JP2011012063A - 3-cyanoquinoline tablet formulation and use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a stable solid composition of 3-cyanoquinoline compounds such as 4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperadin-1-yl)-propoxy]-quinoline-3-carbonitrile, robust against API(active pharmaceutical ingredient) particle size change and more stable for time dependent change and in preservation for use in patients.SOLUTION: The solid composition comprises 3-cyanoquinoline and SKI-606, in addition, croscarmellose sodium, Tween, or both of them.

Description

  The present invention relates to formulations of certain cyanoquinoline compounds. In particular, the present invention relates to 3-cyanoquinoline compounds, 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl)- Propoxy] -quinoline-3-carbonitrile, superdisintegrant croscarmellose sodium, surfactant polyethylene oxide sorbitan monooleate (polysorbate / polyoxyethylene sorbitan monooleate (Tween-80 ™), or both Further included are stable tablets.

  Certain 3-cyanoquinoline compounds and their pharmaceutically acceptable salts are protein kinase inhibitors and have anti-tumor activity, and thus some diseases such as cancer caused at least in part by deregulation of this receptor Useful for treating a condition. Receptor tyrosine kinases are important for the transmission of biochemical signals that initiate cell replication. Receptor tyrosine kinases are large enzymes that span cell membranes, phosphorylating extracellular binding domains for growth factors such as epidermal growth factor receptor (EGFR) and tyrosine amino acids in proteins, thereby promoting cell proliferation. It has an intracellular part that functions as an influencing kinase. Based on a family of growth factors that bind to different receptor tyrosine kinases, various classes of receptor tyrosine kinases are known (Wilks, Advances in Cancer Research, 1993, 60, 43-73). The classification includes class I receptor tyrosine kinases, including the EGFR family of receptor tyrosine kinases such as EGFR, TGFα, Neu and erbB receptors, and receptor tyrosine kinases such as insulin and IGFI receptors and insulin related receptors (IRR). Includes class II receptor tyrosine kinases including the insulin family and class III receptor tyrosine kinases including the platelet derived growth factor (PDGF) family of receptor tyrosine kinases such as PDGFα, PDGFβ and colony stimulating factor 1 (CSF1) receptors .

  Certain tyrosine kinases belong to a class of intracellular non-receptor tyrosine kinases that are biochemical signals such as those that affect tumor cell motility, seeding and invasiveness, and subsequently metastatic tumor growth. (Ulkich et al., Cell, 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, Courtneid et al., Semin. Cancer Biol., 1994, 5, 239-246, Lauffenburger et al., Cell, 1996, 4, 359-369, Hanks et al., BioEssays, 1996, 19, 137-145, Parsons et al., Current Opinion in Cell Biology, 1997, 9, 187-192, Brown et al., Biochimica et Biophysica Acta, 1996, 128-128. 149 and Schlaepfer et al., Progress in Biophysics and Molecular Biology, 1999, 71, 435-478). Various classes of non-receptor tyrosine kinases are known, including the Src-family such as Src, Lyn and Yes tyrosine kinases, the AbI family such as AbI and Arg, and the Jak family such as Jak1 and Tyk2.

  3-Cyanoquinoline compound 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl), also called SKI-606 or bosutinib -Propoxy] -quinoline-3-carbonitrile is a weak base with an intrinsic solubility of approximately 0.06 μg / mL at pH 8.0. Below pH 8, the solubility of compound SKI-606 increases exponentially with decreasing pH due to ionization. However, although degradation of SKI-606 was observed in low pH aqueous solutions (pH 3 and below) through hydrolysis, the compound is relatively stable at pH higher than 5.

Some problems with existing solid preparations of 3-cyanoquinoline include variable elution that appears to depend on the particle size of the active pharmaceutical ingredient (API). Unlike the standard, the smaller API (D ₉₀ about 20 microns) in the Phase III formulation is a result of the problematic elution specifications, and similar processing conditions used for the larger API (D ₉₀ about 40 microns). Below it appeared to delay elution. This was even more observed with larger tablets (higher titers).

  In addition, the accelerated dissolution characteristics of the formulation after aging / storage were also observed at an early time point (small but significant shift in dissolution over time at both room temperature and accelerated conditions). The results are presented in two elution methods: the 0.1N HCl method and the CTAB / pH5 acetate method, discussed further below. The latter method was chosen to better show the elution profile at time points up to 30 minutes as the 0.1N HCl method has been found to release all drug within the first 10-20 minutes.

US Pat. No. 7,297,795 US Pat. No. 6,297,258

Wilks, Advances in Cancer Research, 1993, 60, 43-73 Ulkich et al., Cell 1990, 61, 203-212. Bolen et al., FASEB J. et al. 1992, 6, 3403-3409 Brickell et al., Critical Reviews in Oncogenesis, 1992, 3, 401-406 Bohlen et al., Oncogene, 1993, 8 2025-2031. Courtneid et al., Semin. Cancer Biol. 1994, 5, 239-246 Lauffenburger et al., Cell, 1996, 84, 359-369. Hanks et al., BioEssays, 1996, 19, 137-145. Parsons et al., Current Opinion in Cell Biology, 1997, 9, 187-192. Brown et al., Biochimica et Biophysica Acta, 1996, 1287, 121-149. Schlaepfer et al., Progress in Biophysics and Molecular Biology, 1999, 71, 435-478. Handbook of Pharmaceutical Granulation Technology, 1997, Dilip Parikh, Marcel Dekker, Inc. ISBN 0-8247-9882-1, p. 309 25 Handbook of Pharmaceutical Granulation Technology, 1997, Dilip Parikh, Marcel Dekker, Inc. ISBN 0-8247-9882-1, pages 338-368

  Therefore, 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4, which is resistant to API particle size variation and is more stable over time and storage for use in patients. It would be desirable to provide a stable solid formulation of a 3-cyanoquinoline compound such as -methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile.

  This document describes two innovative techniques: changing the disintegrant type (and disintegrant ratio) to improve the dissolution and stability characteristics, and also the dissolution and stability characteristics. To improve, it is disclosed to replace the poloxamer with a liquid surfactant such as polyethylene oxide sorbitan monooleate (polysorbate / polyoxyethylene sorbitan monooleate (Tween-80)).

  In a first embodiment, the present invention relates to 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] A pharmaceutically acceptable solid composition of 3-cyanoquinoline comprising -quinoline-3-carbonitrile. In certain embodiments, such solid compositions are provided as tablets. In some embodiments, the invention provides 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy A unit dosage form comprising -quinoline-3-carbonitrile is provided.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile 20-80 or 30-80 weight percent and (b) one or more wetting agents 0.1-20 weight percent, Pharmaceutically acceptable compositions are provided.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile 25-80 or 30-80 weight percent and (b) one or more wetting agents 0.1-20 weight percent, A pharmaceutically acceptable composition is provided, wherein the intragranular component of the composition further comprises 82.5 weight percent of the composition and the extragranular component comprises 17.5 weight percent of the composition.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile 25-80 or 30-80 weight percent, (b) 0.1-5.0 weight percent of one or more binders, (c 1) 1 to 25 weight percent of one or more fillers, (d) 0.1 to 5 weight percent of one or more disintegrants, and (e) 0.1 to 5 weight percent of one or more wetting agents. (F) 1 to 25 weight percent of one or more fillers and (g) 0.1 to 5 weight percent of one or more lubricants as extragranular components relative to the weight of the composition. A pharmaceutically acceptable composition comprising To provide.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile 25-80 or 30-80 weight percent, (b) povidone 0.5-5.0 weight percent, (c) microcrystalline cellulose 1 ˜25 weight percent, (d) 0.2-5 weight percent croscarmellose sodium, (e) 0.5-5 weight percent poloxamer, and as an extragranular component relative to the weight of the composition, A pharmaceutically acceptable composition is provided comprising 1 to 25 weight percent microcrystalline cellulose and (g) 0.5 to 5 weight percent magnesium stearate.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile about 69 weight percent, (b) about 2 weight percent povidone, (c) about 6.5 weight percent microcrystalline cellulose, (d) cross About 2 weight percent carmellose sodium, (e) about 3 weight percent poloxamer, and as an extragranular component, (f) about 15 weight percent microcrystalline cellulose and (g) magnesium stearate relative to the weight of the composition A pharmaceutically acceptable composition comprising about 0.5 weight percent.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile 25-80 or 30-80 weight percent, (b) 0.5-5.0 weight percent of one or more binders, (c 1) 25 weight percent of one or more fillers, 0.5-5 weight percent of one or more disintegrants, and 0.2-5 weight percent of one or more wetting agents. (F) 1 to 25 weight percent of one or more fillers, (g) 0.5 to 5 weight percent of one or more disintegrants and ( h) one or more lubricants 0 5-5 comprises a weight percent, to provide a pharmaceutically acceptable composition of fast-dissolving.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile 50-80 weight percent, (b) povidone 0.5-5.0 weight percent, (c) microcrystalline cellulose 1-25 weight percent (D) 0.5 to 5 weight percent croscarmellose sodium, (e) 0.2 to 5 weight percent poloxamer, and (f) microcrystalline cellulose as an extragranular component relative to the weight of the composition 1-25 weight percent, (g) 0.5-5 weight percent croscarmellose sodium and (h) 0.5-5 weight percent magnesium stearate, fast dissolving Providing a pharmaceutically acceptable composition.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile about 69 weight percent, (b) about 2 weight percent povidone, (c) about 6.5 weight percent microcrystalline cellulose, (d) cross About 2 weight percent carmellose sodium, (e) about 3 weight percent poloxamer, and as an extragranular component, (f) about 15 weight percent microcrystalline cellulose, (d) croscarmellose, based on the weight of the composition A pharmaceutically acceptable composition is provided comprising about 2 weight percent sodium and (h) about 0.5 weight percent magnesium stearate.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile 25-80 or 30-80 weight percent, (b) povidone, (c) microcrystalline cellulose, (d) croscarmellose sodium Provided is a pharmaceutically acceptable composition comprising 2-5 weight percent (e) poloxamer and (f) microcrystalline cellulose and (g) magnesium stearate as extragranular components.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile, about 69 weight percent, (b) povidone, (c) microcrystalline cellulose, (d) about 2 weight percent croscarmellose sodium, (e There is provided a pharmaceutically acceptable composition comprising) poloxamer and (f) microcrystalline cellulose and (g) magnesium stearate as extragranular components.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile 50-80 weight percent, (b) povidone, (c) microcrystalline cellulose, (d) croscarmellose sodium 0.5-5 weight (F) microcrystalline cellulose, (g) 0.5-5 weight percent croscarmellose sodium and (h) stearic acid as an extragranular component, based on percent, (e) poloxamer and the weight of the composition A fast dissolving pharmaceutically acceptable composition comprising magnesium is provided.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile, about 69 weight percent, (b) povidone, (c) microcrystalline cellulose, (d) about 2 weight percent croscarmellose sodium, (e A pharmaceutical comprising:) poloxamer and (g) microcrystalline cellulose, (g) about 2 weight percent croscarmellose sodium and (h) magnesium stearate as extragranular components relative to the weight of the composition An acceptable composition is provided.

  The present invention provides 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy] as an intragranular component. Quinoline-3-carbonitrile as low as about 25 weight percent, 20 weight percent, or even 15 weight percent, and croscarmellose sodium about 0.25-5 weight percent, 0.5-5 weight percent, 1-3 Weight percent, 3 weight percent, 2 weight percent, or 1 weight percent, and about croscarmellose sodium as an extragranular component. 25 to 5 percent by weight, 0.5 to 5 percent by weight, 1 to 3 percent by weight, 3 percent by weight, 2 percent by weight or 1 percent by weight within the additional granule as described above occupying the rest of the composition Further provided is a pharmaceutically acceptable composition, eg, a composition suitable for pediatric use, comprising and an extragranular component.

  The present invention relates to 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy] as an intragranular component Quinoline-3-carbonitrile and croscarmellose sodium about 0.25-5 weight percent, 0.5-5 weight percent, 1-3 weight percent, 3 weight percent, 2 weight percent or 1 weight percent granule About croscarmellose sodium as an outer component. 25 to 5 percent by weight, 0.5 to 5 percent by weight, 1 to 3 percent by weight, 3 percent by weight, 2 percent by weight or 1 percent by weight within the additional granule as described above occupying the rest of the composition And a pharmaceutically acceptable composition comprising the composition together with an extragranular component.

  Further embodiments of the present invention include a tablet or tablet core formed by compressing the above granules, said core being coated by conventional means, for example with a polymer film coating of up to 4%. Alternatively, the polymer comprises a conventional coating polymer. Exemplary polymer coatings are applied using polyvinyl alcohol and PEG 3350 (Opadry Red II and Yellow II).

  The present invention relates to 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbohydrate. Also provided are fast dissolving pharmaceutically acceptable solid compositions comprising nitriles.

  The present invention relates to 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbohydrate. A method of preparing a stable pharmaceutically acceptable solid composition comprising a nitrile is also provided.

  The present invention provides an effective amount of 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy] -quinoline- Also provided is a method for treating cancer comprising administering to a subject a pharmaceutically acceptable solid composition comprising 3-carbonitrile.

  The solid compositions of the present invention for SKI-606 are useful for administration to human or animal subjects including, but not limited to, pediatric, young, adult and elderly subjects, among others.

  In a second embodiment, the present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino)-as an intragranular and / or extragranular component relative to the weight of the composition. 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile 25-80 weight percent and (b) one or more wetting agents 0.1 A pharmaceutically acceptable composition is provided comprising -20 weight percent.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile 25-80 weight percent, (b) 0.5-5.0 weight percent of one or more binders, (c) one or 1 to 25 weight percent of a plurality of fillers, (d) 0.5 to 5 weight percent of one or more disintegrants, (e) 0.2 to 5 weight percent of one or more wetting agents, and (F) 1 to 25 weight percent of one or more fillers, (g) 0.5 to 5.0 weight percent of one or more wetting agents and (h) One or more lubricants 0.5-5 weight And a Sento, to provide a pharmaceutically acceptable composition.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile 50-80 weight percent, (b) povidone 0.5-5.0 weight percent, (c) microcrystalline cellulose 1-25 weight percent (D) 0.5 to 5 weight percent crospovidone, (e) 0.5 to 5 weight percent polyoxyethylene sorbitan monooleate (Tween-80) ™, and the granule based on the weight of the composition As external constituents, (f) 1 to 25 weight percent microcrystalline cellulose, (g) 0.5 to 5 weight percent crospovidone and (h) magnesium stearate 0.1 5 and a weight percent, to provide a pharmaceutically acceptable composition.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile, about 69 weight percent, (b) about 2 weight percent povidone, (c) about 19.5 weight percent microcrystalline cellulose, (d) cross About 3 weight percent povidone, (e) about 1 weight percent polyoxyethylene sorbitan monooleate (Tween-80) ™ and, as an extragranular component, (f) microcrystalline, based on the weight of the composition Pharmaceutically comprising about 4 weight percent cellulose, (g) about 1 weight percent crospovidone and (h) about 0.5 weight percent magnesium stearate. Providing containers may composition.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile, about 69 weight percent, (b) about 2 weight percent povidone, (c) about 19.5 weight percent microcrystalline cellulose, (d) cross About 3 weight percent povidone, (e) about 1 weight percent polyoxyethylene sorbitan monooleate (Tween-80) ™ and, as an extragranular component, (f) microcrystalline, based on the weight of the composition Pharmaceutically comprising about 4 weight percent cellulose, (g) about 1 weight percent crospovidone and (h) about 0.5 weight percent magnesium stearate. Providing containers may composition.

  The present invention relates to (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4- Methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile, about 69 weight percent, (b) about 2 weight percent povidone, (c) about 19.5 weight percent microcrystalline cellulose, (d) cross About 1 weight percent povidone, (e) about 1 weight percent polyoxyethylene sorbitan monooleate (Tween-80) ™ and, as an extragranular component, (f) microcrystalline, based on the weight of the composition Pharmaceutically comprising about 4 weight percent cellulose, (g) about 3 weight percent crospovidone and (h) about 0.5 weight percent magnesium stearate. Providing containers may composition.

  The present invention relates to 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbohydrate. A method of preparing a stable pharmaceutically acceptable solid composition comprising a nitrile is also provided.

  The present invention provides an effective amount of 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy] -quinoline- Also provided is a method for treating cancer comprising administering to a subject a pharmaceutically acceptable solid composition comprising 3-carbonitrile.

  The solid compositions of the present invention for SKI-606 are useful for administration to human or animal subjects including, but not limited to, pediatric, young, adult and elderly subjects, among others.

FIG. 6 summarizes the tablet dissolution rate for the SKI-606 formulation comparing different disintegrants (croscarmellose sodium vs. crospovidone). FIG. 7 summarizes dissolution at accelerated stability for a SKI-606 formulation including crospovidone. There appears to be a significant shift in tablet dissolution, especially at the early time points. FIG. 10 summarizes the elution with accelerated stability for a SKI-606 formulation including croscarmellose sodium. In this case, no shift (compared to FIG. 2) is observed. FIG. 6 summarizes the effect of various intragranular and extragranular (IG and EG) croscarmellose sodium concentrations in SKI-606 formulations on tablet dissolution rate. FIG. 6 summarizes the effect of various intragranular and extragranular (IG and EG) crospovidone concentrations in SKI-606 formulations on tablet dissolution rate. Here, a wide elution is observed showing a strong concentration dependence of elution on the ratio of crospovidone. The formulation containing the D90 API appears to be significantly different in elution from the rest containing the D90 = 40 or 60 micron API. FIG. 6 summarizes the effect of active pharmaceutical ingredient (API) particle size on elution for crospovidone-containing SKI-606 formulations containing 2% binder and 2% intragranular and extragranular disintegrant. FIG. 6 summarizes the lack of effect of API particle size in both CTAB / acetate and 0.1 N HCl media for croscarmellose sodium based SKI-606 formulation. CTAB / acetate media was considered a more discriminating media than 0.1N HCl. Compare this with FIGS. 9A and B, which clearly show the effect of uncommon API particle size on tablet dissolution in tablet formulations based on crospovidone. FIG. 6 summarizes the lack of effect of API particle size in both CTAB / acetate and 0.1 N HCl media for croscarmellose sodium based SKI-606 formulation. CTAB / acetate media was considered a more discriminating media than 0.1N HCl. Compare this with FIGS. 9A and B, which clearly show the effect of uncommon API particle size on tablet dissolution in tablet formulations based on crospovidone. Figure 6 summarizes the lack of dissolution dependence of croscarmellose sodium based SKI-606 formulations (Runs A, B and C) for tablet hardness in the range of 120-190 N, demonstrating dissolution robustness of the formulation is doing. Tablet hardness may be routinely required to be modified in manufacturing settings, and this formulation clearly provides the ability to do so. FIG. 6 summarizes the effect of API particle size on tablet (100 and 500 mg titer) dissolution for a formulation based on crospovidone in 0.1 N HCl. Compare and contrast this with FIGS. 7A and B, which do not show this dependency. FIG. 6 summarizes the effect of API particle size on tablet (100 and 500 mg titer) dissolution for a formulation based on crospovidone in 0.1 N HCl. Compare and contrast this with FIGS. 7A and B, which do not show this dependency. FIG. 6 summarizes the upward shift in tablet dissolution of a 500 mg crospovidone-based SKI-606 formulation with open dish accelerated stability up to 2 weeks. Elution data is shown for two formulations with various binder ratios and disintegrant ratios. Significant dissolution differences were observed for both batches early in the tablet dissolution, indicating a lack of dissolution reproducibility with accelerated stability. Compare and contrast this with the croscarmellose sodium-based formulation in FIG. 11, which does not show any difference in stability. FIG. 11 summarizes the lack of any dissolution shift of a croscarmellose sodium (CCS) based formulation with stability under conditions similar to the crospovidone (CPV) batch in FIG. FIG. 5 shows additional dissolution shift data for crospovidone (CPV) SKI-606 formulation in 0.1 N HCl under accelerated aging conditions for 500 and 100 mg titer tablets. A consistent upward trend is observed for both titers at 0.1 N HCl. FIG. 6 summarizes comparative elution profiles for SKI-606 formulations containing various concentrations of wetting agent (poloxamer). Poloxamers are observed to have an unexpected effect of reducing tablet dissolution in a concentration-dependent manner. FIG. 6 summarizes the effect of wetting agents on granule elution in SKI-606 formulations. This effect indicates that increasing poloxamer concentration resulted in increased granule elution. Open dish for up to 6 weeks at both 40 ° C. and 40 ° C./75% RH for SKI-606 formulation (API D ₉₀ = 38 microns) containing polyoxyethylene sorbitan monooleate (Tween-80) as wetting agent It is a figure which summarizes the influence of the acceleration time-dependent change in conditions. It is observed that the shift appears to be negligible even under severe stability conditions in the open dish. Open dish for up to 6 weeks at both 40 ° C. and 40 ° C./75% RH for SKI-606 formulation (API D ₉₀ = 18 microns) containing polyoxyethylene sorbitan monooleate (Tween-80) as wetting agent It is a figure which summarizes the influence of the acceleration time-dependent change in conditions. It is observed that the shift appears to be negligible even under severe stability conditions in the open dish. FIG. 6 summarizes the lack of influence of API particle size on tablet dissolution in SKI-606 formulations containing polyoxyethylene sorbitan monooleate (Tween-80). Elution with accelerated stability in desiccant bottles for 500 mg coated 500 mg titer croscarmellose based formulation (2% binder and 2% intragranular and extragranular CCS) in bottles with desiccant It is a figure which summarizes. There is no elution shift observed at 6 months at 40 ° C./75% RH. With accelerated stability in desiccant-free bottles for 500 mg-coated 500 mg titer croscarmellose-based formulations in desiccant bottles (2% binder and 2% intragranular and extragranular CCS) FIG. 6 summarizes elution. There is only a slight shift observed at 6 months at 40 ° C./75% RH. Elution with accelerated stability in desiccant bottles for 100 mg coated 500 mg titer croscarmellose based formulation (2% binder and 2% intragranular and extragranular CCS) in desiccant bottles It is a figure which summarizes. There is no elution shift observed at 6 months at 40 ° C./75% RH. FIG. 6 summarizes scale-up (100 Kg) batch elution stability in bottles with desiccant. There is no or close shift in elution with stability in CTAB / acetate buffer (A) and no shift in 0.1N HCl (B).

1. Definition:
As used herein, an “effective amount” of a compound or pharmaceutically acceptable composition can achieve a desired therapeutic and / or prophylactic effect. In some embodiments, an “effective amount” is a compound, or a composition containing a compound, that is sufficient to treat one or more symptoms of a disorder or condition associated with modulation of protein tyrosine kinases. At least the minimum amount. In certain embodiments, an “effective amount” of a compound, or a composition containing a compound, is associated with symptoms associated with abnormal tyrosine kinase receptors, related diseases (eg, cancer including malignant and benign tumor growth). Enough to treat.

  The term “subject” as used herein means mammals and includes animal subjects such as humans and domestic animals (eg, horses, dogs, cats, etc.).

  The term “suffering” or “suffering” as used herein refers to one or more conditions in which a patient has been diagnosed or suspected of having.

  The terms “treat” or “treating” as used herein, partially or completely reduce, inhibit, inhibit a disorder or condition, or one or more symptoms of a disorder or condition, Refers to delaying, preventing, ameliorating and / or mitigating its onset.

  “Therapeutically active agent” or “active agent” includes biologically active substances that are useful for therapy (eg, human therapy, veterinary medicine), including prophylactic and therapeutic treatments. Refers to a substance. A therapeutically active agent is linked to a drug compound, an organic molecule, peptide, protein, carbohydrate, monosaccharide, oligosaccharide, polysaccharide, nucleoprotein, mucoprotein, lipoprotein, synthetic polypeptide or protein, protein Includes small molecules, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, and vitamins. A therapeutically active agent includes any substance used as a medicament for the treatment, prevention, delay, reduction or amelioration of a disease, condition or disorder. Therapeutically active agents useful in the formulations of the present invention include opioid receptor antagonist compounds, opioid analgesic compounds and the like. A more detailed description of compounds useful as therapeutically active agents is provided below. A therapeutically active agent includes a compound that increases the efficacy or effectiveness of a second compound, for example, by enhancing the potency of the second compound or reducing the adverse effects of the second compound.

  The expression “unit dosage form” as used herein refers to a physically discrete unit of a formulation of the invention suitable for the subject to be treated. It will be understood, however, that the overall 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 dosage level for any particular subject or organism depends on the disorder being treated and the severity of the disorder, the activity of the specific active agent used, the specific composition used, the subject Age, weight, general health, sex and diet, time of administration, and rate of excretion of specific active drugs used, duration of treatment, combined with specific compound (s) used Will depend on a variety of factors, including drugs and / or additional therapies used, or similar, as well as similar factors well known in the medical arts.

  Briefly, the “dry blend” material is physically blended together before filling the capsule or compressing the tablet. Handbook of Pharmaceutical Granulation Technology, 1997, Dilip Parikh, Marcel Dekker, Inc. See ISBN 0-8247-9882-1, page 309.

  In dry granulation (slagging or roller compaction), the intragranular material is blended to prepare slag or roller compaction. The material is crushed, blended with extragranular material, followed by capsule filling or tablet 20 compression. Wet granulation requires the incorporation of intragranular material. With or without binder, the blend is wet granulated with water (using a high shear, low shear granulator) and dried (using temperatures up to 100 ° C.). The material is crushed, blended with extragranular material, followed by capsule filling or tablet compression. 25 Handbook of Pharmaceutical Granulation Technology, 1997, Dilip Parikh, Marcel Dekker, Inc. See ISBN 0-8247-9882-1, pages 338-368.

2. Pharmaceutically acceptable compositions and formulations:
In certain embodiments, a pharmaceutically acceptable composition of the present invention comprises SKI-606 and, for example, one or more binders, carriers, viscosity modifiers and suspending agents, wetting agents, sweeteners, pH. And one or more other excipients such as conditioning agents, flavoring agents, preservatives, and combinations thereof. One skilled in the art will readily recognize that the category in which a particular component is listed is not intended to be limiting. In some cases, certain components may fit properly in more than one category. It will also be appreciated that the same component may be associated with a particular formulation depending on, for example, the amount of the component and / or the presence of other components and / or active compound (s). , Sometimes performing different functions or performing more than one function.

  In certain embodiments, the present invention provides 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl), also referred to as SKI-606. ) -Propoxy] -quinoline-3-carbonitrile. A pharmaceutically acceptable solid composition is provided. SKI-606 is described in US Pat. No. 6,297,258, along with a method for preparing SKI-606, as described in US Pat. No. 7,297,795. SKI-606 has the following structure:

一水和物として単離される。３−シアノキノリン化合物、４−（２，４−ジクロロ−５−メトキシ−フェニルアミノ）−６−メトキシ−７−［３−（４−メチル−ピペラジン−１−イル）−プロポキシ］−キノリン−３−カルボニトリルは、ｐＨ８．０における固有溶解度がおおよそ０．０６μｇ／ｍＬである弱塩基である。ｐＨ８未満で、化合物ＳＫＩ−６０６の溶解度は、イオン化によって、ｐＨの低下につれて指数関数的に増加する。しかしながら、ＳＫＩ−６０６の分解が、加水分解を通じて低いｐＨの水溶液で観察されたものの、化合物は、５より高いｐＨで比較的安定であり、その場合、４−アミノキノリン基は、イオン化されていない。

Isolated as a monohydrate. 3-cyanoquinoline compound, 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy] -quinoline-3 Carbonitrile is a weak base with an intrinsic solubility of approximately 0.06 μg / mL at pH 8.0. Below pH 8, the solubility of compound SKI-606 increases exponentially with decreasing pH due to ionization. However, although SKI-606 degradation was observed in aqueous solutions at low pH through hydrolysis, the compound is relatively stable at pH higher than 5, in which case the 4-aminoquinoline group is not ionized. .

  In certain embodiments, the SKI-606 formulations of the present invention comprise 3-cyanoquinoline including variable elution that appears to depend on particle size, accelerated elution upon storage, and limited stability upon storage. Eliminate one or more problems with solid formulations. The croscarmellose SKI-606 formulation of the present invention has a faster disintegration time (2-7 minutes) than an equivalent SKI-606 formulation with a conventional disintegrant (eg, crospovidone, disintegration time about 18-20 minutes). ).

  In certain embodiments, the SKI-606 formulations of the present invention include film-coated SKI-606 formulations prepared by high shear wet granulation or pan coating. In other embodiments, film-coated SKI-606 tablet formulations are prepared by other conventional coating techniques.

  The disintegration times were compared for SKI-606 formulations using conventional disintegrants, crospovidone, and croscarmellose sodium and are summarized in Table 2. The intragranular disintegrant in this case was kept constant at 3% w / w. The two formulations have significantly different disintegration times, for example the tablet disintegration time (DT) for the 2% extragranular (EG) SKI-606 / CCS formulation is a SKI-606 / CPV formulation with a DT of 22 minutes Compared to 3.5 minutes. Furthermore, tablet DT is also observed to be strongly dependent on tablet hardness for all SKI-606 / CPV formulations, whereas such dependency is not observed for SKI-606 / CCS formulations. For example, even for the 3% IG and 2% EG SKI-606 / CPV formulations, the DT time for low hardness and high hardness tablets varies by 14 minutes (range), while the SKI-606 / CCS formulation is 3 Only changes up to 5 minutes. This finding shows that the SKI-606 / CCS formulation was robust with respect to tablet hardness and a significant improvement in the tablet manufacturability characteristics of the SKI-606 formulation of the present invention.

  Tablet dissolution (see FIG. 1) of the SKI-606 formulation of the present invention is also performed in 0.1N HCl, with tablet dissolution at 10 and a disintegrant concentration lower than that used for the SKI-606 / CPV formulation. It was revealed to be faster for the SKI-606 / CCS formulation at 15 minutes. Furthermore, the data also suggested that lower binder concentrations enhanced elution, especially at the early time points.

In certain embodiments, the amount of croscarmellose sodium (CCS) in the SKI-606 formulation of the present invention that provides similar elution results is as follows.
1.0-2% w / w intragranular concentration 2.1-3% w / w extragranular concentration The binder (povidone concentration) may also vary from 1-2% w / w.

  In certain embodiments, the ratio of intragranular and extragranular components in the SKI-606 formulation of the present invention was varied from 3: 1 to 2: 2.

  In certain embodiments, a filler comprising one intragranular (IG) component, microcrystalline cellulose (MCC) is transferred from the intragranular portion to the extragranular (EG) component and tableted in the SKI-606 formulation of the present invention. Facilitated faster disintegration time inside. The amount of extragranular filler component was increased from 4% to 15% by weight relative to the weight of the SKI-606 formulation.

  In certain embodiments, the grade of MCC in the EG component was changed from Avicel PH101 ™ to Avicel PH102 ™ to facilitate tablet blend flow.

  In certain embodiments, unlike the general finding that decreasing API particle size generally causes an increase in dissolution rate, for SKI606 formulations, decreasing API particle size can result in higher D90 API particles. It was observed that when processed in the same manner as the size formulation, there was a tendency to reduce the dissolution of the formulation. Therefore, as summarized in FIG. 6, it was observed that the lower the API particle size, the slower the elution rate, and the higher the API particle size, the faster the elution rate.

  In order to maximize dissolution, one possible approach for existing formulations is to increase the particle size of drugs such as SKI-606. To slow down elution, the approach is to use a lower particle size API.

  In certain embodiments, changes in poloxamer concentration in the SKI-606 formulations of the present invention were not made in order to retain in vivo effects when administered to a human or animal subject.

  In certain embodiments, the formulations of the present invention may contain one or more non-rate limiting layers, films or coatings. The location of the non-rate limiting layer in the formulation is not important. For example, a non-rate limiting layer may be present between at least one core and the enteric coating or rate limiting mechanism. Alternatively, the non-rate limiting layer can surround or coat an enteric coating or rate limiting mechanism. The non-rate limiting layer can be made of one or more polymers and other ingredients known in the art, including but not limited to plasticizers, pigments / opacifiers and the like. Examples of polymers that can be used include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, and polyethylene glycol. Examples of plasticizers that can be used include, but are not limited to, polyethylene glycol (s), glycerin, triacetin, triethyl citrate, diethyl phthalate and mineral oil. Examples of pigments / opacifiers that can be used include, but are not limited to, water-soluble dyes, pigments, and natural products.

  In certain embodiments, the formulations of the present invention can also include at least one enteric coating. Methacrylic acid and methacrylate copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, ethyl acrylate / methacrylic acid copolymer, cellulose acetate trimellitate, shellac and combinations thereof Alternatively, any enteric coating can be used in the present invention, including but not limited to dispersions. Furthermore, 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 one skilled in the art, but must be sufficient to protect the formulation in the acidic environment of the stomach.

  In certain embodiments, a solid pharmaceutically acceptable composition of SKI-606 was invented based on replacing one conventional disintegrant, crospovidone, with croscarmellose sodium and improved SKI-606 formulations. The obtained stability and uniform dissolution rate were obtained unexpectedly (see Table 1 and Figures 1-3).

  Wetting agents are well known in the art and typically facilitate drug release and absorption. Exemplary wetting agents are poloxamer, polyoxyethylene ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polysorbate, cetyl alcohol, Glycerol fatty acid esters (for example, triacetin, glycerol monostearate, etc.), polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid ester, sucrose fatty acid ester, benzalkonium chloride, polyethoxylated castor oil, and docusate sodium, etc. As well as combinations thereof. In some embodiments, the wetting agent is, for example, Polysorbate 80 ™, glycerol, Polysorbate 65 ™, polysorbate 60 ™ USP, Polysorbate 40 ™ USP, Polysorbate 20 ™ USP, Octoxynol-9, Nonoxynol. -10 (TM) USP, Poloxamer 235 (TM), Poloxamer 188 (TM) USP, but are not limited to these. In some embodiments, provided humectants are from about 0.1% to about 5%, from about 1.0% to about 4%, or from about 3.% by weight, based on the total weight of the formulation. Occupies 0% by weight. In certain embodiments, the wetting agent is a poloxamer including, but not limited to, Poloxamer 188 ™ (Lutrol F-68), for example.

  Suitable binders (also referred to as “diluents” and / or “fillers”) are known in the art. For example, suitable binders and fillers are starch, dextrin, sucrose, sorbitol, sodium saccharin, acesulfame potassium, xylitol, aspartame, mannitol, starch, PVP (polyvinylpyrrolidone), low molecular weight HPC (hydroxypropylcellulose), microcrystalline Cellulose (MCC), low molecular weight HPMC (hydroxypropylmethylcellulose), low molecular weight carboxymethylcellulose, ethylcellulose, alginate, gelatin, polyethylene oxide, acacia, dextrin, sucrose, magnesium aluminum silicate, and polymethacrylate Is not to be done. Fillers include reagents selected from the group consisting of microcrystalline cellulose, starch, lactitol, lactose, suitable inorganic calcium salts, sucrose, glucose, mannitol, silicic acid, or combinations thereof. In some embodiments, the binder and filler comprise from about 1% to about 25% or about 21.5% by weight relative to the total weight of the formulation. In some embodiments, the binding agent is one or more grades of MCC, including but not limited to Avicel PH101 ™ and Avicel PH102 ™.

  Incorporation of an appropriate disintegrant (s) into the SKI-606 formulation of the present invention facilitates dissolution. Suitable disintegrants are known in the art and include agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, crospovidone (crosslinked PVP), sodium carboxymethyl starch (sodium starch glycolate) , Cross-linked sodium carboxymethylcellulose (croscarmellose), pregelatinized starch (starch 1500), microcrystalline starch, water soluble starch, calcium carboxymethylcellulose, magnesium magnesium silicate (Vegum) or combinations thereof However, it is not limited to these. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant is croscarmellose sodium.

  In some embodiments, suitable lubricants are included in the SKI-606 formulations of the present invention. Suitable lubricants or glidants include, for example, stearate, sodium stearyl fumarate and magnesium salts, magnesium stearate. The amount of lubricant used is 0.2 to 5 weight percent of one or more lubricants, including about 0.5% by weight, based on the weight of the composition. In some embodiments, the lubricant is magnesium stearate.

  The addition of one or more preservatives can be particularly useful in compositions including SKI-606 and can provide protection from degradation and / or precipitation. Suitable 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, propyl paraben, methyl paraben, butylated hydroxytoluene, propionate, potassium sorbate, indinavir and combinations thereof. Is not to be done. In some embodiments, provided preservatives comprise from about 0.05% to about 0.25% or about 0.1% by weight of the total weight of the formulation.

  The provided compositions can be formulated in unit dosage form. Such formulations are well known to those skilled in the art. In certain embodiments, the present invention provides a formulation comprising a solid dosage form as a tablet. In other embodiments, the present invention provides a solution for oral administration. In some embodiments, the unit dosage form is SKI-606 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 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1 75 mg, containing 1300mg, 1325mg, 1350mg, 1375mg, 1400mg, 1425mg, 1450mg, 1475mg, and 1500 mg. In some embodiments, the unit dosage form contains SKI-606 5 mg to 500 mg, or 10 mg to 450 mg. In some embodiments, the unit dosage form contains 50 mg, 75 mg, 100 mg, 150 mg, 250 mg, 300 mg, or 500 mg. In some embodiments, the unit dosage form contains more than 500 mg of SKI-606.

  In some embodiments, the effective dose of SKI-606 used may vary depending on the particular compound used, the mode of administration and the severity of the condition being treated. In general, however, satisfactory results indicate that the compound of the present invention is given in about 2 to 4 divided doses per day or in sustained release form from about 0.5 to about 1000 mg / kg body weight per day. Obtained when administered in doses. The total daily dose is expected to be about 1-1000 mg, preferably about 2-500 mg. Dosage forms suitable for internal use comprise from about 0.5 to 1000 mg of 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 can be administered daily, or the dose can be reduced proportionally as indicated by the urgency of the treatment situation.

  In some embodiments, the pharmaceutical composition of SKI-606 is a solid composition, particularly tablets and hard-filled or liquid-filled capsules, for ease of preparation and administration. In a preferred embodiment, oral administration of SKI-606 is preferred.

  For the treatment of cancer, the SKI-606 formulations of the present invention can be administered in combination with other anti-tumor agents or radiation therapy. These other substances or radiation therapy can be given at the same time or at different times as the compounds of the invention. These combination therapies are synergistic and result in improved efficacy. For example, a compound of the invention may be combined with a mitotic inhibitor such as taxol or vinblastine, an alkylating agent such as cisplatin or cyclophosphamide, an antimetabolite such as 5-fluorouracil or hydroxyurea, a DNA interferant such as adriamycin or bleomycin. It can be used in combination with a calator, a topoisomerase inhibitor such as etoposide or camptothecin, an anti-angiogenic agent such as angiostatin, and an anti-estrogen agent such as tamoxifen.

  Based on the results disclosed for SKI-606 and other 3-cyanoquinoline compounds in US Pat. No. 6,297,258, the SKI-606 formulations of the present invention treat neoplastic growth, Significantly useful anti-neoplastic agents that are useful to inhibit or eradicate neoplasms. In particular, the compounds of the invention treat neoplasms expressing EGFR, such as those of the breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary, or lung, inhibit its growth, or eradicate it. Useful to do. Furthermore, the compounds of the present invention are useful for treating, inhibiting or eradicating breast neoplasms that express the receptor protein produced by the erbB2 (Her2) oncogene. Based on the results obtained, the compounds of the present invention are also useful for the treatment of polycystic kidney disease.

3. Combination product and combination administration:
In certain embodiments, the compositions of the invention, and their formulations, can be administered alone to treat one or more disorders as described herein, or as described herein. Administration in combination with one or more other active agents useful for treating one or more disorders as described in the document (whether simultaneously or sequentially). Accordingly, the compositions of the invention, or formulations thereof, can be administered simultaneously with, prior to, or after one or more active agents.

  In certain embodiments, the compositions of the invention include one or more other active agents that are not SKI-606 in addition to SKI-606. In some embodiments, the formulations of the invention comprise both another anti-cancer compound and SKI-606.

  The amount of additional active agent (s) present in the combination composition of the present invention is typically the amount normally administered as a composition comprising the only therapeutic agent active agent. It will be about the same. In certain embodiments of the invention, the amount of additional active agent will range from about 50-100% of the amount normally present in a composition comprising that compound as the sole therapeutic agent.

  In certain embodiments, the formulations of the present invention can also be used in conjunction and / or in combination with conventional therapies for gastrointestinal disorders that help improve constipation and bowel dysfunction. For example, conventional therapies include functional stimulation of the intestinal tract, fecal softeners, laxatives (eg diphenylmethane laxatives, swallow laxatives, osmotic laxatives, salt laxatives, etc.), swelling and laxatives, lubricants, intravenous hydration As well as, but not limited to, nasogastric decompression.

4). Uses and kits of the composition of the invention:
Provided compositions, and formulations thereof, treat cancers involving angiogenesis, immunosuppression, sickle cell anemia, vascular wounds, and conditions involving retinopathy, inflammation-related disorders (eg, irritable bowel syndrome) It is also useful for immunosuppression and treatment of chronic inflammation.

  In further embodiments, veterinary applications of the compositions of the present invention and the use of these formulations (eg, treatment of livestock, eg, horses, dogs, cats, etc.) are provided. Accordingly, the use of the provided formulations in veterinary applications similar to those discussed above for human subjects is contemplated.

  That the compositions of the invention, and their formulations, can be used in combination therapy, i.e., the compositions of the invention, and their formulations, concurrently with one or more other desirable therapies or medical procedures, It will also be understood that it can be administered prior to or after them. The particular combination therapy (therapeutic agent or procedure) for use in the combination regimen will take into account the suitability of the desired therapeutic agent and / or procedure and the desired therapeutic effect to be achieved. The therapy used can achieve the desired effect for the same disorder (eg, one formulation can be administered simultaneously with another compound used to treat the same disorder), or the therapy used It will also be appreciated that different effects can be achieved (eg, control of any adverse effects). As used herein, additional therapeutic compounds that are normally administered to treat or prevent a particular disease or condition are known as “appropriate for the disease or condition being treated”. It has been.

  In other embodiments, the compositions of the invention, and their formulations, and unit dosage forms are useful for the preparation of pharmaceuticals, including but not limited to pharmaceuticals useful for the treatment of cancer.

  Further encompassed by the present invention are pharmaceutical packs and / or kits comprising the compositions of the invention, and their formulations, and containers (eg, foil or plastic packages, or other suitable containers). In some cases, instructions for use are further provided in such kits.

  In order to more fully understand the invention described herein, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any way.

  All features of each aspect of the invention apply to all other aspects mutatis mutandis.

(Examples 1 and 2)
Preparation of a pharmaceutically acceptable composition of SKI-606 SKI-606 is a method described in detail in one or more of US Pat. Nos. 6,297,258 and 7,297,795. Prepared according to Exemplary inventive formulations of SKI-606 and comparative SKI-606 formulations are summarized in Table 1.

  500 mg titer tablets were compressed using appropriate tooling equipment and the tablets were compressed with low (11-13 kp), target (14-16 kp) and high (17-19 kp) hardness. These tablets were then evaluated for disintegration time in 0.1N HCl.

  The comparative SKI-606 formulation was prepared by a process of high shear wet granulation, wet grinding, fluid bed drying, dry grinding, blending and subsequent compression into film coated tablets. This formulation was associated with a high rate of gastric irritation in fasted individuals.

  The disintegration times were compared for SKI-606 formulations using conventional disintegrants, crospovidone, and croscarmellose sodium and are summarized in Table 2. The intragranular disintegrant in this case was kept constant at 3% w / w. The two formulations have significantly different disintegration times, for example, the tablet disintegration time (DT) for a 2% extragranular (EG) CCS formulation is 3.5 compared to a CPV formulation with a DT of 22 minutes. It's just minutes. Furthermore, tablet DT is also observed to be strongly dependent on tablet hardness for all CPV formulations, while such dependence is not observed for CCS formulations. For example, even for a 2% CPV formulation, the DT time for low and high hardness tablets varies by as much as 14 minutes, while the CCS formulation varies only by 3.5 minutes. This finding indicates the fact that the CCS formulation was robust with respect to tablet hardness. This is a significant improvement in terms of tablet manufacturability characteristics, especially since it means that the tablet is an immediate release tablet.

  Tablet dissolution (see FIG. 1) of the SKI-606 formulation of the present invention is also performed in 0.1N HCl, and tablet dissolution is more for CCS formulations at 10 and 15 minutes at lower concentrations than those used for CPV. Clarified that it was fast. Furthermore, the data also suggested that lower binder concentrations enhanced elution, especially at the early time points.

  These trials are different from CPV preparations whose end point is very sensitive to water input, and the CCS preparation is not affected by tablet hardness because the granulation end point is not reached rapidly and the disintegration time (DT) of CCS is not affected by tablet hardness. It is excellent in terms of processability. Reducing binder may correlate with sufficient elution for CPV.

  It is also clear that for SKI-606 formulations of the present invention that include croscarmellose sodium as a disintegrant, elution is not sensitive to API particle size at 15 minutes, as summarized in Table 3. Furthermore, for all IG / EG ranges tested, the only ratio that gave lower elution for the CCS formulation at 15 minutes was 1% / 0% intragranular / extragranular disintegrant. For all other levels, the release is over 90%.

  These tests made it easy to identify the end point of granulation (reducing the risk of overgranulation), and the disintegration time for croscarmellose sodium formulation was not significantly affected by tablet hardness (Povidone) ) That croscarmellose sodium formulation is superior in terms of manufacturability in that reducing the concentration results in a higher dissolution rate of the CPV formulation as expected by its effect on the rate of tablet disintegration. Show. Binder changes were not considered necessary for CCS formulations that showed excellent tablet disintegration time and dissolution regardless of binder concentration.

  The results of extensive experiments have demonstrated that croscarmellose sodium formulations are more robust with respect to consistency of dissolution profiles for products with drug substance particle size variability and stability. Some advantages are due to changing the intragranular to extragranular ratio of microcrystalline cellulose to improve both tablet disintegration time and blend flow, keeping the poloxamer and binder the same as the reference composition. It was seen.

  It is also apparent that for the SKI-606 formulations of the present invention that include croscarmellose sodium as the disintegrant, the elution is lower for smaller particle sizes, as summarized in Tables 2 and 3.

  In addition, at 40 ° C. (dry and wet), it was observed that neither disintegrant nor incompatibility was seen at 2 and 4 weeks for either disintegrant. Batches with stability testing at 40 ° C. and 40 ° C./75% RH conditions showed that elution shifts were observed with CPV and not with CCS, as summarized in FIGS.

  Based on measured data and results, croscarmellose formulations are superior because both the effects of API variability on elution and the elution shift in stability are addressed with minimal changes to the formulation. SKI-606 tablet formulation (thus, it was decided to keep the binders povidone and poloxamer constant at 2% and 3%, respectively). Disintegrant type and IG / EG disintegrant ratio were changed from 3: 1 to 2: 2 (% w / w) in the clinic. Figures 4 and 5 describe the effect on elution by varying the intragranular and extragranular disintegrant ratio for both croscarmellose and crospovidone, respectively.

(Example 3)
Preparation of Fast Dissolving Pharmaceutically Acceptable Composition of SKI-606 SKI-606 is described in detail in one or more of US Pat. Nos. 6,297,258 and 7,297,795. Prepared according to the method. Exemplary fast dissolving formulations of the present invention and comparative SKI-606 formulations of SKI-606 are summarized in Table 4.

  The gastric irritation effect of the formulation may be the result of prolonged residence times in the stomach and upper gastrointestinal tract. The SKI-606 formulation of the present invention also provides a relatively fast-dissolving salt of the drug that solubilizes more quickly in the gastrointestinal tract. Examples of fast-dissolving salts of drugs include citrate, succinate, fumarate, di-hydrochloride, di-mesylate, acetate, maleate, tartrate and hydrochloric acid, to name a few. Provided are SKI-606 formulations that include salts and are more rapidly eluted or disintegrated in the gastrointestinal tract and are useful for causing rapid drug dissolution.

  A more rapidly disintegrating formulation was prepared by making minor modifications to the current formulation. This was done by incorporating the following changes into the formulation: replacing the disintegrant crospovidone with croscarmellose sodium. This disintegrant acts by a “swelling” action that promotes the initial disintegration time as compared to the “wicking” action by crospovidone that promotes disintegration. It has been found that it exhibits a more rapid disintegration at concentrations comparable to crospovidone. In addition to replacing the disintegrant, an additional change made was a change in the ratio of microcrystalline cellulose. A microcrystalline cellulose, Avicel PH101, was reduced intragranular and increased extragranular to help improve disintegrant efficacy. The grade was also changed from Avicel 101 to 102 with a larger particle size to improve admixture flow and compressibility. This approach has been found to provide tablets that disintegrate and dissolve more rapidly, both of which are expected to improve gastric outcome in the stomach. The SKI-606 formulation of the present invention is based on this approach.

Example 4
Preparation of a pharmaceutically acceptable composition of SKI-606 as a coated tablet SKI-606 is detailed in one or more of US Pat. Nos. 6,297,258 and 7,297,795. Prepared according to the method described in 1. Exemplary coated tablets from the inventive formulation of SKI-606 in two different unit doses are summarized in Table 5.

  Dry blend and coating parts:

  SKI-606 formulations and coated tablets of SKI-606 formulations were prepared as follows:

Manufacturing Procedure SKI-606 formulations and coated tablets of SKI-606 formulations were prepared as follows:
The following ingredients were weighed for a batch size of 25 Kg:
SKI-606 monohydrate 17.241 Kg
Microcrystalline cellulose (Avicel PH101) 1.624Kg
Croscarmellose sodium 0.5Kg
Povidone K-25 0.5Kg
Poloxamer 0.75Kg
1. Povidone and poloxamer were dissolved in purified water.
2. The intragranular portion of SKI-606, microcrystalline cellulose (PH101), and croscarmellose sodium were added to a high shear granulator and mixed for a minimum of 4 minutes or until uniform. The dry ingredients may be passed through a screen as necessary to remove lumps prior to premixing.
3. While mixing, the Step 1 solution was added to a high shear granulator and mixed until proper granulation was achieved. If necessary, the amount of water may be adjusted to achieve a satisfactory granulation endpoint.
4). If desired, the granulation may be passed through a mill or screen to facilitate uniform granulation before drying.
5. The granulate was dried in a fluid bed dryer until a satisfactory end point was reached. The LOD at this point should be less than 3% w / w with a target of 1-1.5% w / w under test temperature conditions.
6). The dried granulation was passed through a mill equipped with a suitable sieve or screen to facilitate a satisfactory particle size distribution for blending. Save this part for step 10.
7). The granulation was added to a suitable blender. If necessary, mix granulate of standard size, dried for a minimum of 5 minutes or until uniform.
8). The amount of extragranular component is calculated based on the yield obtained of the dried granulation.
9. The dry blend component may be passed through a screen prior to blending. If necessary, take a sample of microcrystalline cellulose for blending in Step 10. Add microcrystalline cellulose and croscarmellose sodium to the mixer and mix for 10 minutes or until uniform.
10. Either a portion of the granulation from Step 6 or the microcrystalline cellulose from Step 9 (PH102) was added to the magnesium stearate and mixed to form a lubricant pre-blend. Add the lubricant pre-blend to the blender from step 9 and mix for a minimum of 2 minutes or until uniform.
11. Compress the granulate using a suitable tool with sufficient hardness.

Preparation and application of coating suspension Prior to mixing, the dry color was passed through a screen as needed. Using a suitable mixer and tank, the color coat was added to the purified water and mixed until a satisfactory suspension was formed. The suspension may be screened through a suitable screen.
2. A 5 kg coating suspension was applied to the bed for a total weight gain of 3% wt / wt. This may be verified by increasing the tablet weight, if necessary.

Coated tablets of SKI-606 formulation and SKI-606 formulation were prepared as follows for a core tablet of batch size 1 Kg:
The following ingredients were weighed:
SKI-606 monohydrate 718.4g
46.23g of microcrystalline cellulose (Avicel PH101)
Crospovidone 10.0g
Povidone K-25 20.00g
Poloxamer 188 30.00g
1. SKI-606, microcrystalline cellulose and crospovidone from step 1 were passed through a 20 mesh screen and the ingredients were added to a high shear mixer.
2. The ingredients were mixed in step 2 in a high shear granulator for 2 minutes at low plow speed (impeller only).
3. Poloxamer 188 and povidone K-25 were dissolved in purified water in a separate mixer. A low mixer speed was used to avoid foaming.
4). Set impeller and chopper speed to low settings. The solution from step 4 was added using a pump and the mix in step 3 was granulated. If necessary, mixing was continued for an additional 2-5 minutes with a low speed chopper and impeller when the granulation solution was exhausted. Additional purified water was added as needed with mixing until the end of granulation was reached. The desired granulation end point was checked. Record the total amount of water used to granulate and the total mixing time and power or torque readings where possible.
5. Recommended 1.5% to 2.5% L. in a fluid bed dryer with inlet recommended set point temperature of 70 ° C. ± 5 ° C. O. D. The granulation was dried to the extent. Weighed and recorded the yield.
6). The dried granulation was passed through a low speed Comil (recommended mill speed 700 rpm or less and recommended screen: 20 mesh). Weighed and recorded the yield.
Final blend:
7). Based on the yield in step 7, the amount of ingredients required for the (extragranular) dry additive was calculated.
8). The ground granulation from Step 9 was transferred into an appropriately sized V-blender.
9. Microcrystalline cellulose (PH101) and crospovidone were weighed, passed through a 20 mesh screen and added to the V-blender in step 11. Mix for 10 minutes without intensifying bar activation.
10. Magnesium stearate was passed through a 30 mesh screen, bag blended with an equal portion of the granulation from step 12, and added to the V-blender. Mix for 2 minutes without an intensifier bar.
11. Weighed and recorded the yield.
The tablets were compressed at a known weight and hardness and the compressed tablets were film coated.

  In certain embodiments, the SKI-606 formulations of the present invention, as summarized in FIGS. 10 and 12, have one or more problems with solid formulations of 3-cyanoquinoline, namely certain SKI-606 formulations (comparison) Remove the tendency for variable elution when tested in buffer or acidic conditions and a small but significant elution shift over time in both room temperature and acceleration conditions for (see Examples). FIG. 11 shows the lack of elution shift for the croscarmellose formulation. FIG. 12 shows the dissolution shift in existing formulations. Poloxamer 188 in the SKI-606 comparative formulation was responsible for the observed elution shift. Poloxamers are solid at room temperature but tend to undergo liquefaction at and near their melting point of 48-52 ° C. Indeed, the studies summarized in FIGS. 13 and 14 revealed that the poloxamer in the crospovidone-based formulation is the reason for the tablet shifting on dissolution.

  In certain embodiments, SKI-606 tablet formulations were prepared with varying amounts of poloxamer in the range of 0, 1.5, 3, 4.5 and 6% w / w based on the weight of the SKI-606 formulation. Surprisingly, it was observed that there was a clear dependence of tablet dissolution on the percent poloxamer content of the formulation when tested in 0.1N HCl. FIG. 13 summarizes the effect of various poloxamer contents on tablet dissolution at similar water and binder addition rates in 0.1 N HCl. Indeed, it is observed that poloxamers appear to delay release, particularly at the early time points, for the tablets tested. Poloxamer appeared to delay initial tablet dissolution at 15 and 30 minutes in a concentration-dependent manner. See Table 8.

  Poloxamers in tablets tend to delay dissolution at an early stage, but accelerate dissolution at accelerated stability at a later time in 0.1N HCl media, as can be seen in the data summarized in Table 9. I understood that.

  With accelerated stability, poloxamers cause an elution shift in a concentration-dependent manner from 0% w / w to 3% w / w. Beyond the 3% poloxamer concentration, the elution shift peaks without an obvious trend. These results demonstrate that poloxamers can cause an elution shift with stability. Poloxamer chains at aging and accelerating temperatures are believed to become more mobile, so instead of packing the granules in the tablet, the mobile polymer chains tend to “soften” the tablet. This may be the result of granule softening as well as an increased tendency to disintegrate over time. There is also a decrease in the decay time in stability. As soon as the tablet disintegrates, the granules in the tablet actually behave very much like all known surfactants. Increasing surfactant tends to increase granule elution, as seen in FIG.

  This elution shift problem was eliminated by the SKI-606 formulation of the present invention by replacing the wetting agent poloxamer that also functions as a surfactant in the formulation. The use of low melting surfactants (those that were liquid at room temperature) may help to address this problem. Polyoxyethylene (20) sorbitan monooleate (Tween ™ or polysorbate ™™) is one of the commonly used surfactants in use. The concentration of polyoxyethylene (20) sorbitan monooleate (polyoxyethylene sorbitan monooleate (Tween-80 ™)) tested was 1% instead of 3% poloxamer in the formulation. Used in a CPV formulation containing 3% IG and 1% EG CPV as a disintegrant, which was deemed acceptable because the dissolution and other manufacturability characteristics tested at this concentration are acceptable In addition, polyoxyethylene sorbitan monooleate (Tween-80) ™ is a commonly used pharmaceutically acceptable wetting agent and also functions as a surfactant.

  In addition to addressing elution shifts, testing of the robustness of these formulations with respect to active pharmaceutical ingredient API particle size is desirable. The comparative SKI-606 formulation API particle size appears to affect dissolution, ie, the smaller the API particle size, the slower the dissolution. For SKI / Tween-80 formulations, this effect is minimal or negligible (FIG. 17), and SKI with an alternative wetting agent polyoxyethylene sorbitan monooleate (Tween-80) ™. The -606 formulation was superior in aging over the comparative SKI-606 formulation (Figures 15 and 16).

(Examples 11 and 12)
Preparation of a pharmaceutically acceptable composition of SKI-606 SKI-606 is a method described in detail in one or more of US Pat. Nos. 6,297,258 and 7,297,795. Prepared according to Exemplary inventive formulations of SKI-606 and comparative SKI-606 formulations are summarized in Table 10.

  Alternative SKI-606 formulations containing polyoxyethylene sorbitan monooleate (Tween-80) as a wetting agent are summarized in Tables 11-13.

  The comparative SKI-606 formulation was prepared by a process of high shear wet granulation, wet grinding, fluid bed drying, dry grinding, blending and subsequent compression into film coated tablets.

In certain embodiments, the SKI-606 formulations of the present invention include film-coated SKI-606 formulations prepared by high shear wet granulation or pan coating. In other embodiments, film-coated SKI-606 tablet formulations are prepared by other conventional coating techniques.

Claims (20)

  As an intragranular component, (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazine-1) relative to the weight of the composition -Yl) -propoxy] -quinoline-3-carbonitrile 20-80 weight percent, (b) povidone, (c) microcrystalline cellulose, (d) croscarmellose sodium 0.25 to weight of composition A pharmaceutically acceptable composition comprising 5 weight percent (e) poloxamer and (f) microcrystalline cellulose and (g) magnesium stearate as extragranular components.   As an intragranular component, (a) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazine-1) relative to the weight of the composition -Yl) -propoxy] -quinoline-3-carbonitrile 25-80 weight percent, (b) povidone, (c) microcrystalline cellulose, (d) croscarmellose sodium 0.25-2.5% by weight of the composition A pharmaceutically acceptable composition comprising 5 weight percent (e) poloxamer and (f) microcrystalline cellulose and (g) magnesium stearate as extragranular components.   The amount of 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile is The composition of claim 1, wherein the composition is about 69% by weight relative to the weight of the composition.   4. The composition according to any one of claims 1 to 3, wherein the amount of croscarmellose sodium is about 1-3% by weight in the intragranular portion relative to the weight of the composition.   4. The composition according to any one of claims 1 to 3, wherein the amount of croscarmellose sodium is about 1-3% by weight in the extragranular portion relative to the weight of the composition.   The composition of claim 1, wherein the amount of povidone is about 2% by weight, based on the weight of the composition.   The composition of claim 1, wherein the amount of microcrystalline cellulose is about 21.5% by weight based on the weight of the composition.   The amount of microcrystalline cellulose as an intragranular component is about 6.5% by weight based on the weight of the composition, and the amount of microcrystalline cellulose as an extragranular component is about 8. A composition according to claim 7, which is 15% by weight or both.   The composition of claim 1, wherein the amount of poloxamer is about 3% by weight, based on the weight of the composition.   The composition of claim 1, wherein the amount of magnesium stearate is about 0.5% by weight based on the weight of the composition.   (A) 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazine-) as an intragranular component relative to the weight of the composition 1-yl) -propoxy] -quinoline-3-carbonitrile 25-80 weight percent, (b) povidone 0.5-5.0 weight percent, (c) microcrystalline cellulose 1-25 weight percent, (d) Croscarmellose sodium 0.5-5 weight percent, (e) poloxamer 0.2-5 weight percent, and as an extragranular component, (f) microcrystals, based on the weight of the uncoated / core tablet composition 1 to 25 weight percent functional cellulose, (g) 0.5 to 5 weight percent croscarmellose sodium and (h) 0.5 to 5 weight percent magnesium stearate Pharmaceutically acceptable compositions for oral administration.   The amount of 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile is 9. The composition of claim 8, wherein the composition is about 69% by weight based on the weight of the composition.   13. A composition according to claim 11 or 12, wherein the amount of croscarmellose sodium is about 1-3% by weight in the intragranular portion relative to the weight of the composition.   13. A composition according to claim 11 or 12, wherein the amount of croscarmellose sodium is about 1-3% by weight in the extragranular portion relative to the weight of the composition.   The amount of povidone is about 2% by weight based on the weight of the composition, the amount of microcrystalline cellulose is about 21.5% by weight based on the weight of the composition, and the amount of poloxamer is based on the weight of the composition. 12. A composition according to claim 11, wherein the composition is about 3% by weight or the amount of magnesium stearate is about 0.5% by weight relative to the weight of the composition.   The amount of microcrystalline cellulose as an intragranular component is about 6.5% by weight based on the weight of the composition, and the amount of microcrystalline cellulose as an extragranular component is about 16. A composition according to claim 15 which is 15% by weight or both.   As an intragranular component, 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl) relative to the weight of the composition -Propoxy] -quinoline-3-carbonitrile 25-80 weight percent, and croscarmellose sodium 0.25-5 weight percent based on the weight of the composition, microcrystalline cellulose, and magnesium stearate And a pharmaceutically acceptable composition comprising an extra-granular component.   Oral suspension of 4- (2,4-dichloro-5-methoxy-phenylamino) -6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy] -quinoline-3-carbonitrile 12. A composition according to claim 1 or 11 which is in the form of a suspension.   12. A composition according to claim 1 or claim 11 which is in the form of a wet granulated film-coated tablet or a pan-coated tablet. 12. A method for treating cancer comprising administering an effective amount of the composition of claim 1 or claim 11.

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