EP2448563A2 - Formulations de comprimé de 3- cyanoquinoline et leurs utilisations - Google Patents

Formulations de comprimé de 3- cyanoquinoline et leurs utilisations

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Publication number
EP2448563A2
EP2448563A2 EP10732568A EP10732568A EP2448563A2 EP 2448563 A2 EP2448563 A2 EP 2448563A2 EP 10732568 A EP10732568 A EP 10732568A EP 10732568 A EP10732568 A EP 10732568A EP 2448563 A2 EP2448563 A2 EP 2448563A2
Authority
EP
European Patent Office
Prior art keywords
weight
composition
weight percent
methoxy
ski
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10732568A
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German (de)
English (en)
Inventor
Goldi Kaul
Ramarao Chatlapalli
Arwinder Nagi
Krishnendu Ghosh
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Wyeth LLC
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Wyeth LLC
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Publication date
Application filed by Wyeth LLC filed Critical Wyeth LLC
Publication of EP2448563A2 publication Critical patent/EP2448563A2/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to formulations of certain cyanoquinoline compounds.
  • the invention is directed to stable tablets of a 3- cyanoquinoline compound, 4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4- methyl-piperazin-1-yl)-propoxy]-quinoline-3-carbonithle, and further comprising the super-disintegrant croscarmellose sodium, a surfactant polyethylene oxide sorbitan monooleate (polysorbate/Polyoxyethylene sorbitan monooleate (Tween-80TM), or both
  • Certain 3-cyanoquinoline compounds and pharmaceutically-acceptable salts thereof are protein kinase inhibitors and possess anti-tumor activity and are therefore useful for treating certain disease states, such as cancer, that result, at least in part, from deregulation of this receptor.
  • Receptor tyrosine kinases are important in the transmission of biochemical signals, which initiate cell replication. They are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor receptor (EGFR) and an intracellular portion which functions as a kinase to phosphorylate tyrosine amino acids in proteins and hence to influence cell proliferation.
  • EGFR epidermal growth factor receptor
  • Class I receptor tyrosine kinases comprising the EGFR family of receptor tyrosine kinases such as the EGFR, TGF ⁇ , Neu and erbB receptors
  • Class Il receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGFI receptors and insulin-related receptor (IRR)
  • Class III receptor tyrosine kinases comprising the platelet-derived growth factor (PDGF) family of receptor tyrosine kinases such as the PDGF ⁇ , PDGF ⁇ and colony-stimulating factor 1 (CSF1 ) receptors.
  • PDGF platelet-derived growth factor
  • tyrosine kinases belong to a class of nonreceptor tyrosine kinases which are located intracellular ⁇ and are involved in the transmission of biochemical signals such as those that influence tumor cell motility, dissemination and invasiveness and subsequently metastatic tumor growth (Ulkich et al., Ce//, 1990, 61 , 203-212, Bolen et al., FASEB J., 1992, 6, 3403-3409, Brickell et al., Critical Reviews in Oncogenesis, 1992, 3, 401-406, Bohlen et al., Oncogene, 1993, 8 2025-2031 , Courtneidge et al., Semin.
  • non-receptor tyrosine kinases including the Src-family such as the Src, Lyn and Yes tyrosine kinases, the AbI family such as AbI and Arg and the Jak family such as Jak 1 and Tyk 2.
  • the 3-cyanoquinoline compound 4-(2,4-dichloro-5-methoxy-phenylamino)- 6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-quinoline-3-carbonithle also referred to as SKI-606, or bosutinib
  • SKI-606 is a weak base with an intrinsic solubility of approximately 0.06 ⁇ g/mL at pH 8.0. Below pH 8, the solubility of the compound SKI-606 increases exponentially with decreasing pH due to ionization. However, degradation of SKI-606 was observed at low pH aqueous solution (pH 3 and below) through hydrolysis, although the compound is relatively stable at pH higher than 5.
  • variable dissolution which appears to depend on the active pharmaceutical ingredient's (API) particle size. Contrary to the norm, the smaller API (Dg O ⁇ 2O microns) in the PIII formulation appeared to retard dissolution, under similar processing conditions used for the larger API (Dg O ⁇ 4O microns), as a result failing dissolution specification. This was observed more so with larger tablets (higher strength).
  • 3- cyanoquinoline compounds such as 4-(2,4-dichloro-5-methoxy-phenylamino)-6- methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-quinoline-3-carbonithle, which is resistant to API particle size variation, and which is more stable during aging and storage, for use in patients.
  • the present invention provides pharmaceutically acceptable solid compositions of 3-cyanoquinolines comprising 4-(2,4-dichloro-5- methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoline-3- carbonitrile.
  • solid compositions are provided as a tablet.
  • the present invention provides a unit dosage form comprising 4- (2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinoline-3-carbonithle.
  • the present invention provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising: intragranular components (a) 25-80, or 30-80 weight percent of 4-(2,4- dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinoline-3-carbonitrile; (b) 0.5-5.0 weight percent of povidone; (c) 1-25 weight percent of microcrystalline cellulose; (d) 0.2-5 weight percent of croscarmellose sodium, (e) 0.5- 5 weight percent of poloxamer, based on the weight of the composition; and extragranular components (f) 1-25 weight percent of microcrystalline cellulose; and (g) 0.5-5 weight percent of magnesium stearate, based on the weight of the composition.
  • the present invention provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising: intragranular components (a) about 69 weight percent of 4-(2,4-dichloro-5- methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoline-3- carbonitrile; (b) about 2 weight percent of povidone; (c) about 6.5 weight percent of microcrystalline cellulose; (d) about 2 weight percent of croscarmellose sodium; (e) about 3 weight percent of poloxamer, based on the weight of the composition; and extragranular components (f) about 15 weight percent of microcrystalline cellulose; and (g) about 0.5 weight percent of magnesium stearate, based on the weight of the composition.
  • the present invention provides a fast dissolving pharmaceutically acceptable composition
  • a fast dissolving pharmaceutically acceptable composition comprising: intragranular components (a) 25-80, or 30-80 weight percent of 4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinoline-3-carbonithle; (b) 0.5-5.0 weight percent of one or more binders; (c) 1-25 weight percent of one or more fillers; (d) 0.5-5 weight percent of one or more disintegrants; (e) 0.2-5 weight percent of one or more wetting agents, based on the weight of the composition; and extragranular components (f) 1-25 weight percent of one or more fillers; (g) 0.5-5 weight percent of one or more disintegrants; and (h) 0.5-5 weight percent of one or more lubricants, based on the weight of the composition.
  • the present invention provides a fast dissolving pharmaceutically acceptable composition
  • a fast dissolving pharmaceutically acceptable composition comprising: intragranular components (a) 50-80 weight percent of 4-(2,4- dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinoline-3-carbonithle; (b) 0.5-5.0 weight percent of povidone; (c) 1-25 weight percent of microcrystalline cellulose; (d) 0.5-5 weight percent of croscarmellose sodium, (e) 0.2- 5 weight percent of poloxamer, based on the weight of the composition; and extragranular components (f) 1-25 weight percent of microcrystalline cellulose; (g) 0.5-5 weight percent of croscarmellose sodium; and (h) 0.5-5 weight percent of magnesium stearate, based on the weight of the composition.
  • the present invention provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising: intragranular components (a) about 69 weight percent of 4-(2,4-dichloro-5- methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoline-3- carbonitrile; (b) about 2 weight percent of povidone; (c) about 6.5 weight percent of microcrystalline cellulose; (d) about 2 weight percent of croscarmellose sodium; (e) about 3 weight percent of poloxamer, based on the weight of the composition; and extragranular components (f) about 15 weight percent of microcrystalline cellulose; (g) about 2 weight percent of croscarmellose sodium; and (h) about 0.5 weight percent of magnesium stearate, based on the weight of the composition.
  • the present invention provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising: intragranular components (a) 25-80, or 30-80 weight percent of 4-(2,4- dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinoline-3-carbonithle; (b) povidone; (c) microcrystalline cellulose; (d) 0.2-5 weight percent of croscarmellose sodium, (e) poloxamer, based on the weight of the composition; and extragranular components (f) microcrystalline cellulose; and (g) magnesium stearate.
  • the present invention provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising: intragranular components (a) about 69 weight percent of 4-(2,4-dichloro-5- methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoline-3- carbonitrile; (b) povidone; (c) microcrystalline cellulose; (d) about 2 weight percent of croscarmellose sodium; (e) poloxamer, based on the weight of the composition; and extragranular components (f) microcrystalline cellulose; and (g) magnesium stearate.
  • the present invention provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising: intragranular components (a) about 69 weight percent of 4-(2,4-dichloro-5- methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoline-3- carbonitrile; (b) povidone; (c) microcrystalline cellulose; (d) about 2 weight percent of croscarmellose sodium; (e) poloxamer, based on the weight of the composition; and extragranular components (f) microcrystalline cellulose; (g) about 2 weight percent of croscarmellose sodium; and (h) magnesium stearate, based on the weight of the composition.
  • the present invention further provides a pharmaceutically acceptable compositions comprising 4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4- methyl-piperazin-1-yl)-propoxy]-quinoline-3-carbonithle, and about 0.25-5 weight percent, 0.5-5 weight percent, 1-3 weight percent, 3 weight percent, 2 weight percent or
  • croscarmellose sodium 1 weight percent croscarmellose sodium as intragranular components, and about .25-5 weight percent, 0.5-5 weight percent, 1-3 weight percent, 3 weight percent, 2 weight percent or 1 weight percent croscarmellose sodium as an extragranular component, with additional intra- and extra-granular components such as those described above comprising the remaining portions of the composition.
  • a further embodiment of the invention includes tablets or tablet cores formed by compressing the above granules, wherein said cores are optionally coated by conventional means, for instance with an up to 4 % polymer film coating, said polymer comprised of conventional coating polymers.
  • An exemplary polymer coating is applied using polyvinyl alcohol and PEG 3350 (Opadry red Il and Yellow II)
  • the present invention also provides a fast dissolving pharmaceutically acceptable solid compositions comprising 4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3- (4-methyl-piperazin-1 -yl)-propoxy]-quinoline-3-carbonitrile.
  • the present invention also provides methods of preparing stable, pharmaceutically acceptable solid compositions comprising 4-(2,4-dichloro-5-methoxy- phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoline-3- carbonithle.
  • the present invention also provides methods for treating cancer comprising administering to a subject an effective amount of a pharmaceutically acceptable solid compositions comprising 4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4- methyl-piperazin-1-yl)-propoxy]-quinoline-3-carbonithle.
  • a pharmaceutically acceptable solid compositions comprising 4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4- methyl-piperazin-1-yl)-propoxy]-quinoline-3-carbonithle.
  • inventive solid compositions of SKI-606 are useful, among other things, for administering to human or animal subjects, including but not limited to pediatric, juvenile, adult and geriatric subjects.
  • the present invention provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising: (a) 25-80 weight percent of 4-(2,4-dichloro-5- methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoline-3- carbonitrile; and (b) 0.1-20 weight percent of one or more wetting agents, as intragranular and or extragranular components, based on the weight of the composition.
  • the present invention provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising: intragranular components (a) 25-80 weight percent of 4-(2,4-dichloro-5- methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoline-3- carbonitrile; (b) 0.5-5.0 weight percent of one or more binders; (c) 1-25 weight percent of one or more fillers; (d) 0.5-5 weight percent of one or more disintegrants, (e) 0.2-5 weight percent of one or more wetting agents, based on the weight of the composition; and extragranular components (f) 1-25 weight percent of one or more fillers; (g) 0.5-5.0 weight percent of one or more wetting agents; and (h) 0.5-5 weight percent of one or more lubricants, based on the weight of the composition.
  • the present invention provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising: intragranular components (a) 50-80 weight percent of 4-(2,4-dichloro-5- methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoline-3- carbonitrile; (b) 0.5-5.0 weight percent of povidone; (c) 1-25 weight percent of microcrystalline cellulose; (d) 0.5-5 weight percent of crospovidone; (e) 0.5-5 weight percent of Polyoxyethylene sorbitan monooleate (Tween-80)TM, based on the weight of the composition; and extragranular components (f) 1-25 weight percent of microcrystalline cellulose; (g) 0.5-5 weight percent of crospovidone; and (h) 0.1-5 weight percent of magnesium stearate, based on the weight of the composition.
  • intragranular components (a) 50-80 weight percent of 4-(2,4-dichloro-5
  • the present invention provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising: intragranular components (a) about 69 weight percent of 4-(2,4-dichloro-5- methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoline-3- carbonitrile; (b) about 2 weight percent of povidone; (c) about 19.5 weight percent of microcrystalline cellulose; (d) about 3 weight percent of crospovidone, (e) about 1 weight percent of Polyoxyethylene sorbitan monooleate (Tween-80)TM, based on the weight of the composition; and extragranular components (f) about 4 weight percent of microcrystalline cellulose; (g) about 1 weight percent of crospovidone and (h) about 0.5 weight percent of magnesium stearate, based on the weight of the composition.
  • intragranular components (a) about 69 weight percent of 4-(2,4-dichloro-5- methoxy-
  • the present invention provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising: intragranular components (a) about 69 weight percent of 4-(2,4-dichloro-5- methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoline-3- carbonitrile; (b) about 2 weight percent of povidone; (c) about 19.5 weight percent of microcrystalline cellulose; (d) about 3 weight percent of crospovidone, (e) about 1 weight percent of Polyoxyethylene sorbitan monooleate (Tween-80)TM, based on the weight of the composition; and extragranular components (f) about 4 weight percent of microcrystalline cellulose; (g) about 1 weight percent of crospovidone and (h) about 0.5 weight percent of magnesium stearate, based on the weight of the composition.
  • intragranular components (a) about 69 weight percent of 4-(2,4-dichloro-5- methoxy-
  • the present invention provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising: intragranular components (a) about 69 weight percent of 4-(2,4-dichloro-5- methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoline-3- carbonitrile; (b) about 2 weight percent of povidone; (c) about 19.5 weight percent of microcrystalline cellulose; (d) about 1 weight percent of crospovidone, (e) about 1 weight percent of Polyoxyethylene sorbitan monooleate (Tween-80)TM, based on the weight of the composition; and extragranular components (f) about 4 weight percent of microcrystalline cellulose; (g) about 3 weight percent of crospovidone and (h) about 0.5 weight percent of magnesium stearate, based on the weight of the composition.
  • intragranular components (a) about 69 weight percent of 4-(2,4-dichloro-5- methoxy-
  • the present invention also provides methods for treating cancer comprising administering to a subject an effective amount of a pharmaceutically acceptable solid compositions comprising 4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4- methyl-piperazin-i-yO-propoxyj-quinoline-S-carbonitrile.
  • inventive solid compositions of SKI-606 are useful, among other things, for administering to human or animal subjects, including but not limited to pediatric, juvenile, adult and geriatric subjects.
  • Figure 1 summarizes tablet dissolution rates for SKI-606 formulations comparing different disintegrating agents (croscarmellose sodium versus crospovidone).
  • Croscarmellose sodium concentrations in a SKI-606 formulation on tablet dissolution rates are similar to Croscarmellose sodium concentrations in a SKI-606 formulation on tablet dissolution rates.
  • Figure 5 summarizes effects of varying Intra and Extragranular (IG and EG) Crospovidone concentration in a SKI-606 formulation on tablet dissolution rates. A wider dissolution is observed here showing strong concentration dependency of dissolution on ratios of Crospovidone.
  • Figure 6 summarizes effects of active pharmaceutical ingredient (API) particle size on Dissolution for Crospovidone containing SKI-606 Formulation containing 2% binder, and 2% intragranular and extragranular disintegrant.
  • API active pharmaceutical ingredient
  • Figure 7A and B summarizes the lack of effect of API particle size in both CTAB/acetate and 0.1 N HCI medias for the croscarmellose sodium based SKI-606 formulations.
  • the CTAB/acetate media was considered a more discriminating media than the 0.1 N HCI. Compare this to Figure 9A and B that clearly show the disparate effect of API particle size on tablet dissolution in a Crospovidone based tablet formulation.
  • Figure 8 summarizes the lack of dissolution dependency of croscarmellose based SKI-606 formulations (Runs A, B and C) on tablet hardness within a range of 120-190 N thus attesting to the dissolution robustness of the formulation. Hardness of a tablet may routinely need to be modified in a manufacturing setting and this formulation clearly offers that ability to do so.
  • Figure 9A and B summarizes effect of API particle size on tablet (100 and 500 mg strengths) dissolution for Crospovidone based formulations in 0.1 N HCI. Compare and contrast this to Figure 7A and B that do not show this dependency.
  • CCS Crospovidone
  • Figure 14 summarizes effects of wetting agent on granule dissolution in SKI-606 formulations. This effect shows that increases in poloxamer concentration resulted in increase in granule dissolution.
  • Tween-80 Polyoxyethylene sorbitan monooleate
  • Figure 17 summarizes the lack of effect of API particle size on tablet dissolution in an SKI-606 formulation containing Polyoxyethylene sorbitan monooleate (Tween-80).
  • Figure 18 summarizes dissolution on accelerated stability in bottles with desiccant for the 500 mg strength croscarmellose based formulation (2% binder and 2% intra and extragranular CCS) 500 mg coated in Bottles with Desiccant. There is no shift in dissolution observed at 6M at 40Deg C/75% RH.
  • Figure 19 summarizes dissolution on accelerated stability in bottles without desiccant for the 500 mg strength croscarmellose based formulation (2% binder and 2% intra and extragranular CCS) 500 mg coated in Bottles with Desiccant. There is very little shift in dissolution observed at 6M at 40Deg C/75% RH
  • Figure 20 summarizes dissolution on accelerated stability in bottles with desiccant for the 500 mg strength croscarmellose based formulation (2% binder and 2% intra and extragranular CCS) 100 mg coated in Bottles with Desiccant. There is no shift in dissolution observed at 6M at 40Deg C/75% RH.
  • an "effective amount" of a compound or pharmaceutically acceptable composition can achieve a desired therapeutic and/or prophylactic effect.
  • an "effective amount” is at least a minimal amount of a compound, or composition containing a compound, which is sufficient for treating one or more symptoms of a disorder or condition associated with modulation of protein tyrosine kinases.
  • an "effective amount" of a compound, or composition containing a compound is sufficient for treating symptoms associated with, a disease associated with an aberrant tyrosine kinase receptor (e.g. cancer, including malignant and benign tumor growths).
  • Therapeutically active agents include any substance used as a medicine for treatment, prevention, delay, reduction or amelioration of a disease, condition, or disorder.
  • therapeutically active agents useful in the formulations of the present invention are opioid receptor antagonist compounds, opioid analgesic compounds, and the like. Further detailed description of compounds useful as therapeutically active agents is provided below.
  • a therapeutically active agent includes a compound that increases the effect or effectiveness of a second compound, for example, by enhancing potency or reducing adverse effects of a second compound.
  • unit dosage form refers to a physically discrete unit of inventive formulation appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active agent employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active agent employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.
  • dry blend materials are physically blended together before filling capsules or compressing tablets. See, Handbook of Pharmaceutical Granulation Technology, 1997, DiNp Parikh, Marcel Dekker, Inc. ISBN 0-8247-9882-1 , page 309.
  • dry granulation slugging or roller compaction
  • intragranular materials are blended to prepare slugs or roller compaction.
  • Material is milled and blended with extragranular materials followed by capsule filling or tablet 20 compression.
  • Wet granulation entails blending intragranular materials.
  • the present invention provides a pharmaceutically acceptable solid composition
  • a pharmaceutically acceptable solid composition comprising: 4-(2,4-dichloro-5-methoxy-phenylamino)-6- methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoline-3-carbonithle, also referred to as SKI-606.
  • SKI-606 is described in U.S. Pat No, 6,297,258, along with methods of preparing SKI-606, as described in U.S. Pat. No. 7, 297,795.
  • SKI-606 has the following structure
  • the 3-cyanoquinoline compound 4-(2,4-dichloro-5- methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoline-3- carbonithle, is a weak base with an intrinsic solubility of approximately 0.06 ⁇ g/mL at pH 8.0. Below pH 8, the solubility of the compound SKI-606 increases exponentially with decreasing pH due to ionization. However, degradation of SKI-606 was observed at low pH aqueous solution through hydrolysis, although the compound is relatively stable at pH higher than 5, when the 4 aminoquinoline group is not ionized.
  • the inventive SKI-606 formulation obviates one or more problems with solid formulations of 3-cyanoquinolines including variable dissolution, which appears to depend on particle size, accelerated dissolution on storage, and limited stability upon storage.
  • the inventive croscarmellose SKI-606 formulations exhibit disintegration times (of 2-7 minutes) faster than comparable SKI-606 formulations employing a conventional disintegrating agent (e.g. crospovidone, disintegration times about 18-20 minutes).
  • the inventive SKI-606 formulation comprises a film coated SKI-606 formulation that is prepared by high shear wet granulation or pan coating. In other embodiments, the film coated SKI-606 tablet formulation is prepared by other conventional coating techniques.
  • Disintegration times were compared for SKI-606 formulation using a conventional disintegrating agent, crospovidone, and croscarmellose sodium and summarized in Table 2.
  • the intragranular disintegrant in this case was kept constant at 3 % w/w.
  • the two formulations have markedly different disintegration times, for instance tablet disintegration times (DT) with the 2% extragranular (EG) SKI-606/CCS formulation is only 3.5 minutes as compared to the SKI-606/CPV formulation with a DT of 22 minutes. Additionally it is also observed that tablet DT is strongly dependent on tablet hardness for all the SKI-606/CPV formulations, whereas no such dependence is observed for the SKI-606/CCS formulations.
  • Tablet dissolution of the inventive SKI-606 formulation was also carried out in 0.1 N HCI, which revealed that the tablet dissolution was faster for the SKI-606/CCS formulations at the 10 and 15 minutes at disintegrant concentrations lower than the ones used for SKI-606/CPV formulations.
  • the lower binder concentrations enhanced dissolution especially at early time points.
  • amounts of croscarmellose sodium (CCS) in the inventive SKI-606 formulation that provide similar dissolution results are as follows: 1. 0- 2 % w/w intragranular concentration
  • Binder may also vary from 1-2% w/w.
  • the intragranular component to extragranular component ratio in the inventive SKI-606 formulation was changed from 3:1 to 2:2.
  • one intragranular (IG) component a filler comprising microcrystalline cellulose (MCC)
  • MCC microcrystalline cellulose
  • the amount of extragranular filler component was increased to 15 weight % from 4 weight %, based on the weight of the SKI-606 formulation.
  • the grade of MCC in the EG component was changed from Avicel PH 101TM to Avicel PH 102TM to facilitate tablet blend flow.
  • the formulation of the present invention can contain one or more non-rate-controlling layers, membranes or coatings.
  • the location of the non-rate-controlling layer in the formulation is not critical.
  • the non-rate- controlling layer may be present between the at least one core and an enteric coating or a rate-controlling mechanism.
  • the non-rate-controlling layer may surround or coat an enteric coating or a rate-controlling mechanism.
  • the non-rate-controlling layer can be made of one or more polymers, as well as, other ingredients known in the art, such as, but not limited to, plasticizers, pigments/opacifiers, etc.
  • polymers that can be used include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, and polyethylene glycol.
  • plasticizers that can be used include, but limited to, polyethylene glycol(s), glycerin, triacetin, triethyl citrate, diethyl phthalate and mineral oils.
  • the formulations of the present invention can also include at least one enteric coating.
  • Any enteric coating can be used in the present invention, including, but not limited to, solutions or dispersions of methacrylic acid and methacrylic ester copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, ethyl acrylate/methacrylic acid copolymers, cellulose acetate thmellitate, shellac and combinations thereof.
  • the enteric coating used in the formulations of the present invention can be formed as a single or multiple layers.
  • the thickness of the coating can be readily determined by those skilled in the art, but must be sufficient to protect the formulation in the acidic environment of the stomach.
  • wetting agents are well known in the art and typically facilitate drug release and absorption.
  • Exemplary wetting agents include poloxamer, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polysorbates, cetyl alcohol, glycerol fatty acid esters (e.g., thacetin, glycerol monostearate, and the like), polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters, sucrose fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, and docusate sodium, and the like, and combinations thereof.
  • wetting agents include but are not limted to for example Polysorbate 80TM, glycerin, Polysorbate 65TM, polysorbate 60TM USP, Polysorbate 40TM USP, Polysorbate 20TM USP, Octoxynol-9, Nonoxynol-10TM USP, Poloxamer 235TM, Poloxamer 188TM USP.
  • provided wetting agents comprise from about 0.1 weight % to about 5 weight %, about 1 .0 weight % to about 4 weight %, or about 3.0 weight % based upon total weight of the formulation.
  • the wetting agent is a poloxamer, including but not limited for example Poloxamer 188TM (Lutrol F-68).
  • Fillers include agents selected from the group consisting of microcrystalline cellulose, starch, lactitol, lactose, a suitable inorganic calcium salt, sucrose, glucose, mannitol, silicic acid, or a combination thereof.
  • binders and fillers comprise from about 1 weight % to about 25% or about 21.5 weight %, based upon total weight of the formulation.
  • the binder is one or more grades of MCC, including but not limited to Avicel PH 101TM and Avicel PH 102TM.
  • Suitable disintegrants include but are not limited to, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, crospovidone (cross-linked PVP), sodium carboxymethyl starch (sodium starch glycolate), cross-linked sodium carboxymethyl cellulose (croscarmellose), pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum) or a combination thereof.
  • a disintegrant is crospovidone.
  • a disintegrant is croscarmellose sodium.
  • a suitable lubricant is included in the inventive SKI-606 formulation.
  • Suitable lubricants or glidants include for example stearates, sodium stearyl fumarate and magnesium salts, magnesium stearate.
  • the amount of lubricants used is 0.2-5 weight percent of one or more lubricants, including about 0.5 weight %, based on the weight of the composition.
  • the lubricant is magnesium stearate.
  • preservatives may be particularly useful in compositions that include SKI-606, and may provide protection from degradation and/or from precipitation.
  • Appropriate preservatives are known to those skilled in the art, and include any pharmaceutically acceptable preservative.
  • Conventional preservatives include, but are not limited to sodium benzoate, Propyl parahydroxybenzoate, Sorbic acid, Propylparaben, Methylparaben, Butylated hydroxytoluene, Propionates, Potassium sorbate, Indinavir and combinations thereof.
  • provided preservatives comprise from about 0.05 weight %, to about 0.25 weight % or about 0.1 %, based upon total weight of the formulation.
  • the present invention provides a solution for oral administration.
  • a unit dosage form contains 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg,
  • a unit dosage form contains between 5 mg and 500 mg, inclusive, or between 10 mg and 450 mg, inclusive, of SKI-606. In some embodiments, a unit dosage form contains 50 mg, 75 mg, 100 mg, 150 mg, 250 mg, 300 mg, or 500 mg. In some embodiments, a unit dosage form contains more than 500 mg of SKI-606.
  • the effective dosage of SKI-606 employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 1000 mg/kg of body weight, optionally given in divided doses two to four times a day, or in sustained release form. The total daily dosage is projected to be from about 1 to 1000 mg, preferably from about 2 to 500 mg.
  • Dosage forms suitable for internal use comprise from about 0.5 to 1000 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • compositions of SKI-606 from the standpoint of
  • SKI-606 is preferred.
  • inventive SKI-606 formulations of this invention can be administered in combination with other anti-tumor substances or with radiation therapy. These other substances or radiation treatments can be given at the same or at different times as the compounds of this invention. These combined therapies may affect synergy and result in improved efficacy.
  • the compounds of this invention can be used in combination with mitotic inhibitors such as taxol or vinblastine, alkylating agents such as cisplatin or cyclophosamide, anti-metabolites such as 5- fluorouracil or hydroxyurea, DNA intercalators such as adhamycin or bleomycin, topoisomerase inhibitors such as etoposide or camptothecin, antiangiogenic agents such as angiostatin, and antiestrogens such as tamoxifen.
  • mitotic inhibitors such as taxol or vinblastine
  • alkylating agents such as cisplatin or cyclophosamide
  • anti-metabolites such as 5- fluorouracil or hydroxyurea
  • DNA intercalators such as adhamycin or bleomycin
  • topoisomerase inhibitors such as etoposide or camptothecin
  • antiangiogenic agents such as angiostatin
  • antiestrogens such as tamoxifen.
  • inventive compositions, and formulations thereof may be administered alone to treat one or more disorders as described herein, or alternatively may be administered in combination with (whether simultaneously or sequentially) one or more other active agents useful to treat one or more disorders as described herein.
  • an inventive composition, or formulation thereof can be administered concurrently with, prior to, or subsequent to, one or more active agents.
  • inventive compositions include one or more other active agents in addition to SKI-606 that is not SKI-606. In some embodiments, inventive formulations comprise both another anticancer compound and SKI-606.
  • the amount of additional active agent(s) present in combination compositions of this invention will typically be no more than the amount that would normally be administered in a composition comprising that active agent as the only therapeutic agent. In certain embodiments of the present invention, the amount of additional active agent will range from about 50% to 100% of the amount normally present in a composition comprising that compound as the only therapeutic agent. In certain embodiments, inventive formulations may also be used in conjunction with and/or in combination with conventional therapies for gastrointestinal dysfunction to aid in the amelioration of constipation and bowel dysfunction.
  • inventive compositions, and formulations thereof can be employed in combination therapies, that is, an inventive composition, or formulation thereof, can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • Particular combination therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • therapies employed may achieve a desired effect for the same disorder (for example, a formulation may be administered concurrently with another compound used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects).
  • Tablets of the 500 mg strength were compressed using the appropriate tooling equipment and the tablets were compressed at low (1 1-13kp), target (14-16 kp) and high (17-19 kp) hardnesses. These tablets were then evaluated for disintegration time in 0.1 N HCI.
  • Tablet dissolution of the inventive SKI-606 formulation was also carried out in 0.1 N HCI, which revealed that the tablet dissolution was faster for the
  • SKI-606 is prepared according to the methods described in detail in one or more of U.S. Pat Nos. 6,297,258 and 7,297,795.
  • An exemplary inventive fast dissolving formulation of SKI-606 and a comparative SKI-606 formulation are summarized in Table 4.
  • the grade was also changed from Avicel 101 to a larger particle sized 102 to improve blend flow and compressibility. This approach was found to yield faster disintegrating and dissolving tablets, both of which are expected to improve the gastric outcome in the stomach.
  • the inventive SKI-606 formulation is based on this approach.
  • SKI-606 is prepared according to the methods described in detail in one or more of U.S. Pat Nos. 6,297,258 and 7,297,795.
  • An exemplary coated tablet from inventive formulation of SKI-606 at two different unit dosages is summarized in Table 5.
  • the SKI-606 formulation and coated tablets of the SKI-606 formulation were prepared as follows:
  • Microcrystalline cellulose (Avicel PH 101 ) 1.624 Kg
  • Step 1 solution While mixing, added the Step 1 solution to the high shear granulator and mix until a suitable granulation is achieved. The water quantity may be adjusted to achieve a satisfactory granulation endpoint if required. 4. The granulation may be passed through a mill or screen, if necessary, to facilitate a uniform granulation before drying.
  • the LOD at this point should be below 3% w/w with a target between 1-1.5 % w/w under test temperature conditions.
  • Step 10 Passed the dried granulation through a mill equipped with an appropriate sieve or screen to facilitate a satisfactory particle size distribution for blending. Retain a portion of this for Step 10.
  • the dry blend ingredients may be passed through a screen, prior to blending.
  • Step 10 Retain a sample of microcrystalline cellulose if required for blending in Step 10. Add the microcrystalline cellulose and croscarmellose sodium to the mixer and blend for 10 minutes, or until uniform.
  • Step 9 Added either a portion of granulation from Step 6 or microcrystalline cellulose (PH 102) from Step 9 to the magnesium stearate and mix to form a lubricant pre- blend. Add the lubricant pre-blend to the Step 9 blender and mix for a minimum of 2 minutes, or until uniform.
  • the SKI-606 formulation and coated tablets of the SKI-606 formulation were prepared as follows for a batch size of 1 Kg core tablets:
  • Microcrystalline cellulose (Avicel PH 101 ) 46.23 g
  • step 1 Passed SKI-606, Microcrystalline Cellulose and Crospovidone from step 1 through a 20 mesh screen and ingredients were added to a high shear mixer. 2. Mixed the ingredients in step 2 in a high shear granulator for 2 minutes at low plow speed (Impeller only).
  • Step 3 using a pump to granulate the mix in Step 3. If necessary, when the granulation solution was exhausted, continued mixing for an additional 2- 5 minutes with the chopper and impeller at low speed. Added additional Purified Water if necessary while mixing until the granulation end point is reached. Checked for the desired granulation end point. Record the total amount of water used to granulate and the total mixing time as well as power or torque reading if available.
  • the inventive SKI-606 formulation obviates one or more problems with solid formulations of 3-cyanoquinolines, namely, variable dissolution and a tendency for certain SKI-606 formulations (see comparative Example) to undergo small yet significant shifts on in dissolution on aging at both room temperature and under accelerated conditions when tested in buffer solution or under acidic conditions, as summarized in Figures 10 and 12.
  • Figure 1 1 shows the lack of dissolution shift for the croscarmellose formulation.
  • Figure 12 shows the dissolution shifts in existing formulation.
  • the poloxamer 188 in the SKI-606 comparative formulation was responsible for the shift in dissolution observed. Poloxamer though a solid at room temperature tends to undergo liquefaction at and around temperatures near its melting point of 48-52° C.
  • SKI-606 tablet formulations were prepared with varying amounts of poloxamer, ranging from 0, 1.5, 3, 4.5 and 6% w/w, based on the weight of the SKI-606 formulation.
  • poloxamer ranging from 0, 1.5, 3, 4.5 and 6% w/w, based on the weight of the SKI-606 formulation.
  • Figure 13 summarizes the effects of varying poloxamer content on tablet dissolution at similar water and binder addition rates in 0.1 N HCI. It is observed that the poloxamer actually appears to retard the release especially at early time points for the tablets tested. Poloxamer appeared to retard initial tablet dissolution at 15 and 30 minutes in a concentration dependent manner. See Table 8.
  • SKI-606 is prepared according to the methods described in detail in one or more of U.S. Pat Nos. 6,297,258 and 7,297,795.
  • An exemplary inventive formulation of SKI- 606 and a comparative SKI-606 formulation are summarized in Table 10. Table 10. SKI-606 Formulations
  • the comparative SKI-606 formulation was prepared by the process of high shear wet granulation, wet milling, fluidized bed drying, dry milling, blending and compression to tablets that are subsequently film coated.
  • the inventive SKI-606 formulation comprises a film coated SKI-606 formulation that is prepared by high shear wet granulation or pan coating.
  • the film coated SKI-606 tablet formulation is prepared by other conventional coating techniques.

Abstract

L’invention concerne des compositions solides comprenant un 3-cyanoquinoline, SKI-606, ainsi qu’une croscarmellose sodique, un Tween, ou les deux.
EP10732568A 2009-07-02 2010-06-30 Formulations de comprimé de 3- cyanoquinoline et leurs utilisations Withdrawn EP2448563A2 (fr)

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