Amorphous solid dispersion of dasatinib and use thereof

Abstract

To provide an amorphous solid dispersion ("ASD") comprising dasatinib, a pharmaceutical composition comprising ASD, and a method of treatment comprising administration of the pharmaceutical composition.SOLUTION: Amorphous solid dispersions and pharmaceutical compositions of the protein kinase inhibitor dasatinib. The pharmaceutical compositions can be used in methods of treating a proliferative disorder, such as cancer, or in methods of delivering dasatinib to a patient regardless of whether the patient is concurrently using a gastric acid reducing agent or the patient has an elevated gastric pH. The composition may be particularly suitable for patients suffering from achlorhydria or hypoacidity, or Helicobacter pylori infection.SELECTED DRAWING: Figure 7

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 965,650 (filed January 24, 2020) and U.S. Provisional Application No. 63 / 018,182 (filed April 30, 2020), the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Protein kinase inhibitors (PKIs) are being investigated for their potential use in treating various disorders of cell proliferation, including cancer. The therapeutic potential of PKIs is based on the role that protein kinases are known to play in regulating many cellular pathways, including those involved in signal transduction. Dysregulation of protein kinases has been implicated in the development and progression of many cancers, suggesting that PKIs may be useful as treatments for disorders or diseases, such as cancer, caused by the uncontrolled overexpression or upregulation of protein kinases. One such PKI is dasatinib, currently marketed as an immediate-release formulation for oral administration under the brand name Sprycel. Sprycel is a pharmaceutical formulation of dasatinib monohydrate crystal. Sprycel is indicated for the treatment of (a) newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase; (b) adult patients with Ph+ CML in chronic phase, accelerated phase, or myeloid or lymphoid blast phase who are resistant or intolerant to prior therapy, including imatinib; (c) adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who are resistant or intolerant to prior therapy; (d) pediatric patients aged 1 year and older with Ph+ CML in chronic phase; and (e) pediatric patients aged 1 year and older with newly diagnosed Ph+ ALL in combination with chemotherapy.

[0003] Currently, it is known that the oral dosing of Sprycel can be affected by coadministration with other medications. For example, the oral bioavailability of Sprycel is significantly affected by coadministration with gastric acid-reducing agents, such as H2 antagonists (e.g., famotidine), proton pump inhibitors (e.g., omeprazole), or antacids. In particular, the prescribing information for Sprycel states that "coadministration of Sprycel with gastric acid-reducing agents may decrease dasatinib concentrations" and that "decreased dasatinib concentrations may result in reduced efficacy." The aqueous solubility of dasatinib is pH-dependent. As a result, the exposure (expressed as area under the curve, or "AUC") achieved by an oral dose of Sprycel after administration may be significantly reduced if patients are also taking an H2 antagonist or proton pump inhibitor. According to Sprycel's prescribing information, a single dose of Sprycel administered 10 hours after administration of famotidine (an H2 antagonist) reduces the mean AUC of dasatinib by 61%, and a single dose of 100 mg of Sprycel administered 22 hours after administration of 40 mg of omeprazole (a proton pump inhibitor) at steady state reduces the mean AUC of dasatinib by 43%.

[0004] As a result of these clinical findings, the prescribing information for Sprycel includes a warning: "Do not administer H2 antagonists or proton pump inhibitors with Sprycel." The prescribing information further suggests that an antacid (e.g., aluminum hydroxide / magnesium hydroxide) may be considered instead of an H2 antagonist or proton pump inhibitor, but that coadministration of Sprycel with an antacid should be avoided; the antacid should be administered at least 2 hours before and 2 hours after the prescribed dose of Sprycel. The limitations on how patients can treat indigestion or excessive gastric acidity while on Sprycel treatment are troubling, especially in light of how frequently such symptoms occur within the patient population. Furthermore, failure to fully adhere to the prescribing information warnings regarding taking gastric acid-reducing agents while on Sprycel treatment could potentially harm patients. Thus, there remains a need in the art for dasatinib treatment that does not require patients to avoid concomitant use of gastric acid-reducing agents. Another drawback of currently available dasatinib products is that Sprycel-based pharmacokinetic parameters are known to exhibit significant inter- and intra-patient variability. The large variability may be due to several factors, including differences in absorption, metabolism, excretion, or other variables. However, in some cases, drug variability can be reduced by improving the administered formulation. Summary of the Invention

[0005] Certain aspects of the present disclosure relate to amorphous solid dispersions ("ASDs") comprising dasatinib. The present disclosure also relates to pharmaceutical compositions comprising the ASDs, and methods of treatment comprising administering the pharmaceutical compositions. In some embodiments, the ASD or pharmaceutical composition is administered regardless of whether the patient or subject is receiving a gastric acid-reducing agent. In some embodiments of the methods of the present disclosure, the ASD or pharmaceutical composition is administered to the patient or subject together with a gastric acid-reducing agent. The gastric acid-reducing agent can be selected from an H2 antagonist, a proton pump inhibitor, or an antacid. In some embodiments, the ASD or pharmaceutical composition is administered regardless of whether the patient or subject has elevated gastric pH. In some embodiments, the ASD or pharmaceutical composition is administered to a patient or subject with elevated gastric pH. In some embodiments, the condition associated with elevated gastric pH in the patient is achlorhydria or hypochlorhydria. In some embodiments, the condition associated with elevated gastric pH in the patient is Helicobacter pylori infection.

[0006] A further aspect of the present disclosure relates to a therapeutic regimen for treating a proliferative disorder in a patient in need thereof. An additional aspect of the present disclosure relates to a kit for sale to a user, the kit comprising a pharmaceutical composition and a package insert. In some embodiments, the package insert informs the user that the pharmaceutical composition can be used in combination with a gastric acid-reducing agent. In some embodiments, the package insert does not include a warning that the pharmaceutical composition should not be used in combination with an H2 antagonist or a proton pump inhibitor. In some embodiments, the package insert informs the user that the pharmaceutical composition can be suitably administered if the user's gastric pH is chronically elevated. In some embodiments, the package insert informs the user that the pharmaceutical composition can be suitably administered if the user has been diagnosed with or is suffering from achlorhydria or hypochlorhydria. In some embodiments, the package insert informs the user that the pharmaceutical composition can be suitably administered if the user has been diagnosed with or is suffering from Helicobacter pylori infection.

[0007] In other embodiments, the present disclosure provides amorphous solid dispersions having high drug loadings of dasatinib ranging from 70% to 95%. The amorphous solid dispersions of the present disclosure are surprisingly stable at such high drug loadings. In yet another aspect, the present disclosure provides pharmaceutical compositions that can achieve reduced inter-subject and / or intra-subject variability compared to the variability observed for Sprycel. [Brief explanation of the drawings]

[0008] [Figure 1]1 shows the in vitro dissolution profiles of dasatinib for an ASD of dasatinib and Eudragit L100-55 at a w / w ratio of 60:40 (dasatinib:Eudragit L100-55), an ASD of dasatinib and Eudragit E100 at a w / w ratio of 50:50 (dasatinib:Eudragit E100), and Sprycel, dissolved in fasted-state simulated gastric fluid (FaSSGF) (pH 1.6) and transferred to fasted-state simulated intestinal fluid (FaSSIF) (pH 6.4) at t=30 minutes, as described in Example 3. Each data point represents the mean of three replicates. [Figure 2] 2 shows the in vitro dissolution profiles of dasatinib for ASDs of dasatinib and Eudragit L100-55 at a w / w ratio of 60:40 (dasatinib:Eudragit L100-55), ASDs of dasatinib and Eudragit E100 at a w / w ratio of 50:50 (dasatinib:Eudragit E100), and Sprycel, dissolved in fasted-state simulated gastric fluid (FaSSGF) (pH 4.0) and transferred to fasted-state simulated intestinal fluid (FaSSIF) (pH 6.4) at t=30 minutes, as described in Example 3. Each data point represents the mean of three replicates. [Figure 3] 3 shows the in vitro dissolution profiles of dasatinib for ASDs of dasatinib and Eudragit L100-55 at a w / w ratio of 60:40 (dasatinib:Eudragit L100-55), ASDs of dasatinib and Eudragit E100 at a w / w ratio of 50:50 (dasatinib:Eudragit E100), and Sprycel, dissolved in fasted-state simulated gastric fluid (FaSSGF) (pH 6.0) and transferred to fasted-state simulated intestinal fluid (FaSSIF) (pH 6.4) at t=30 minutes, as described in Example 3. Each data point represents the mean of three replicates. [Figure 4]FIG. 4 shows the in vivo pharmacokinetic profiles in dogs obtained by administration of an ASD of dasatinib and Eudragit L100-55 in a w / w ratio of 60:40 (dasatinib:Eudragit L100-55), an ASD of dasatinib and Eudragit E100 in a w / w ratio of 50:50 (dasatinib:Eudragit E100), and Sprycel after pentagastrin pretreatment (pH 1-2), as described in Example 4. [Figure 5] FIG. 5 shows the in vivo pharmacokinetic profiles in dogs obtained by administration of an ASD of dasatinib and Eudragit L100-55 at a w / w ratio of 60:40 (dasatinib:Eudragit L100-55), an ASD of dasatinib and Eudragit E100 at a w / w ratio of 50:50 (dasatinib:Eudragit E100), and Sprycel after famotidine pretreatment (pH 6-8), as described in Example 4. [Figure 6] FIG. 6 shows the in vivo pharmacokinetic profiles in humans obtained by administration of dasatinib ASD tablets and Sprycel tablets after famotidine pretreatment (pH 5+), as described in Example 5. [Figure 7] FIG. 7 shows the in vivo pharmacokinetic profiles in humans obtained by administering dasatinib ASD tablets and Sprycel tablets under fasting conditions, and by administering dasatinib ASD tablets and Sprycel tablets after famotidine pretreatment (pH 5+), as described in Example 5. [Figure 8] FIG. 8 shows box plots graphing the AUC data and certain calculated statistical parameters from the study described in Example 5. [Figure 9] FIG. 9 shows box plots graphing Cmax data and certain calculated statistical parameters from the study described in Example 5. [Figure 10]FIG. 10 shows the in vitro dissolution profiles obtained using pH 4 buffer (vehicle A) for tablets containing the ASD of dasatinib:Eudragit L100-55, and the Sprycel reference product, as described in Example 7. [Figure 11] FIG. 11 shows the in vitro dissolution profiles obtained using pH 4 buffer (Vehicle A) for tablets containing the ASD of dasatinib:METHOCEL E5, as well as the Sprycel reference product, as described in Example 7. [Figure 12] FIG. 12 shows the in vitro dissolution profiles obtained using FeSSIF at pH 5.8 (medium B) for tablets containing ASD of dasatinib:Eudragit L100-55 at 60% and 80% drug loads, tablets containing ASD of dasatinib:Methocel E5 at 80% drug load, and the Sprycel reference product, as described in Example 7. [Figure 13] FIG. 13 shows the in vitro dissolution profiles obtained using pH 5.5 buffer (Vehicle C) for tablets containing dasatinib:Eudragit L100-55 ASD at 60% and 80% drug loads, tablets containing dasatinib:Methocel E5 ASD at 80% drug load, and the Sprycel reference product, as described in Example 7. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present disclosure relates to dasatinib ASDs, pharmaceutical compositions of dasatinib ASDs, and methods of use including the administration of dasatinib ASDs or pharmaceutical compositions. The dasatinib ASDs and pharmaceutical compositions of the present disclosure may offer particular advantages over standard, commercially available immediate-release dasatinib compositions, such as Sprycel. For example, as described herein, the prescribing information for Sprycel warns against co-administration with certain gastric acid-reducing agents, as such co-administration may adversely affect dasatinib blood levels, potentially resulting in reduced efficacy. In contrast, the co-administration of the ASDs and pharmaceutical compositions of the present disclosure with gastric acid-reducing agents surprisingly does not exhibit such adverse effects. Another advantage is that the pharmaceutical compositions of the present disclosure may achieve reduced inter- and / or intra-subject variability compared to the variability observed with Sprycel. Thus, the dasatinib ASD and pharmaceutical compositions of the present disclosure provide an advantageous presentation of dasatinib compared to currently available commercial immediate release products.

[0010] Dasatinib Dasatinib is a tyrosine kinase inhibitor whose chemical name is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide. Dasatinib is a 22 H 26 C l It has the molecular formula N7O2S and is shown in the following structure: [ka] The molecular weight of dasatinib is 488.01 g / mol, while the molecular weight of dasatinib monohydrate is 506.02 g / mol. Sprycel is a commercially available pharmaceutical formulation of dasatinib monohydrate crystals, marketed in the United States under New Drug Application 21-986. Sprycel is currently available as immediate-release tablets containing 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, or 140 mg of dasatinib. Crystalline dasatinib is classified as a Biopharmaceutical Classification System ("BCS") Class II (low solubility / high permeability) compound. Dasatinib is known to exhibit pH-dependent aqueous solubility. Based on internal studies, aqueous solubility at pH 2 is approximately 1.4 mg / mL and decreases rapidly with increasing pH; at pH 6.2, solubility is less than 1 μg / mL. Formulating dasatinib in a manner intended to increase its solubility can increase its bioavailability. One approach to increasing solubility is to produce an amorphous solid dispersion.

[0011] Amorphous solid dispersions of dasatinib Certain aspects of the present disclosure relate to amorphous solid dispersions ("ASD") comprising dasatinib and one or more polymers. Pharmaceutically suitable amorphous solid dispersions generally comprise an active pharmaceutical ingredient, such as dasatinib, dispersed in a pharmacologically inert carrier, such as a polymer. One aim of pharmaceutically suitable amorphous solid dispersions is to improve the bioavailability of the active pharmaceutical ingredient. This improvement can occur, for example, through increased surface area, improved wettability or dispersibility, increased dissolution rate, or other factors. It is generally preferred that the pharmaceutically active ingredient be dispersed in the polymer to form what is referred to in the art as a "glass solution." However, other forms of dispersion, such as those referred to as "solid solutions" or "glass suspensions," may also be suitable. The exact characterization of the solid dispersion is not critical, provided that the amorphous solid dispersion can provide the desired properties and performance. In the ASD of the present disclosure, dasatinib may be a free base or a salt such as hydrochloride. In some embodiments, dasatinib is a free base and anhydrous. Such forms of dasatinib and processes for preparing dasatinib are disclosed, for example, in WO2005 / 077945, WO2007 / 035874, WO2009 / 053854, and WO2015 / 181573. In the following description of the amorphous solid dispersions and pharmaceutical compositions and in the claims, any reference to "dasatinib" broadly refers to, as suitable alternatives, dasatinib free base, a dasatinib salt, dasatinib anhydrate (or a salt thereof), dasatinib hydrate or dasatinib solvate, and a hydrate or solvate of a dasatinib salt, unless otherwise specified.

[0012] The one or more polymers, which must be pharmacologically inert, should be suitable for providing structure and stability to the ASD. "Pharmacologically inert" means a material that does not initiate a pharmacological or adverse reaction when introduced into the relevant biological system (e.g., the gastrointestinal tract). In some embodiments, the ASD comprises dasatinib and one or more polymers. In certain embodiments, the ASD consists of dasatinib and one or more polymers. In certain other embodiments, the ASD consists essentially of dasatinib and one or more polymers. Polymers that can be used in the ASDs of the present disclosure include, but are not limited to, those described below. The term "polymer" includes, but is not limited to, organic homopolymers, copolymers (e.g., block polymers, graft polymers, random polymers, terpolymers, etc.), and blends and modifications thereof. The term "copolymer" refers to a polymer containing two or more different monomer units or segments, including terpolymers, tetrapolymers, etc.

[0013] Polymers that can be used in the ASDs of the present disclosure can include ionizable or non-ionizable polymers, or a combination thereof. In some embodiments, the one or more polymers may be non-ionizable polymers. In some embodiments, the ASD consists of dasatinib and one or more non-ionizable polymers. In some other embodiments, the ASD consists essentially of dasatinib and one or more non-ionizable polymers. In some embodiments, the one or more polymers may be ionizable polymers. In some embodiments, the ASD consists of dasatinib and one or more ionizable polymers. In some other embodiments, the ASD consists essentially of dasatinib and one or more ionizable polymers. In yet another embodiment, a combination of an ionizable polymer and a non-ionizable polymer can be used. In some embodiments, the ASD consists of dasatinib and a combination of one or more non-ionizable polymers and one or more ionizable polymers. In some other embodiments, the ASD consists essentially of dasatinib and a combination of one or more non-ionizable polymers and one or more ionizable polymers.

[0014] Polymers that can be used in the ASDs of the present disclosure can include polymers that exhibit pH-dependent solubility, generally pH-insensitive polymers, or combinations thereof. In some embodiments, the one or more polymers may exhibit pH-dependent solubility. In certain embodiments, the ASD consists of dasatinib and one or more polymers that exhibit pH-dependent solubility. In certain other embodiments, the ASD consists essentially of dasatinib and one or more polymers that exhibit pH-dependent solubility. In other embodiments, the one or more polymers may be generally pH-insensitive. In some embodiments, the ASD consists of dasatinib and one or more generally pH-insensitive polymers. In some other embodiments, the ASD consists essentially of dasatinib and one or more generally pH-insensitive polymers. In yet another embodiment, the polymer combination can include one or more polymers that exhibit pH-dependent solubility and one or more generally pH-insensitive polymers. In some embodiments, the ASD consists of dasatinib and a combination of one or more polymers that exhibit pH-dependent solubility and one or more generally pH-insensitive polymers. In some other embodiments, the ASD consists essentially of dasatinib and a combination of one or more polymers that exhibit pH-dependent solubility and one or more generally pH-insensitive polymers.

[0015] Non-ionizable polymers. Suitable non-ionizable polymers can include polysaccharides and polysaccharide derivatives (including cellulose ethers and non-ionizable cellulose esters); polymers or copolymers of N-vinylpyrrolidone and / or vinyl acetate; polymers of ethylene oxide; homopolymers or copolymers of lactic acid and / or glycolic acid; maleic anhydride copolymers; polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers; and poloxamers. Suitable non-ionizable polysaccharides and polysaccharide derivatives can include cellulose ethers and non-ionizable cellulose esters.Suitable examples of cellulose ethers include methylcellulose ("MC"; for example, Methocel A15 LV, Methocel A4M), ethylcellulose ("EC"; for example, ETHOCEL), hypromellose or hydroxypropylmethylcellulose ("HPMC"; for example, Methocel E3, Methocel E5, Methocel E6, Methocel E15, AFFINISOL HPMC HME), hydroxyethylcellulose ("HEC"; for example, Natrosol 250 Pharm), and hydroxypropylcellulose ("HPC"; for example, HPC EF, HPC LF, HPC JF, HPC L, KLUCEL). Examples of non-ionizable cellulose esters that may be suitable include cellulose acetate, cellulose propionate, cellulose butyrate, and cellulose acetate butyrate.

[0016] Examples of suitable polymers or copolymers of N-vinylpyrrolidone and / or vinyl acetate include polyvinylpyrrolidone ("PVP"; e.g., PVP K25, PVP K90, VIVAPHARM PVP), crospovidone or crosslinked polyvinylpyrrolidone (e.g., KOLLIDON CL, VIVAPHARM PVPP), copovidone or vinylpyrrolidone / vinyl acetate copolymer ("PVP / VA"; e.g., KOLLIDON VA 64, VIVAPHARM PVP / VA 64), and polyvinyl alcohol ("PVA"; e.g., VIVAPHARM PVA). Examples of suitable polymers of ethylene oxide include polyethylene glycol ("PEG"; e.g., KOLLISOLV PEG 8000), and poly(ethylene oxide) ("PEO"; e.g., POLYOX). Examples of suitable homopolymers or copolymers of lactic acid and / or glycolic acid include polylactide or poly(lactic acid) (“PLA”), polyglycolide or poly(glycolic acid) (“PGA”), and poly(lactic-co-glycolic acid) (“PLGA”). Non-ionizable maleic anhydride copolymers, such as poly(methyl vinyl ether / maleic anhydride) ("PVM / MA"), may also be suitable. Non-ionizable poloxamers (e.g., PLURONIC, KOLLIPHOR) may also be suitable. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (eg, SOLUPLUS) may also be a suitable non-ionizable polymer.

[0017] Ionizable Polymers. Suitable ionizable polymers may be considered "anionic" or "cationic" polymers. Anionic and cationic polymers often exhibit pH-dependent solubility. Anionic polymers often contain carboxylate (e.g., acetate), phthalate, succinate, or acrylate functionality. Anionic polymers are generally insoluble at low pH and become more soluble at higher pH. Suitable anionic polymers include, for example, anionic polysaccharides and polysaccharide derivatives (e.g., ionizable cellulose esters), methacrylic acid and / or alkyl acrylate copolymers, and derivatized vinyl acetate polymers.

[0018] An example of a suitable ionizable polysaccharide is xanthan gum. Examples of suitable ionizable cellulose esters include carboxymethylcellulose ("CMC"; carboxymethylcellulose sodium), hypromellose acetate succinate or hydroxypropylmethylcellulose acetate succinate ("HPMC-AS"; for example, AFFINISOL HPMC-AS, AQUASOLVE, AQOAT), hydroxypropylmethylcellulose phthalate ("HPMC-P"; for example, HP-50, HP-55), and cellulose acetate phthalate ("CAP"; for example, EASTMAN CAP). Suitable copolymers of methacrylic acid and / or alkyl methacrylates include methacrylic acid / methyl methacrylate copolymers (e.g., Eudragit L100) and methacrylic acid / ethyl acrylate copolymers (e.g., Eudragit L100-55, KOLLICOAT MAE). An example of a derivatized vinyl acetate polymer that may be suitable is polyvinyl acetate phthalate (PVA-P; PHTHALAVIN).

[0019] Cationic polymers often contain amine functionality. Cationic polymers are generally soluble at low pH and less soluble at higher pH. Suitable cationic polymers include, for example, cationic polysaccharides and polysaccharide derivatives, and amine-functionalized copolymers of methacrylic acid and / or alkyl acrylate. An example of a cationic polysaccharide that may be suitable is chitosan. Suitable amine-functionalized copolymers of methacrylic acid and / or alkyl acrylates include, for example, dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer (e.g., Eudragit E100), and aminoalkyl methacrylate copolymers such as poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) (e.g., Eudragit RL100, Eudragit RL PO, Eudragit RS PO). In some embodiments, the one or more polymers comprise a polymer characterized by pH-dependent solubility. In some embodiments, the one or more polymers comprise an anionic polymer characterized by pH-dependent solubility. In some embodiments, the one or more polymers comprise a copolymer of methacrylic acid and / or alkyl methacrylate. In some embodiments, the one or more polymers comprise a methacrylic acid / methyl methacrylate copolymer (e.g., Eudragit L100) or a methacrylic acid / ethyl acrylate copolymer (e.g., Eudragit L100-55).

[0020] In some embodiments, the one or more polymers comprise methacrylic acid and ethyl acrylate copolymer. In certain embodiments, the polymer consists of methacrylic acid / ethyl acrylate copolymer. In certain embodiments, the polymer consists essentially of methacrylic acid / ethyl acrylate copolymer. In some embodiments, the ASD comprises dasatinib and methacrylic acid / ethyl acrylate copolymer. In certain embodiments, the ASD consists of dasatinib and methacrylic acid / ethyl acrylate copolymer. In certain other embodiments, the ASD consists essentially of dasatinib and methacrylic acid / ethyl acrylate copolymer. In certain embodiments, the ASD comprises anhydrous dasatinib free base and methacrylic acid / ethyl acrylate copolymer. In certain embodiments, the ASD consists of anhydrous dasatinib free base and methacrylic acid / ethyl acrylate copolymer. In certain embodiments, the ASD consists essentially of anhydrous dasatinib free base and methacrylic acid / ethyl acrylate copolymer. In any of the above, the methacrylic acid / ethyl acrylate copolymer may be, for example, Eudragit L100-55. Eudragit L100-55 is an anionic copolymer that exhibits pH-dependent water solubility. Generally, Eudragit L100-55 is practically insoluble in aqueous media at pH 5 or below, but is almost soluble in aqueous media at pH 5.5 or above.

[0021] In other embodiments, the one or more polymers comprise cationic polymers characterized by pH-dependent solubility, hi certain embodiments, the one or more polymers comprise amine-functionalized copolymers of methacrylic acid and / or alkyl acrylate characterized by pH-dependent solubility. In some embodiments, the one or more polymers comprise dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer. In certain embodiments, the polymer consists of dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer. In certain embodiments, the polymer consists essentially of dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer. In some embodiments, the ASD comprises dasatinib and dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer. In certain embodiments, the ASD consists of dasatinib and dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer. In certain other embodiments, the ASD consists essentially of dasatinib and dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer. In some embodiments, the ASD comprises anhydrous dasatinib free base and dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer. In some embodiments, the ASD consists of anhydrous dasatinib free base and dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer. In some embodiments, the ASD consists essentially of anhydrous dasatinib free base and dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer.

[0022] In any of the above, the dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer may be, for example, Eudragit E100. Eudragit E100 is a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate in a 2:1:1 ratio, and exhibits pH-dependent water solubility. Generally, Eudragit E100 is mostly soluble in aqueous media at pH 5 or below, and also mostly soluble in aqueous media at pH 5.5 or above. In some embodiments, the one or more polymers may comprise generally pH-insensitive polymers. In some embodiments, the one or more polymers may be generally non-ionizable polymers characterized by pH insensitivity. In some embodiments, the one or more polymers may include non-ionizable polysaccharides and polysaccharide derivatives. In yet other embodiments, the one or more polymers may include cellulose ethers and non-ionizable cellulose esters.

[0023] In some embodiments, the one or more polymers comprise hydroxypropyl methylcellulose (also known as "hypromellose" or "HPMC"). In some embodiments, the one or more polymers consist of one or more hydroxypropyl methylcellulose polymers. In some embodiments, the one or more polymers consist essentially of one or more hydroxypropyl methylcellulose polymers. In some embodiments, the ASD comprises dasatinib and one or more hydroxypropyl methylcellulose polymers. In some embodiments, the ASD consists of dasatinib and one or more hydroxypropyl methylcellulose polymers. In some other embodiments, the ASD consists essentially of dasatinib and one or more hydroxypropyl methylcellulose polymers. In some embodiments, the ASD comprises anhydrous dasatinib free base and one or more hydroxypropyl methylcellulose polymers. In some embodiments, the ASD consists of anhydrous dasatinib free base and one or more hydroxypropyl methylcellulose polymers. In some embodiments, the ASD consists essentially of anhydrous dasatinib free base and one or more hydroxypropyl methylcellulose polymers.

[0024] In any of the above, the hydroxypropyl methylcellulose polymer can be a suitable Methocel, e.g., Methocel E3, Methocel E5, Methocel E6, or Methocel E15. Such Methocel grades are non-ionizable, water-soluble cellulose ethers characterized by 28-30% methoxyl substitution and 7-12% hydroxypropoxyl substitution. These grades are characterized by low solution viscosity (determined at 20°C for a 2% aqueous solution according to the manufacturer's specifications), with the grade number indicating the midpoint of the viscosity range (e.g., Methocel E3 is characterized by a viscosity of 2.4-3.6 mPa·s; Methocel E5 is characterized by a viscosity of 4.0-6.0 mPa·s). These grades are considered low molecular weight HPMC products, having a number average molecular weight (Mn) of about 20 kD or less. All such grades are suitable for use in the ASD of the present disclosure, although Methocel E5 has been shown to be particularly suitable. Combinations or mixtures of grades of hydroxypropyl methylcellulose may also be used. In some embodiments, the one or more polymers comprise low molecular weight hydroxypropyl methylcellulose. In some embodiments, the one or more polymers consist of low molecular weight hydroxypropyl methylcellulose. In some embodiments, the one or more polymers consist essentially of low molecular weight hydroxypropyl methylcellulose. In any of the above, Methocel E5 may be particularly suitable.

[0025] In some embodiments, the one or more polymers comprise a low molecular weight hydroxypropyl methylcellulose characterized by a solution viscosity of 4.0-6.0 mPa·s. In some embodiments, the one or more polymers consist of a low molecular weight hydroxypropyl methylcellulose characterized by a solution viscosity of 4.0-6.0 mPa·s. In some embodiments, the one or more polymers consist essentially of a low molecular weight hydroxypropyl methylcellulose characterized by a solution viscosity of 4.0-6.0 mPa·s. In any of the above, Methocel E5 may be particularly suitable. In some embodiments of the ASD, the one or more polymers do not include polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., Soluplus). In some embodiments, the ASD is substantially devoid of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, the ASD is essentially devoid of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, the ASD is devoid of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In yet other embodiments, the ASD comprises dasatinib and one or more polymers, with the proviso that the one or more polymers are not polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0026] As used herein, the phrase "substantially devoid" means that the recited component represents 10% or less by weight of the ASD. The phrase "essentially devoid" means that the recited component represents 5% or less by weight of the ASD. The term "devoid" means that the recited component represents 2% or less by weight of the ASD. In some embodiments of the ASD, the one or more polymers do not include an N-vinylpyrrolidone polymer or copolymer. In some embodiments, the ASD lacks an N-vinylpyrrolidone polymer or copolymer. In yet other embodiments, the ASD comprises dasatinib and one or more polymers, with the proviso that the one or more polymers are not an N-vinylpyrrolidone polymer or copolymer. In the above, the N-vinylpyrrolidone polymer or copolymer can be polyvinylpyrrolidone, crospovidone, cross-linked polyvinylpyrrolidone, copovidone, or vinylpyrrolidone / vinyl acetate copolymer. In some embodiments of the ASD, the one or more polymers do not include polyvinylpyrrolidone. In some embodiments, the ASD lacks polyvinylpyrrolidone. In yet other embodiments, the ASD comprises dasatinib and one or more polymers, with the proviso that the one or more polymers are not polyvinylpyrrolidone.

[0027] In some embodiments of the ASD, the one or more polymers do not comprise vinylpyrrolidone / vinyl acetate copolymer. In some embodiments, the ASD lacks vinylpyrrolidone / vinyl acetate copolymer. In yet other embodiments, the ASD comprises dasatinib and one or more polymers, with the proviso that the one or more polymers are not vinylpyrrolidone / vinyl acetate copolymer. In the ASDs described herein, the amount of dasatinib relative to the amount of one or more polymers may vary. For example, dasatinib and one or more polymers may be present in a w / w ratio (dasatinib:polymer) of 30:70 to 95:5. In some embodiments, dasatinib and one or more polymers may be present in a w / w ratio of 40:60 to 90:10. In other embodiments, dasatinib and one or more polymers may be present in a w / w ratio of 40:60 to 70:30. In some embodiments, dasatinib and one or more polymers may be present in a ratio of 70:30 to 95:5. In certain embodiments, the w / w ratio is 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, 80:20, 85:15, 90:10, or 95:5.

[0028] Although amorphous solid dispersions can exhibit high solubility in biologically relevant fluids, the proportion of active ingredient in the particles is usually limited by stability issues. Generally, stable amorphous solid dispersions with a high proportion of active ingredient are rare because active ingredients tend to move toward more thermodynamically stable crystalline forms. However, amorphous solid dispersions with a higher proportion of active ingredient are desirable because their apparent solubility may be enhanced (compared to amorphous solid dispersions with a lower proportion). Another benefit of having a higher proportion of active ingredient in an amorphous solid dispersion is that it can achieve a smaller overall dosage form due to the reduced amount of inactive ingredients included. Thus, the present disclosure further provides amorphous solid dispersions with a high drug load of dasatinib. In such embodiments, dasatinib and one or more polymers may be present in a ratio of 70:30 to 95:5. In certain embodiments, the w / w ratio is 70:30, 75:25, 80:20, 85:15, 90:10, or 95:5. Such embodiments have been found to have surprisingly and unexpectedly high levels of chemical and physical stability.

[0029] In some embodiments, the ASD consists of dasatinib and one or more polymers. In some embodiments, the ASD consists essentially of dasatinib and one or more polymers. In other embodiments, the ASD of the present disclosure may further comprise one or more other pharmaceutically acceptable functional ingredients, such as one or more antioxidants, humectants, or solubilizers. As used herein, the phrase "pharmaceutically acceptable" means that an ingredient does not initiate a pharmacological or adverse reaction when introduced into a relevant biological system. By way of non-limiting example only, a substance found on the U.S. Food and Drug Administration's "Generally Recognized as Safe" ("GRAS") list, or a substance used in accordance with the guidelines in the U.S. Food and Drug Administration's Inactive Ingredients Database, would be considered pharmaceutically acceptable. Similarly, substances in corresponding databases or lists maintained by comparable regulatory agencies, such as the European Medicines Agency, would also be considered pharmaceutically acceptable. In general, it is desirable to use only ingredients in the pharmaceutical compositions of the present disclosure that do not cause unacceptable levels of physical or chemical instability in the resulting composition.

[0030] Examples of antioxidants that can be used in the ASDs of the present disclosure include, but are not limited to, acetylcysteine, ascorbyl palmitate, butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), monothioglycerol, potassium nitrate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium disulfite, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, ethylenediaminetetraacetic acid ("EDTA") (e.g., edetate disodium), diethylenetriaminepentaacetic acid ("DTPA"), bismuth sodium triglycollamate, or combinations thereof. Antioxidants may also include amino acids, such as methionine, histidine, cysteine, and amino acids with charged side chains, such as arginine, lysine, aspartic acid, and glutamic acid. Any stereoisomer (e.g., l-, d-, or combinations thereof) of a particular amino acid (e.g., methionine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine, and combinations thereof), or combinations of these stereoisomers, can be present, so long as the amino acid is present in its free base form or in a salt form.

[0031] In some embodiments, the one or more antioxidants include BHT. In some embodiments, the one or more antioxidants include propyl gallate. In some embodiments, the one or more antioxidants consist essentially of BHT. In some embodiments, the one or more antioxidants consist essentially of propyl gallate. In some embodiments, the one or more antioxidants consist of BHT. In some embodiments, the one or more antioxidants consist of propyl gallate. The one or more antioxidants may be present in the ASD in an amount of from 0.001% to 2.0% by weight, or from 0.005% to 1.5% by weight, or from 0.01% to 1.0% by weight, or from 0.05% to 0.5% by weight. Examples of amounts of one or more antioxidants in an ASD include 0.001%, or 0.003%, or 0.005%, or 0.008%, or 0.01%, or 0.015%, or 0.02%, or 0.025%, or 0.03%, or 0.035%, or 0.04%, or 0.05%, or 0.075%, or 0.1%, or 0.2%, or 0.25%, or 0.3%, or 0.4%, or 0.5%, or 0.75%, or 1.0%, or 1.5%, or 2.0% by weight. Various pharmaceutically acceptable humectants may be included. Non-limiting examples of humectants include poloxamers such as poloxamer 407 (e.g., Pluronic F-127) or poloxamer 188 (e.g., Pluronic F-68). Other known pharmaceutically acceptable humectants may also be used. The humectant may be included in the ASD in an amount of 0.5% to 10% by weight, or 1% to 8% by weight, or 2% to 6% by weight.

[0032] Various pharmaceutically acceptable solubilizers may be included. Non-limiting examples of suitable solubilizers include vitamin E TPGS (D-α-tocopherol polyethylene glycol succinate), SLS (sodium lauryl sulfate), and docusate sodium. Other known pharmaceutically acceptable solubilizers may also be used. The solubilizer may be included in the ASD in an amount of 0.1% to 10% by weight, 0.25% to 5% by weight, or 0.5 to 1% by weight. In some embodiments, the ASD comprises dasatinib, one or more polymers, and one or more antioxidants. In some embodiments, the ASD consists essentially of dasatinib, one or more polymers, and one or more antioxidants. In certain embodiments, the ASD consists of dasatinib, one or more polymers, and one or more antioxidants. In some embodiments, the ASD comprises dasatinib, a methacrylic acid / ethyl acrylate copolymer (such as Eudragit L100-55), and propyl gallate. In certain embodiments, the ASD consists essentially of dasatinib, a methacrylic acid and ethyl acrylate copolymer (such as Eudragit L100-55), and propyl gallate. In certain embodiments, the ASD consists of dasatinib, a methacrylic acid / ethyl acrylate copolymer (such as Eudragit L100-55), and propyl gallate. In certain embodiments, the ASD consists of dasatinib, a methacrylic acid / ethyl acrylate copolymer (such as Eudragit L100-55), and propyl gallate at a level of 0.1 to 0.5% by weight of the ASD. In certain embodiments, the ASD consists of dasatinib and methacrylic acid / ethyl acrylate copolymer (such as Eudragit L100-55) in an 80:20 ratio, and propyl gallate at a level of 0.1-0.5% by weight of the ASD.

[0033] In some embodiments, the ASD comprises dasatinib, dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer (such as Eudragit E100), and propyl gallate. In certain embodiments, the ASD consists essentially of dasatinib, dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer (such as Eudragit E100), and propyl gallate. In certain embodiments, the ASD consists of dasatinib, dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer (such as Eudragit E100), and propyl gallate. In certain embodiments, the ASD consists of dasatinib, dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer (such as Eudragit E100), and propyl gallate at a level of 0.1-0.5% by weight of the ASD. In certain embodiments, the ASD consists of dasatinib and dimethylaminoethyl methacrylate / butyl methacrylate / methyl methacrylate copolymer (such as Eudragit E100) in a 60:40 ratio, and propyl gallate at a level of 0.1-0.5% by weight of the ASD. In some embodiments, the ASD comprises dasatinib, hydroxypropyl methylcellulose (such as Methocel E3 or Methocel E5), and propyl gallate. In certain embodiments, the ASD consists essentially of dasatinib, hydroxypropyl methylcellulose (such as Methocel E3 or Methocel E5), and propyl gallate. In certain embodiments, the ASD consists of dasatinib, hydroxypropyl methylcellulose (such as Methocel E3 or Methocel E5), and propyl gallate. In certain embodiments, the ASD consists of dasatinib, hydroxypropyl methylcellulose (such as Methocel E3 or Methocel E5), and propyl gallate at a level of 0.1-0.5% by weight of the ASD. In certain embodiments, the ASD consists of dasatinib and hydroxypropyl methylcellulose (such as Methocel E3 or Methocel E5) in an 80:20 ratio, and propyl gallate at a level of 0.1-0.5% by weight of the ASD.

[0034] As used herein, the phrase "drug loading" refers to the ratio (% by weight) of dasatinib in an ASD relative to the total solid mass of the ASD. By way of example, for an ASD consisting of dasatinib and a polymer, a 1:1 w / w ratio of dasatinib:polymer would represent a 50% drug loading; a 4:1 w / w ratio of dasatinib:polymer would represent an 80% drug loading, etc. As a second example, an ASD containing 40% by weight dasatinib, 50% by weight polymer, and 10% by weight other pharmaceutically acceptable functional ingredients would have a 40% drug loading. The drug loading of dasatinib in the ASD of the present disclosure may suitably range from 25% to 95%, or 30% to 90%, or 40% to 90%, or 40% to 70%. Examples of drug loading of dasatinib in the ASD include 25%, or 30%, or 35%, or 40%, or 45%, or 50%, or 55%, or 60%, or 65%, or 70%, or 75%, or 80%, or 85%, or 90%, or 95%.

[0035] In certain embodiments, the present disclosure provides amorphous solid dispersions with high drug loads of dasatinib, ranging from 70% to 95%. The amorphous solid dispersions of the present disclosure are surprisingly stable at such high drug loads. The amorphous solid dispersions may enhance apparent solubility in biologically relevant fluids, potentially enhancing in vivo bioavailability. Another benefit of high drug load amorphous solid dispersions is that they contain fewer inactive ingredients, allowing for smaller overall dosage forms. For high drug loading embodiments of the ASD of the present disclosure, the drug loading may suitably range from 70% to 95%, or 75% to 95%, or 80% to 90%. Examples of drug loading of dasatinib in the amorphous solid dispersion include 70%, or 75%, or 80%, or 85%, or 90%, or 95%.

[0036] The dasatinib ASD may be in the form of particles. In some embodiments, the particles do not contain a surfactant. In other embodiments, the particles do not contain a wetting agent. In yet other embodiments, the particles do not contain a solubilizer. In other embodiments, the particles do not contain a surfactant or a solubilizer. In other embodiments, the particles lack a surfactant, a wetting agent, and a solubilizer. In other embodiments, the particles consist of a polymer and dasatinib, and do not contain any additional functional components. The particles of the ASD of the present disclosure may generally have a spheroid shape. The particle size, as measured by conventional light scattering or laser diffraction techniques, may generally range from about 0.05 μm to about 100 μm. The median particle size distribution (D50 or Dv0.5) may range from 0.2 μm to 60 μm, or from 0.5 μm to 50 μm, or from 0.5 μm to 40 μm. In some embodiments, the median particle distribution may range from 1 μm to 40 μm, or from 2 μm to 25 μm, or from 3 μm to 20 μm. By way of example only, such particle distributions may be achieved by known methods of spray drying. In some embodiments, the median particle size may be between 0.1 μm and 10 μm, or between 0.2 μm and 5 μm, or between 0.5 μm and 2 μm. By way of example only, such particle distributions may be achieved by methods including electrospraying, discussed further below.

[0037] The dasatinib ASD of the present disclosure may exhibit desirable levels of physical and / or chemical stability, which can be assessed by different measures. Stability is generally assessed using conventional analytical techniques commonly known in pharmaceutical sciences. Physical and chemical stability is generally evaluated after storage under controlled, elevated environmental conditions ("accelerated conditions") for a specified period of time. Storage conditions can be one or more of 25°C / 60% relative humidity ("RH"), or 25°C / protected, or 30°C / 65% RH, or 40°C / 75% RH, or 40°C / protected, or 50°C / 80% RH (as used in this context, "protected" means that the sample is sealed in a foil pouch and placed in a controlled chamber during the storage period). The period can be one or more of 1 week, or 2 weeks, or 4 weeks, or 1 month, or 2 months, or 3 months, or 4 months, or 6 months, or 9 months, or 12 months, or 15 months, or 18 months, or 21 months, or 24 months, or any period in between.

[0038] Dasatinib ASD may demonstrate stability by having a specific quantification value or a specific level of total related substances (e.g., impurities) as measured by high performance liquid chromatography ("HPLC") after storage under accelerated conditions for a specified period of time. Quantification values ​​are generally expressed as a percentage of the amount of analyte detected relative to the expected amount of analyte (e.g., dasatinib), with 100% being a favorable result and significant deviations from 100% being unfavorable. Total related substances are generally expressed as a percentage of the total amount of material detected (i.e., analyte plus impurities), with values ​​approaching 0% being favorable and significant deviations from 0% being unfavorable. In some embodiments, the dasatinib ASD may have a quantitation as measured by HPLC of at least 90%, or at least 93%, or at least 95%, or at least 97%, or at least 98%, or at least 99%. In some embodiments, the dasatinib ASD may have a level of total related substances as measured by HPLC of 3% or less, or 2.5% or less, or 2%, or 1.5% or less, or 1% or less, or 0.9% or less, or 0.8% or less, or 0.7% or less, or 0.6% or less, or 0.5%.

[0039] In some embodiments, the dasatinib ASD may have an HPLC assay of at least 90%, or at least 93%, or at least 95%, or at least 97%, or at least 98% after 1 month, or 2 months, or 3 months, or 6 months of storage at 25° C. / 60% RH. In some embodiments, the dasatinib ASD may have an HPLC level of total related substances of 1.5% or less, or 1% or less, or 0.9% or less, or 0.8% or less, or 0.7% or less, or 0.6% or less, or 0.5% or less after 1 month, or 2 months, or 3 months, or 6 months of storage at 25° C. / 60% RH. In some embodiments, the dasatinib ASD may have an HPLC assay of at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% after 1 month, or 2 months, or 3 months, or 6 months of storage at 40° C. / 75% RH. In some embodiments, the dasatinib ASD may have an HPLC level of total related substances of 2% or less, or 1.5% or less, or 1% or less, or 0.9% or less, or 0.8% or less, or 0.7% or less, or 0.6% or less, or 0.5% or less after 1 month, or 2 months, or 3 months, or 6 months of storage at 40° C. / 75% RH.

[0040] Stability may also be assessed by evaluating the change in the glass transition temperature of the dasatinib ASD over time under different storage conditions. The glass transition temperature can be assessed by modulated DSC ("mDSC") using conventional techniques. In some embodiments, the ASD is characterized by a single glass transition, which is observed by mDSC in the range of 25°C to 200°C, more preferably 40°C to 150°C. In other embodiments, the ASD is characterized by more than one transition, which is observed by mDSC in the range of 25°C to 200°C, more preferably 40°C to 150°C. In some embodiments, the glass transition temperature as measured by mDSC changes by more than 5° C., or more than 4° C., or by more than 3° C. after 1 month, or 2 months, or 3 months, or 6 months of storage at 25° C. / 60% RH. In some embodiments, the glass transition temperature as measured by mDSC changes by more than 6° C., or more than 5° C., or more than 4° C., or more than 3° C., or by more than 2° C., or by more than 1° C. after 1 month, or 2 months, or 3 months, or 6 months of storage at 40° C. / 75% RH.

[0041] Furthermore, stability can be assessed by evaluating the change in crystallinity of dasatinib ASD over time under different storage conditions, for example, by a suitable conventional powder X-ray diffraction technique (herein referred to as XRD). In the practice of the present disclosure, it is preferred (but not essential) that dasatinib ASD remain amorphous or essentially amorphous. In some embodiments, "amorphous" can be defined as having no detectable crystallinity, as determined by methods known in the art, for example, by XRD. An example of determining amorphicity using XRD is provided in Example 1. In some embodiments, "amorphous" may be defined as having a percent crystallinity of 5% or less, or 4% or less, or 3% or less, or 2% or less, or 1% or less, as measured by XRD. In some embodiments, "essentially amorphous" may be defined as having a percent crystallinity of 8% or less, or 7% or less, or 6% or less, as measured by XRD. The ASD of the present disclosure may be amorphous or essentially amorphous when analyzed promptly after preparation (i.e., at t=0). For these purposes, the phrase "promptly after preparation" means analyzing the ASD within a few days after preparation, and storing the ASD under protected conditions at ambient temperature and humidity after preparation and prior to analysis.

[0042] The ASD can be amorphous or essentially amorphous after storage under various storage conditions (e.g., 25°C / 60% RH, 25°C / protected, 40°C / 75% RH, 40°C / protected, 50°C / 80% RH, etc.) for a period of at least 1 week, or at least 2 weeks, or at least 3 weeks, or at least 4 weeks or 1 month, or at least 2 months, or at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or at least 8 months, or at least 9 months, or at least 10 months, or at least 11 months, or at least 12 months or 1 year. In some embodiments, the ASD of the present disclosure may be amorphous or essentially amorphous under conditions of high temperature and humidity (e.g., 40°C / 75% RH) for a period of at least 1 month, or at least 2 months, or at least 3 months, or at least 6 months.

[0043] The dasatinib ASD of the present disclosure can be characterized for water content, for example, by using standard Karl Fischer coulometric titration. In some embodiments, the dasatinib ASD can contain a water content, as assessed by Karl Fischer coulometric titration, of 3% or less, or 2.5% or less, or 2% or less, or 1.5% or less, or 1% or less. In some embodiments, the dasatinib ASD may contain a water content, as assessed by Karl Fischer coulometric titration, of 8% or less, or 7% or less, or 6% or less, or 5% or less, or 4.5% or less, or 4% or less, or 3.5% or less, or 3% or less, or 2.5% or less, or 2% or less, or 1.5% or less, or 1% or less after 1 month, or 2 months, or 3 months, or 6 months of storage at 25° C. / 60% RH. In some embodiments, the dasatinib ASD may contain a water content, as assessed by Karl Fischer coulometric titration, of 8% or less, or 7% or less, or 6% or less, or 5% or less, or 4.5% or less, or 4% or less, or 3.5% or less, or 3% or less, or 2.5% or less, or 2% or less after 1 month, or 2 months, or 3 months, or 6 months of storage at 40° C. / 75% RH.

[0044] Method for producing amorphous solid dispersions The dasatinib ASD of the present disclosure can be prepared by various methods known in the art. Suitable methods generally involve mixing, dissolving, or blending dasatinib, one or more polymers, and, if present, one or more other functional ingredients (such as antioxidants, humectants, or solubilizers) to combine the various components. In carrying out the various methods, dasatinib can be introduced as dasatinib free base, a salt of dasatinib, or a solvate or hydrate of dasatinib. Suitable methods are commonly known in the art and include kneading, co-grinding, melting, melt extrusion, melt agglomeration, dripping, etc. After the consolidation step, the material may be further processed by drying, grinding or crushing, sieving, etc. In carrying out some methods, dasatinib and one or more polymers (and other functional components, if present) can be mixed or dissolved in one or more solvents to provide a liquid feedstock. Suitable solvents include, but are not limited to, water; alcohols such as ethanol, methanol, propanol, or isopropanol; ethers such as ethyl ether or methyl tert-butyl ether; acetonitrile; tetrahydrofuran or methyltetrahydrofuran; acetates such as methyl acetate or ethyl acetate; ketones such as acetone or 2-butanone (methyl ethyl ketone or "MEK"); toluene; ethyl formate; 1,4-dioxane; dimethyl sulfoxide; N-methyl-2-pyrrolidone; volatile halogenated solvents such as chloroform or dichloromethane; and combinations thereof. These ingredients can be mixed or dissolved by methods known in the art. For example, the ingredients can be mixed manually, or mixed continuously, periodically, or by a mixing device, or by a combination thereof. Examples of mixing devices can include, but are not limited to, a magnetic stirrer, a shaker, a paddle mixer, a homogenizer, and any combination thereof.

[0045] After mixing dasatinib and one or more polymers (and other functional components, if present), the liquid feed may be formed into an ASD by, for example, solvent evaporation, lyophilization, precipitation or co-precipitation, spray drying, electrospray, supercritical fluid extraction, etc. Such methods are known and commonly understood in the art. In certain embodiments of the present disclosure, liquid feedstocks may be formed into ASDs by electrospraying. Electrospraying, also known as electrohydrodynamic atomization, has been used to produce micron- or submicron-scale amorphous solid dispersion particles from suitable liquid feedstocks. In one preferred electrospray technique, a liquid feedstock is ejected through one or more nozzles toward a substrate in the presence of an applied electric potential between the nozzle and the substrate. The liquid feedstock is subjected to an electric shear stress due to the applied electric potential. When the shear stress overcomes the surface tension of the liquid feedstock, droplets are ejected from the tip of the nozzle. Conditions are controlled so that an annular jet of droplets is emitted from the tip of the nozzle. The droplets are electrically charged and repel each other, preventing droplet coalescence and promoting self-dispersion. As a result of the applied electric field, the charged droplets accelerate toward the substrate.

[0046] During the short flight path, the solvent "flashes off" from the charged droplets. This rapid evaporation creates a situation where the charged droplets decrease in size but their charge density increases. At a critical point, the droplets break up into even smaller droplets, ultimately producing an essentially monodisperse population of fine droplets. Droplet sizes can range from submicrons to several microns. Essentially complete evaporation of the solvent from the charged droplets results in the formation of relatively uniform particles of the non-volatile component from the liquid feedstock. The evaporation process occurs on a timescale that does not allow crystallization of the non-volatile component. In addition, the evaporative cooling that accompanies extremely rapid solvent evaporation contributes to a quenching effect that keeps the particles in an amorphous state. Furthermore, electrospray conditions can be selected and the system configured so that the amorphous particles contain little residual solvent.

[0047] In some embodiments of the present disclosure, electrospray techniques and / or apparatus may be used to form a liquid feedstock into an ASD. Suitable methods and apparatus are described, for example, in U.S. Patent Nos. 6,746,869, 6,764,720, 7,279,322, 7,498,063, 7,951,428, 7,972,661, 8,992,603, 9,040,816, 9,050,611, 9,108,217, and 9,108,218. No. 642,694, U.S. Pat. No. 10,562,048, U.S. Pat. Publication No. 2014-0158787, U.S. Pat. Publication No. 2015-0190253, U.S. Pat. Publication No. 2016-0038968, U.S. Pat. Publication No. 2016-0175881, U.S. Pat. Publication No. 2016-0235677, U.S. Pat. Publication No. 2019-0193109, and U.S. Pat. Publication No. 2020-0179963. As described above, by using electrospray technology, the median particle distribution of dasatinib ASD can be 0.1 μm to 10 μm, or 0.2 μm to 5 μm, or 0.5 μm to 2 μm. It should be further noted that the dasatinib in the electrosprayed amorphous particles is generally considered to be unsolvated. Even if a solvate form of dasatinib (e.g., dasatinib monohydrate) is used to prepare the liquid feedstock, it is understood that the solvate will evaporate and separate along with other solvents, and the electrosprayed amorphous particles will contain unsolvated dasatinib (e.g., anhydrous dasatinib).

[0048] In some embodiments, the electrospray technique may be performed at room temperature. In certain embodiments, heated air is not used. In other embodiments, the liquid feedstock is maintained at an elevated temperature during the electrospray process. In some embodiments, the electrospray technique may be performed using one or more capillary nozzles. In certain embodiments, the electrospray technique does not use pneumatic nozzles, such as nozzles that rely on kinetic energy; pressure nozzles; nozzles that rely on rotary or centrifugal energy; or ultrasonic nozzles, such as nozzles that rely on acoustic energy. In some embodiments, the electrospray technique results in a yield of greater than 85%, or greater than 90%, or greater than 95%, or greater than 98%. In other embodiments, liquid feedstocks can be formed into ASDs by spray drying. Generally, spray drying involves atomizing a liquid feedstock into very small droplets in a hot, drying gas. The feedstock is pumped or propelled through a nozzle or other atomizing device to form droplets in a drying chamber. Within the drying chamber, the droplets are exposed to an environment of heated, drying gas (usually flowing air or nitrogen), causing the droplets to flash dry (by evaporating off the solvent), resulting in solid particles. The dried particles are typically collected at an outlet of the drying chamber.

[0049] Various spray drying devices and methods can be used to form the ASDs of the present disclosure. In practicing the present disclosure, the median particle size distribution of the ASD obtained by spray drying can be 1 μm to 40 μm, or 2 μm to 25 μm, or 3 μm to 20 μm. In some embodiments, the process for forming ASD does not require a second drying step, i.e., a drying step after generating the particles. In other embodiments, a second drying step is used to further remove most or all of the residual solvent. The second drying step can be performed under appropriate conditions that allow for the removal of the solvent but do not result in recrystallization of the dasatinib. For example, the second drying step can be performed below the glass transition temperature. The second drying step can also be performed under reduced pressure. A combination of elevated temperature and reduced pressure can also be used for the second drying step.

[0050] Pharmaceutical Composition Aspects of the present disclosure relate to pharmaceutical compositions comprising dasatinib ASD. The pharmaceutical compositions of the present disclosure may be in a dosage form suitable for oral administration. In some embodiments, the pharmaceutical composition may be in the form of granules, or may be prepared as granules as an intermediate step in forming another oral dosage form, such as a tablet, sprinkles, or pellets. In some embodiments, the pharmaceutical composition may be in a solid dosage form for oral administration, such as a capsule, tablet, sprinkles, or pellets. The pharmaceutical composition may also be in the form of an aqueous or non-aqueous suspension or solution. Known excipients and known preparation methods may be used to prepare such compositions. The compositions may comprise a dasatinib ASD of the present disclosure and one or more pharmaceutically acceptable excipients, such as one or more solubilizers, one or more buffering agents, one or more pH adjusting agents, one or more surfactants, one or more antioxidants, and / or one or more carriers. Pharmaceutical compositions in the form of solid oral dosage forms may also comprise, for example, one or more fillers, one or more binders, one or more lubricants, one or more disintegrants, and / or other conventional excipients, such as one or more glidants.

[0051] The pharmaceutical composition of the present disclosure can be prepared by using known methods in the art.For example, dasatinib ASD and one or more pharmaceutically acceptable additives can be mixed by simple mixing, or can be mixed by a mixing device continuously, periodically, or by a combination thereof.Examples of mixing devices can include, but are not limited to, a magnetic stirrer, a shaker, a paddle mixer, a homogenizer, and any combination thereof. Solubilizing agents that can be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus), d-α-tocopheryl acid polyethylene glycol (PEG) 1000 succinate (TPGS), PEG-40 hydrogenated castor oil (Cremophor RH40), PEG-35 castor oil (Cremophor EL), PEG-40 stearate (MYRJ 540), hard fats (such as Gelucire 33 / 01), polyoxylglycerides (such as Gelucire 44 / 14), stearoyl polyoxylglycerides (such as Gelucire 50 / 13), PEG-8 caprylic / capric glycerides (such as Labrasol), and poloxamers (such as Pluronic, Corifol). In some embodiments, the pharmaceutical composition can include dasatinib ASD and one or more pharmaceutically acceptable excipients, provided that the pharmaceutically acceptable excipients do not include polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., Soluplus).

[0052] Buffering agents that can be used in the pharmaceutical compositions of the present disclosure include triethylamine, meglumine, diethanolamine, ammonium acetate, arginine, lysine, histidine, phosphate buffer (e.g., sodium phosphate tribasic, sodium phosphate dibasic, sodium phosphate monobasic, or o-phosphate), sodium bicarbonate, Britton-Robinson buffer, Tris buffer (containing tris(hydroxymethyl)-aminomethane), HEPES buffer (containing N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid), acetate, citrate buffer (e.g., citric acid, citric acid anhydride, citrate monobasic, citrate dibasic, citrate tribasic), and the like. tribasic), citrate), ascorbate, glycine, glutamate, lactate, malate, formate, sulfate, and mixtures thereof. Furthermore, pH adjusters that can be used in the pharmaceutical compositions of the present disclosure include pharmaceutically acceptable acids or bases. For example, the acid can include, but is not limited to, one or more inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; or one or more organic acids such as acetic acid, succinic acid, tartaric acid, ascorbic acid, citric acid, glutamic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc. The base can be one or more inorganic or organic bases, including, but not limited to, alkali carbonates, alkali bicarbonates, alkaline earth metal carbonates, alkali hydroxides, alkaline earth metal hydroxides, or amines. For example, the inorganic or organic base can be an alkali hydroxide such as lithium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydroxide, etc.; an alkali carbonate such as calcium carbonate, sodium carbonate, etc.; or an alkali bicarbonate such as sodium bicarbonate, etc. The organic base can also be sodium acetate.

[0053] Surfactants that can be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, sodium lauryl sulfate, docusate sodium, dioctyl sodium sulfosuccinate, dioctyl sodium sulfonate, benzalkonium chloride, benzethonium chloride, lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene hydrogenated castor oil 10, 50, or 60), glycerol monostearate, polysorbates (e.g., polysorbate 40, 60, 65, or 80), sucrose fatty acid esters, methylcellulose, polyalcohols and ethoxylated polyalcohols, thiols (e.g., mercaptans) and derivatives, poloxamers, polyethylene glycol-fatty acid esters (e.g., Corifol RH40, Corifol EL), lecithin, and mixtures thereof.

[0054] Antioxidants that can be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, acetylcysteine, ascorbyl palmitate, BHA, BHT, monothioglycerol, potassium nitrate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, EDTA (e.g., edetate disodium), DTPA, bismuth sodium triglycolamate, or combinations thereof. Antioxidants may also include amino acids, such as methionine, histidine, cysteine, and amino acids with charged side chains, such as arginine, lysine, aspartic acid, and glutamic acid. Any stereoisomer (e.g., l-, d-, or combinations thereof) of a particular amino acid (e.g., methionine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine, and combinations thereof), or combinations of these stereoisomers, can be present, so long as the amino acid is present in its free base form or in a salt form. Carriers that can be used in pharmaceutical compositions of the present disclosure include, but are not limited to, water, saline (e.g., Ringer's solution), alcohol, oil, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, and mixtures or solutions containing any of the above. Carriers can be used in combination with buffering agents.

[0055] In some embodiments, the compositions of the present disclosure may include a carrier having a pH of 5 to 9, or 6 to 8. In certain embodiments, the compositions may include a carrier having a neutral pH. In certain embodiments, the pH of the carrier may be at or near physiological pH. In some embodiments, the pharmaceutical compositions of the present disclosure may include other suitable excipients, such as tonicity-adjusting agents, preservatives, emulsifiers, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity adjusters, stabilizers, and osmolality adjusters. A pharmaceutical composition in solid form may, for example, include one or more fillers, one or more binders, one or more lubricants, one or more disintegrants, and / or other conventional excipients, such as one or more glidants. Suitable fillers include acacia, calcium carbonate, calcium sulfate, calcium sulfate dihydrate, compressible sugar, dibasic calcium phosphate anhydrous (e.g., FUJICALIN, EMCOMPRESS), dibasic calcium phosphate dihydrate, tribasic calcium phosphate, monobasic sodium phosphate, dibasic sodium phosphate, lactose monohydrate, lactose anhydrous, magnesium oxide, magnesium carbonate, silicon dioxide, magnesium aluminum silicate, maltodextrin, mannitol, methylcellulose, microcrystalline cellulose (e.g., AVICEL PH-101, AVICEL PH-102), powdered cellulose, starch, sorbitol, dextrose, dextrates, dextrin, sucrose, xylitol, and mixtures thereof.

[0056] Suitable binders include, for example, various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose (e.g., Avicel PH-101, Avicel PH-102, Avicel PH-105), or silicified microcrystalline cellulose (e.g., PROSOLV SMCC). One or more lubricants may be included to reduce friction with and adhesion to processing equipment during processing. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, stearic acid, stearyl alcohol, glyceryl monostearate, sodium stearyl fumarate, talc, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, and the like. When a lubricant is included, the one or more lubricants are typically present in an amount ranging from 0.1% to 5% by weight of the pharmaceutical composition. In some embodiments, the one or more lubricants are typically present in an amount ranging from 0.25% to 2% by weight of the pharmaceutical composition. In one embodiment, the lubricant is magnesium stearate.

[0057] Suitable disintegrants in the practice of the present disclosure include natural starch, modified or pregelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpolypyrrolidone, and mixtures thereof. Glidants are used to improve the flowability of powder or granular mixtures prior to further processing (e.g., tablet compression). Suitable glidants for use in the compositions of the present disclosure include, but are not limited to, colloidal silica (e.g., hydrophobic colloidal silica such as AEROSIL), silica gel, precipitated silica, and the like. When included, one or more glidants are typically present in the range of 0.1% to 5% by weight of the pharmaceutical composition. In some embodiments, one or more glidants are typically present in the range of 0.25% to 2% by weight of the pharmaceutical composition.

[0058] In some cases, a single excipient may serve multiple functions. For example, microcrystalline cellulose (if present) may function as both a filler and a binder. Alternatively, such multifunctional excipients may be used in combination with other functional excipients (e.g., microcrystalline cellulose may be used with other fillers and / or other binders). In some embodiments, the pharmaceutical composition may be in the form of granules, or may be prepared as granules as an intermediate step in forming another oral dosage form, such as a tablet or pellet, or as a fill for a capsule. In some embodiments, the granules may contain one or more of the pharmaceutically acceptable excipients described above. In certain embodiments, the granules may contain: ASD in an amount of 20% to 70% by weight of the granules; one or more fillers in an amount of 20% to 70% by weight of the granules; one or more disintegrants in an amount of 2% to 10% by weight of the granules; and one or more lubricants in an amount of 0.2% to 5% by weight of the granules. In certain embodiments, the granules may contain the ingredients shown in Table 1.

[0059] Table 1. Ingredients of exemplary granule formulations according to certain embodiments of the present disclosure [Table 1]

[0060] In some embodiments, the pharmaceutical composition is in the form of a tablet. In certain embodiments, the tablet may comprise: ASD in an amount of 20% to 60% by weight of the tablet; one or more fillers in an amount of 40% to 80% by weight of the tablet; one or more disintegrants in an amount of 1% to 10% by weight of the tablet; and one or more lubricants in an amount of 0.25% to 5% by weight of the tablet. In certain embodiments, the amount of granules in a tablet may depend on the dasatinib drug load of the ASD used to prepare the granules. In other words, the higher the drug load in the ASD, the higher the amount of dasatinib in the granules, and therefore the less granules required for the tablet. By way of example only, Tables 2 and 3 show the components of an exemplary tablet formulation, including granules having ASDs with drug loads of 60% and 80%, respectively.

[0061] Table 2. Ingredients of an exemplary tablet formulation comprising granules of dasatinib ASD particles (60% drug load) according to certain embodiments of the present disclosure. [Table 2]

[0062] Table 3. Ingredients of an exemplary tablet formulation comprising granules of dasatinib ASD particles (80% drug load) according to certain embodiments of the present disclosure. [Table 3]

[0063] The pharmaceutical composition of the present disclosure in tablet form can be prepared using methods known in the art. For example, dasatinib ASD and one or more pharmaceutically acceptable excipients can be blended by hand, by bag blending, or by using a suitable device to provide a tableting blend. Examples of suitable blending devices include, but are not limited to, tumbler mixers, V-blenders, acoustic mixers, paddle mixers, screw mixers, etc. A suitable tableting blend may then be compressed into tablets weighing 100 to 1000 mg using, for example, a manual tablet press or a conventional mechanical tablet press. The compression force is selected to obtain the desired mechanical properties of the tablet without compromising performance. In some embodiments, it may be desirable to form granules as an intermediate step in forming a tablet formulation. Granules typically have improved flow, handling, mixability, and compressibility compared to ungranulated materials. Granules may be prepared from ASD particles by processes known in the art, including wet granulation and dry granulation. In some embodiments, the granule components are dry-mixed to form a granule blend, which is then compacted, typically using a roller compactor to form ribbons of material. The ribbons are then reduced in size by milling to form the granules.

[0064] Wet granulation techniques can also be used to form granules, provided that the solvent and process selected do not alter the properties of the ASD. As noted above, the inclusion of suitable excipients can provide improved wettability, disintegration, dispersibility, and solubility. The granule blend (and the resulting granules) can contain some or all of the tablet ingredients. In some embodiments, the granules can contain one or more pharmaceutically acceptable excipients as described above. As described above, after granulation, the granules can be included in a tableting blend and compressed into tablets. Pharmaceutical compositions of the present disclosure may exhibit a desired level of physical and / or chemical stability for an appropriate period of time, and optionally under accelerated conditions. The stability of a pharmaceutical composition may be assessed by various means. For example, a pharmaceutical composition may exhibit chemical stability by having a particular quantitative value or a particular level of total related substances (e.g., impurities) measured after storage under accelerated conditions for a specified period of time. In some embodiments, a pharmaceutical composition may be amorphous (i.e., no crystallinity is detectable) as assessed using XRD after storage under specified conditions.

[0065] In some embodiments, the pharmaceutical composition may be essentially amorphous as assessed using XRD after storage under specified conditions. The storage conditions may be one or more of 25°C / 60% RH, or 30°C / 65% RH, or 40°C / 75% RH. The storage time may be one or more of 1 week, or 2 weeks, or 1 month, or 2 months, or 3 months, or 4 months, or 6 months, or 9 months, or 12 months, or 15 months, or 18 months, or 21 months, or 2 years, or any time period therebetween. In some embodiments, a pharmaceutical composition of the present disclosure is a "gastric acid-insensitive composition," as further described below. In some embodiments, a pharmaceutical composition of the present disclosure is a "variability-improved composition," as further described below.

[0066] Treatment of proliferative disorders Aspects of the present disclosure relate to the use of the dasatinib ASD of the present disclosure or pharmaceutical compositions comprising the ASD. In practicing such embodiments of the present disclosure, the dasatinib ASD and pharmaceutical compositions may be suitably administered to a subject or patient. In some embodiments, the dasatinib ASD or pharmaceutical composition is administered to a subject. The subject in the methods of the present disclosure may be a mammal, including, but not limited to, humans, monkeys, cows, pigs, sheep, horses, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a human. As used herein, the phrase "healthy human subject" refers to a person who is generally healthy and not undergoing treatment for a disease or condition that a pharmaceutically active ingredient (e.g., dasatinib) is typically used to treat. The selection of suitable healthy human subjects for pharmacokinetic evaluation is within the expertise of a person skilled in the art of clinical trial design. In other embodiments, the dasatinib ASD or pharmaceutical composition is administered to a human patient. The human patient may be an adult or a child, for example, under 17 years of age. In some embodiments, the human patient is 1 year of age or older. As used herein, a "patient" refers to a subject, particularly a human, who is being treated for a disease or condition for which a pharmaceutically active ingredient (e.g., dasatinib) is commonly used to treat.

[0067] Aspects of the present disclosure relate to the use of a dasatinib ASD or pharmaceutical composition of the present disclosure for treating a proliferative disorder. Some embodiments relate to a method of treating a proliferative disorder, comprising administering an ASD or pharmaceutical composition of the present disclosure to a patient in need of such treatment. Some embodiments relate to the use of a dasatinib ASD or pharmaceutical composition of the present disclosure for treating a proliferative disorder in a patient in need of such treatment, comprising administering the dasatinib ASD or pharmaceutical composition to the patient. Some embodiments relate to a dasatinib ASD or pharmaceutical composition of the present disclosure for use in treating a proliferative disorder in a patient in need of such treatment, comprising administering the dasatinib ASD or pharmaceutical composition to the patient. Some embodiments relate to the use of a dasatinib ASD or pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a proliferative disorder. In certain aspects, the present disclosure relates to a method of treating a proliferative disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an ASD of the present disclosure or a pharmaceutical composition of the present disclosure.

[0068] The proliferative disorder may be cancer. Examples of such proliferative disorders include leukemia, such as acute lymphocytic leukemia (or acute lymphoblastic leukemia), acute myeloid leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia (or chronic lymphoblastic leukemia), chronic myelogenous leukemia; age-related macular degeneration and diabetic retinopathy; anal and oral cancer; angiosarcoma, basal cell carcinoma and squamous cell carcinoma; bladder cancer; brain cancer; breast cancer; cancer of the central nervous system; cervical cancer; choriocarcinoma; colon cancer; gastrointestinal stromal tumor; uterine cancer; esophageal cancer; Ewing's sarcoma; eye or ocular cancer; cancer), head and neck cancer, hemangioendothelioma, hemangioma and lymphangiogenesis, Kaposi's sarcoma, laryngeal cancer, liver cancer, lung cancer, lymphoma, oral / pharyngeal cancer, multiple myeloma; cardiomegaly, neuroblastoma, neurofibromatosis, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, rhabdomyosarcoma, cutaneous melanoma, small cell lung cancer, gastric cancer, testicular cancer, pharyngeal cancer, tuberous sclerosis, and Wilms' tumor.

[0069] In certain embodiments, the proliferative disorder can be Philadelphia chromosome positive ("Ph+") chronic myeloid leukemia ("CML") in chronic phase. In certain embodiments, the proliferative disorder can be Ph+ CML in chronic phase, accelerated phase, or myeloid or lymphoid blast crisis phase that is resistant or intolerant to previous treatments, including imatinib. In certain embodiments, the proliferative disorder can be Ph+ acute lymphoblastic leukemia ("ALL") that is resistant or intolerant to previous treatments. In some embodiments, the proliferative disorder can be Ph+ ALL, and dasatinib can be administered in combination with chemotherapy. In the methods and uses of the present disclosure, the therapeutically effective amount of the dasatinib ASD or pharmaceutical composition of the present disclosure will be based on, among other factors, the route of administration, the age and size of the patient, and the proliferative disorder being treated. As used herein, the term "therapeutically effective amount" means an amount expected to elicit the biological or medical response sought by the clinician.

[0070] In some embodiments, the therapeutically effective amount may be 0.01 to 10 mg / kg / day, or 0.05 to 7 mg / kg / day of dasatinib. In other embodiments, the therapeutically effective amount may be a fixed dose. For example, the fixed dose may be 5 mg to 400 mg, 10 mg to 300 mg, or 10 mg to 200 mg of dasatinib per day. In certain embodiments, the fixed dose may be 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, or 200 mg of dasatinib per day. Depending on the treatment regimen, the amount of dasatinib administered daily may be given all at once (once daily) or may be divided into more frequent doses (e.g., twice daily).

[0071] As further described below, the pharmaceutical compositions of the present disclosure may provide enhanced or otherwise desirable bioavailability under various administration conditions. The term "bioavailability" refers to the rate and extent to which an active ingredient is absorbed from a pharmaceutical composition and becomes available at the site of action. For orally administered pharmaceuticals, bioavailability is generally assessed by monitoring a subject's plasma over time for the presence of the active ingredient (or a suitable surrogate, e.g., a metabolite) after administration of the pharmaceutical composition and assessing the pharmacokinetic profile. From the pharmacokinetic profile, certain relevant pharmacokinetic parameters can be established. Such pharmacokinetic parameters include, for example, C max , T max , and / or AUC. max indicates the maximum plasma concentration observed over the observable period. max indicates the time point at which the maximum plasma concentration was observed.

[0072] AUC indicates the numerical area under the curve ("AUC") for the concentration-time curve, and AUC 0-t (or AUC t AUC can be evaluated over a specific time interval 0-t. 0-t is typically obtained by numerical integration of the concentration-time curve over the period t=0 to time "t" (e.g., AUC 0-24h or AUC 24h indicates the integral over the period t = 0 to t = 24 hours). 0-last (or AUC last AUC (expressed as ) indicates the integral from t=0 to the last time point at which a sample was taken in the observed period. 0-inf (or AUC inf ) denotes the integral from t=0 to t=“infinity” as determined by extrapolation of data obtained using commonly used pharmacokinetic statistical modeling techniques. Typically, plasma concentration data are log-transformed for analysis. For most pharmacokinetic analyses, data from many subjects are pooled for analysis. Once the data are pooled, relevant pharmacokinetic parameters can be expressed as population geometric means, according to conventional pharmacokinetic statistical analysis and methods. Administration of an ASD or pharmaceutical composition of the present disclosure can be characterized by a pharmacokinetic profile, or observed or calculated pharmacokinetic parameters obtained upon administration of a particular dose of the ASD or pharmaceutical composition to a subject or patient under defined administration conditions.

[0073] By way of example only (as further described below), administration of an ASD or pharmaceutical composition of the present disclosure in a fasted state or under fasting conditions can be characterized by the pharmacokinetic profile or observed pharmacokinetic parameters resulting from the administration. As used herein, the phrase "fasted state" or "fasting condition" for a human subject refers to a subject at least 2 hours, more preferably at least 4 hours, or more preferably at least 8 hours after the subject's last meal. Preferably, the fasted state or fasting condition follows an overnight fast of at least 10 hours. Similarly, as used herein, the phrase "fasted state" or "fasting condition" refers to a condition in which a subject has not eaten for at least 2 hours, more preferably at least 4 hours, or more preferably at least 8 hours; or a condition in a subject following an overnight fast of at least 10 hours. Furthermore, the fasted state or fasting condition may require continuous fasting for at least 1 hour, more preferably at least 2 hours, and more preferably at least 4 hours after administration. Also, as used herein, reference to administration to a human subject in a "fed state" or under "fed conditions" refers to administration to the subject from 30 minutes after the subject begins consuming a meal to 1 hour after the subject has completely consumed a meal. Similarly, "fed state" or "fed conditions" refers to conditions from 30 minutes after the subject begins consuming a meal to 1 hour after the subject has completely consumed a meal.

[0074] Combined use with stomach acid reducers In some embodiments, a dasatinib ASD or pharmaceutical composition of the disclosure can be used in combination with a gastric acid-reducing agent. As used herein, the term "gastric acid-reducing agent" refers to any agent that significantly reduces the amount of acid in a subject's or patient's stomach. Acid reduction can be due to the suppression or inhibition of acid secretion or by neutralizing gastric acid. Examples of gastric acid-reducing agents include, but are not limited to, histamine-2 receptor antagonists (or H2 antagonists) such as famotidine, cimetidine, nizatidine, and ranitidine; proton pump inhibitors (or PPIs) such as rabeprazole, esoomeprazole, lansoprazole, omeprazole, pantoprazole, and dexlansoprazole; and antacids (which neutralize gastric acidity, thereby increasing gastric pH) such as aluminum hydroxide, magnesium hydroxide, sodium citrate, sodium carbonate, sodium bicarbonate, calcium carbonate, and magnesium trisilicate.

[0075] The gastric acid-reducing agent may be administered according to dosage information known in the art for gastric acid-reducing agents or as directed by a physician. As used herein, "standard dosage" refers to a dosage of a gastric acid-reducing agent within a range suitable for a patient following a dosing recommendation from the product label or as directed by a physician. As used herein, "co-administration" (or "co-administered") refers to a situation in which a patient is treated for two or more conditions simultaneously through the administration of two or more therapeutic agents. By way of example only, a patient may be treated for a proliferative disorder described herein with dasatinib, while also being treated for another condition, such as acid reflux or an ulcer, with a second therapeutic agent, such as a proton pump inhibitor. Both therapeutic agents are "co-administered" because they are administered at least once daily. Consideration must be given to whether the administration of one therapeutic agent will affect the absorption or efficacy of the other.

[0076] In the context of this disclosure, the phrase "can be used in combination" means that the two (or more) intended therapeutic agents can be used in combination without a deleterious reduction in the exposure of dasatinib. "Without a deleterious reduction" indicates that the exposure achieved is similar to the exposure achieved when the gastric acid-reducing agent is not used in combination. Any difference in the achieved exposure is insubstantial and / or not therapeutically significant. In contrast, if a deleterious reduction in exposure is achieved, the combination should be avoided. "Detrimental reduction" means a substantial and significant reduction in the achieved exposure. By way of example, if the achieved exposure is below a level recognized as subtherapeutic exposure, the combination would result in a deleterious reduction in exposure.

[0077] As used herein, "therapeutically relevant exposure" means an exposure comparable to that expected when a conventional, commercially available, immediate-release formulation of dasatinib of a corresponding strength is administered according to label instructions. "Comparable" means that administration of an ASD or pharmaceutical composition of the present disclosure to a subject results in a similar therapeutic effect compared to the AUC 0-t (e.g., AUC 0-24h , AUC last or AUC 0-inf ) and C max By way of example only, one method for determining similar therapeutic effects is to measure AUC 0-t or C max is within 80% to 125% bioequivalence criteria when compared to administration to the same subject of a conventional commercially available immediate-release composition administered according to its label directions. As used herein, the phrase "gastric acid-insensitive composition" refers to a pharmaceutical composition of the present disclosure that can be administered regardless of the patient's or subject's stomach pH. A gastric acid-insensitive composition provides a therapeutically appropriate exposure to a patient or subject over a range of stomach pH values. Thus, a gastric acid-insensitive composition can be administered regardless of whether the patient or subject takes a gastric acid-reducing agent or whether the patient has a condition that causes an increase in stomach pH (as further described below).

[0078] Embodiments of the present disclosure relate to administering a gastric acid-reducing agent immediately before, simultaneously with, or immediately after a dasatinib ASD or pharmaceutical composition of the present disclosure. As used herein, the term "immediately before" means administering the gastric acid-reducing agent to a subject within 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, or 15 minutes before administering the dasatinib ASD or pharmaceutical composition. As used herein, the terms "concurrently" or "concomitantly" mean administering the gastric acid-reducing agent to a subject within 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, or simultaneously after administering the dasatinib ASD or pharmaceutical composition. As used herein, the term "immediately after" means that the gastric acid-reducing agent is administered to the subject within 4 hours, or within 3 hours, or within 2 hours, or within 1 hour, or within 45 minutes, or within 30 minutes, or within 15 minutes after administration of the dasatinib ASD or pharmaceutical composition.

[0079] In some embodiments, administration of an ASD or pharmaceutical composition of the present disclosure to a subject concurrently administered with a gastric acid-reducing agent results in a pharmacokinetic profile of dasatinib similar to the pharmacokinetic profile of dasatinib obtained by administration of the ASD or pharmaceutical composition to a subject not concurrently administered with a gastric acid-reducing agent. In certain embodiments, administration of a single dose of an ASD or pharmaceutical composition to a subject concurrently with a gastric acid-reducing agent results in an AUC of dasatinib within 50%, or within 40%, or within 30% of the AUC of dasatinib obtained by administration of the ASD not concurrently administered with the gastric acid-reducing agent. In certain embodiments, the AUC is AUC 0-24h In other embodiments, the AUC is 0-inf is. In some embodiments, a single administration of an ASD or pharmaceutical composition of the present disclosure to a subject or patient concurrently, immediately before, or immediately after the administration of a gastric acid-reducing agent results in a greater AUC and / or C compared to a single administration of a standard, commercially available immediate release composition of dasatinib (e.g., Sprycel) to a subject or patient concurrently, immediately before, or immediately after the administration of a gastric acid-reducing agent. max In certain embodiments, a single administration of the ASD or pharmaceutical composition to a subject administered simultaneously with, immediately before, or immediately after a gastric acid-reducing agent results in an AUC and / or C of dasatinib that is comparable to that obtained by administering a standard, commercially available immediate release composition of dasatinib simultaneously with, immediately before, or immediately after the gastric acid-reducing agent. max AUC and / or C of dasatinib that is at least 80% greater, or at least 100% greater, or at least 150% greater, or at least 200% greater than max and the ASD or pharmaceutical composition contains the same dosage as a standard, commercially available immediate release composition of dasatinib. In one embodiment, the AUC 0-24h In other embodiments, the AUC is 0-inf is.

[0080] In some embodiments, a single administration of an ASD or pharmaceutical composition of the present disclosure to a subject or patient concurrently administered a gastric acid-reducing agent may result in a greater AUC and / or C compared to a single administration of a standard, commercially available immediate release composition of dasatinib (e.g., Sprycel) to a subject or patient concurrently administered a gastric acid-reducing agent. max In one embodiment, administration of the amorphous solid dispersion or pharmaceutical composition in combination with a gastric acid-reducing agent to a subject or patient at a single dose reduces the AUC and / or C of dasatinib obtained by administration of a standard, commercially available immediate release composition of dasatinib in combination with a gastric acid-reducing agent. max AUC and / or C of dasatinib that is at least 80% greater, or at least 100% greater, or at least 150% greater, or at least 200% greater than max wherein the amorphous solid dispersion or pharmaceutical composition contains the same dosage as a standard, commercially available immediate release composition of dasatinib. In one embodiment, the AUC0-24h In other embodiments, the AUC is 0-inf is.

[0081] In some embodiments, the dasatinib ASD or pharmaceutical composition of the present disclosure may be administered to a subject regardless of whether the subject is receiving a gastric acid-reducing agent. Thus, the dasatinib ASD or pharmaceutical composition may be administered to a subject regardless of whether the subject is receiving a gastric acid-reducing agent immediately before the dasatinib ASD or pharmaceutical composition, whether the subject is receiving a gastric acid-reducing agent simultaneously with or immediately after the administration of the dasatinib ASD or pharmaceutical composition, or whether the subject is receiving no gastric acid-reducing agent at all. Some embodiments relate to methods of delivering dasatinib to a subject, regardless of whether a gastric acid-reducing agent is administered to the subject, the methods comprising administering an ASD or pharmaceutical composition of the present disclosure to the subject. Some embodiments relate to the use of a dasatinib ASD or pharmaceutical composition of the present disclosure for delivering dasatinib to a subject, regardless of whether a gastric acid-reducing agent is administered to the subject, the use comprising administering an ASD or pharmaceutical composition to the subject. Some embodiments relate to a dasatinib ASD or pharmaceutical composition of the present disclosure for use in delivering dasatinib to a subject, regardless of whether a gastric acid-reducing agent is administered to the subject, the use comprising administering an ASD or pharmaceutical composition to the subject. Some embodiments relate to the use of a dasatinib ASD or pharmaceutical composition of the present disclosure in the manufacture of a medicament for delivering dasatinib to a subject, regardless of whether a gastric acid-reducing agent is administered to the subject, the delivery comprising administering an ASD or pharmaceutical composition to the subject. According to such embodiments, the dasatinib ASD or pharmaceutical composition may be administered to the subject regardless of whether the subject was administered a gastric acid-reducing agent immediately prior to the dasatinib ASD or pharmaceutical composition, whether the gastric acid-reducing agent was administered simultaneously with or immediately after administration of the dasatinib ASD or pharmaceutical composition, or whether the gastric acid-reducing agent was not administered at all.

[0082] Embodiments of the present disclosure relate to therapeutic regimens for treating a proliferative disorder in a patient in need thereof. In some embodiments, the regimen may include: (a) administering to the patient a first dose comprising a standard dose of a proton pump inhibitor or H2 antagonist; and (b) administering to the patient a second dose comprising a therapeutically effective amount of a dasatinib ASD or pharmaceutical composition of the present disclosure within 20 hours after the first dose. In certain embodiments, the second dose is administered within 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, or 2 hours after the first dose. In some embodiments, the regimen may include: (a) administering to the patient a first dose comprising a standard dose of an antacid; and (b) administering to the patient a second dose comprising a dasatinib ASD or pharmaceutical composition of the present disclosure within 2 hours before the first dose. In some embodiments, the regimen may include (a) administering to the patient a first dose comprising a standard dose of an antacid; and (b) administering to the patient a second dose comprising a dasatinib ASD or pharmaceutical composition of the disclosure within two hours after the first dose. In some embodiments, the regimen may include (a) administering to the patient a first dose comprising a standard dose of an antacid; and (b) administering to the patient a second dose comprising a dasatinib ASD or pharmaceutical composition of the disclosure within two hours before or two hours after the first dose.

[0083] How to treat a patient with elevated gastric pH The dasatinib ASD or pharmaceutical composition of the present disclosure may be suitably administered to subjects or patients with elevated gastric pH (in contrast, conventional immediate release compositions of dasatinib would not be suitable for therapeutic administration to patients with elevated gastric pH). Certain aspects of the present disclosure relate to the use of a dasatinib ASD or pharmaceutical composition of the present disclosure for delivering dasatinib to a subject or patient experiencing elevated gastric pH. Some embodiments relate to a method of delivering dasatinib to a subject experiencing elevated gastric pH, comprising administering an ASD or pharmaceutical composition of the present disclosure to the subject or patient. Some embodiments relate to the use of a dasatinib ASD or pharmaceutical composition of the present disclosure for delivering dasatinib to a subject or patient experiencing elevated gastric pH, comprising administering the ASD or pharmaceutical composition to the subject or patient. Some embodiments relate to a dasatinib ASD or pharmaceutical composition of the present disclosure for use in delivering dasatinib to a subject or patient experiencing elevated gastric pH, comprising administering the ASD or pharmaceutical composition to the subject or patient. Some embodiments relate to the use of a dasatinib ASD or pharmaceutical composition of the present disclosure in the manufacture of a medicament for delivering dasatinib to a subject or patient having elevated gastric pH, wherein the delivery comprises administering the ASD or pharmaceutical composition to the subject or patient.

[0084] As used herein, "gastric pH" refers to the internal pH of a subject's or patient's stomach. Gastric pH can be considered "elevated" if the gastric pH measured under fasting conditions is greater than 3.5, or greater than 4, or greater than 5. Gastric pH can be assessed using standard methods, or elevated gastric pH can be inferred from the known effects of, for example, treatment with gastric acid-reducing agents, or from identified conditions that typically cause a measurably elevated gastric pH. In the practice of the present disclosure, a subject's or patient's gastric pH may be elevated due to different causes, including, but not limited to, the subject's or patient's administration of a gastric acid-reducing agent, or the subject's or patient's condition causing an elevated gastric pH, which may be caused by conditions such as hypochlorhydria or achlorhydria, or infection with the bacterium Helicobacter pylori (H. pylori). As used herein, the phrase "chronically elevated" with respect to gastric pH means that a subject or patient experiences persistent or recurrent elevated gastric pH. Chronically elevated gastric pH can result from conditions such as hypochlorhydria or achlorhydria, or Helicobacter pylori infection. In particular, conventional immediate-release compositions of dasatinib would not be suitable for therapeutic administration to subjects or patients with chronically elevated gastric pH due to the potential for adversely reduced exposure to dasatinib as a result.

[0085] In some embodiments, the methods of the present disclosure may include identifying a patient with an elevated gastric pH (including a chronically elevated state). Such a step may include diagnosing the underlying cause of the elevated gastric pH. Methods for diagnosing hypochlorhydria or achlorhydria in a patient or for testing for Helicobacter pylori infection are known in the medical field. Hypochlorhydria or achlorhydria can be diagnosed, for example, by measuring gastric acid levels under different conditions. Helicobacter pylori infection can be diagnosed, for example, by appropriate blood tests, stool tests, breath tests, or endoscopy. In some embodiments, the dasatinib ASD or pharmaceutical composition may be administered to a subject or patient regardless of gastric pH. Thus, the dasatinib ASD or pharmaceutical composition may be administered to a subject or patient regardless of whether the subject's or patient's gastric pH is normal (i.e., a gastric pH below 3.5, generally within the range of 1.5 to 3), or whether the subject's or patient's gastric pH is elevated as described herein. This is beneficial, for example, when the subject's or patient's gastric pH fluctuates due to irregular or episodic use of gastric acid-reducing agents, or when the subject or patient has hypochlorhydria (resulting in a gastric pH that can fluctuate depending on factors such as whether the subject or patient has recently eaten a meal).

[0086] In some embodiments, administration of an ASD or pharmaceutical composition of the present disclosure to a subject or patient with elevated gastric pH exhibits a pharmacokinetic profile for dasatinib similar to the pharmacokinetic profile for dasatinib obtained by administration of the ASD or pharmaceutical composition to a subject or patient with normal gastric pH. In certain embodiments, administration of a single dose of the ASD or pharmaceutical composition to a subject or patient with elevated gastric pH exhibits a pharmacokinetic profile for dasatinib similar to the pharmacokinetic profile for dasatinib obtained by administration of a single dose of the ASD or pharmaceutical composition to a subject or patient with normal gastric pH. 0-t and / or C. max AUC of dasatinib within 50%, 40%, or 30% of 0-t (e.g., AUC 0-24h , AUC last or AUC 0-inf ) and / or C max In one embodiment, the AUC 0-t is the AUC 0-24h In another embodiment, AUC 0-t is the AUC 0-inf is. In certain embodiments, administration of an ASD or pharmaceutical composition of the present disclosure in a subject or patient with elevated gastric pH results in an AUC 0.01 in the plasma of the subject or patient within 80% to 125% bioequivalence criteria compared to administration of a conventional commercially available immediate release composition administered to a subject or patient with normal gastric pH. 0-t (e.g., AUC 0-24h , AUC last or AUC 0-inf ) and C max In one embodiment, AUC 0-t is the AUC 0-24h In another embodiment, AUC 0-t is the AUC 0-inf is.

[0087] In practicing the present disclosure, administration of an ASD or pharmaceutical composition can provide enhanced exposure compared to standard immediate release compositions. In some embodiments, a single administration of an ASD or pharmaceutical composition of the present disclosure to a subject or patient with elevated gastric pH can provide a greater AUC and / or C compared to a single administration of a standard commercially available immediate release composition of dasatinib (e.g., Sprycel) to a subject or patient with elevated gastric pH. max (It is understood that in each case the same molar or "label claim" amount of dasatinib is administered.) In one embodiment, the AUC is 0-24h In other embodiments, the AUC is 0-inf In certain embodiments, a single administration of the ASD or pharmaceutical composition to a subject or patient with elevated gastric pH results in an AUC of dasatinib that is less than or equal to that obtained by administration of a standard, commercially available immediate release composition of dasatinib to a subject or patient with elevated gastric pH. 0-t and / or C. max AUC of dasatinib that is at least 80% greater, or at least 100% greater, or at least 150% greater, or at least 200% greater than 0-t and / or C. max In one embodiment, the AUC 0-24h In other embodiments, the AUC is 0-inf is.

[0088] Furthermore, certain aspects of the present disclosure relate to the use of a dasatinib ASD or pharmaceutical composition of the present disclosure for delivering dasatinib to a subject regardless of the pH of the subject's stomach. Some embodiments relate to a method for delivering dasatinib to a subject regardless of the pH of the subject's stomach, the method comprising administering an ASD or pharmaceutical composition of the present disclosure to the subject. Some embodiments relate to the use of a dasatinib ASD or pharmaceutical composition of the present disclosure for delivering dasatinib to a subject regardless of the pH of the subject's stomach, the use comprising administering the ASD or pharmaceutical composition to the subject. Some embodiments relate to a dasatinib ASD or pharmaceutical composition of the present disclosure for use in delivering dasatinib to a subject regardless of the pH of the subject's stomach, the use comprising administering the ASD or pharmaceutical composition to the subject. Some embodiments relate to the use of a dasatinib ASD or pharmaceutical composition of the present disclosure in the manufacture of a medicament for delivering dasatinib to a subject regardless of the pH of the subject's stomach, the delivery comprising administering the ASD or pharmaceutical composition to the subject. According to such embodiments, the dasatinib ASD or pharmaceutical composition may be administered to a subject regardless of whether the subject's gastric pH is normal or whether the subject's gastric pH is elevated as described herein.

[0089] Pharmaceutical compositions with improved variability The pharmaceutical compositions of the present disclosure may, in some embodiments, provide less variable in vivo pharmacokinetic performance. As used herein, the phrase "variability-improved composition" refers to a composition of the present disclosure that exhibits a lower coefficient of variation for one or more pharmacokinetic parameters when administered under similar conditions compared to the coefficient of variation observed when a standard, commercially available immediate release composition of dasatinib (e.g., Sprycel) is administered to healthy human subjects.

[0090] In some embodiments, the improved variability compositions provide a coefficient of variation for at least one pharmacokinetic parameter that is 30% lower, 25% lower, 20% lower, 15% lower, or 10% lower than the coefficient of variation observed when a standard, commercially available immediate release composition of dasatinib (e.g., Sprycel) is administered under similar conditions. The pharmacokinetic parameter is C max , AUC last and AUC 0-inf In some embodiments, the composition with improved variability may be C max , and AUC last and AUC 0-inf In another embodiment, the composition with improved variability provides an improvement in at least one of C max , AUC last and AUC 0-inf Provide improvements on all aspects of the In particular, it has been observed that the compositions of the present disclosure can provide lower coefficients of variation for pharmacokinetic parameters when administered to healthy human subjects in a normal gastric pH and fasted state. As shown in Example 8, the test compositions exhibited a C max , AUC last and AUC 0-inf The CVs observed for the test compositions were at least 30% lower for each of these parameters compared to the test compositions.

[0091] Kit containing pharmaceutical composition and package insert In some embodiments, the present disclosure provides a kit comprising any of the pharmaceutical compositions of the above-described aspects of the present disclosure and a package insert. As used herein, a "kit" is a unit of sale and may contain a fixed number of doses of the pharmaceutical composition. By way of example only, the kit may provide a 30-day supply of one or more fixed-strength dosage units, including 30 dosage units, 60 dosage units, 90 dosage units, 120 dosage units, or other suitable quantities based on a physician's instructions. As another example, the kit may provide a 90-day supply of dosage units. As used herein, "package insert" means a document that provides information regarding the use of a pharmaceutical composition, safety information, and other information required by regulatory authorities. In some embodiments, the package insert may be a physical printed document. Alternatively, the package insert may be made available to users electronically, for example, through the National Institutes of Health's National Library of Medicine's Daily Med service, which provides up-to-date prescribing information (see https: / / dailymed.nlm.nih.gov / dailymed / index.cfm).

[0092] In some embodiments, the package insert informs the user of the kit that the pharmaceutical composition can be used in combination with a stomach acid-reducing agent, hi some embodiments, the package insert does not include a warning that the pharmaceutical composition should not be used in combination with an H2 antagonist or a proton pump inhibitor. In some embodiments, the package insert may inform the user of the kit that an antacid can be used in combination with the pharmaceutical composition. In some embodiments, the package insert may not inform the user to use an antacid approximately two hours before or approximately two hours after administration of the pharmaceutical composition. In some embodiments, the package insert may inform the user that an antacid can be used within approximately two hours before or approximately two hours after administration of the pharmaceutical composition. In some embodiments, the package insert informs a user of the kit that the pharmaceutical composition is suitable for administration to a patient with chronically elevated gastric pH. In some embodiments, the package insert informs a user of the kit that the pharmaceutical composition is suitable for administration to a patient diagnosed with or suffering from achlorhydria or hypochlorhydria. In some embodiments, the package insert informs a user of the kit that the pharmaceutical composition is suitable for administration to a patient diagnosed with or suffering from Helicobacter pylori infection. The present disclosure is further described and / or illustrated by the following examples, which are provided for illustrative / indicative purposes only and are not intended to limit the present disclosure in any way.

[0093] Embodiments of the present disclosure include the following. Embodiment ASD1 is an amorphous solid dispersion comprising dasatinib and one or more polymers. Embodiment ASD2 is an amorphous solid dispersion comprising dasatinib and one or more polymers, wherein the dasatinib and one or more polymers are present in the amorphous solid dispersion in a w / w ratio of 30:70 to 95:5 (dasatinib:polymer).Embodiment ASD3 is an amorphous solid dispersion comprising dasatinib and one or more polymers, wherein the dasatinib and one or more polymers are present in the amorphous solid dispersion in a w / w ratio of 40:60 to 90:10 (dasatinib:polymer).Embodiment ASD4 is an amorphous solid dispersion comprising dasatinib and one or more polymers, wherein the dasatinib and one or more polymers are present in the amorphous solid dispersion in a w / w ratio of 40:60 to 70:30 (dasatinib:polymer). Embodiment ASD5 is an amorphous solid dispersion comprising dasatinib and one or more polymers, wherein the dasatinib and one or more polymers are present in the amorphous solid dispersion in a w / w ratio of 70:30 to 95:5 (dasatinib:polymer).

[0094] Embodiment ASD6 is the amorphous solid dispersion of any of embodiments ASD1-ASD5, wherein the one or more polymers exhibit pH-dependent solubility. Embodiment ASD7 is the amorphous solid dispersion of any of embodiments ASD1-ASD6, wherein the one or more polymers comprise a methacrylic acid and ethyl acrylate copolymer. Embodiment ASD8 is the amorphous solid dispersion of any of embodiments ASD1-ASD7, wherein the one or more polymers consist essentially of a methacrylic acid and ethyl acrylate copolymer. Embodiment ASD9 is the amorphous solid dispersion of any of embodiments ASD1-ASD8, wherein the one or more polymers comprise a methacrylic acid and ethyl acrylate copolymer that is insoluble in aqueous media at a pH of 5 or less and soluble in aqueous media at a pH of 5.5 or more. Embodiment ASD10 is the amorphous solid dispersion of any of embodiments ASD1-ASD9, wherein the one or more polymers comprise a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.Embodiment ASD11 is the amorphous solid dispersion of any of embodiments ASD1-ASD10, wherein the one or more polymers consist essentially of a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

[0095] Embodiment ASD12 is the amorphous solid dispersion of any of embodiments ASD1-ASD11, wherein the one or more polymers comprise hydroxypropyl methylcellulose. Embodiment ASD13 is the amorphous solid dispersion of any of embodiments ASD1-ASD12, wherein the one or more polymers consist essentially of hydroxypropyl methylcellulose. Embodiment ASD14 is the amorphous solid dispersion of any of embodiments ASD1-ASD13, wherein the one or more polymers comprise hydroxypropyl methylcellulose characterized by 28-30% methoxyl substitution and 7-12% hydroxypropoxyl substitution. Embodiment ASD15 is the amorphous solid dispersion of any of embodiments ASD1-ASD14, wherein the one or more polymers comprise hydroxypropyl methylcellulose characterized by a viscosity of about 2 to about 18 mPa·s for a 2% aqueous solution, determined at 20°C. Embodiment ASD16 is the amorphous solid dispersion of any of embodiments ASD1-ASD15, wherein the one or more polymers comprises hydroxypropyl methylcellulose characterized by a number average molecular weight (Mn) of about 20 kDa or less.

[0096] Embodiment ASD17 is the amorphous solid dispersion of any of embodiments ASD1-ASD16, wherein the amorphous solid dispersion consists essentially of dasatinib and one or more polymers. Embodiment ASD18 is the amorphous solid dispersion of any of embodiments ASD1-ASD17, wherein the amorphous solid dispersion comprises one or more antioxidants. Embodiment ASD19 is the amorphous solid dispersion of any of embodiments ASD1-ASD18, wherein the amorphous solid dispersion comprises one or more antioxidants present in an amount of from about 0.001% to about 2.0% by weight of the amorphous solid dispersion. Embodiment ASD20 is the amorphous solid dispersion of any of embodiments ASD1-ASD19, wherein the amorphous solid dispersion comprises one or more antioxidants present in an amount of from about 0.05% to about 0.5% by weight of the amorphous solid dispersion. Embodiment ASD21 is the amorphous solid dispersion of any of embodiments ASD1-ASD20, wherein the amorphous solid dispersion comprises one or more antioxidants selected from propyl gallate.

[0097] Embodiment ASD22 is the amorphous solid dispersion of any of embodiments ASD1-ASD21, wherein the amorphous solid dispersion is produced by a process comprising electrospraying. Embodiment ASD23 is the amorphous solid dispersion of any of embodiments ASD1-ASD22, wherein the amorphous solid dispersion is an electrosprayed amorphous solid dispersion. Embodiment ASD24 is the amorphous solid dispersion of any of embodiments ASD1-ASD23, wherein the amorphous solid dispersion is produced by a process comprising spray drying. Embodiment ASD25 is the amorphous solid dispersion of any of embodiments ASD1-ASD24, wherein the amorphous solid dispersion is a spray-dried amorphous solid dispersion. Embodiment ASD26 is the amorphous solid dispersion of any of embodiments ASD1-ASD25, wherein the amorphous solid dispersion remains amorphous or essentially amorphous as determined by powder X-ray diffraction (XRD) after 6 months of storage at 40°C / 75% relative humidity.Embodiment ASD27 is the amorphous solid dispersion of any of embodiments ASD1-ASD26, wherein the amorphous solid dispersion remains amorphous or essentially amorphous as determined by powder X-ray diffraction after 6 months of storage at 25°C / 60% relative humidity.

[0098] Embodiment ASD28 is the amorphous solid dispersion of any of embodiments ASD1-ASD27, wherein the amorphous solid dispersion comprises a water content, as measured by Karl Fischer coulometric titration, of less than about 8% after 6 months of storage at 25°C / 60% RH.Embodiment ASD29 is the amorphous solid dispersion of any of embodiments ASD1-ASD28, wherein the amorphous solid dispersion comprises a water content, as measured by Karl Fischer coulometric titration, of less than about 8% after 6 months of storage at 40°C / 75% RH. Embodiment ASD30 is the amorphous solid dispersion of any of embodiments ASD1-ASD29, wherein the amorphous solid dispersion is characterized by a level of quantitation of at least 95% as measured by high performance liquid chromatography (HPLC) after 6 months of storage at 40°C / 75% relative humidity.Embodiment ASD31 is the amorphous solid dispersion of any of embodiments ASD1-ASD30, wherein the level of quantitation of the amorphous solid dispersion after 6 months of storage at 40°C / 75% relative humidity is at least 97%.

[0099] Embodiment ASD32 is the amorphous solid dispersion of any of embodiments ASD1-ASD31, wherein the amorphous solid dispersion contains less than 1.5% total related substances as measured by HPLC after 12 months storage at 25°C / 60%RH.Embodiment ASD33 is the amorphous solid dispersion of any of embodiments ASD1-ASD32, wherein the amorphous solid dispersion contains less than 2% total related substances as measured by HPLC after 6 months storage at 40°C / 75%RH. Embodiment ASD34 is the amorphous solid dispersion of any of embodiments ASD1-ASD33, wherein the amorphous solid dispersion comprises a glass transition temperature, as measured by modulated differential scanning calorimetry, that changes by less than 5°C after 6 months of storage at 25°C / 60% RH. Embodiment ASD35 is the amorphous solid dispersion of any of embodiments ASD1-ASD34, wherein the amorphous solid dispersion comprises a glass transition temperature, as measured by modulated differential scanning calorimetry, that does not change by more than 10°C after 6 months of storage at 40°C / 75% RH. Embodiment ASD36 is the amorphous solid dispersion of any of embodiments ASD1-ASD35, wherein the amorphous solid dispersion comprises a glass transition temperature, as measured by modulated differential scanning calorimetry, that changes by less than about 6°C after up to 6 months of storage at 40°C / 75% RH.

[0100] Embodiment PC1 is a pharmaceutical composition comprising an amorphous solid dispersion according to any one of Embodiments ASD1-ASD36. Embodiment PC2 is a pharmaceutical composition comprising an amorphous solid dispersion according to any one of Embodiments ASD1-ASD36 and one or more pharmaceutically acceptable excipients. Embodiment PC3 is the pharmaceutical composition of Embodiment PC2, wherein the one or more pharmaceutically acceptable excipients comprise one or more solubilizers, one or more buffering agents, one or more pH adjusting agents, one or more surfactants, one or more antioxidants, one or more carriers, or a combination thereof. Embodiment PC4 is the pharmaceutical composition of Embodiment PC2, wherein the one or more pharmaceutically acceptable excipients comprise one or more fillers, one or more binders, one or more lubricants, one or more disintegrants, one or more glidants, or a combination thereof. Embodiment PC5 is the pharmaceutical composition of Embodiment PC4, wherein the pharmaceutical composition is a solid dosage form suitable for oral administration. Embodiment PC6 is the pharmaceutical composition of any of Embodiments PC1 to PC5, wherein the pharmaceutical composition is a gastric acid-insensitive composition. Embodiment PC7 is the pharmaceutical composition of any one of Embodiments PC1 to PC6, in which the pharmaceutical composition is a composition with improved variability.

[0101] Embodiment MT1 is a method of treating a proliferative disorder in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition of any of embodiments PC1-PC7. Embodiment MT2 is a method of treating a proliferative disorder in a patient in need thereof, comprising administering to the patient a pharmaceutical composition described in any of embodiments PC1-PC7, wherein the pharmaceutical composition is administered regardless of whether the patient is also taking a gastric acid-reducing agent. Embodiment MT3 is a method of treating a proliferative disorder in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition described in any of Embodiments PC1-PC7, wherein the pharmaceutical composition is administered to the patient together with a gastric acid-reducing agent. Embodiment MT4 is the method described in Embodiment MT3, wherein the gastric acid-reducing agent is administered to the patient immediately before the pharmaceutical composition is administered. Embodiment MT5 is the method described in Embodiment MT3, wherein the gastric acid-reducing agent is administered to the patient simultaneously with the administration of the pharmaceutical composition. Embodiment MT6 is the method described in Embodiment MT3, wherein the gastric acid-reducing agent is administered to the patient immediately after the pharmaceutical composition is administered. Embodiment MT7 is the method described in any of Embodiments MT3-MT6, wherein the gastric acid-reducing agent is selected from an H2 antagonist, a proton pump inhibitor, and an antacid.

[0102] Embodiment MT8 is the method of any of embodiments MT3-MT7, wherein administering a single dose of the pharmaceutical composition to a patient concurrently with or immediately thereafter a gastric acid-reducing agent results in an area under the curve (AUC) of dasatinib that is within 50% of the AUC of dasatinib achieved by administering the pharmaceutical composition not concurrently with the gastric acid-reducing agent.Embodiment MT9 is the method of any of embodiments MT3-MT7, wherein administering a single dose of the pharmaceutical composition to a patient concurrently with or immediately thereafter a gastric acid-reducing agent results in an AUC of dasatinib that is within 50% of the AUC of dasatinib achieved by administering the pharmaceutical composition not concurrently with the gastric acid-reducing agent. max ) C of dasatinib within 50% of max Embodiment MT10 is the method of any of embodiments MT3-MT7, wherein a single administration of the pharmaceutical composition to a patient concurrently with or immediately thereafter a gastric acid-reducing agent results in an area under the curve (AUC) of dasatinib that is at least 100% greater than the AUC of dasatinib achieved by administration of a standard, commercially available immediate-release composition of dasatinib concurrently with the gastric acid-reducing agent, and wherein the pharmaceutical composition comprises the same dose of dasatinib as a standard, commercially available immediate-release composition of dasatinib. Embodiment MT11 is the method of any of embodiments MT3-MT7, wherein a single administration of the pharmaceutical composition to a patient concurrently with a gastric acid-reducing agent results in a peak plasma concentration (C ) of dasatinib that is at least 100% greater than the AUC of dasatinib achieved by administration of a standard, commercially available immediate-release composition of dasatinib concurrently with the gastric acid-reducing agent.max ) C of dasatinib at least 200% higher than max and the pharmaceutical composition contains the same dasatinib dosage as the standard, commercially available immediate release composition of dasatinib.

[0103] Embodiment MT12 is a method of treating a proliferative disorder in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition described in any of embodiments PC1-PC7, wherein the pharmaceutical composition is administered regardless of whether the patient has an elevated gastric pH. Embodiment MT13 is a method of treating a proliferative disorder in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition described in any of embodiments PC1-PC7, wherein the patient has an elevated gastric pH. Embodiment MT14 is a method of treating a proliferative disorder in a patient in need thereof, the method comprising: (a) identifying a condition in which the patient has a chronically elevated gastric pH; and (b) administering to the patient a therapeutically effective amount of a pharmaceutical composition of any of Embodiments PC1-PC7, wherein the therapeutically effective amount comprises about 20 mg to about 140 mg of dasatinib. Embodiment MT15 is the method of Embodiment MT14, wherein the condition in which the patient has an elevated gastric pH is achlorhydria or hypochlorhydria. Embodiment MT16 is the method of Embodiment MT14, wherein the condition in which the patient has an elevated gastric pH is a Helicobacter pylori infection.

[0104] Embodiment MT17 is the method of any of embodiments MT13-MT16, wherein a single administration of the pharmaceutical composition when the patient's gastric pH is elevated results in an area under the curve (AUC) of dasatinib that is within 50% of the AUC of dasatinib achieved by administration of the pharmaceutical composition when the patient's gastric pH is not elevated. Embodiment MT18 is the method of any of embodiments MT13-MT16, wherein a single administration of the pharmaceutical composition when the patient's gastric pH is elevated results in a peak plasma concentration (C ) of dasatinib that is within 50% of the AUC of dasatinib achieved by administration of the pharmaceutical composition when the patient's gastric pH is not elevated. max) C of dasatinib within 50% of max Embodiment MT19 is the method of any of embodiments MT13-MT16, wherein a single administration of the pharmaceutical composition when the patient's gastric pH is elevated results in an area under the curve (AUC) of dasatinib that is at least 100% greater than the AUC of dasatinib achieved by administration of a standard commercially available immediate release composition of dasatinib when the patient's gastric pH is elevated. Embodiment MT20 is the method of any of embodiments MT13-MT16, wherein a single administration of the pharmaceutical composition when the patient's gastric pH is elevated results in an area under the curve (AUC) of dasatinib that is at least 100% greater than the AUC of dasatinib achieved by administration of a standard commercially available immediate release composition of dasatinib when the patient's gastric pH is elevated. max ) C of dasatinib is at least 200% higher than max results.

[0105] Embodiment MT21 is the method of any one of embodiments MT1-MT20, wherein the proliferative disorder is cancer.Embodiment MT22 is the method of any one of embodiments MT1-MT20, wherein the proliferative disorder is Philadelphia chromosome-positive chronic myeloid leukemia.Embodiment MT23 is the method of any one of embodiments MT1-MT20, wherein the proliferative disorder is Philadelphia chromosome-positive acute lymphoblastic leukemia. Embodiment MS1 is a method for delivering a therapeutically relevant exposure of dasatinib to a subject, with or without administering a gastric acid-reducing agent to the subject, the method comprising administering to the subject a pharmaceutical composition described in any of embodiments PC1-PC7. Embodiment MS2 is a method of delivering a therapeutically relevant exposure of dasatinib to a subject, the method comprising administering to the subject a pharmaceutical composition described in any of Embodiments PC1-PC7, wherein the pharmaceutical composition is administered to the subject in conjunction with a gastric acid-reducing agent. Embodiment MS3 is the method of Embodiment MS2, wherein the gastric acid-reducing agent is administered to the patient immediately prior to administration of the pharmaceutical composition. Embodiment MS4 is the method of Embodiment MS2, wherein the gastric acid-reducing agent is administered to the patient simultaneously with administration of the pharmaceutical composition. Embodiment MS5 is the method of Embodiment MS2, wherein the gastric acid-reducing agent is administered to the patient immediately after administration of the pharmaceutical composition. Embodiment MS6 is the method of any of Embodiments MS2-MS5, wherein the gastric acid-reducing agent is selected from an H2 antagonist, a proton pump inhibitor, and an antacid.

[0106] Embodiment MS7 is the method of any of Embodiments MS2-MS6, wherein administering a single dose of the pharmaceutical composition to a patient concurrently with or immediately thereafter a gastric acid-reducing agent results in an area under the curve (AUC) of dasatinib that is within 50% of the AUC of dasatinib achieved by administering the pharmaceutical composition not concurrently with the gastric acid-reducing agent.Embodiment MS8 is the method of any of Embodiments MS2-MS6, wherein administering a single dose of the pharmaceutical composition to a patient concurrently with or immediately thereafter a gastric acid-reducing agent results in an AUC of dasatinib that is within 50% of the AUC of dasatinib achieved by administering the pharmaceutical composition not concurrently with the gastric acid-reducing agent. max ) C of dasatinib within 50% of max Embodiment MS9 is the method of any of Embodiments MS2-MS6, wherein a single administration of the pharmaceutical composition to a patient concurrently with or immediately thereafter a gastric acid-reducing agent results in an area under the curve (AUC) of dasatinib that is at least 100% greater than the AUC of dasatinib achieved by administration of a standard, commercially available immediate-release composition of dasatinib concurrently with the gastric acid-reducing agent, and wherein the pharmaceutical composition comprises the same dose of dasatinib as a standard, commercially available immediate-release composition of dasatinib. Embodiment MS10 is the method of any of Embodiments MS2-MS6, wherein a single administration of the pharmaceutical composition to a patient concurrently with a gastric acid-reducing agent results in a peak plasma concentration (C ) of dasatinib that is at least 100% greater than the AUC of dasatinib achieved by administration of a standard, commercially available immediate-release composition of dasatinib concurrently with the gastric acid-reducing agent.max ) C of dasatinib is at least 200% higher than max and the pharmaceutical composition contains the same dasatinib dosage as the standard, commercially available immediate release composition of dasatinib.

[0107] Embodiment MS11 is a method for delivering a therapeutically relevant exposure of dasatinib to a subject, regardless of whether the subject's gastric pH is elevated, the method comprising administering to the subject a pharmaceutical composition described in any of embodiments PC1-PC7. Embodiment MS12 is a method for delivering a therapeutically relevant exposure of dasatinib to a subject with elevated gastric pH, the method comprising administering to the subject a pharmaceutical composition described in any of embodiments PC1 to PC7. Embodiment MS13 is the method of any of Embodiments MS11-MS12, wherein a single administration of the pharmaceutical composition when the subject's gastric pH is elevated results in an area under the curve (AUC) of dasatinib that is within 50% of the AUC of dasatinib achieved by administration of the pharmaceutical composition when the subject's gastric pH is not elevated. Embodiment MS14 is the method of any of Embodiments MS11-MS12, wherein a single administration of the pharmaceutical composition when the subject's gastric pH is elevated results in an area under the curve (AUC) of dasatinib that is within 50% of the AUC of dasatinib achieved by administration of the pharmaceutical composition when the subject's gastric pH is not elevated. max ) C of dasatinib within 50% of max Embodiment MS15 is the method of any of Embodiments MS11-MS12, wherein a single administration of the pharmaceutical composition when the patient's gastric pH is elevated results in an area under the curve (AUC) of dasatinib that is at least 100% greater than the AUC of dasatinib achieved by administration of a standard commercially available immediate release composition of dasatinib when the patient's gastric pH is elevated. Embodiment MS16 is the method of any of Embodiments MS11-MS12, wherein a single administration of the pharmaceutical composition when the patient's gastric pH is elevated results in an area under the curve (AUC) of dasatinib that is at least 100% greater than the AUC of dasatinib achieved by administration of a standard commercially available immediate release composition of dasatinib when the patient's gastric pH is elevated. max) C of dasatinib is at least 200% higher than max results.

[0108] Embodiment TR1 is a treatment regimen for treating a proliferative disorder in a patient in need thereof, the regimen comprising: (a) administering to the patient a first dose comprising a standard dose of a proton pump inhibitor or an H2 antagonist; and (b) administering to the patient, within 20 hours after the first dose, a second dose comprising a therapeutically effective amount of a pharmaceutical composition of any of Embodiments PC1-PC7, the therapeutically effective amount comprising about 20 mg to about 140 mg of dasatinib. Embodiment TR2 is the treatment regimen of Embodiment TR1, wherein the second dose is administered within 16 hours after the first dose. Embodiment TR3 is the treatment regimen of Embodiment TR1, wherein the second dose is administered within 12 hours after the first dose. Embodiment TR4 is the treatment regimen of Embodiment TR1, wherein the second dose is administered within 8 hours after the first dose. Embodiment TR5 is the treatment regimen of Embodiment TR1, wherein the second dose is administered within 6 hours after the first dose. Embodiment TR6 is the treatment regimen of embodiment TR1, wherein the second dose is administered within 4 hours after the first dose.Embodiment TR7 is the treatment regimen of embodiment TR1, wherein the second dose is administered within 2 hours after the first dose.

[0109] Embodiment TR8 is a treatment regimen of any of embodiments TR1-TR7, wherein the first dose comprises a standard dose of a proton pump inhibitor selected from rabeprazole, esoomeprazole, lansoprazole, omeprazole, pantoprazole, dexlansoprazole, and combinations thereof. Embodiment TR9 is a treatment regimen of any of embodiments TR1-TR7, wherein the first dose comprises a standard dose of omeprazole. Embodiment TR10 is a treatment regimen of any of embodiments TR1-TR7, wherein the first dose comprises a standard dose of an H2 antagonist selected from famotidine, cimetidine, nizatidine, ranitidine, and combinations thereof. Embodiment TR11 is a treatment regimen of any of embodiments TR1-TR7, wherein the first dose comprises a standard dose of famotidine. Embodiment TR12 is a treatment regimen for treating a proliferative disorder in a patient in need thereof, the regimen comprising: (a) administering to the patient a first dose comprising a standard dose of an antacid; and (b) administering to the patient a second dose comprising a pharmaceutical composition described in any of embodiments PC1-PC7 within two hours before or two hours after the first dose, wherein administration of the second dose provides the patient with a therapeutically adequate exposure of dasatinib. Embodiment TR13 is the treatment regimen of any of embodiments TR1-TR12, wherein the proliferative disorder is cancer.Embodiment TR14 is the treatment regimen of any of embodiments TR1-TR12, wherein the proliferative disorder is Philadelphia chromosome-positive chronic myeloid leukemia.Embodiment TR15 is the treatment regimen of any of embodiments TR1-TR12, wherein the proliferative disorder is Philadelphia chromosome-positive acute lymphoblastic leukemia.

[0110] Embodiment KT1 is a kit for sale to a user, the kit comprising a pharmaceutical composition described in any of embodiments PC1 to PC7 and an accompanying instruction, the accompanying instruction informing the user that the pharmaceutical composition can be used in combination with a gastric acid-reducing agent. Embodiment KT2 is a kit for sale to users, which includes a pharmaceutical composition described in any of embodiments PC1 to PC7 and a package insert, and the package insert does not include a warning that the pharmaceutical composition should not be used in combination with an H2 antagonist or a proton pump inhibitor. Embodiment KT3 is a kit for sale to a user, the kit comprising a pharmaceutical composition described in any of embodiments PC1 to PC7 and an accompanying instruction, the accompanying instruction informing the user that the pharmaceutical composition can be suitably administered even if the user has a chronically elevated gastric pH. Embodiment KT4 is a kit for sale to a user, the kit comprising the pharmaceutical composition of any of embodiments PC1-PC7 and a package insert, the package insert informing the user that the pharmaceutical composition can be suitably administered if the user has been diagnosed with or is suffering from achlorhydria or hypochlorhydria. Embodiment KT5 is a kit for sale to a user, the kit comprising a pharmaceutical composition described in any of embodiments PC1 to PC7 and an accompanying instruction, the accompanying instruction informing the user that the pharmaceutical composition can be suitably administered if the user has been diagnosed with Helicobacter pylori infection or if the user is suffering from Helicobacter pylori infection. [Example]

[0111] Objects and advantages of the present disclosure are further illustrated by the following examples, but the particular materials and amounts thereof recited in such examples, as well as other conditions and details, should not be construed to unduly limit the present disclosure.

[0112] Example 1. Amorphous nature and stability of dasatinib ASD A study was conducted to investigate the effect of drug loading on the chemical and physical stability of six different ASDs containing dasatinib and either Eudragit L100-55 or Eudragit E100 as the polymer. The drug:polymer ratio in the ASD was 50:50, 60:40, or 70:30 (w / w). To prepare ASDs, appropriate amounts of dasatinib monohydrate and polymer were dissolved in a 50:50 (v / v) solvent mixture of ethanol and methanol to provide a liquid feedstock with a drug concentration of 4 mg / mL. The liquid feedstock was electrosprayed using a Nanocopoeia sprayer ENS-P to form ASDs. The ENS-P machine utilized six nozzle slots arranged in a circular array. Each nozzle had 24 tips (D24). For each spray run, spray process parameters, such as extractor voltage and flow rate, were adjusted to obtain an acceptable spray plume. Each of the resulting ASDs was placed under accelerated conditions of 40°C / 75%RH for stability. The ASDs were evaluated for appearance, amorphousness, loss on drying, glass transition temperature, assay / impurities, and particle morphology at t=0, 2 weeks, 1 month, 2 months, and 3 months.

[0113] exterior Each ASD was evaluated for physical appearance after spraying (t=0) and at each time point for stability. All six ASDs were white to off-white powders at t=0 and showed no visible changes in stability. Amorphous ASD was evaluated for amorphousness (i.e., lack of crystallinity) by XRD. Diffraction patterns were obtained using a Rigaku MiniFlex 600. The X-ray source was a Cu Kα with a long anode. Samples were prepared by placing a small amount of ASD powder into a Rigaku zero-background sample holder with a 0.1 mm indent. A glass slide was then used to firmly pack the powder so that the surface of the sample was flush with the edge of the sample holder. The percent crystallinity was determined using Rigaku data analysis software PDXL 2.4.2.0. Briefly, a linear background was obtained by connecting the beginning and end of each diffractogram. The peaks were then fitted to a split pseudo-Voigt shape using a Lorentzian function. Generally, narrow peaks with a full width at half maximum (FWHM) of less than 1° were considered to be crystalline phases. Amorphous halos had FWHMs greater than 1°, typically greater than 5°. The percent crystallinity was calculated as follows: Crystallinity % = Area of ​​crystalline peak / (Area of ​​crystalline peak + Area of ​​amorphous peak) This analysis revealed that all ASDs, regardless of drug loading or polymer, remained completely amorphous for 3 months at 40°C / 75% RH.

[0114] drying loss Loss on drying (LOD) was evaluated by thermogravimetric analysis (TGA) using a TA Instruments Model Q500. Typically, approximately 5–10 mg of ASD material was placed on a platinum sample pan. Each ASD was evaluated for LOD after spraying (t=0) and at each time point for stability. Because TGA simply measures the mass loss of a sample as a function of temperature, the technique provides a measure of the total residual solvent present, but cannot distinguish between organic solvents and water. The LOD results for the six ASDs are shown in Table 4.

[0115] Table 4. Summary of LOD (TGA) data for the composition of Example 1 [Table 4]

[0116] As shown in Table 4, for all drug:polymer ratios, the Eudragit L100-55 ASDs had higher levels of residual solvent and / or moisture compared to the Eudragit E100 ASDs. Despite some variability in the data, all ASDs showed consistent loss on drying throughout the stability study. Glass transition temperature The glass transition temperatures (T) of the ASDs were determined using modulated differential scanning calorimetry (mDSC) performed on a TA Instruments model Q200 equipped with an RCS90 refrigerated cooling system. g ) was analyzed. Generally, about 5 to 10 mg of ASD powder was analyzed. zero Placed on a low-mass aluminum dish, T zero The lid was sealed. The details of the apparatus and the measurement conditions are provided in Table 5. The results of the mDSC analysis are provided in Table 6.

[0117] Table 5. TA Q200 DSC equipment and measurement conditions [Table 5]

[0118] Table 6. Glass transition temperature data for the ASDs of Example 1 [Table 6]

[0119] All three Eudragit L100-55 ASDs were tested for stability. g In the case of the Eudragit E100 ASD, a thermal event consistent with the glass transition temperature was observed in only a few samples. g Although the solubility of Eudragit E100 was not measurable, the Eudragit E100 ASD remained amorphous over the entire three months with respect to stability and showed no signs of change based on visual appearance. Quantitation / Impurities Both Agilent 1200 HPLC and Waters Alliance e2695 HPLC were used to assess the quantitation / impurities of ASD. The instruments and measurement conditions are specified in Table 7, while the gradient profile is shown in Table 8.

[0120] Table 7. HPLC equipment and measurement conditions used for quantitative / impurity analysis in Example 1 [Table 7]

[0121] Table 8. Gradient profile of the HPLC system used for quantitation / impurity analysis in Example 1 [Table 8]

[0122] Quantitative values ​​are shown in Table 9 and total impurities in Table 10 for each ASD at t=0 and 3-month stability time points. Table 9. Summary of quantitative (HPLC) data for the composition of Example 1 [Table 9]

[0123] Table 10. Summary of total impurities (HPLC) data for the composition of Example 1 [Table 10] Table 10 shows that the Eudragit L100-55 ASD had slightly lower levels of total impurities at 3 months than the Eudragit E100 ASD. For the Eudragit L100-55 ASD, the levels of total impurities did increase slightly with increasing drug load, but the difference was small. Conversely, for the Eudragit E100 ASD, there was no clear effect of drug load on total impurities.

[0124] particle morphology The particle morphology of each ASD was analyzed by scanning electron microscopy (SEM) using a JEOL JSM-6010Plus / LV at t = 0 and all stability time points. Prior to analysis, a small amount of each ENS powder was coated with a thin layer of platinum using a JEOL sputter coater. Based on SEM images, the particle size range of the ASDs of Eudragit L100-55 was approximately 200 nm to 2 μm, while the particle size range of the ASDs of Eudragit E100 was 500 nm to 4 μm. All ASDs appeared to retain their ASD morphology after several months of open-dish exposure under accelerated conditions. There were no obvious changes to the ASD particles, and no signs of particle fusion were evident, suggesting that the ASDs remained physically stable. This data was in good agreement with the physical appearance and XRD assessments, which indicated that there were no observable changes to the powders or any transformation from an amorphous to a crystalline state with respect to stability. In another experiment, a similar technique was used to prepare an ASD containing dasatinib and polyvinylpyrrolidone (PVP K25) as the polymer at a 50:50 drug:polymer ratio. The ASD was kept under harsh conditions of 50°C / 80% RH (with the dish open). After two weeks, the ASD showed some crystallinity, and after four weeks, a significant portion of the material had converted to crystals.

[0125] Example 2. Long-term stability of dasatinib ASD under accelerated conditions A study was conducted to evaluate the long-term physical and chemical stability of an ASD containing dasatinib at a 60:40 (drug:polymer) w / w ratio and Eudragit L100-55 as a stabilizing polymer. To prepare the ASD, appropriate amounts of dasatinib (anhydrous) and polymer were dissolved in a 40:10:50 (v / v / v) solvent mixture of methanol:ethanol:ethyl acetate to prepare a liquid stock with a drug concentration of 12.83 mg / mL, which was electrosprayed as in Example 1. The resulting ASDs were evaluated at 1 month, 3 months, and 6 months under storage conditions of 25°C / 60% RH, 25°C / protected, 40°C / 75% RH, and 40°C / protected. ASDs stored at 25°C / 60% RH and 25°C / protected were further evaluated at 9 months and 12 months.

[0126] For each time point and condition, approximately 300 mg aliquots of ASD powder were manually filled into 7 mL vials. Vials exposed to humid conditions were loosely capped (open dish) and kept in an upright position inside the chamber. Protected conditions were achieved by sealing the closed vials in aluminum pouches, which were also kept in an upright position. Each sample was evaluated for amorphousness, glass transition temperature, water content, LOD, and quantitation / impurities. The methods described in Example 1 were used to evaluate amorphousness and glass transition temperature. Karl Fischer coulometric titration was used to determine water content. Approximately 40-50 mg of ASD powder was weighed into a glass Stromboli sample vial, the vial was immediately sealed with a foil-covered vial cover, and a rubber vial cap cover was placed on the sample vial. LOD was assessed using a Computrac Max 4000, with approximately 0.5 g of material evenly spread across the entire sample pan. ASD quantitation / impurity was assessed using the instrument parameters, measurement conditions, and gradient profile specified in Table 11.

[0127] Table 11. HPLC equipment and measurement conditions [Table 11]

[0128] The results of this study are shown in Tables 12 to 15. The LOD, measured only at t=0, was determined to be 2.14%. Under each storage condition, ASD demonstrated chemical and physical stability throughout the study. Table 12. ASD evaluation of dasatinib:Eudragit L100-55 (60:40) under storage conditions of 25°C / 60% RH [Table 12]

[0129] Table 13. ASD evaluation of dasatinib:Eudragit L100-55 (60:40) under 25°C / protected storage conditions [Table 13]

[0130] Table 14. ASD evaluation of dasatinib:Eudragit L100-55 (60:40) under storage conditions of 40°C / 75% RH [Table 14]

[0131] Table 15. ASD evaluation of dasatinib:Eudragit L100-55 (60:40) under 40°C / protected storage conditions [Table 15]

[0132] Example 3. In vitro dissolution of dasatinib ASD A study was conducted to investigate the in vitro dissolution performance of an ASD containing dasatinib and Eudragit L100-55 in a 60:40 (w / w) ratio, and an ASD containing dasatinib and Eudragit E100 in a 50:50 (w / w) ratio. The reference drug, Sprycel, was also included in the study as a benchmark in the form of a powder prepared by manually grinding an appropriate number of tablets. To prepare Eudragit L100-55 ASDs, liquid feedstocks were prepared by dissolving appropriate amounts of dasatinib (anhydrous) and polymer in a 65:20:15 (v / v / v) solvent mixture of methanol:ethanol:MEK to give a drug concentration of 15 mg / mL. To prepare Eudragit E100 ASDs, liquid feedstocks were prepared by dissolving appropriate amounts of dasatinib (anhydrous) and polymer in a 65:35 (v / v) solvent mixture of methanol:MEK to give a drug concentration of 7.5 mg / mL. Each liquid feedstock was then electrosprayed using a Nanocopoeia ENS-P sprayer to form ASDs. The ENS-P machine utilized six nozzle slots arranged in a circular array. Each nozzle had 24 tips (D24). For each spray run, spray process parameters, such as extractor voltage and flow rate, were adjusted to obtain an acceptable spray plume.

[0133] For in vitro studies, a two-stage dissolution method was developed to mimic the conditions in the stomach and upper intestine and to mimic the transition between the two regions of the gastrointestinal tract. The first stage of dissolution was performed in fasted-state simulated gastric fluid (FaSSGF) using three media that differed only in pH: media A (pH 1.6), media B (pH 4.0), and media C (pH 6.0). Three transition media (D, E, and F) were developed to convert the three FaSSGF media into the second stage dissolution media, fasted-state simulated intestinal fluid (FaSSIF). For the two-stage dissolution, a Wankel Model VK7000 dissolution bath was fitted with a USP Apparatus II system equipped with mini-vessels and mini-paddles. A Rainbow Dynamic Dissolution Monitor System (Delphian Technology Inc., Woburn, MA) was used to monitor the solution concentration of dasatinib in situ. The Rainbow system included a Cathodeon type J75 deuterium (D2) lamp, which transmitted its signal to six stainless steel probes (20 mm path) via a furcation cable that provided the primary signal. The probes were positioned at each dissolution stage. Samples were quantified against a seven-point calibration curve developed for each ASD at each dissolution stage.

[0134] The compositions of the three FaSSGF media (A, B, and C) used for the first stage of lysis are shown in Table 16. Table 16. Composition of FaSSGF media A, B, and C for first stage lysis [Table 16]

[0135] For the dissolution procedure, 75 mL of one FaSSGF medium (A, B, or C) was filled into the dissolution vessel, followed by accurately weighing the sample (ASD or Sprycel powder) to provide 42 mg of dasatinib for each vessel (sample mass varied depending on the drug loading of the sample composition). The concentration of dasatinib was measured 10, 20, and 30 minutes after introducing the sample into the vessel. The compositions of the three transition media (D, E, and F) used to convert the three FaSSGF media to second-stage dissolution media (FaSSIF) are shown in Table 17. Table 17. Composition of migration media D, E, and F [Table 17]

[0136] Second-stage dissolution media, FaSSIF, were prepared by adding 25 mL of the appropriate transition medium to 75 mL of the corresponding first-stage FaSSGF medium, as summarized in Table 18. The composition of the resulting FaSSIF was the same for the three combinations (A+D, B+E, and C+F), and the pH of the FaSSIF medium in each combination was 6.4. Table 18. Composition of Second-Stage Dissolution Medium (FaSSIF) [Table 18]

[0137] For the second-stage dissolution procedure, 25 mL of the appropriate transfer medium (D, E, or F) was added to a separate vessel 30 minutes after addition of the ASD sample. The concentration of dasatinib was measured at 45, 60, and 90 minutes (the time elapsed after the sample was introduced into the vessel). As described below, the data reported in the figures are expressed as the % dasatinib measured in solution relative to the total dasatinib introduced into the vessel.

[0138] Transition from FaSSGF (pH 1.6) to FaSSIF (pH 6.4) Dissolution drug-time profiles for dasatinib transferred from FaSSGF (pH 1.6) to FaSSIF (pH 6.4) are shown in Figure 1. ASD and Sprycel each released almost all of the dasatinib into solution within the first 10 minutes, maintaining a relatively stable concentration until transfer to FaSSIF at t = 30 minutes. For Sprycel, this result was expected based on the known moderate solubility of dasatinib in acidic environments. Given the poor solubility of Eudragit L100-55 in acidic environments, it was unexpected that ASD also released almost all of the dasatinib within the first 10 minutes at pH 1.6. However, after the transition from FaSSGF to FaSSIF at t = 30 min, results were different for Sprycel compared to ASD. With Sprycel, only approximately 10% of dasatinib remained in solution after 90 min, likely a result of dasatinib's known poor solubility at neutral pH. In contrast, ASD was able to maintain much higher concentrations of dasatinib in solution, ranging from 70% to 80% for the Eudragit L100-55 ASD and 90% to 100% for the Eudragit E100 ASD.

[0139] Transition from FaSSGF (pH 4.0) to FaSSIF (pH 6.4) Dissolution drug-time profiles for dasatinib transferred from FaSSGF (pH 4.0) to FaSSIF (pH 6.4) are shown in Figure 2. ASDs and Sprycel each released dasatinib to a much lesser extent into solution in the same medium adjusted to pH 4.0 compared with FaSSGF at pH 1.6 (Figure 1). Sprycel and Eudragit L100-55 ASDs achieved very similar concentrations (approximately 7%) after 10 minutes and maintained them until transfer to FaSSIF at t = 30 minutes. Eudragit E100 ASDs released dasatinib to a lesser extent, achieving slightly lower dasatinib concentrations (approximately 5%) by 30 minutes. Upon addition of the transfer medium at t = 30 min, the solution concentration of dasatinib in Sprycel rapidly decreased, ultimately reaching approximately 2% after 90 min. In contrast, the solution concentration of dasatinib in ASD increased after transfer to FaSSIF. Although this increase was modest, ASD was able to maintain a solution concentration of 9%-10% after 90 min.

[0140] Transition from FaSSGF (pH 6.0) to FaSSIF (pH 6.4) The dissolution drug-time profile for dasatinib transferred from FaSSGF (pH 6.0) to FaSSIF (pH 6.4) is shown in Figure 3. The release of dasatinib into solution in FaSSGF at pH 6.0 was even lower than that observed in the pH 4.0 medium. As shown in Figure 3, Sprycel released very little dasatinib into solution during both the first and second phases of dissolution. This result was not unexpected based on the similar pH conditions for FaSSGF and FaSSIF in this study and the known low solubility of dasatinib at near-neutral pH conditions. ASD and Sprycel each achieved approximately 3% to 4% dasatinib concentration in neutral FaSSGF. However, after transfer to FaSSIF, ASD achieved significantly higher solution concentrations of dasatinib compared to Sprycel. For Eudragit E100 ASD, the solution concentration of dasatinib increased slowly, eventually reaching approximately 7% after 90 minutes, while Eudragit L100-55 ASD achieved approximately 13% in solution after 90 minutes. Collectively, these results demonstrate that at low pH, ASD and Sprycel each exhibited excellent dissolution in FaSSGF, achieving dasatinib concentrations greater than 80%. However, upon transfer to FaSSIF, the two ASDs significantly outperformed Sprycel. Initially, the performance of ASD and Sprycel was similar in FaSSGF at moderate and high pH, ​​but upon transfer to neutral pH FaSSIF, ASD significantly outperformed Sprycel.

[0141] Example 4. In vivo studies in dogs An in vivo study was conducted in canine subjects to investigate the effect of gastric pH on the pharmacokinetics observed after administration of dasatinib ASDs. The study included ASDs containing dasatinib and Eudragit L100-55 at a 60:40 (w / w) ratio, ASDs containing dasatinib and Eudragit E100 at a 50:50 (w / w) ratio, and Sprycel (prepared as described below). The ASDs were manufactured using electrospray techniques similar to those used in the previous example. The pharmacokinetics of three test compositions (two ASDs and Sprycel) were evaluated in male beagle dogs. This study incorporated pentagastrin and famotidine pretreatment to adjust the dogs' gastric pH prior to dosing. Based on published protocols, pentagastrin pretreatment was expected to control the pH in the range of 1-2, while famotidine pretreatment was expected to control the pH in the range of 6-8. Thus, the study included six time periods, with each of the three compositions administered during each of the two pretreatment periods.

[0142] A summary of the study design is provided in Table 19. The study employed a crossover design in which the same dogs received each dose, followed by a one-week washout period between each arm of the study. The dogs were fasted for a minimum of 12 hours before dose administration. The dogs had free access to water and were housed one per cage. Each study section had five dogs. In study sections 1, 2, and 5, the dogs were pretreated with famotidine (40 mg oral tablets) 3 hours before dosing with the test compositions. In study sections 3, 4, and 6, the dogs were pretreated with pentagastrin (6 μg / kg dose, intramuscular injection) 30 minutes before dosing with the test compositions. Then, at time zero, each dog received the appropriate oral dose of one of the test compositions. Blood samples were collected 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 10 hours, 16 hours, 24 hours, and 36 hours after dosing.

[0143] Table 19. Study Design for Example 4 [Table 19]

[0144] Test compositions were orally administered as suspensions containing a buffered aqueous vehicle. The vehicle used for each composition is provided in Table 20. For the Sprycel test compositions, Sprycel tablets were crushed and mixed with the vehicle. All test composition suspensions were prepared at a final dasatinib concentration of 9.64 mg / mL and were prepared fresh on the day of dosing. Table 20. Dosing vehicles for study intervals 1-6 of Example 4 [Table 20]

[0145] Pharmacokinetics Pharmacokinetic parameters were calculated from the time course of plasma concentrations. From the data, the maximum plasma concentration (C max ) and time to reach maximum plasma drug concentration (T max ) was determined. All samples with plasma concentrations below the limit of quantitation (0.5 ng / mL) were treated as zero for pharmacokinetic data analysis. The original study protocol called for aspirating approximately 1 mL of gastric fluid for pH measurement. However, after interval 1, there was very little fluid in the dogs' stomachs, and it was clear that the procedure would be traumatic for the animals. For this reason, it was decided not to obtain gastric fluid samples for study intervals 2-6. The calculated pharmacokinetic parameters are given in Tables 21 to 26. The tables below include the following abbreviations and notations: C max : Maximum plasma concentration; t max :Time of peak plasma concentration; t 1 / 2 : Half-life; MRT last : Mean residence time calculated to the last measurable time point; AUC last : Area under the curve calculated up to the last measurable time point; AUC 0-inf : area under the curve extrapolated to infinity; ND: Not tested.

[0146] Table 21. Individual and mean pharmacokinetic parameters for interval 1 of Example 4 [Table 21] a Dose normalized by dividing the parameter by the nominal dose (mg / kg) b Not determined because the terminal elimination phase was not observed c AUC 0-inf is the AUC last The extrapolation was more than 25% so it was not decided.

[0147] Table 22. Individual and mean pharmacokinetic parameters for interval 2 of Example 4 [Table 22] a Dose normalized by dividing the parameter by the nominal dose (mg / kg)

[0148] Table 23. Individual and mean pharmacokinetic parameters for interval 3 of Example 4 [Table 23] a Dose normalized by dividing the parameters by the nominal dose (mg / kg

[0149] Table 24. Individual and mean pharmacokinetic parameters for interval 4 of Example 4 [Table 24] a Dose normalized by dividing the parameter by the nominal dose (mg / kg)

[0150] Table 25. Individual and mean pharmacokinetic parameters for interval 5 of Example 4 [Table 25] a Dose normalized by dividing the parameter by the nominal dose (mg / kg)

[0151] Table 26. Individual and mean pharmacokinetic parameters for interval 6 of Example 4 [Table 26] a Dose normalized by dividing the parameter by the nominal dose (mg / kg)

[0152] The pharmacokinetic profiles obtained by administration of the test composition and Sprycel after pentagastrin pretreatment are shown in Figure 4, and the pharmacokinetic profiles obtained by administration of the test composition and Sprycel after famotidine pretreatment are shown in Figure 5. As shown in Figure 4, all three compositions performed essentially the same after pentagastrin pretreatment (i.e., at acidic pH). The mean C of the two ASD compositions max The values ​​were almost the same (83.6 and 83.7 ng / mL), and the mean C max Similarly, despite significant variability in the dog data, the dose-normalized AUC last Values ​​were in good agreement across all three compositions (observed range: 87.1 to 94.3 hr·kg·ng / mL / mg). The data demonstrate that the absorption of dasatinib at low pH conditions was consistent across the three test compositions.

[0153] Surprisingly, the performance of the two ASD compositions was similar, even though Eudragit L100-55 and Eudragit E100 have very different polymer chemistries. Eudragit E100 is known to be soluble in gastric fluid up to pH 5.0, while Eudragit L100-55 is known to be insoluble in gastric fluid up to pH 5.5. Based on this information, it was unexpected that the Eudragit L100-55 ASD composition released drug at the same rate or to the same extent as the Eudragit E100 ASD composition under low pH conditions. As shown in Figure 5, pretreatment with famotidine produced significantly different results. Sprycel performance was significantly different at neutral pH than at acidic pH. C of Sprycel at neutral pH after famotidine pretreatment max (3.2 ng / mL) was almost two orders of magnitude lower than that observed at acidic pH (112 ng / mL). Similarly, the dose-normalized AUC last The solubility of dasatinib was also dramatically reduced after famotidine (7.94 hr·kg·ng / mL / mg) compared with pentagastrin (87.1 hr·kg·ng / mL / mg). These results were somewhat expected based on published literature and the known poor solubility of dasatinib at high pH values.

[0154] In contrast, after famotidine pretreatment, the two ASD compositions exhibited significantly higher C max The C values ​​and AUC values ​​for the two types of ASD are shown. max The values ​​varied widely but were dramatically higher than those for Sprycel. Surprisingly, despite the higher solubility of dasatinib at low pH, these peak concentrations were also higher than those observed after pentagastrin pretreatment. Both ASD compositions had similar dose-normalized AUC lastThe AUC values ​​achieved (153 ng / mL for the Eudragit L100-55 ASD and 128 ng / mL for the Eudragit E100 ASD) were also dramatically higher than those observed for Sprycel (7.94 hr·kg·ng / mL / mg). The AUC values ​​for the ASD compositions after famotidine pretreatment were also relatively consistent with those obtained after pentagastrin pretreatment, indicating that formulating dasatinib in an ASD can significantly reduce the effect of pH on the absorption kinetics of dasatinib.

[0155] Example 5. Human in vivo studies A study was conducted in human subjects to investigate the effect of elevated gastric pH on the pharmacokinetics observed after administration of an ASD containing dasatinib and Eudragit L100-55 in a 60:40 (w / w) ratio compared to administration of Sprycel (100 mg tablets) in the fasted state. The ASD was administered via an immediate-release tablet containing the ASD. To prepare the ASD, an appropriate amount of dasatinib (anhydrous) and polymer was dissolved in a 1:1:1 (v / v / v) solvent mixture of methanol:ethanol:isopropyl acetate to provide a drug concentration of 1% by weight. The ASD was prepared by electrospraying, similar to that used in the previous example. The resulting ASD was formulated into tablets containing 100 mg of dasatinib. Granules were first formed by dry granulation of ASD (50% w / w) with Fujicalin, Avicel PH-105, Vivasol, Aerosil R972, and magnesium stearate. Appropriate amounts of the dry ingredients were bag-blended and roller-compressed to provide ribbons. The ribbons were processed in an oscillating granulator and sieved to provide suitable-sized granules (20-24 mesh). Approximately 80% (w / w) of the granules were then used, along with additional amounts of Avicel PH-105, Vivasol, Aerosil R972, and magnesium stearate, to prepare the tableting formulation. The formulation ingredients were thoroughly v-blended and then tableted using a tablet press to provide tablets containing 100 mg of dasatinib ("dasatinib ASD tablets").

[0156] This human study employed a balanced, two-treatment, two-period, two-sequence, single-dose crossover design. Subjects were randomly assigned to receive dasatinib ASD tablets in the first study period and Sprycel tablets in the second study period, or vice versa. During each study period, subjects received a single oral dose of 20 mg famotidine under fasting conditions approximately 3 hours before receiving dasatinib ASD tablets (100 mg) or Sprycel tablets (100 mg). There was a 12-day washout period between the two periods. Plasma samples were collected within 1 hour before dosing with dasatinib ASD or Sprycel tablets. Plasma samples were collected at appropriate time points after dosing to assess the pharmacokinetic profile up to 24 hours. A total of 24 subjects participated in the study. Plasma samples were analyzed for dasatinib content. Pharmacokinetic parameters were calculated from the data. Figure 6, which depicts the pharmacokinetic profiles based on untransformed data, shows that there was a substantial difference in the plasma concentrations of dasatinib after administration of the dasatinib ASD tablet compared to administration of the Sprycel tablet. The calculated pharmacokinetic parameters are presented in Table 27. The results indicate that in subjects whose gastric pH was elevated due to pretreatment with famotidine, AUC and C were significantly lower after administration of the dasatinib ASD tablet compared to administration of the Sprycel tablet, where little dasatinib was absorbed. max shows a significant improvement.

[0157] Table 27. Calculated pharmacokinetic parameters upon elevated gastric pH for Example 5 [Table 27] K el =disappearance rate constant n / a = no data

[0158] Another study was conducted similarly, except that subjects were not given famotidine pretreatment, and therefore gastric pH was not artificially altered. (Note that both studies utilized different sets of subjects; high inter-subject variability in dasatinib absorption has been observed.) The calculated pharmacokinetic parameters for this study are presented in Table 28. Under these study conditions, dasatinib ASD tablets were administered similarly to Sprycel tablets. Table 28. Pharmacokinetic parameters calculated at unaltered gastric pH for Example 5 [Table 28] K el =disappearance rate constant n / a = no data

[0159] Figure 7 shows the pharmacokinetic profiles for this study and the pH elevation study, demonstrating that the pharmacokinetic profiles obtained with dasatinib ASD tablets were similar regardless of whether subjects' gastric pH was artificially elevated. In other words, elevated gastric pH had little effect on the absorption of dasatinib delivered by the dasatinib ASD tablets. This is in contrast to Sprycel tablets, where a dramatic decrease in exposure was observed after pretreatment with famotidine. Of note, the pharmacokinetic profile and plasma concentration levels obtained with administration of dasatinib ASD tablets with famotidine pretreatment were similar to those obtained with administration of Sprycel tablets without famotidine pretreatment. Figures 8 and 9 show the AUC data (Figure 8) and C max Figure 9 is a box plot illustrating the data and calculated statistical parameters. The plot visually demonstrates that (i) the performance of the dasatinib ASD tablet was similar regardless of whether the subjects' gastric pH was artificially elevated; (ii) when gastric pH was not altered, the performance of the dasatinib ASD tablet was similar to that of the Sprycel tablet; and (iii) when gastric pH was artificially elevated, the dasatinib ASD tablet performed better than the Sprycel tablet.

[0160] As can be seen in Figures 8 and 9, at least one subject had little exposure to Sprycel even without famotidine pretreatment (this data point is shown by the AUC in Figure 8 and the C in Figure 9). max(Graphed by black dots near the bottom of the scale for both. Without wishing to be bound, it is believed that this subject had a condition that elevated gastric pH (e.g., hypochlorhydria or Helicobacter pylori infection). If such a person were prescribed dasatinib treatment with Sprycel, this person would not experience therapeutic exposure to dasatinib. However, when administered the dasatinib ASD tablet, this subject did experience significant exposure to dasatinib, as shown by the graphical representation of the leftmost box plot for the same subject. Thus, in a surprising and unexpected benefit, embodiments of the present disclosure may provide treatment to certain patients who may not benefit from dasatinib treatment when using conventional, commercially available immediate release formulations of dasatinib.

[0161] Comparative Example As a control, a 100% dasatinib spray-dried material (i.e., no polymer) was prepared. A feedstock containing 8 mg / mL of dasatinib anhydrate dissolved in a 60:40 (v / v) solvent mixture of methanol:MEK was prepared and spray-dried, as in the amorphous solid dispersion in Example 6 below. After spray-drying, the recovered material was dried under vacuum at 60°C for approximately 18 hours to remove residual solvent. The spray-dried material was then immediately characterized by XRD, which showed crystallinity. g ) was evaluated and a transition event was detected at 125.61°C. The measured water content was 0.81% and the measured quantitative value was 97.4%. This material reverted to crystallinity essentially immediately and was not subjected to stability testing or further characterization.

[0162] Example 6. Preparation and stability of high drug-loaded dasatinib ASD A study was conducted to investigate the effect of drug loading on the chemical and physical stability of several different ASDs containing dasatinib and either Eudragit L100-55 or Methocel E5 as the polymer. For this study, the drug:polymer ratio (w / w) in the ASD was 70:30, 75:25, 80:20, 85:15, and 90:10. To prepare ASDs, appropriate amounts of dasatinib anhydride and polymer were dissolved in a 60:40 (v / v) solvent mixture of methanol and MEK to provide a liquid feedstock with a drug concentration of approximately 6 to approximately 10 mg / mL and a total solids concentration of approximately 8 to approximately 15 mg / mL. The liquid feedstock was spray-dried to form ASDs using a Buchi B-290 spray dryer equipped with a two-fluid nozzle and a Buchi B-295 inert loop. For each spray run, spray process parameters, such as inlet temperature, pump speed, and outlet temperature, were adjusted to obtain acceptable results. The inlet temperature was set at 115 to 125°C, the pump speed at 20%, and the outlet temperature at 70 to 85°C. A cyclone separator was used to collect the resulting ASDs. After spray drying, each ASD was dried under vacuum at 60°C for approximately 18 hours to remove residual solvent. Each of the resulting ASDs was placed under accelerated conditions of 40°C / 75%RH for stability. The ASDs were evaluated for appearance, amorphousness, glass transition temperature, water content, and quantity / impurities at t=0 (i.e., after the second drying step), 2 weeks, 1 month, 2 months, 3 months, and 6 months.

[0163] exterior Each ASD was evaluated for physical appearance at the beginning (t=0) and at each time point of the stability study. All ASDs were white or off-white powders at t=0 and showed no visible changes after 6 months of storage under accelerated conditions. Amorphous ASD was evaluated for amorphousness (i.e., lack of crystallinity) by XRD. Diffraction patterns were obtained using a Rigaku MiniFlex 600. The X-ray source was a Cu Kα with a long anode. Samples were prepared by placing a small amount of ASD powder into a Rigaku zero-background sample holder with a 0.1 mm recess. A glass slide was then used to firmly pack the powder so that the sample surface was flush with the edge of the sample holder. The crystallinity was determined using Rigaku data analysis software PDXL 2.4.2.0. Briefly, a linear background was obtained by connecting the beginning and end of each diffractogram. The peaks were then fitted to an asymmetric pseudo-Voigt shape using a Lorentzian function. Generally, narrow peaks with a full width at half maximum (FWHM) of less than 1° were considered to be crystalline phases. If no crystalline phase was detected, the sample was considered amorphous.

[0164] Regardless of drug loading, all dasatinib:Eudragit L100-55 ASDs remained completely amorphous after 6 months of storage at 40°C / 75% RH. For the dasatinib:methocel E5 ASDs, the 70:30 ASD showed some crystallinity after 2 months of storage at 40°C / 75%RH, the 75:25 and 80:20 ASDs showed some crystallinity after 6 months of storage at 40°C / 75%RH, however, the 85:15 and 90:10 ASDs remained completely amorphous after 6 months of storage at 40°C / 75%RH. These results indicate that for such dasatinib ASDs, higher drug loading is beneficial in providing physical stability under accelerated conditions and represents a promising approach for stability under real-world storage conditions.

[0165] Glass transition temperature The glass transition temperatures (T ) of the ASDs were determined using modulated differential scanning calorimetry (mDSC) performed on a TA Instruments Model Q200 equipped with an RCS90 refrigerated cooling system. g ) was analyzed. Generally, about 5 to 10 mg of ASD powder was analyzed. zeroPlaced on a low-mass aluminum dish, T zero The lid was sealed. The details of the apparatus and the measurement conditions are provided in Table 29. The results of the mDSC analysis are provided in Tables 30 and 31. Table 29. TA Q200 DSC equipment and measurement conditions [Table 29]

[0166] Table 30. Glass transition temperature data for ASD of Dasatinib:Eudragit L100-55 of Example 6 stored at 40°C / 75% RH for 6 months [Table 30]

[0167] Table 31. Glass transition temperature data for ASD of Dasatinib:Methocel E5 of Example 6 stored at 40°C / 75% RH for 6 months [Table 31] For all ASDs, T g Although there was slight variation in the temperature, each sample did exhibit a thermal event consistent with the glass transition temperature.

[0168] water content Water content was determined using Karl Fischer coulometric titration. Approximately 40-50 mg of ASD powder was weighed into a glass Stromboli sample vial, the vial was immediately sealed with a foil-covered vial cover, and a rubber vial cap cover was placed on the sample vial. The results shown in Tables 32 and 33 show that the water content increased from t=0 to 2 weeks due to moisture absorption from the controlled environment. The water content then generally remained stable from 2 weeks to 6 months, indicating that the water in the solid amorphous dispersions had reached equilibrium with the environment.

[0169] Table 32. Moisture content data for ASD of Dasatinib: Eudragit L100-55 of Example 6 stored at 40°C / 75% RH for 6 months [Table 32]

[0170] Table 33. Moisture content data for ASD of Dasatinib:Methocel E5 of Example 6 stored at 40°C / 75% RH for 6 months [Table 33]

[0171] Quantitation / Impurities The quantification of ASD and the impurities were evaluated using an Agilent 1200 HPLC or a Waters Alliance e2695 HPLC. The instrument and measurement conditions are specified in Table 34, and the gradient profile is specified in Table 35. Table 34. HPLC equipment and measurement conditions used for quantitative / impurity analysis in Example 6 [Table 34]

[0172] Table 35. Gradient profile of the HPLC system used for quantitation / impurity analysis in Example 6 [Table 35]

[0173] Quantitative values ​​for the dasatinib:Eudragit L100-55 ASD at t=0 and at each stability time point are shown in Table 36, and quantitative values ​​for the dasatinib:Methocel E5 ASD at t=0 and at each stability time point are shown in Table 37. The reported quantitative values ​​were corrected for the water content measured for the samples. Table 36. Quantitative data for ASD of Dasatinib: Eudragit L100-55 of Example 6 stored at 40°C / 75% RH for 6 months [Table 36] a-No data due to methodological error

[0174] Table 37. Quantitative data for ASD of Dasatinib:Methocel E5 of Example 6 stored at 40°C / 75% RH for 6 months [Table 37] a-No data due to methodological error

[0175] For the ASD of dasatinib:Eudragit L100-55, the total impurities measured are reported in Table 38, and for the ASD of dasatinib:Methocel E5, the total impurities measured are reported in Table 39. Table 38. Total impurity data for ASD of Dasatinib: Eudragit L100-55 of Example 6 stored at 40°C / 75% RH for 6 months [Table 38] a-No data due to methodological error

[0176] Table 39. Total impurity data for ASD of Dasatinib:Methocel E5 of Example 6 stored at 40°C / 75% RH for 6 months [Table 39] a-No data due to methodological error Based on the quantitative and total impurity data, it can be concluded that ASD demonstrated acceptable chemical stability under accelerated conditions throughout this stability study.

[0177] Example 7. In vitro dissolution of tablets containing dasatinib ASD A study was conducted to examine the in vitro dissolution performance of tablets containing the ASD of the present disclosure in various biorelevant dissolution media. The reference drug, Sprycel, in the form of a 100 mg immediate release tablet, was also included in the study as a benchmark. Test tablets containing 100 mg of dasatinib (in the form of dasatinib:Eudragit L100-55 ASD or dasatinib:Methocel E5 ASD) were prepared using the appropriate ASD as follows: ASDs with various drug loads (60:40, 70:30, and 80:20 drug:polymer ratios) were first prepared according to the method described in Example 1. Granules were then formed by dry granulation of the ASD with Fujicalin, Avicel PH-105, Vivasol, Aerosil R972, and magnesium stearate. The appropriate amounts of dry ingredients were bag blended and subsequently roller compressed to provide ribbons. The ribbons were processed using an oscillatory granulator and sieved to provide the appropriate size granules (20-24 mesh).

[0178] Approximately 80% (w / w) of the granules were then used with appropriate amounts of Avicel PH-102, Vivasol, Aerosil R972, and magnesium stearate to prepare a tablet formulation. The formulation ingredients were thoroughly blended in a V-blender and then tableted using a tablet press to provide test tablets containing 100 mg of dasatinib ("dasatinib ASD tablets"). For dissolution testing, biorelevant dissolution media include: Medium A: acetate buffer (50 mM) at pH 4 with 1% Triton 100; Medium B: fed-state simulated intestinal fluid (“FeSSIF”) at pH 5.8; Medium C: acetate buffer (50 mM) at pH 5.5.

[0179] The composition of Medium B is shown in Table 40. Table 40. Medium B: Composition of FeSSIF at pH 5.8 [Table 40]

[0180] For dissolution testing, a Wankel Model VK7000 dissolution bath was equipped with a USP Apparatus II system equipped with a 1000 mL vessel and a paddle (60 rpm). The vessels were filled with one of the dissolution media (A, B, or C), and the media was equilibrated to 37°C. At t = 0, a sample (dasatinib ASD tablet or Sprycel) was introduced into each vessel. Sampling time points were t = 10, 15, 30, and 45 minutes. At the sampling time points, samples were taken from each vessel using a stainless steel cannula and syringe equipped with a 10 μm full-flow filter. The samples were immediately filtered through a 0.2 μm nylon filter and then diluted 1:1 (v / v) with a 50:50 (v / v) mixture of ethanol:methanol. The samples were then analyzed by HPLC using an Agilent 1200 HPLC or a Waters Alliance e2695 HPLC. The instrument and measurement conditions are specified in Table 41, and the gradient profile in Table 42.

[0181] Table 41. HPLC equipment and measurement conditions used for analyzing the dissolved concentrations in Example 7 [Table 41]

[0182] Table 42. Gradient profile of the HPLC system used to analyze the dissolved concentrations of Example 7 [Table 42]

[0183] The resulting dissolution curves are shown in Figures 10-13. Figure 10 shows the dissolution curve obtained at pH 4 (Vehicle A) for tablets containing the dasatinib:Eudragit L100-55 ASD. Figure 11 shows the dissolution curve obtained at pH 4 (Vehicle A) for tablets containing the dasatinib:Methocel E5 ASD. For both ASD systems, ASDs with 70% or greater drug loading performed equally well or better (i.e., faster and / or more complete dissolution) than the Sprycel reference. In contrast, ASDs with 60% drug loading did not perform as well as the Sprycel reference.

[0184] Figure 12 shows dissolution curves obtained in FeSSIF at pH 5.8 (medium B) for tablets containing the dasatinib:Eudragit L100-55 ASD at 60% and 80% drug loadings, and tablets containing the dasatinib:Methocel E5 ASD at 80% drug loading. Under these conditions, each ASD tablet performed better than the Sprycel reference drug. Figure 13 shows the dissolution curves obtained at pH 5.5 (medium C) for tablets containing an ASD of dasatinib:Eudragit L100-55 at 80% drug loading and tablets containing an ASD of dasatinib:Methocel E5 at 80% drug loading. Under these conditions, the performance of each ASD tablet was better than that of the Sprycel reference drug. Taken as a whole, these data support the conclusion that the ASDs of the present disclosure have enhanced solubility in biologically relevant media under conditions of elevated pH relative to normal fasting gastric pH, indicating that the ASDs may enhance in vivo bioavailability under elevated pH conditions relative to formulations containing crystalline dasatinib.

[0185] Example 8. In vivo pharmacokinetic study of tablets containing dasatinib ASD A study was conducted to evaluate the in vivo pharmacokinetic performance of tablets containing the ASD of the present disclosure. The reference drug, Sprycel, in the form of a 100 mg immediate release tablet, was also included in the study as a benchmark. The test tablets were the dasatinib ASD tablets from Example 5. Sprycel, in the form of a 100 mg immediate release tablet, was included in the study as a reference product. This human study employed a balanced, two-treatment, four-period, two-sequence, single-dose, completely repeated crossover design. Individual studies were conducted under fasted and fed conditions (note that different sets of subjects were used for both studies; high inter-subject variability in dasatinib absorption has been observed).

[0186] Subjects were randomized according to the order in which they received the test product (dasatinib ASD tablets) and the reference product (Sprycel tablets) during the study, with at least a 7-day washout period between periods. For fasting studies, subjects fasted overnight (at least 10 hours before dosing and at least 4 hours after dosing) during each study period. Administered with 240 mL of water. In the fed study, subjects fasted overnight (at least 10 hours) and then consumed a high-fat, high-calorie breakfast 30 minutes before dosing. After each study period, subjects were then prevented from eating again for at least 4 hours after dosing. The dose was administered with 240 mL of water. Plasma samples were collected within 1 hour before dosing. Plasma samples were collected at appropriate time points up to 24 hours after dosing to assess the pharmacokinetic profile. At least 18 subjects completed each period.

[0187] Plasma samples were analyzed for dasatinib content. Pharmacokinetic parameters were calculated from the data. The calculated pharmacokinetic parameters are presented in Table 43 for the fasted study (n=19) and in Table 44 for the fed study (n=18). Table 43. Pharmacokinetic parameters calculated under fasting conditions for Example 8 [Table 43] K el =disappearance rate constant n / a = No applicable data

[0188] Table 44. Pharmacokinetic parameters calculated under fed conditions for Example 8 [Table 44] K el =disappearance rate constant n / a = No applicable data

[0189] TIFF2026004291000047.tif27170Based on statistical analysis of the fasting study, the log-transformed pharmacokinetic parameter AUC last The estimated 90% confidence interval for was not within the 80-125% acceptance criteria. Therefore, it was concluded that the test product (dasatinib ASD tablets) was not bioequivalent to the reference product (Sprycel tablets) under fasting conditions. max For , the intrasubject variability for the reference product was significant, indicating that using the scaled average bioequivalence (SABE) method is better than using the average bioequivalence (ABE) method for this parameter.

[0190] Based on statistical analysis of the feeding study, C max , AUC last , and AUC 0-inf The estimated 90% confidence interval for the ratio of the geometric means of the test and reference products was within the 80-125% limits of bioequivalence under fed conditions. Therefore, it was concluded that the test product (dasatinib ASD tablets) was bioequivalent to the reference product (Sprycel tablets) under fed conditions. Furthermore, the test product (dasatinib ASD tablets) showed variability, as measured by the coefficient of variation (CV in %), for most parameters under all conditions, comparable to or greater than that of the reference product (Sprycel tablets). max , AUC last , and AUC 0-infThe variability was quite similar for the test and reference products. Under fasting conditions, all relevant parameters C max , AUC last , and AUC 0-inf For variability, the variability was significantly improved in the test product compared to the reference product. Furthermore, the test product (dasatinib ASD tablets) exhibited similar variability in both fasted and fed states, in contrast to the reference product, which exhibited significantly higher variability under fasted conditions. * * * * *

[0191] The foregoing description is given for clarity of understanding only, and no unnecessary limitations should be understood from such description. Various modifications and alterations to the present disclosure will become apparent to those skilled in the art without departing from the scope and spirit of the present disclosure. It is understood that the present disclosure is not intended to be unduly limited by the exemplary embodiments and examples set forth herein, and that such examples and embodiments are presented by way of example only. Throughout this specification, references to "one embodiment," "an embodiment," "certain embodiments," or "some embodiments" or the like mean that the particular feature, configuration, composition, or characteristic described in connection with an embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of such phrases in various places throughout this specification are not necessarily all referring to the same embodiment of the present disclosure. Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments. Throughout this specification, when a composition is described as comprising components or materials, unless otherwise specified, it is intended that the composition also can consist essentially of, or consist of, any combination of the listed components or materials. Similarly, when a method is described as comprising particular steps, it is intended that the method also can consist essentially of, or consist of, any combination of the listed steps, unless otherwise specified.

[0192] The implementation of the methods disclosed herein, and the individual steps of the methods, can be performed manually and / or with the aid of or automated by electronic devices. While processes have been described with reference to specific embodiments, those skilled in the art will readily understand that other ways of performing the acts associated with the methods can be practiced. Unless otherwise indicated, for example, the order of various steps can be changed without departing from the scope or spirit of the methods. In addition, some individual steps can be combined, omitted, or further subdivided into additional steps. The term "comprises," and variations such as "comprises" and "comprising," when appearing in the description and claims, do not have a limiting meaning. Such terms will be understood to imply the inclusion of stated steps or elements, or groups of stated steps or elements, but not the exclusion of other steps or elements, or groups of other steps or elements.

[0193] "Consists of" means including and limited to everything that precedes the phrase "consisting of." Thus, the phrase "consisting" indicates that the indicated elements are required or essential, and that no other elements may be present. "Consists essentially of" means including all the elements that precede the phrase, and is limited to other elements that do not interfere with or contribute to the activity or function specified in this disclosure for the indicated element. Thus, the phrase "consisting essentially of" indicates that the indicated elements are required or essential, but that other elements are optional, and may or may not be present depending on whether they have a substantial effect on the activity or function of the indicated element. The words "preferred" and "preferably" refer to embodiments of the present disclosure that may offer certain benefits, under particular circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Moreover, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the present disclosure.

[0194] As used herein, terms such as "a," "an," and "the" are not intended to refer only to a singular entity, but also include the general class of illustrative examples that may be used for purposes of illustration. The terms "a" and "the" are used interchangeably with the term "at least one." The phrases "at least one" and "including at least one," when preceded by a list, refer to any one item in the list, and any combination of two or more items in the list. As used herein, the term "or" is generally used in its ordinary sense, including "and / or," unless the context clearly dictates otherwise. The term "and / or" refers to one or all of the stated elements or a combination of any two or more of the stated elements (e.g., preventing and / or treating pain means preventing pain, treating pain, or treating and preventing pain).

[0195] Also, herein, all numbers are intended to be modified by the term "about," preferably the term "exactly." As used herein with respect to a measurand, the term "about" refers to the variation in that measurand that would be expected by one of ordinary skill in the art making the measurement and exercising a level of care commensurate with the purpose of the measurement and the precision of the measuring device used. As used herein, references "up to" a number (e.g., up to 50) include that number (e.g., 50). Also, herein, the recitation of numerical ranges by endpoints includes all numbers and endpoints subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.) and all subranges (e.g., 1 to 5 includes 1 to 4, 1 to 3, 2 to 4, etc.).

[0196] The complete disclosures of the patents, patent publications, and publications cited herein are incorporated by reference in their entirety as if each were individually incorporated. To the extent there is a conflict or inconsistency between this disclosure and any document incorporated by reference herein, the disclosure of this disclosure will control.

Claims

1. 1. A pharmaceutical composition comprising an amorphous solid dispersion, the amorphous solid dispersion comprising dasatinib and one or more polymers; the one or more polymers include a polymer that exhibits pH-dependent solubility; The pharmaceutical composition, wherein dasatinib and one or more polymers are present in the amorphous solid dispersion in a w / w ratio of 30:70 to 95:5 (dasatinib:polymer).

2. 10. The pharmaceutical composition of claim 1, wherein the one or more polymers comprise a copolymer of methacrylic acid and ethyl acrylate that exhibits pH-dependent solubility.

3. 10. The pharmaceutical composition of claim 1, wherein the one or more polymers consist essentially of a copolymer of methacrylic acid and ethyl acrylate that exhibits pH-dependent solubility.

4. 10. The pharmaceutical composition of claim 1, wherein the one or more polymers comprise a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate that exhibits pH-dependent solubility.

5. 10. The pharmaceutical composition of claim 1, wherein the one or more polymers consist essentially of a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate that exhibits pH-dependent solubility.

6. 10. The pharmaceutical composition of claim 1, wherein the one or more polymers consist essentially of a polymer that exhibits pH-dependent solubility.

7. 1. A pharmaceutical composition comprising an amorphous solid dispersion, the amorphous solid dispersion comprising dasatinib and one or more polymers; the one or more polymers include hydroxypropyl methylcellulose; The pharmaceutical composition, wherein dasatinib and one or more polymers are present in the amorphous solid dispersion in a w / w ratio of 30:70 to 95:5 (dasatinib:polymer).

8. 8. The pharmaceutical composition of claim 7, wherein the one or more polymers consist essentially of hydroxypropyl methylcellulose.

9. 9. The pharmaceutical composition of any one of claims 1 to 8, wherein the amorphous solid dispersion comprises one or more antioxidants comprising propyl gallate.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the solid amorphous dispersion comprises one or more antioxidants present in an amount of 0.001% to 2.0% by weight of the solid amorphous dispersion.

11. 9. The pharmaceutical composition of any one of claims 1 to 8, wherein the amorphous solid dispersion consists essentially of dasatinib and one or more polymers.

12. 12. The pharmaceutical composition of any one of claims 1 to 11, wherein dasatinib and the one or more polymers are present in the amorphous solid dispersion in a w / w ratio of 40:60 to 70:30 (dasatinib:polymer).

13. The pharmaceutical composition according to any one of claims 1 to 12, comprising an amorphous solid dispersion and one or more pharmaceutically acceptable excipients.

14. A method of treating a proliferative disorder in a patient in need thereof, comprising administering to the patient a pharmaceutical composition according to any one of claims 1 to 13, The method, wherein the pharmaceutical composition is administered regardless of whether the patient is also taking a gastric acid-reducing agent.

15. A method of treating a proliferative disorder in a patient in need thereof, comprising administering to the patient a pharmaceutical composition according to any one of claims 1 to 13, The method, wherein the pharmaceutical composition is administered to the patient in conjunction with a gastric acid-reducing agent.

16. 16. The method of claim 15, wherein the stomach acid reducing agent is administered to the patient immediately prior to administering the pharmaceutical composition.

17. 16. The method of claim 15, wherein the stomach acid reducing agent is administered to the patient simultaneously with administration of the pharmaceutical composition.

18. 16. The method of claim 15, wherein the stomach acid reducing agent is administered to the patient immediately after the pharmaceutical composition is administered.

19. A method of treating a proliferative disorder in a patient in need thereof, comprising administering to the patient a pharmaceutical composition according to any one of claims 1 to 13, The method, wherein the solid amorphous dispersion is administered regardless of whether the patient's gastric pH is elevated.

20. A method of treating a proliferative disorder in a patient in need thereof, comprising administering to the patient a pharmaceutical composition according to any one of claims 1 to 13, The patient has an elevated gastric pH.

21. 1. A method of treating a proliferative disorder in a patient in need thereof, comprising: (a) identifying a condition in a patient where the patient has a chronically elevated gastric pH; (b) administering to a patient a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 13; The method, wherein the therapeutically effective amount comprises 20 mg to 140 mg of dasatinib.

22. The method of any one of claims 14 to 21, wherein the proliferative disorder is cancer.

23. The method of any one of claims 14 to 21, wherein the proliferative disorder is Philadelphia chromosome-positive chronic myeloid leukemia.

24. The method of any one of claims 14 to 21, wherein the proliferative disorder is Philadelphia chromosome-positive acute lymphoblastic leukemia.

25. 1. A therapeutic regimen for treating a proliferative disorder in a patient in need thereof, comprising: (a) a standard dose of a proton pump inhibitor or H 2 administering to the patient a first dose comprising an antagonist; (b) administering to the patient within 20 hours after the first dose a second dose comprising a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 13; The foregoing regimens, wherein the therapeutically effective amount comprises 20 mg to 140 mg of dasatinib.

26. 1. A therapeutic regimen for treating a proliferative disorder in a patient in need thereof, comprising: (a) administering to a patient a first dose comprising a standard dose of an antacid; (b) administering to the patient a second dose comprising the pharmaceutical composition of any one of claims 1 to 13 within 2 hours before or within 2 hours after the first dose; The regimen, wherein administration of the second dose provides the patient with a therapeutically adequate exposure to dasatinib.

27. A kit for sale to a user, comprising the pharmaceutical composition according to any one of claims 1 to 13 and an accompanying instruction, The kit, wherein the package insert informs the user that the pharmaceutical composition can be used in combination with a stomach acid-reducing agent.

28. A kit for sale to a user, comprising the pharmaceutical composition according to any one of claims 1 to 13 and an accompanying instruction, The package insert states that the pharmaceutical composition is H 2 The kit does not include a warning that the drug should not be used in combination with an antagonist or proton pump inhibitor.

29. A kit for sale to a user, comprising the pharmaceutical composition according to any one of claims 1 to 13 and an accompanying instruction, The kit, wherein the package insert informs the user that the pharmaceutical composition can be suitably administered if the user has chronically elevated gastric pH.

30. A kit for sale to a user, comprising the pharmaceutical composition according to any one of claims 1 to 13 and an accompanying instruction, The kit, wherein the package insert informs the user that the pharmaceutical composition can be suitably administered if the user has been diagnosed with or is suffering from achlorhydria or hypochlorhydria.

31. A kit for sale to a user, comprising the pharmaceutical composition according to any one of claims 1 to 13 and an accompanying instruction, The kit, wherein the package insert informs the user that the pharmaceutical composition can be suitably administered if the user has been diagnosed with Helicobacter pylori infection or if the user is suffering from Helicobacter pylori infection.

32. 1. An amorphous solid dispersion comprising dasatinib and one or more polymers, the one or more polymers include a polymer that exhibits pH-dependent solubility; The amorphous solid dispersion, wherein dasatinib and one or more polymers are present in the amorphous solid dispersion in a w / w ratio of 30:70 to 95:5 (dasatinib:polymer).

33. 33. The amorphous solid dispersion of claim 32, wherein the one or more polymers comprise a copolymer of methacrylic acid and ethyl acrylate that exhibits pH-dependent solubility.

34. 33. The amorphous solid dispersion of claim 32, wherein the one or more polymers consist essentially of a copolymer of methacrylic acid and ethyl acrylate that exhibits pH-dependent solubility.

35. 33. The amorphous solid dispersion of claim 32, wherein the one or more polymers comprise a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate that exhibits pH-dependent solubility.

36. 33. The amorphous solid dispersion of claim 32, wherein the one or more polymers consist essentially of a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate that exhibits pH-dependent solubility.

37. 33. The amorphous solid dispersion of claim 32, wherein the one or more polymers consist essentially of a polymer that exhibits pH-dependent solubility.

38. 1. An amorphous solid dispersion comprising dasatinib and one or more polymers, the one or more polymers include hydroxypropyl methylcellulose; The amorphous solid dispersion, wherein dasatinib and one or more polymers are present in the amorphous solid dispersion in a w / w ratio of 30:70 to 95:5 (dasatinib:polymer).

39. 39. The amorphous solid dispersion of claim 38, wherein the one or more polymers consist essentially of hydroxypropyl methylcellulose.

40. 40. The amorphous solid dispersion of any one of claims 32 to 39, wherein the amorphous solid dispersion comprises one or more antioxidants comprising propyl gallate.

41. 40. The amorphous solid dispersion of any one of claims 32 to 39, wherein the amorphous solid dispersion comprises one or more antioxidants present in an amount of 0.001% to 2.0% by weight of the amorphous solid dispersion.

42. 40. The amorphous solid dispersion of any one of claims 32 to 39, wherein the amorphous solid dispersion consists essentially of dasatinib and one or more polymers.

43. 43. The amorphous solid dispersion of any one of claims 32 to 42, wherein dasatinib and the one or more polymers are present in the amorphous solid dispersion in a w / w ratio of 40:60 to 70:30 (dasatinib:polymer).

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