a new chemical species that is formed between neutral compounds, resulting in the compound and cin additional molecular species in the same crystal structure
• Compound I is complexed with an acid or a base, including base addition salts such as ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, t- butylamine, piperazme, meglumine; acid addition salts, such as acetate, acetylsahcylate, besylate, camsylate, citrate, formate, fumarate, glutarate, hydrochlorate, maleate, mesylate, nitrate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate and tosylate; and amino acids such as alanine, argimne, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine.
• base addition salts such as ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, t- butylamine, pipe
• an amorphous complex is preferably formed rather than a crystalline material such as a typical salt or co-crystal
• the amorphous form of the complex is facilitated by additional processing, such as by spray-drying, mcchanochcmical methods such as roller compaction, or microwave irradiation of the parent compound mixed with the acid or base
• additional processing such as by spray-drying, mcchanochcmical methods such as roller compaction, or microwave irradiation of the parent compound mixed with the acid or base
• lowering of the melting temperature relative to the free base facilitates additional processing, such as hot melt extrusion, to further improve the biopharmaccutical properties of the compound
• additional processing such as hot melt extrusion
• the amorphous complex is readily friable, which provides improved compression for loading of the solid into capsule or tablet form.
• Compound I or salts thereof described herein are intended to cover hydrated or solvated as well as unhydrated or unsolvated forms of the identified material
• Compound I or salts thereof includes both hydrated and non- hydrated forms.
• Other examples of solv ates include the structures in combination with a suitable solvent, such as isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic aud or ethanolamine
• Compound I or any form thereof as desc ⁇ bed herein will typically be used in therapy for human subjects
• Compound I and compositions thereof ma also be used to tieat similar or identical indications m other animal subjects, and can be administered b> different routes, including injection (i e parenteral, including intravenous, intraperitoneal, subcutaneous, and intramuscular), oral, transdermal, transmucosal, rectal, or inhalant
• Such dosage forms should allow the compound to reach target cells
• Other factors are well known in the art, and include considerations such as toxicity and dosage forms that retard the compound or composition from exerting its effects 1 echniques and formulations generally may be found in Remington The Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (hereby incorporated by reference herein)
• compositions include pharmaceutically acceptable carriers or cxcipients, such as fillers, binders, disintegrants, ghdants, lub ⁇ cants, complexing agents, solubihzers, and surfactants, which may be chosen to facilitate administration of the compound by a particular route
• carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, types of starch, cellulose de ⁇ vatives, gelatin, lipids, liposomes, nanoparticles, and the like
• Carriers also include physiologically compatible liquids as solvents or for suspensions, including, for example, sterile solutions of water for injection (WFI), saline solution, dextrose solution, Hank s solution, Ringei 's solution, vegetable oils, mineral oils, animal oils, polyethylene glycols liquid paraffin, and the like
• Excipients may also include for example, colloidal silicon dioxide, silica gel, tal
• a formulation which comprises the aforementioned solid complex suspended in an aqueous vehicle
• the formulation may further comp ⁇ se colloidal silicon dioxide which has been found to stabilize the suspension
• the silicon dioxide is preferably present in an amount of at least 0 5% by weight of the formulation
• the aqueous vehicle preferably is about 2% by weight hydroxypropyl cellulose
• oral administration may be used
• Pharmaceutical preparations for oral use can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops
• Compound I may be combined with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e g aqueous, alcoholic, or oily solutions) and the like
• suitable excipients are, in particular, fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol, cellulose preparations, for example, corn starch, wheat starch, ⁇ ce starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/ or polyvinylpy ⁇ ohdone
• concentrated sugar solutions may be used, which may optionally contain, for example, gum arable, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures
• compositions that can be used orally include push-fit capsules made of gelatin (“gelcaps”), as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol
• the push-fit capsules can contain the active ingredients in admixture with fillei such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearatc and, optionally, stabilizers
• the active compound may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
• injection parenteral administration
• Compound 1 and compositions thereof for injection may be formulated in sterile liquid solutions, preferably in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
• Dispersions may also be prepared in non-aqueous solutions, such as glycerol, propylene glycol, ethanol, liquid polyethylene glycols, triacetm, and vegetable oils.
• Solutions may also contain a preservative, such as methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
• a preservative such as methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
• Compound I or compositions thereof may be formulated in solid form, including, for example, lyophilized forms, and redissolved or suspended prior to use.
• transmucosal, topical or transdermal administration may be used in such formulations of Compound I
• penetrants approp ⁇ ate to the barrier to be permeated are used
• penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives hi addition, detergents may be used to facilitate permeation
• Transmucosal administration for example, may be through nasal sprays or suppositories (rectal or vaginal).
• Compositions of Compound I for topical administration may be formulated as oils, creams, lotions, ointments, and the like by choice of appropriate carriers known in the art.
• Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils animal fats and high molecular w eight alcohol (greater than Cj 2 )
• earners are selected such that the activ e ingredient is soluble
• Fmulsifiers stabilizers humectants and antioxidants may also be included as well as agents imparting color or fragrance
• Creams for topical application are preferably formulated from a mixture of mineral oil, self-emulsify mg beeswax and w ater m which mixture the active ingredient, dissoh ed in a small amount of solvent (e g , an oil), is admixed
• administration by transdermal means may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more earners or diluents known in the art To be administered in the form of a transdermal delivery system, the dosage administration will be continuous rather than intermittent throughout the dosage regimen
• Compound I or compositions thereof are administered as inhalants
• Compound I or compositions thereof may be formulated as dry powder or a suitable solution, suspension, or aerosol Powders and solutions may be formulated with suitable additrv es known in the art
• powders may include a suitable powder base such as lactose or starch, and solutions may comprise propylene glycol, sterile water, ethanol, sodium chloride and other additives, such as acid, alkali and butler salts
• Such solutions or suspensions may be administered by inhaling via spray, pump, atomizer, or nebulizer, and the like
• Compound I or compositions thereof may also be used in combination with other inhaled therapies, for example corticosteroids such as fluticasone propnonate, beclomethasonc dipropionate, triamcinolone acetonide, budesomde, and mometasone furoate, beta agonists such as albuterol, salmctcrol and lor
• compositions thereof to be administered can be determined by standard procedures taking into account factors such as the compound activ ity (in ⁇ itro, e g the compound IC, ⁇ vs target, or in iivo activity m animal efficacy models) pharmacokinetic results in animal models (e g biological half life or bioavailability), the age, size, and weight of the subject, and the disorder associated with the subject.
• factors such as the compound activ ity (in ⁇ itro, e g the compound IC, ⁇ vs target, or in iivo activity m animal efficacy models) pharmacokinetic results in animal models (e g biological half life or bioavailability), the age, size, and weight of the subject, and the disorder associated with the subject.
• a dose will be in the range of about 0 01 to 50 mg, kg, also about 0 1 to 20 mg'kg of the subject being treated Pvlultiple doses may be used
• Compound I or compositions thereof may also be used in combination v. ith other therapies for treating the same disease
• Such combination use includes administration of Compound I and one or more other therapeutics at different tunes, or co-administration of Compound I and one or more other therapies
• dosage may be modified for Compound 1 or other therapeutics used in combination, e g , reduction in the amount dosed relative to a compound or therapy used alone, by methods well known to those of ordinary skill in the art
• use in combination includes use with other therapies, drugs, medical procedures etc , where the other therapy or procedure may be administered at different times (e g within a short time, such as within hours (e g 1, 2, 3, 4-24 hours), or within a longer time (e g 1 -2 days, 2-4 days, 4-7 days, 1-4 weeks)) than Compound I or compositions thereof, or at the same time as Compound I or compositions thereof
• Use in combination also includes use with a therapy or medical procedure that is administered once or infrequently, such as surgery, along with Compound 1 or compositions thereof administered within a short time or longer time before or after the other therapy or procedure
• the present invention provides for delivery of Compound I or compositions thereof and one or more other drug therapeutics delivered by a different route of administration or by the same route of administration
• the use in combination for any route of administration includes delivery of Compound I or compositions thereof and one or more other drug therapeutics delivered by the same route of administration together in any formulation, including formulations where the two compounds are chemically linked
• Solid molecular complexes comprising Compound I and HPMC-AS were prepared using methods analogous to that used in Example 1 to produce solid molecular complexes wherein the ratio of the amount by weight of propane- 1 -sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-lH-pyrrolo[2,3- b]pyridine-3-carbonyl]-2,4-difluoro-phcnyl ⁇ -amidc within the solid molecular complex to the amount by weight of the ionic polymer therein is 3:7, 5:5, 5:5, 4:6, 4:6, and 2:8, respectively.
• the solid molecular complexes produced in Examples 1 to 7 were evaluated for amorphous nature by powder XRD.
• the samples were exposed under OPEN conditions by placing the sample in a bottle in the stability chamber without a lid or closure or cap on the at 4O 0 C and 75% relative humidity (RH) and the properties of the solid molecular complexes following such exposure were observed.
• the exposure periods are shown in the table below.
• a sample ⁇ f the powder was taken from the bottle and placed in powder X-ray diffraction (XRD) chamber and diffraction pattern obtained.
• the samples were deemed stable if the powder XRD profile did not show crystalline peaks.
• the prepared and stored samples were also evaluated by polarized light microscopy. The incidence of polarized light results in a birefringence phenomenon, if crystals are present in the sample. For an amorphous sample, such a test could indicate presence of crystal material which indicates that amorphous material is unstable.
• This example describes the formation of a solid molecular complex comprising propane- 1 -sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro- pheny] ⁇ -amide and EUDRAG1T® L 100
• Eudragit L 100 is another anionic polymer, a polvmethyl methacrylate ester with methacrylic acid as a functional group and dissolves at pH 6 0 and above
• This example describes the formation of a solid molecular complex comp ⁇ sing the propane- 1 -sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)- lH-pyrrolo[2,3-b]py ⁇ dine-3-carbonyl]-2,4- difluoro-phenyl ⁇ -amide and hydroxypropylmethylcellulose phthalate (HPMCP), another anionic polymer used for enteric purposes HPMCP is a cellulose polymer in which some of the hydroxyl groups are replaced with phthalyl esters from 27 — 35% It starts dissolving at pH 5 5 and higher Solid molecular complexes containing propane-1-sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-l H- pyrrolo[2,3-b]py ⁇ dine-3-carbonyl]-2,4-difluoro-phenyl ⁇ -amide and HPMCP in 1 1 ratio w ere prepared using same process as
• Examples 12 - 16 were prepared by a microprecipitation process similar to that for Example 1.
• the dried powder samples were evaluated for amorphous nature right after preparation by powder XRD.
• the samples were further subjected to storage under OPEN conditions at 40C/75% RH for varying pe ⁇ ods of time similar to that shown in Examples 1 7
• the results are shown in Fable 3 below
• Samples prepared in Examples 12 and 14 did not indicate any crystalline peak in powder XRD profiles up to the end of 4 weeks of storage. [0159] In order to further differentiate the samples from Examples 12 and 14, the samples were subject to dissolution test by placing an amount of solid molecular complex equivalent to 80 mg of propane- 1 sulfonic acid ⁇ 3 [5 (4 chloro-phenyl)-l H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2 4- difluoro-phenyl ⁇ -amide in 900 ml_ of pH 6 8 phosphate buffer medium containing 0 09% H l AB surfactant in USP Paddle dissolution apparatus at a speed of 75 rpm
• a sie ⁇ e cut of granules of Examples 12 and 14 were obtained by separating the # 25/40 mesh sie ⁇ e size fraction and subjecting to dissolution test
• the HPMC-AS solid molecular complexes had increased amounts with iespect to % dissolved as compared to Eudragit I 100-55 solid molecular complexes with the HPMC-AS solid molecular complexes being about 85% dissolved at 200 minutes and with the Eudragit L 100-55 solid molecular complexes being about 40% dissolved at 200 minutes
• the HPMC-AS was a superior polymer in stabilizing the drug upon storage under stress conditions but also enabling drug release and maintaining supersaturation of amorphous drug during dissolution without reverting to crystalline form within the pe ⁇ od of testing
• the Eudragit L 100-55 did not enhance drug release as compared to HPMC-AS and therefore is not expected to provide the exposure and bioavailability as well as HPMC AS
• Example 12 HPMC-AS
• Example 14 (Eudragit L- 100-55) had only about 50% drug released
• This Example demonstrates the stabilization of solid molecular complexes in aqueous systems.
• the solid molecular complex of drug-HPMC-AS is suspended in an aqueous vehicle containing 2% hydroxypropylcellulose (Klucel LF).
• Klucel LF 2% hydroxypropylcellulose
• the resulting suspension was found to be stable for up to 8 h under normal conditions and for up to 24 h under refrigerated conditions.
• Propane- 1 -sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]- 2,4-difluoro-phenyl ⁇ -amide can exist in polymorphic forms, for example as polymorphic forms 1 or 2, where such polymorphic forms may be isolated as the substantially pure polymorph.
• the desired polymorphic form may be prepared, for example, by using appropriate crystallization conditions.
• Form 1 was isolated by recrystallization from acetone/absolute ethanol (e.g. 1 : 1 to 5: 1 , preferably 2: 1 by volume) as explained in detail herein.
• Form 2 can be formed for example directly via crystallization from dimethylacetamide/ methanol or under a variety of recrystallization conditions, for example, is formed by recrystallization from methyl-t-butyl ether/tetrahydrofuran, ethyl acetate, acetone, or is formed by heating/melting and re-solidifying any solid form, such as polymorph Form 1 , or a mixture of solid forms.
• the substantially pure isolated polymorphic forms were characterized by X-Ray Powder Diffraction (XRPD), differential scanning calorimetry (DSC) and infrared spectroscopy (See Example 20 below).
• Solids were treated with tetrahydrofuran (26,6 kg), and the suspension was heated to 60 0 C + 5 "C for at least 30 minutes and agitated. The mixture was cooled to 55 0 C + 5 0 C and methyl-t-butyl ether (92.3 kg) was added. The resulting suspension was cooled to 20 ⁇ C + 5 0 C for at least 1 hour, The contents were filtered and the solids were washed with methyl-t-butyl ether and dried. The solid was treated with acetone:absolute ethanol (2: 1 by volume) in a reactor. The contents were agitated and the suspension was heated at 60 0 C until a solution was achieved.
• Form 1 was also prepared treating a sample with 120 mL of acetone:ethanol (1 :1 by volume) at refluxing, then filtering hot and removing solvent from the filtrate under vacuum until solid precipitates out.
• the divergence and scattering slits were set at 1° and the receiving slit was set at 0, 15 mm. Diffracted radiation was detected by a NaI scintillation detector. A ⁇ -2 ⁇ continuous scan at 3°/min (0.4 sec/0.02° step) from 2.5° to 40° 2 ⁇ was used. A silicon standard was analyzed to check the instrument alignment. Data were collected and analyzed using XRD-6100/7000 v.5,0. Sample was prepared for analysis by placing it in an aluminum holder with silicon insert. The results are provided in Figure 1 (Form 1) and Figure 2 (Form 2) and the following Table 4.
• Propane- 1- sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-lH-pyrrolo[2,3-b]py ⁇ dine-3-carbonyl]- 2,4-difluoro-phenyl ⁇ -amide is characterized as having functionalities providing both weakly bdsic and weakly acidic centers which can form organic salt complexes, resulting in improved solubility
• the N-7 of the azamdole portion is weakly basic (pKa approximately 4-5) and can form an acid addition salt complex with an organic acid such as benzenesulfomc acid, methvlsulfonic acid or toluenesulfonic acid, preferably methanesulfonic acid or toluenesulfomc acid
• mesylate or tosylate salts provide advantage over the free base, such as an improved solubility, improved intrinsic dissolution rate, and lower melting point than the free base lhe improved intrinsic dis
• Acid addition salts including sulfonic acid series of organic anions such as tosylate, besylate or mesylate, of Propane- 1 -sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-lH-pyrrolo[2,3-b]py ⁇ dine- 3-carbonyl]-2,4-difluoro-phenyl ⁇ -amide are preferably formed using acetone, which provides solubility of the free base and is a non-solvent once the salt is formed
• Propane- 1 - sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)- lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl ⁇ - amide is added to 20-50 solvent volumes of acetone with stirring and heating (30-35 0 C), followed by the addition of 1 equivalent of the desired acid counter ion The solution is slowly
• the mesylate salt of propane- 1 -sulfonic acid ⁇ 3-[5-(4-chloro-phenyl)-l II-pyrrolo[2,3- b]pyridine-3-carbonyl]-2,4-difluoro-phenyl ⁇ -amide was prepared by suspending 5 g (9 7 mmol) of polymorph Form 2 in 100 ⁇ iL of acetone, mixing with heating 30-35 0 C. Methanesulfonic acid (0.63 mL, 9.7 mmol) was added and the solution cooled to 5 0 C over 30 minutes. The resulting solid was isolated by filtration, washed and dried under vacuum to provide the desired salt. The tosylate salt was prepared similarly.
• Exemplary XRPD patterns for the mesylate and tosylate salts are provided in Figures 3 and 4, respectively, as compared to the free base polymorph Form 2.
• the DSC thermogram for the mesylate salt shows an endothermic peak at approximately 231 0 C.
• the DSC thermogram for the tosylate salt shows an endothermic peak at approximately 223 0 C and another at approximately 253 0 C.
• the resulting salts are processed through the techniques discussed in the above examples, such as spray drying, solvent controlled precipitation, pH controlled precipitation, or hot melt extrusion to provide the preferred amorphous form, or further processed with suitable excipient materials to provide for a directly compressible or encapsulated dosage form.
• the salt forms have advantages in such processes, such as to minimize solvent utilization, increase yield, purity and throughput, as well as achieve constructs not attainable using conventional solvent techniques.
• the concentration of Compound I and HPMCAS in the organic solvent was 35 % (w/w), while the ratio of Compound I and HPMCAS is 30 to 70: The temperature of the solution was adjusted to 70 0 C.
• High Shear Mixer HSM
• the tip speed of the rotor in the high shear mixer was set 25 m/sec.
• a rotor/stator combination with one teeth row, each for rotor and stator was used.
• the DMA solution tempered at 70 0 C was dosed with a gear pump via an injector nozzle, which was pointing into the mixing chamber of the high shear mixer, into the circulating aqueous phase.
• the DMA solution was dosed into the aque ⁇ us phase resulting in a ratio of HClOMA, in the mixing chamber of the high shear mixer of 100/1.
• the obtained MBP suspension was dispersed for an additional time, corresponding to equivalents of the batch passing the high shear mixer.
• the time was corresponding to a turnover in calculated recirculation times of the batch of 6 times.
• the obtained suspension, held at 5 - 10 0 C was separated from the solid MBP. This was done by using a suction filter.
• the isolated MBP was washed with 0,01 N HCl (15 kg 0.01 N HCl/'kg MBP) followed by washing with water (5 kg water/kg MBP) in order to remove the DMA
• the isolated (wet) MBP had a water content between 60 and 70 %. Dclumpi ⁇ g and Dn ing
• This example describes the spray dry formation of a solid molecular complex comprising Compound I and HPMC-AS
• Compound I is prepared with a polymer such as HPMCAS, optionally including a surfactant (e g an ionic surfactant such as sodium, l ! 4-bis(2-ethylhexoxy)-l ,4-dioxobutane-2- sulfonate (Docusate Sodium) or a nonionic surfactant such as Polysorbate 80)
• a suitable solvent system such as 20 80 (w/w) tetrahydrofuran acetone is equilibrated to 30 0 C, and Compound I is added to a level of 2-10% solids in 4-6 portions with stirring HPMCAS at a suitable ratio, for example 70 30 w w HPMCAS Compound I, is added (alternatively HPMCAS and surfactant at for example 65 5 30 HPMC ⁇ S surfactant Compound I) is added
• HPMCAS an ionic surfactant
• surfactant such as sodium, l ! 4-bis(2-ethylhe
• a 200 mesh screen was attached to the end of the feed hose to remove any un-dissolved particles and the solution was spray dried using the Mobile Manor Spray Dryer
• the mlet'outlet conditions were 100 0 C and 55 0 C, respectively, with atomization gas pressure at 1 0 bar, with gas flow rate of 90 kg/hi
• the material was spray dried over two days, and material collected after the first day was subjected to vacuum drying at 45 0 C to remove residual solvents
• the collected mate ⁇ al was assessed for bulk density (0 23 gm/mL), particle size (8 microns with a normal distribution and standard deviation of 3 microns) residual solvent (after 89 hours of vacuum drying, the large batch had residual solvents of 0 001 % acetone and 0 017 % tetrahydroiuran), polarized light microscopy, DSC
• the invention illustratively desc ⁇ bed herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.
• any of the terms “comprising”, “consisting essentially of and “consisting of may be replaced with either of the other two terms.
• the invention also includes another embodiment wherein one of these terms is replaced with another of these terms. In each embodiment, the terms have their established meaning.
• one embodiment may encompass a method “comprising” a series of steps, another embodiment would encompass a method “consisting essentially of the same steps, and a third embodiment would encompass a method “consisting of the same steps.
• the terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and desc ⁇ bed or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed.

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