Amorphous nilotinib microparticles and their use

Abstract

To provide a pharmaceutical composition of an amorphous solid dispersion of nilotinib. [Solution] A pharmaceutical composition comprising an amorphous solid dispersion, wherein the amorphous solid dispersion comprises nilotinib and one or more polymers, One or more polymers include a polymer that exhibits pH-dependent solubility. The pharmaceutical composition comprising nilotinib and one or more polymers present in an amorphous solid dispersion in a w / w ratio of 20:80 to 95:5 (nilotinib:polymer).

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 968,749 (filed on 31 January 2020), all of which are incorporated herein by reference. [Background technology]

[0002] Protein kinase inhibitors (PKIs) are being studied for their potential use in treating various disorders of cell proliferation, including cancer. The potential of PKIs as a therapy is based on the role of protein kinases, which are known to play in regulating many cellular pathways, including those involved in signal transduction. Dysregulation of protein kinases is associated with the development and progression of many cancers, which suggests that PKIs may be useful as a treatment for disorders or diseases, such as cancer, caused by uncontrolled overexpression or upward regulation of protein kinases. One such PKI is nilotinib, currently marketed under the brand name Tasigna as an oral, immediate-release formulation. Tasigna is indicated for (a) the treatment of newly diagnosed adult patients and children aged 1 year and older with chronic-phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML); (b) the treatment of adult patients with chronic and transitional-phase Ph+CML who are resistant to or intolerant of prior treatments including imatinib; and (c) the treatment of children aged 1 year and older with chronic-phase Ph+CML who are resistant to or intolerant of prior tyrosine kinase inhibitor treatments.

[0003] Currently, oral administration of Tasigna is affected by food. In fact, the prescribing information for Tasigna includes a framed warning that states, "Avoid eating for 2 hours before taking the medication and 1 hour after taking it." According to the same prescribing information, "Tasigna may cause significant QT interval prolongation if taken inappropriately with food and / or potent CYP3A4 inhibitors and / or medications known to potentially prolong the QT interval. Therefore, concomitant use with food should be avoided..." This effect on the QT interval may occur when Tasigna is taken with food, affecting the exposure (expressed as area under the curve or AUC) and / or the peak plasma concentration (C). max This may be due to an increase in AUC and C(A) obtained under fasting conditions. For example, a single dose of 400 mg of Tasigna 30 minutes after a high-fat meal may result in an increase in AUC and C(A) obtained under fasting conditions. max Compared to the level of AUC and C max These increase by 82% and 112%, respectively. Such increases in serum levels may also worsen or increase the prevalence of more serious side effects, such as decreased blood cell counts, reduced blood flow to the heart or brain, pancreatitis, liver damage, and hemorrhagic disorders, as well as common side effects such as nausea, diarrhea, rash, headache, muscle and joint pain, fatigue, vomiting, and fever. Current prescribing information for Tasigna instructs patients to take it twice daily on an empty stomach, avoiding food for two hours before and one hour after taking the medication. The need to take Tasigna twice daily without food (with a three-hour gap between doses) is a significant burden for patients. Furthermore, given the potential side effects of Tasigna, failure to adequately adhere to the recommended dosage could be extremely harmful to patients.

[0004] In addition, the solubility of nilotinib decreases significantly with increasing pH, and therefore, when Tasigna is administered with an acid-reducing agent, the absorption of nilotinib may be impaired. According to prescribing information, the concomitant use of Tasigna with common acid-reducing agents is restricted. For example, the prescribing information for Tasigna explicitly states, "Avoid concomitant use of Tasigna with [proton pump inhibitors]." The prescribing information further suggests that "concomitant use with [proton pump inhibitors] may reduce the concentration of nilotinib compared to Tasigna alone...and may reduce the efficacy of Tasigna," and therefore, "use a short-acting antacid or H2 blocker as an alternative to a proton pump inhibitor." For the safe combined use of Tasigna and acid-reducing agents, the prescribing information provides the following instructions: "Use an H2 blocker as an alternative to a PPI approximately 10 hours before or approximately 2 hours after administering Tasigna, or use an antacid approximately 2 hours before or approximately 2 hours after administering Tasigna." The limitations on how patients can cope with dyspepsia or excessive gastric acidity while being treated with Tasigna are problematic, especially considering how frequently these symptoms occur in the patient population. Furthermore, failure to fully adhere to the warnings in the prescribing information regarding the use of acid-reducing agents while being treated with Tasigna may be harmful to patients. Therefore, there remains a need in the field of nilotinib therapy for ways to minimize the risk of experiencing adverse side effects, particularly those associated with the effects of food on tasigna, while allowing patients to receive all the benefits of nilotinib, and for eliminating the need to thus restrict the concomitant use of nilotinib with acid-reducing agents. [Overview of the project]

[0005] Certain aspects of this disclosure relate to amorphous solid dispersions ("ASDs") containing nilotinib. The ASD comprises nilotinib and one or more polymers. In some embodiments, the ASD comprises nilotinib and one or more polymers exhibiting pH-dependent solubility. In another embodiment, the present disclosure provides a pharmaceutical composition containing ASD. Furthermore, another aspect of the present disclosure relates to a method for treating diseases that respond to inhibition of protein kinase activity, such as proliferative disorders. In some embodiments, the method includes the step of administering the ASD or pharmaceutical composition of the present disclosure to a patient. In some embodiments, the composition is administered regardless of food consumption. In some embodiments, the composition is administered regardless of whether the patient is fasting or feeding.

[0006] In another embodiment, the Disclosure provides a method for safely delivering nilotinib to a patient who requires the safe delivery of nilotinib to the patient, the method comprising the steps of (a) administering a therapeutically effective amount of the pharmaceutical composition of the Disclosure to the patient and (b) providing the patient with a meal, wherein steps (a) and (b) occur within two hours of each other. In other embodiments, the Disclosure provides a kit for sale to a user. The kit includes the pharmaceutical composition of the Disclosure and a package insert. In one embodiment, the package insert informs the user that the pharmaceutical composition may be administered with food. In another embodiment, the package insert informs the user that the pharmaceutical composition may be administered with or without food. In yet another embodiment, the package insert does not include a warning that the pharmaceutical composition should not be administered with food. [Brief explanation of the drawing]

[0007] [Figure 1] Figure 1 shows the pharmacokinetic profiles for (a) fasted male beagle dogs administered with Tasigna suspension after pentagastrin pretreatment (pH 1-2) (section A1), or (b) fasted male beagle dogs administered with Tasigna capsules after phosphate buffer pretreatment (pH 2.5) (section B1), as described in Example 4. [Figure 2]Figure 2 shows the pharmacokinetic profiles of (a) fasted male beagle dogs (section B1) administered with Tasigna capsules after phosphate buffer pretreatment (pH ~2.5), as described in Example 4, and (b) fed male beagle dogs (section A3) administered with Tasigna suspension. [Figure 3] Figure 3 shows the pharmacokinetic profiles of (a) fasted male beagle dogs administered with Tasigna capsules after phosphate buffer pretreatment (pH ~2.5) (section B1), (b) fasted male beagle dogs administered with ASD capsules (nilotinib and HPMC-AS) after phosphate buffer pretreatment (pH ~2.5) (section B2), (c) fasted male beagle dogs administered with ASD suspension (nilotinib and HPMC-AS) after phosphate buffer pretreatment (pH ~2.5) (section B3), and (d) fasted male beagle dogs administered with ASD tablets (nilotinib and HPMC-AS) after phosphate buffer pretreatment (pH ~2.5) (section B4), as described in Example 4. [Figure 4] Figure 4 shows the pharmacokinetic profiles of (a) fasted male beagle dogs administered with Tasigna capsules after phosphate buffer pretreatment (pH ~2.5) (section B1), (b) fasted male beagle dogs administered with an ASD suspension containing SOLUPLUS (nilotinib and Eudragit L100-55) after phosphate buffer pretreatment (pH ~2.5) (section C1), (c) fasted male beagle dogs administered with an ASD suspension containing SOLUPLUS (nilotinib and HPMC-AS) after phosphate buffer pretreatment (pH ~2.5) (section C2), and (d) fasted male beagle dogs administered with an ASD suspension (nilotinib and HPMC-AS) after phosphate buffer pretreatment (pH ~2.5) (section C3), as described in Example 4. [Figure 5]Figure 5 shows the pharmacokinetic profiles of (a) healthy human subjects in a fasted state who were orally administered 200 mg Tasigna IR capsules, (b) healthy human subjects in a fasted state who were orally administered 50 mg Composition 1 (ASD of nilotinib and HPMC-AS), and (c) healthy human subjects in a fasted state who were orally administered 50 mg Composition 2 (ASD of nilotinib and HPMC-AS containing Solplus), as described in Example 5. [Figure 6] Figure 6 shows the pharmacokinetic profiles for (a) healthy human subjects in a fasted state who were orally administered 200 mg Tasigna IR capsules, (b) healthy human subjects in a fasted state who were orally administered 50 mg Composition 1 (Nilotinib and HPMC-AS ASD), and (c) healthy human subjects in a fed state who were orally administered 50 mg Composition 1 (Nilotinib and HPMC-AS ASD), as described in Example 5. [Figure 7] Figure 7 shows the pharmacokinetic profiles for (a) healthy human subjects in a fasted state who were orally administered 200 mg Tasigna IR capsules, (b) healthy human subjects in a fasted state who were orally administered 65 mg Composition 2 (containing Solplus, nilotinib and HPMC-AS ASD), and (c) healthy human subjects in a fed state who were orally administered 65 mg Composition 2 (containing Solplus, nilotinib and HPMC-AS ASD), as described in Example 5. [Modes for carrying out the invention]

[0008] This disclosure relates to nilotinib ASD, pharmaceutical compositions of nilotinib ASD, and methods of use including the administration of nilotinib ASD or the pharmaceutical compositions. The nilotinib ASD and pharmaceutical compositions of this disclosure can offer special advantages over conventional immediate-release formulations of nilotinib crystals, such as Tasigna. For example, as described herein, the prescribing information for Tasigna warns against eating two hours before administration and one hour after administration. In contrast, some ASDs and pharmaceutical compositions of this disclosure can be administered regardless of food consumption. Furthermore, certain ASDs and pharmaceutical compositions in this disclosure unexpectedly provide a pharmacokinetic profile similar to that of Tasigna, even when the dose of nilotinib administered by the pharmaceutical composition is a fraction of the dose of nilotinib typically administered when using Tasigna. Therefore, this disclosure provides pharmaceutical compositions that can be administered at lower doses than Tasigna but are expected to provide comparable therapeutic effects. Another advantage is that the pharmaceutical compositions of this disclosure can reduce inter- and / or intra-subject variability compared to the variability observed for tasigna. Therefore, the ASD and pharmaceutical compositions of this disclosure can provide a safer and equally effective expression of nilotinib compared to currently available immediate-release products.

[0009] Nilotinib Nilotinib is a kinase inhibitor with the following structure: [ka] The chemical name of nilotinib is 4-methyl-N-[3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide. The molecular formula is C 28 H 22 It is F3N7O, which corresponds to a molecular weight of 529 g / mol (nilotinib base, anhydrous). Nilotinib is marketed under the brand name Tasigna as an immediate-release formulation containing nilotinib monohydrochloride monohydrate. The nilotinib monohydrochloride monohydrate in Tasigna is believed to be in crystalline form. Currently available Tasigna capsules (marketed in the United States under new drug application 22-068) are labeled as containing 50 mg, 150 mg, or 200 mg of anhydrous nilotinib base (equivalent to 55 mg, 166 mg, and 221 mg of nilotinib monohydrochloride monohydrate, respectively). As used herein, “Tasigna IR Capsules” refers to commercially available Tasigna immediate-release capsules. According to the Biopharmaceutical Classification System ("BCS"), nilotinib monohydrochloride monohydrate is classified as a Class IV compound (low / moderate water solubility and low permeability). The bioavailability of nilotinib can be increased by preparing it in a form intended to enhance its solubility. One approach to increasing solubility is to produce an amorphous solid dispersion.

[0010] Amorphous solid dispersion of nilotinib Certain aspects of this disclosure relate to amorphous solid dispersions ("ASDs") comprising nilotinib and one or more polymers. A pharmaceutically suitable amorphous solid dispersion generally contains a pharmaceutically active ingredient, such as nilotinib, dispersed in a pharmacologically inert carrier, such as a polymer. One objective of a pharmaceutically suitable amorphous solid dispersion is to improve the bioavailability of the pharmaceutically active ingredient. This improvement may occur, for example, by increasing the surface area, improving wettability or dispersibility, increasing the dissolution rate, or by other factors. Generally, it is preferable that the active pharmaceutical ingredient is dispersed in a polymer to form what is referred to in this art as a "glass solution." However, other forms of dispersions, such as "solid solutions" or "glass suspensions," may also be suitable. Precise characterization of the solid dispersion is not important if the amorphous solid dispersion can provide the desired properties and performance. In the ASD of this disclosure, nilotinib may be a free base or a salt such as a hydrochloride. In some embodiments, nilotinib is a free base and an anhydride. Such forms of nilotinib and processes for preparing nilotinib are disclosed, for example, in WO2004 / 005281 and WO2007 / 015871. In the following descriptions of amorphous solid dispersions and pharmaceutical compositions, and in the claims, any reference to “nilotinib” broadly refers to the free base of nilotinib, a salt of nilotinib, an anhydride of nilotinib (or a salt thereof), nilotinib hydrate or nilotinib solvate, and hydrates or solvates of salts of nilotinib, unless otherwise specified.

[0011] One or more polymers that must be pharmacologically inert should be suitable for providing structure and stability to 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 nilotinib and one or more polymers. In one embodiment, the ASD consists of nilotinib and one or more polymers. In another embodiment, the ASD essentially consists of nilotinib and one or more polymers. The polymers that can be used in ASDs as disclosed herein include, but are not limited to, those listed below. The term "polymer" includes, but is not limited to, organic homopolymers, copolymers (e.g., block polymers, graft polymers, random polymers, and terpolymers), as well as blends and modifications thereof. The term "copolymer" refers to a polymer comprising two or more different monomer units or segments, including terpolymers, tetrapolymers, etc. Information regarding suitable polymers and commercial sources for such polymers can be found in Sheskey PJ(ed.) Handbook of Pharmaceutical Excipients, 9 th It can be found in the edition ed. London: Pharmaceutical Press; 2020 (ISBN 0857113755), or you can refer to the latest edition with the same title.

[0012] Examples of polymers that can be used for ASD according to this disclosure include ionizable polymers, non-ionizable polymers, or combinations thereof. In some embodiments, one or more polymers may be non-ionizable polymers. In one embodiment, ASD consists of nilotinib and one or more non-ionizable polymers. In another embodiment, ASD essentially consists of nilotinib and one or more non-ionizable polymers. In some embodiments, one or more polymers may be ionizable polymers. In one embodiment, ASD consists of nilotinib and one or more ionizable polymers. In another embodiment, ASD essentially consists of nilotinib and one or more ionizable polymers. In yet another embodiment, a combination of ionizable polymers and non-ionizable polymers may be used. In one embodiment, the ASD consists of nilotinib and a combination of one or more non-ionizable polymers and one or more ionizable polymers. In yet another embodiment, the ASD essentially consists of nilotinib and a combination of one or more non-ionizable polymers and one or more ionizable polymers.

[0013] Examples of polymers that can be used for ASD according to this disclosure include polymers that exhibit pH-dependent solubility, polymers that are generally pH-insensitive, or combinations thereof. In some embodiments, one or more polymers may exhibit pH-dependent solubility. In one embodiment, ASD consists of nilotinib and one or more polymers exhibiting pH-dependent solubility. In another embodiment, ASD essentially consists of nilotinib and one or more polymers exhibiting pH-dependent solubility. In other embodiments, one or more polymers may generally be pH insensitive. In one embodiment, ASD consists of nilotinib and one or more polymers that are generally pH insensitive. In another embodiment, ASD essentially consists of nilotinib and one or more polymers that are generally pH insensitive. In yet another embodiment, the polymer combination may include one or more polymers exhibiting pH-dependent solubility and one or more polymers that are generally pH-insensitive. In one embodiment, ASD consists of nilotinib and a combination of one or more polymers exhibiting pH-dependent solubility and one or more polymers that are generally pH-insensitive. In yet another embodiment, ASD essentially consists of nilotinib and a combination of one or more polymers exhibiting pH-dependent solubility and one or more polymers that are generally pH-insensitive.

[0014] Non-ionizable polymers. Suitable non-ionizable polymers 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; polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers; and poloxamers. Suitable non-ionizable polysaccharides and polysaccharide derivatives include cellulose ethers and non-ionizable cellulose esters. Examples of suitable cellulose ethers include methylcellulose ("MC"; e.g., Methocel A15 LV, Methocel A4M), ethylcellulose ("EC"; e.g., Ethocel), hypromellose or hydroxypropyl methylcellulose ("HPMC"; e.g., Methocel E3, Methocel E5, Methocel E6, Methocel E15, AFFINISOL HPMC HME), hydroxyethylcellulose ("HEC"; e.g., Natrosol 250 Pharm), and hydroxypropylcellulose ("HPC"; e.g., HPC EF, HPC LF, HPC JF, HPC L, Klucel). Suitable examples of non-ionizable cellulose esters include cellulose acetate, cellulose propionate, cellulose butyrate, and cellulose acetate-butyrate.

[0015] 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). Suitable polymers of ethylene oxide include polyethylene glycol ("PEG"; e.g., Kollisolv PEG 8000) and poly(ethylene oxide) ("PEO"; e.g., Polyox). 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 acid-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. Polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., SOLUPLUS) can also be a suitable non-ionizable polymer.

[0016] Ionizable polymers. Suitable ionizable polymers can be considered as "anionic" polymers or "cationic" polymers. Anionic and cationic polymers often exhibit pH-dependent solubility. Anionic polymers often contain carboxylate (such as acetate), phthalate, succinate, or acrylate functionalities. 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 (such as ionizable cellulose esters), methacrylic acid and / or alkyl acrylate copolymers, and derivatized vinyl acetate polymers.

[0017] A suitable example of an ionizable polysaccharide is xanthan gum. Suitable examples of ionizable cellulose esters include carboxymethylcellulose ("CMC"; sodium carboxymethylcellulose), hypromellose acetate succinate, or hydroxypropyl methylcellulose acetate succinate ("HPMC-AS"; e.g., AFFINISOL HPMC-AS, AQUASOLVE, AQOAT), hydroxypropyl methylcellulose phthalate ("HPMC-P"; e.g., HP-50, HP-55), and cellulose acetate phthalate ("CAP"; e.g., EASTMAN CAP). Suitable copolymers of methacrylic acid and / or alkyl methacrylate include methacrylic acid / methyl methacrylate copolymer (e.g., Eudragit L100) and methacrylic acid / ethyl acrylate copolymer (e.g., Eudragit L100-55, Kollicoat MAE). A suitable example of a derivatized vinyl acetate polymer is polyvinyl acetate phthalate (PVA-P; PHTHALAVIN).

[0018] Cationic polymers often contain amine functionality. Cationic polymers are generally soluble at low pH and become less soluble at higher pH. Suitable cationic polymers include, for example, cationic polysaccharides and polysaccharide derivatives, as well as amine-functionalized copolymers of methacrylic acid and / or alkyl acrylate. A suitable example of a cationic polysaccharide is chitosan. Suitable amine-functionalized copolymers of methacrylic acid and / or alkyl acrylate 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-trimethylammoniumethyl methacrylate) (e.g., Eudragit RL100, Eudragit RL PO, Eudragit RS PO). In some embodiments, one or more polymers include polymers characterized by pH-dependent solubility. In some embodiments, one or more polymers include anionic polymers characterized by pH-dependent solubility. In some embodiments, one or more polymers essentially consist of one or more anionic polymers characterized by pH-dependent solubility. In some embodiments, one or more polymers consist of one or more anionic polymers characterized by pH-dependent solubility.

[0019] HPMC-AS and Eudragit L100-55 are examples of suitable anionic polymers that exhibit pH-dependent solubility, but other polymers exhibiting pH-dependent solubility may also be used. In one embodiment, one or more polymers include HPMC-AS. In one embodiment, the polymer consists of HPMC-AS. In one embodiment, the polymer is essentially made of HPMC-AS. Various grades of HPMC-AS are available, and each HPMC-AS exhibits pH-dependent water solubility. Generally, HPMC-AS is practically insoluble in aqueous media with a pH of 4 or lower, but is nearly soluble in aqueous media with a pH of 7 or higher. HPMC-AS is insoluble in normal gastric juice, but swells and dissolves in the higher pH environment of the upper small intestine. The grades of HPMC-AS are distinguished by the relative ratio of acetyl / succinyl substituents. Low-grade HPMC-AS contains 5-9% acetyl substituents and 14-18% succinyl substituents; medium-grade HPMC-AS contains 7-11% acetyl substituents and 10-14% succinyl substituents; and high-grade HPMC-AS contains 10-14% acetyl substituents and 4-8% succinyl substituents. In the implementation of this disclosure, any grade of HPMC-AS may be preferred, or mixtures of two or more grades may also be preferred. In one embodiment, intermediate-grade HPMC-AS may be particularly preferred.

[0020] In one embodiment, the ASD consists of nilotinib and HPMC-AS. In one embodiment, the ASD is essentially composed of nilotinib and HPMC-AS. In one embodiment, the ASD consists of anhydrous nilotinib free base and HPMC-AS. In one embodiment, the ASD is essentially composed of anhydrous nilotinib free base and HPMC-AS. In one embodiment, the ASD consists of nilotinib and intermediate grade HPMC-AS. In one embodiment, the ASD is essentially composed of nilotinib and intermediate grade HPMC-AS. In one embodiment, the ASD consists of anhydrous nilotinib free base and intermediate grade HPMC-AS. In one embodiment, the ASD is essentially composed of anhydrous nilotinib free base and intermediate grade HPMC-AS. In some embodiments, one or more polymers include a copolymer of methacrylic acid and / or alkyl methacrylate. In some embodiments, one or more polymers include a methacrylic acid / methyl methacrylate copolymer (e.g., Eudragit L100) or a methacrylic acid / ethyl acrylate copolymer (e.g., Eudragit L100-55).

[0021] In some embodiments, one or more polymers include a methacrylic acid / ethyl acrylate copolymer. In some embodiments, the polymer consists of a methacrylic acid / ethyl acrylate copolymer. In some embodiments, the polymer is essentially composed of a methacrylic acid / ethyl acrylate copolymer. In some embodiments, the ASD comprises nilotinib and methacrylic acid / ethyl acrylate copolymer. In one embodiment, the ASD consists of nilotinib and methacrylic acid / ethyl acrylate copolymer. In another embodiment, the ASD essentially consists of nilotinib and methacrylic acid / ethyl acrylate copolymer. In one embodiment, the ASD comprises anhydrous nilotinib free base and methacrylic acid / ethyl acrylate copolymer. In one embodiment, the ASD consists of anhydrous nilotinib free base and methacrylic acid / ethyl acrylate copolymer. In one embodiment, the ASD essentially consists of anhydrous nilotinib 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 almost insoluble in aqueous media with a pH of 5 or less, but is almost soluble in aqueous media with a pH of 5.5 or more.

[0022] In some embodiments of ASD, one or more polymers do not include polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., Solplus). In some embodiments, ASD substantially lacks polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, ASD essentially lacks polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, ASD lacks polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In yet another embodiment, ASD comprises nilotinib and one or more polymers, wherein the one or more polymers are not polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments of ASD, one or more polymers do not contain poloxamers. In some embodiments, ASD substantially lacks poloxamers. In some embodiments, ASD essentially lacks poloxamers. In some embodiments, ASD lacks poloxamers. In yet another embodiment, ASD comprises nilotinib and one or more polymers, wherein the one or more polymers are not poloxamers.

[0023] In some embodiments of ASD, one or more polymers do not contain anionic polymers containing phthalate functionality. In some embodiments, ASD substantially lacks anionic polymers containing phthalate functionality. In some embodiments, ASD essentially lacks anionic polymers containing phthalate functionality. In some embodiments, ASD lacks anionic polymers containing phthalate functionality. In yet another embodiment, ASD comprises nilotinib and one or more polymers, wherein the one or more polymers are not anionic polymers containing phthalate functionality. In some embodiments of ASD, one or more polymers do not contain hydroxypropyl methylcellulose phthalate. In some embodiments, ASD substantially lacks hydroxypropyl methylcellulose phthalate. In some embodiments, ASD essentially lacks hydroxypropyl methylcellulose phthalate. In some embodiments, ASD lacks hydroxypropyl methylcellulose phthalate. In yet another embodiment, ASD comprises nilotinib and one or more polymers, wherein the one or more polymers are not hydroxypropyl methylcellulose phthalate.

[0024] In some embodiments of ASD, one or more polymers do not contain polyvinyl acetate phthalate. In some embodiments, ASD substantially lacks polyvinyl acetate phthalate. In some embodiments, ASD essentially lacks polyvinyl acetate phthalate. In some embodiments, ASD lacks polyvinyl acetate phthalate. In yet another embodiment, ASD comprises nilotinib and one or more polymers, wherein the one or more polymers are not polyvinyl acetate phthalate. In some embodiments of ASD, one or more polymers do not contain a polymer or copolymer of N-vinylpyrrolidone. In some embodiments, ASD substantially lacks a polymer or copolymer of N-vinylpyrrolidone. In some embodiments, ASD essentially lacks a polymer or copolymer of N-vinylpyrrolidone. In some embodiments, ASD lacks a polymer or copolymer of N-vinylpyrrolidone. In yet another embodiment, ASD comprises nilotinib and one or more polymers, wherein the one or more polymers are not a polymer or copolymer of N-vinylpyrrolidone. In the above, the polymer or copolymer of N-vinylpyrrolidone may be polyvinylpyrrolidone, crospovidone, or crosslinked polyvinylpyrrolidone, copovidone, or vinylpyrrolidone / vinyl acetate copolymer.

[0025] As used herein, the phrase “substantially deficient” means that the listed component represents 10% by mass or less of the ASD. The phrase “essentially deficient” means that the listed component represents 5% by mass or less of the ASD. The term “deficient” means that the listed component represents 2% by mass or less of the ASD. In the ASD described herein, the amount of nilotinib may be varied in relation to the amount of one or more polymers. For example, nilotinib and one or more polymers may exist in a w / w ratio of 20:80 to 95:5 (nilotinib:polymer). In some embodiments, nilotinib and one or more polymers may exist in a w / w ratio of 25:75 to 90:10, or 30:70 to 85:15, or 35:65 to 80:20. In some embodiments, nilotinib and one or more polymers may exist in a w / w ratio of 40:60 to 70:30. In certain embodiments, the w / w ratio is 20:80, 25:75, 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.

[0026] In some embodiments, the ASD comprises nilotinib and one or more polymers. In some embodiments, the ASD essentially consists of nilotinib and one or more polymers. In other embodiments, the ASD of the Disclosure may further comprise one or more other pharmaceutically acceptable functional ingredients, such as one or more antioxidants, wetting agents, or solubilizers. As used herein, the phrase “pharmaceutically acceptable” means that when introduced into the relevant biological system, the component does not initiate a pharmacological response or adverse reaction. As a purely non-limiting example, substances found on the U.S. Food and Drug Administration’s “Generally Recognized as Safe” (“GRAS”) list, or substances used in accordance with the U.S. Food and Drug Administration’s database of ineffective ingredients, would likely be considered pharmaceutically acceptable. Similarly, substances on corresponding databases or lists maintained by equivalent regulatory bodies, such as the European Medicines Agency, would also likely be considered pharmaceutically acceptable. Generally, it is desirable that the pharmaceutical compositions of this disclosure use only components that do not cause unacceptable levels of physical or chemical instability in the resulting composition.

[0027] Examples of antioxidants that may be used for ASD as disclosed herein 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 its derivatives, propyl gallate, ethylenediaminetetraacetic acid ("EDTA") (e.g., disodium edetate), diethylenetriaminepentaacetic acid ("DTPA"), sodium triglycolamate bismuth, or combinations thereof. The antioxidants may also include amino acids, such as methionine, histidine, cysteine, and amino acids having charged side chains, such as arginine, lysine, aspartic acid, and glutamic acid. As long as an amino acid exists in the form of its free base or salt, any stereoisomer (e.g., l-, d-, or any combination thereof) of any particular amino acid (e.g., methionine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine, and any combination thereof), or any combination of these stereoisomers, may exist.

[0028] In some embodiments, one or more antioxidants include BHT. In some embodiments, one or more antioxidants consist of BHT. One or more antioxidants may be present in ASD in amounts of 0.001% to 2.0% by mass, or 0.01% to 1.5% by mass, or 0.05% to 1.0% by mass, or 0.1% to 0.5% by mass, or 0.3% to 0.4% by mass. Examples of amounts of one or more antioxidants in ASD include 0.001% by mass, or 0.003% by mass, or 0.005% by mass, or 0.008% by mass, or 0.01% by mass, or 0.015% by mass, or 0.02% by mass, or 0.025% by mass, or 0.03% by mass, or 0.035% by mass, or 0.04% by mass, or 0.05% by mass, or 0.075% by mass, or 0.1% by mass, or 0.2% by mass, or 0.3% by mass, or 0.4% by mass, or 0.5% by mass, or 0.75% by mass, or 1.0% by mass, or 1.5% by mass, or 2.0% by mass. The ASD may contain a variety of pharmaceutically acceptable wetting agents. Non-limiting examples of wetting agents include poloxamers such as poloxamer 407 (e.g., Pluronic F-127) or poloxamer 188 (e.g., Pluronic F-68). Other known pharmaceutically acceptable wetting agents may be suitably used. The wetting agent may be included in the ASD in amounts of 0.5% to 10% by mass, or 1% to 8% by mass, or 2% to 6% by mass.

[0029] The ASD may contain various pharmaceutically acceptable solubilizers. Non-limiting examples of suitable solubilizers include vitamin E TPGS (D-α-tocopherol polyethylene glycol succinate), SLS (sodium lauryl sulfate), and sodium doxate. Other known pharmaceutically acceptable solubilizers may be suitably used. The solubilizer may be included in the ASD in amounts of 0.1% to 10% by mass, or 0.25% to 5% by mass, or 0.5% to 1% by mass. In some embodiments, ASD comprises nilotinib, one or more polymers, and one or more antioxidants. In some embodiments, ASD essentially consists of nilotinib, one or more polymers, and one or more antioxidants. In some embodiments, ASD consists of nilotinib, one or more polymers, and one or more antioxidants.

[0030] In some embodiments, the ASD comprises nilotinib, HPMC-AS, and BHT. In some embodiments, the ASD essentially consists of nilotinib, HPMC-AS, and BHT. In some embodiments, the ASD consists of nilotinib, HPMC-AS, and BHT. In some embodiments, the ASD comprises nilotinib, intermediate-grade HPMC-AS, and BHT. In some embodiments, the ASD essentially consists of nilotinib, intermediate-grade HPMC-AS, and BHT. In some embodiments, the ASD consists of nilotinib, intermediate-grade HPMC-AS, and BHT. In certain embodiments, ASD essentially consists of nilotinib and HPMC-AS in a 50:50 ratio, and BHT at a level of 0.1–0.5 mass% of ASD.

[0031] In some embodiments, ASD comprises nilotinib, a methacrylate / ethyl acrylate copolymer (such as Eudragit L100-55), and BHT. In some embodiments, ASD essentially consists of nilotinib, methacrylate / ethyl acrylate copolymer, and BHT. In some embodiments, ASD consists of nilotinib, methacrylate / ethyl acrylate copolymer, and BHT. In certain embodiments, ASD essentially consists of nilotinib, methacrylate / ethyl acrylate copolymer (such as Eudragit L100-55), and BHT at a level of 0.1 to 0.5% by mass of ASD.

[0032] The drug load of nilotinib in the ASD of this disclosure may appropriately range from 20% to 95%, or 25% to 90%, or 30% to 80%, or 35% to 70%, or 40% to 60%, or 45% to 55%. As used herein, the phrase “drug load” refers to the ratio (mass%) of nilotinib in the ASD to the total solid matter content of the ASD. For example, for an ASD consisting of nilotinib and polymer, a w / w ratio of nilotinib:polymer of 1:1 would represent a 50% drug load; a w / w ratio of nilotinib:polymer of 1:2 would represent a 33.3% drug load, and so on. Examples of nilotinib drug loads in ASD in specific embodiments include 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%. Nilotinib ASD may be in the form of particles. In some embodiments, the particles do not contain surfactants. In other embodiments, the particles do not contain wetting agents. In other embodiments, the particles do not contain solubilizers. In other embodiments, the particles do not contain surfactants or solubilizers. In other embodiments, the particles lack surfactants, wetting agents, and solubilizers. In other embodiments, the particles consist of a polymer and nilotinib and do not contain further functional ingredients.

[0033] The ASD particles of this disclosure may generally include a spheroidal shape. As measured by conventional light scattering or laser diffraction techniques, the particle size may generally range from about 0.05 μm to about 100 μm. The median of the particle 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 of the particle distribution may be in the range of 1 μm to 40 μm, 2 μm to 25 μm, or 3 μm to 20 μm. As just one example, such a particle distribution can be achieved by known methods of spray drying. In some embodiments, the median diameter of the particle distribution may be 0.1 μm to 10 μm, or 0.2 μm to 5 μm, or 0.5 μm to 2 μm. As just one example, such a particle distribution can be achieved by a method including electrospraying, which will be discussed further below.

[0034] The nilotinib ASD of this disclosure may exhibit desirable levels of physical and / or chemical stability, which can be assessed by different measurements. Stability is generally assessed using conventional analytical techniques commonly known in pharmacy. Physical and chemical stability is generally evaluated after storage for a specified period under controlled elevated environmental conditions ("accelerated conditions"). Storage conditions may be one or more of the following: 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 during the storage period, the sample is sealed in a foil pouch and placed in a controlled chamber). The period may be one week, or two weeks, or four weeks, or one month, or two months, or three months, or four months, or six months, or nine months, or twelve months, or fifteen months, or eighteen months, or twenty-one months, or twenty-four months, or any one or more of these periods.

[0035] Nilotinib ASD may exhibit stability by having a specific quantitative (assay) value or a specific level of total related substances (e.g., impurities) as measured by high-performance liquid chromatography ("HPLC") after storage for a specified period under accelerated conditions. The quantitative value is generally expressed as a percentage of the detected amount of analyte (e.g., nilotinib) relative to the expected amount of analyte, with 100% being a desirable result and a large deviation from 100% being undesirable. Total related substances are generally expressed as a percentage of the total amount of substances detected (i.e., analyte + impurities), with a value close to 0% being desirable and a large deviation from 0% being undesirable. In some embodiments, nilotinib ASD may have an HPLC-measured quantitative analysis 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, nilotinib ASD may have an HPLC-measured total related substance level of 3% or less, 2.5% or less, 2% or less, 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%.

[0036] In some embodiments, nilotinib ASD may have an HPLC-measured quantitative determination of at least 90%, at least 93%, at least 95%, at least 97%, or at least 98% after storage at 25°C / 60%RH for 1, 2, 3, 6, 9, or 12 months, or after storage at 40°C / 75%RH for 1, 2, 3, or 6 months. In some embodiments, nilotinib ASD may have levels 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 of total related substances as measured by HPLC, after storage at 25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, or 12 months, or after storage at 40°C / 75%RH for 1 month, 2 months, 3 months, or 6 months.

[0037] Stability can also be assessed by evaluating the change over time of the glass transition temperature of nilotinib ASD under different storage conditions. The glass transition temperature can be assessed by modulated DSC ("mDSC") using the prior art. In some embodiments, the ASD is characterized by a single glass transition, which is observed by DSC or 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 DSC or mDSC in the range of 25°C to 200°C, more preferably 40°C to 150°C. In some embodiments, the glass transition temperature measured by mDSC does not change by more than 5°C, more than 4°C, more than 3°C, or more than 2°C after storage at 25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, 9 months, or 12 months. In some embodiments, the glass transition temperature measured by mDSC does not change by more than 6°C, more than 5°C, more than 4°C, more than 3°C, more than 2°C, or more than 1°C after storage at 40°C / 75%RH for 1 month, 2 months, 3 months, or 6 months.

[0038] Furthermore, stability can be assessed by evaluating the change in crystallinity of nilotinib ASD over time under different storage conditions, for example, by a suitable conventional X-ray diffraction ("XRD") technique (also known in the art as powder XRD or PXRD). In the implementation of this disclosure, it is preferable (but not required) that nilotinib ASD remains amorphous or essentially amorphous. In some embodiments, "amorphous" may be defined as not having detectable crystallinity, as determined by known methods in the art, for example, by using XRD. An example of determining amorphousness using XRD is shown in Example 1. In some embodiments, "amorphous" may be defined as having a crystallinity percentage 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 crystallinity percentage of 8% or less, or 7% or less, or 6% or less, as measured by XRD. The ASDs of this 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 that the ASDs are analyzed within a few days after preparation, and that the ASDs are stored under protective conditions at ambient temperature and humidity after preparation and before analysis.

[0039] ASD may be amorphous or essentially amorphous after storage for a period of at least one week, or at least two weeks, or at least three weeks, or at least four weeks or one month, or at least two months, or at least three months, or at least four months, or at least five months, or at least six months, or at least nine months, or at least twelve months or one year, 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.). In some embodiments, the ASD of the present disclosure may be amorphous or essentially amorphous after storage for a period of at least one month, or at least two months, or at least three months, or at least six months, under high temperature and high humidity conditions (e.g., 40°C / 75%RH).

[0040] The nilotinib ASD of this disclosure may be characterized by its water content, for example, by using a standard Karl Fischer coulometric titration method. In some embodiments, the nilotinib ASD may contain a water content of 3% or less, or 2.5% or less, or 2% or less, or 1.5% or less, or 1% or less, as assessed by Karl Fischer coulometric titration. In some embodiments, nilotinib ASD may contain a water content of 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, as assessed by Karl Fischer coulometric titration, after storage at 25°C / 60%RH for 1 month, 2 months, 3 months, 6 months, 9 months, or 12 months. In some embodiments, nilotinib ASD may contain a water content 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, as assessed by Karl Fischer coulometric titration, after storage at 40°C / 75%RH for 1 month, 2 months, 3 months, 6 months, 9 months, or 12 months.

[0041] Method for producing amorphous solid dispersions The nilotinib ASD of this disclosure can be prepared by various methods known in the art. Preferred methods generally involve mixing, dissolving, or compounding nilotinib with one or more polymers and, if present, one or more other functional components (such as antioxidants, wetting agents, or solubilizers) to integrate the various components. In the implementation of various methods, nilotinib may be introduced as a free nilotinib base, a salt of nilotinib, or a solvate or hydrate of nilotinib. Suitable methods are generally known in the art and include kneading, co-grinding, melting, melt extrusion, melt agglomeration, and dripping. After the integration process, the material can be further processed by drying, grinding or crushing, sieving, etc. In one method, nilotinib and one or more polymers (and other functional components, if present) may 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 contents may be mixed or dissolved by methods known in the art. For example, the contents may be mixed manually, continuously and periodically using a mixing apparatus, or in combination thereof. Examples of mixing devices include, but are not limited to, magnetic stirrers, shakers, paddle mixers, homogenizers, and any combination thereof.

[0042] After mixing nilotinib with one or more polymers (and other functional components, if present), the liquid raw material can be formed into an amorphous solid dispersion by methods such as solvent evaporation, freeze-drying, precipitation or co-precipitation, spray drying, electrospraying, or supercritical fluid extraction. Such methods are known and generally understood in the art. In some embodiments of this disclosure, a liquid raw material can be formed into an amorphous solid dispersion by electrospraying. Electrospraying, also known as electrohydrodynamic atomization, is used to produce amorphous solid dispersion particles of the micron or submicron scale from a suitable liquid raw material. In a preferred electrospray technique, a liquid material is sprayed toward a substrate through one or more nozzles in the presence of an applied potential between the nozzle and the substrate. The liquid material is subjected to electrical shear stress due to the applied potential. When the shear stress overcomes the surface tension of the liquid material, droplets are released from the tip of the nozzle. The conditions are controlled so that an annular jet of droplets is emitted from the nozzle tip. The droplets become electrically charged and repel each other, preventing droplet aggregation and promoting self-dispersion. As a result of the applied electric field, the charged droplets are accelerated toward the substrate.

[0043] During the short flight path, the solvent "flashes off" from the charged droplet. This rapid evaporation creates a situation where the size of the charged droplet decreases, but its charge density increases. At a critical point, the droplet splits into even smaller droplets. Finally, it produces an essentially monodisperse collection of fine droplets. The size of the droplets can range from submicrons to several microns. The virtually complete evaporation of the solvent from the charged droplets results in the formation of relatively uniform particles of non-volatile components from the liquid raw material. The evaporation process occurs on a timescale that does not allow for crystallization of the non-volatile components. In addition, the evaporative cooling associated with extremely rapid solvent evaporation contributes to a rapid cooling effect that keeps the particles in an amorphous state. Furthermore, the electrospray conditions can be selected and the system configured so that the amorphous particles contain very little residual solvent.

[0044] In some embodiments of this disclosure, an electrospray technique and / or apparatus may be used to form an ASD from a liquid raw material. Suitable methods and apparatus include, for example, 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, 9, This is described in U.S. Patent No. 642,694, U.S. Patent No. 10,562,048, U.S. Patent Publication No. 2014-0158787, U.S. Patent Publication No. 2015-0190253, U.S. Patent Publication No. 2016-0038968, U.S. Patent Publication No. 2016-0175881, U.S. Patent Publication No. 2016-0235677, U.S. Patent Publication No. 2019-0193109, and U.S. Patent Publication No. 2020-0179963. As described above, by using electrospray technology, the median diameter of the nilotinib ASD particle distribution 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 nilotinib in amorphous particles is generally considered to be unsolvated. Even if the liquid raw material is prepared using the form of nilotinib solvate or hydrate, it is understood that the solvate or hydrate evaporates and separates with other solvents, and the electrosprayed amorphous particles contain unsolvated nilotinib (such as anhydrous nilotinib).

[0045] In some embodiments, the electrospray technique can be performed at room temperature. In some embodiments, heated air is not used. In other embodiments, the liquid raw material is kept at a high temperature during the electrospray process. In some embodiments, electrospray technology can be performed using one or more capillary nozzles. In some embodiments, electrospray technology does not use pneumatic nozzles such as kinetic energy-dependent nozzles; pressure nozzles; rotary nozzles; or centrifugal energy-dependent nozzles; or ultrasonic nozzles such as acoustic energy-dependent nozzles. In some embodiments, electrospray technology yields yields of over 85%, over 90%, over 95%, or over 98%. In other embodiments, liquid raw materials can be formed into ASDs by spray drying. Generally, spray drying involves atomizing a liquid raw material into very small droplets in a hot, dry gas. The raw material is fed or propelled by a nozzle or other atomizing device to form droplets in a drying chamber. In the drying chamber, the droplets are exposed to a heated, dry gas environment (usually flowing air or nitrogen) to cause rapid drying of the droplets (flash drying) (by evaporation and removal of the solvent), resulting in the formation of solid particles. Generally, the dried particles are collected at the outlet of the drying chamber.

[0046] Various spray-drying apparatuses and methods can be used to form the ASDs of this disclosure. In the implementation of this disclosure, the median of the particle distribution of the ASDs obtained by spray-drying may be 1 μm to 40 μm, 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 particle formation. In other embodiments, the second drying step is used to further remove almost all or all of the residual solvent. The second drying step can be carried out under suitable conditions that allow for solvent removal but do not result in nilotinib recrystallization. For example, the second drying step can be carried out below the glass transition temperature. The second drying step can also be carried out under reduced pressure. A combination of high temperature and reduced pressure can also be used for the second drying step.

[0047] Pharmaceutical composition Aspects of this disclosure relate to pharmaceutical compositions comprising nilotinib ASD. The pharmaceutical compositions of this disclosure may be in dosage forms suitable for oral administration. In some embodiments, the pharmaceutical compositions 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 tablets, sprinkles, or pellets. In some embodiments, the pharmaceutical compositions may be in solid dosage forms for oral administration such as capsules, tablets, sprinkles, or pellets. The pharmaceutical compositions may also be in the form of aqueous or non-aqueous suspensions or solutions. Such compositions may be prepared using known excipients and known preparation methods. The composition may comprise nilotinib ASD of the present disclosure and one or more pharmaceutically acceptable excipients, such as one or more solubilizers, one or more buffers, one or more pH adjusters, one or more surfactants, one or more antioxidants, and / or one or more carriers. The pharmaceutical composition in the form of a solid oral dosage form 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 fluidizers. Information regarding suitable excipients and commercial suppliers of such excipients can be found in Sheskey PJ(ed.) Handbook of Pharmaceutical Excipients, 9 thIt can be found in the edition ed. London: Pharmaceutical Press; 2020 (ISBN 0857113755), or you can refer to the latest edition with the same title.

[0048] The pharmaceutical compositions of this disclosure can be prepared using methods known in the art. For example, nilotinib ASD and one or more pharmaceutically acceptable additives can be mixed by simple mixing, or by continuous and periodic mixing using a mixing apparatus, or by a combination thereof. Examples of mixing apparatus include, but are not limited to, magnetic stirrers, shakers, paddle mixers, homogenizers, and any combination thereof. Examples of solubilizers that can be used in the pharmaceutical compositions of this disclosure include, but are not limited to, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (Solplus), d-α-tocopherolate polyethylene glycol (PEG) 1000 succinate (TPGS), PEG-40 hydrogenated castor oil (Cremofor RH40), PEG-35 castor oil (Cremofor EL), PEG-40 stearate (MYRJ 540), hard fat (Gelucire 33 / 01, etc.), polyoxylglycerides (Gelucire 44 / 14, etc.), stearoyl polyoxylglycerides (Gelucire 50 / 13, etc.), PEG-8 caprylic / capric acid glycerides (Labrasol, etc.), and poloxamers (Pluronic, Corifor, etc.). In some embodiments, the pharmaceutical composition may include nilotinib ASD and one or more pharmaceutically acceptable excipients, provided that the pharmaceutically acceptable excipients do not include polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., Solplus).

[0049] Buffering agents that can be used in the pharmaceutical compositions of this 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, citrate anhydride, citrate monobasic, citrate dibasic, citrate Examples include, but are not limited to, tribasic salts, citrates, ascorbic acid salts, glycine, glutamate salts, lactate salts, malate salts, formate salts, sulfate salts, and mixtures thereof. Furthermore, the pH adjusters usable in the pharmaceutical compositions of this disclosure include pharmaceutically acceptable acids or bases. For example, the acids include one or more inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid; 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, and trifluoroacetic acid, but are not limited to these. The base may be one or more inorganic or organic bases, and may include, but are 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 may be an alkaline hydroxide such as lithium hydroxide, potassium hydroxide, cesium hydroxide, or sodium hydroxide; an alkali carbonate such as calcium carbonate or sodium carbonate; or an alkali bicarbonate such as sodium bicarbonate. The organic base may also be sodium acetate.

[0050] Examples of surfactants that can be used in the pharmaceutical compositions of this disclosure include, but are not limited to, sodium lauryl sulfate, sodium doxate, sodium dioctyl sulfosuccinate, sodium dioctyl sulfonate, benzalkonium chloride, benzethonium chloride, lauromacrogol 400, polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene hydrogenated castor oil 10, 50, or 60), glycerol monostearate, polysorbates (e.g., polysorbates 40, 60, 65, or 80), sucrose fatty acid esters, methylcellulose, polyalcohols and ethoxylated polyalcohols, thiols (e.g., mercaptans) and their derivatives, poloxamers, polyethylene glycol fatty acid esters (e.g., corifor RH40, corifor EL), lecithin, and mixtures thereof.

[0051] Antioxidants that can be used in the pharmaceutical compositions of this 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 its derivatives, propyl gallate, EDTA (e.g., disodium edetate), DTPA, sodium triglycolamate bismuth, or combinations thereof. Antioxidants may also include amino acids, such as methionine, histidine, cysteine, and amino acids having charged side chains, such as arginine, lysine, aspartic acid, and glutamic acid. As long as an amino acid exists in the form of its free base or salt, any stereoisomer (e.g., l-, d-, or any combination thereof) of any particular amino acid (e.g., methionine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine, and any combination thereof), or any combination of these stereoisomers, may exist. Examples of carriers that can be used in the pharmaceutical compositions of this disclosure include, but are not limited to, water, salt solutions (e.g., Ringer's solution), alcohol, oil, gelatin, and carbohydrates such as lactose, amylose, or starch, fatty acid esters, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, and mixtures or solutions containing any of the above. The carrier may be used in combination with a buffering agent.

[0052] In some embodiments, the compositions of the present disclosure may comprise a carrier having a pH of 5 to 9, or 6 to 8. In some embodiments, the composition may comprise a carrier having a neutral pH. In some embodiments, the pH of the carrier may be physiological pH or close to it. In some embodiments, the pharmaceutical compositions of the present disclosure may also contain other suitable pharmaceutical additives, such as tonicity-adjusting agents, preservatives, emulsifiers, sweeteners, flavorings, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers, and osmotic pressure modifiers. The pharmaceutical composition in solid form may include, 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 fluidizers. Suitable fillers include acacia, calcium carbonate, calcium sulfate, calcium sulfate dihydrate, compressed 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, aluminum magnesium silicate, maltodextrin, mannitol, methylcellulose, microcrystalline cellulose (e.g., AVICEL PH-101, AVICEL PH-102), powdered cellulose, starch, sorbitol, dextrose, dextrate, dextrin, sucrose, xylitol, and mixtures thereof.

[0053] Suitable binders include, for example, various celluloses and crosslinked polyvinylpyrrolidone, microcrystalline cellulose (e.g., Avicel PH-101, Avicel PH-102, Avicel PH-105), or silicified microcrystalline cellulose (e.g., Prosolve SMCC). To reduce friction with processing equipment and adhesion to processing equipment during processing, one or more lubricants may be included. 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, and sodium lauryl sulfate. When lubricants are included, one or more lubricants are generally present in an amount ranging from 0.1% to 5% by mass of the pharmaceutical composition. In some embodiments, one or more lubricants are generally present in an amount ranging from 0.25% to 2% by mass of the pharmaceutical composition. In one embodiment, the lubricant is magnesium stearate.

[0054] Suitable disintegrants for the implementation of this disclosure include natural starch, modified starch or pregelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose, crospovidone, polyvinylpolypyrrolidone, and mixtures thereof. Before further processing (e.g., tablet compression), a fluidizer is used to improve the fluidity of the powder or granular mixture. Suitable fluidizers that can be used in the compositions of this disclosure include, but are not limited to, colloidal silica (e.g., hydrophobic colloidal silica such as AEROSIL), silica gel, precipitated silica, etc. When a fluidizer is included, one or more fluidizers are generally present in an amount ranging from 0.1% to 5% by mass of the pharmaceutical composition. In some embodiments, one or more fluidizers are generally present in an amount ranging from 0.25% to 2% by mass of the pharmaceutical composition.

[0055] In some cases, a single excipient may provide multiple functions. For example, microcrystalline cellulose (if present) can function as both a filler and a binder. Alternatively, such a multifunctional excipient can be used in combination with other functional excipients (for example, microcrystalline cellulose can be used with other fillers and / or 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 tablets or pellets, or as a filler for capsules. In some embodiments, the granules may contain one or more of the pharmaceutically acceptable excipients described above. In one embodiment, the granules may contain 50% to 70% by mass of the granules of ASD; 20% to 40% by mass of the granules of one or more fillers; 1% to 15% by mass of the granules of one or more disintegrants; and 0.2% to 5% by mass of one or more lubricants. In certain embodiments, the granules may contain the components shown in Table 1.

[0056] Table 1. Components of exemplary granular formulations according to specific embodiments of this disclosure [Table 1]

[0057] In some embodiments, the pharmaceutical composition is in the form of a tablet. In one embodiment, the tablet may contain 20% to 40% by mass of ASD; 40% to 70% by mass of one or more fillers (such as mannitol and / or microcrystalline cellulose); 5% to 15% by mass of one or more disintegrants (such as croscarmellose sodium); 0.5% to 5% by mass of one or more lubricants and / or fluidizers (such as hydrophobic colloidal silica and / or magnesium stearate); and 1% to 10% by mass of one or more binders (such as crospovidone).

[0058] The pharmaceutical compositions of this disclosure in tablet form can be prepared using methods known in the art. For example, nilotinib ASD and one or more pharmaceutically acceptable additives can be blended by hand, by bag blending, or by using suitable equipment to provide tablet blends. Examples of suitable blending equipment include, but are not limited to, tumbler mixers, V-type mixers, acoustic mixers, paddle mixers, screw mixers, and the like. Next, a suitable tableting blend can be compressed into tablets weighing 100 to 1000 mg, for example, using a manual tablet press or a conventional mechanical tablet press. The compression force is selected to obtain the desired mechanical properties of the tablets without compromising performance. In some embodiments, it may be desirable to form granules as an intermediate step in forming a tablet blend. Granules typically have improved fluidity, handling, mixability, and compressibility compared to ungranulated material. Granules can be prepared from ASD particles by known processes in the art, including wet granulation and dry granulation. In some embodiments, a granular blend is formed by dry mixing of granular components, followed by densification of the granular blend using a roller compressor, which typically forms ribbons of the material. The ribbons are then reduced in size by grinding to form granules.

[0059] Provided that the selected solvent and process do not alter the properties of ASD, granules can also be formed using wet granulation techniques. As described above, improved wetting, disintegration, dispersibility, and solubility can be obtained by incorporating suitable excipients. The granule blend (and the granules obtained thereby) may contain some or all of the components of the tablet. In some embodiments, the granules may contain one or more of the pharmaceutically acceptable excipients described above. As described above, after granulation, the granules can be incorporated into the tablet blend and compressed into tablets. The pharmaceutical compositions of this disclosure may exhibit desirable levels of physical and / or chemical stability over a suitable period, and optionally under accelerated conditions. The stability of the pharmaceutical compositions can be evaluated by various means. For example, a pharmaceutical composition may exhibit chemical stability by having specific quantitative values ​​or specific levels of total relevant substances (e.g., impurities) measured after storage for a specified period under accelerated conditions. In some embodiments, the pharmaceutical composition may be amorphous (i.e., crystallinity is not detected) as evaluated using XRD after storage under specified conditions.

[0060] In some embodiments, the pharmaceutical composition may be substantially amorphous so as to be evaluated using XRD after storage under specified conditions. The storage conditions may be one or more of 25°C / 60%RH, 30°C / 65%RH, or 40°C / 75%RH. The period may be one or more of one week, two weeks, one month, two months, three months, four months, six months, nine months, twelve months, fifteen months, eighteen months, twenty-one months, twenty-four months, or any period in between. In some embodiments, the pharmaceutical compositions of the present disclosure are "stomach acid-insensitive compositions," as further described below. In some embodiments, the pharmaceutical compositions of the present disclosure are "food-insensitive compositions," as further described below. In some embodiments, the pharmaceutical compositions of the present disclosure are "compositions with improved variability," as further described below.

[0061] Treatment of proliferative disorders Aspects of this disclosure relate to the use of nilotinib ASD or a pharmaceutical composition containing said ASD. In carrying out such embodiments of this disclosure, nilotinib ASD or the pharmaceutical composition may be suitably administered to subjects or patients. In some embodiments, nilotinib ASD or the pharmaceutical composition is administered to a subject. The subjects in the methods of this disclosure may be mammals, including but not limited to humans, monkeys, cattle, pigs, sheep, horses, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is human. As used herein, the phrase “healthy human subject” means a person who is generally healthy and not receiving treatment for a disease or condition in which the pharmaceutically active ingredient (e.g., nilotinib) is commonly used to treat. The selection of a suitable healthy human subject for pharmacokinetic evaluation is within the expertise of those skilled in the art in the field of clinical trial design. In other embodiments, the pharmaceutical composition is administered to a human patient. The human patient may be of adult or child age, for example, under 17 years of age. In some embodiments, the human patient is 1 year of age or older. As used herein, “patient” means a person, in particular a human, who is being treated for a disease or condition for which a pharmaceutically active ingredient (e.g., nilotinib) is commonly used.

[0062] Aspects of this disclosure relate to the use of nilotinib ASD or the pharmaceutical compositions of this disclosure for the treatment of proliferative disorders. Some embodiments relate to a method for treating a proliferative disorder, the method comprising the step of administering nilotinib ASD or the pharmaceutical compositions of this disclosure to a patient in need of treatment for a proliferative disorder. Some embodiments relate to the use of nilotinib ASD or the pharmaceutical compositions of this disclosure for the treatment of a proliferative disorder in a patient in need of treatment for a proliferative disorder, the use comprising administering nilotinib ASD or the pharmaceutical composition to the patient. Some embodiments relate to the use of nilotinib ASD or the pharmaceutical compositions of this disclosure for use in the treatment of a proliferative disorder in a patient in need of treatment for a proliferative disorder, the use comprising administering nilotinib ASD or the pharmaceutical composition to the patient. Some embodiments relate to the use of nilotinib ASD or the pharmaceutical compositions of this disclosure in the manufacture of a pharmaceutical for the treatment of a proliferative disorder. In one embodiment, the Disclosure relates to a method for treating a proliferative disorder in a patient requiring treatment for a proliferative disorder, the method comprising administering to the patient a therapeutically effective amount of nilotinib ASD of the Disclosure or a pharmaceutical composition of the Disclosure.

[0063] Proliferative disorders can be cancerous. Examples of such proliferative disorders include leukemia, such as acute lymphoblastic leukemia (or acute lymphoblastic leukemia), acute myeloid leukemia (acute myeloid leukemia, acute myelogenous leukemia), chronic lymphoblastic leukemia (or chronic lymphoblastic leukemia), chronic myeloid leukemia (chronic myeloid leukemia, chronic myelogenous leukemia); age-related macular degeneration and diabetic retinopathy; anal and oral cancers; angiosarcoma, basal cell carcinoma and squamous cell carcinoma; bladder cancer; brain cancer; glioma; breast cancer; central nervous system cancers; cervical cancer (cervical, cervix uteri cancer); choriocarcinoma; colon cancer; gastrointestinal stromal tumors; endometrial cancer; esophageal cancer; Ewing's sarcoma; and eye or ocular cancer. Examples of cancers that may be included, but are not limited to, include head and neck cancer, hemangioendothelioma, hemangiomas and lymphangiovascular neoplasia, 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.

[0064] In some embodiments, the proliferative disorder may be chronic-phase Philadelphia chromosome-positive ("Ph+") chronic myeloid leukemia ("CML"). In some embodiments, the proliferative disorder may be transitional Ph+CML. In some embodiments, the proliferative disorder may be Ph+CML that is resistant to or intolerant to prior tyrosine kinase inhibitor treatment. In some embodiments, the proliferative disorder may be chronic or transitional Ph+CML that is resistant to or intolerant to prior treatment including imatinib. Nilotinib is being further investigated for use in treating Parkinson's disease, Huntington's disease, Alzheimer's disease, Lewy body dementia, cerebellar ataxia, and other non-proliferative disorders. The compositions, treatment regimens, kits, and other embodiments disclosed herein may be suitably used for treating such non-proliferative conditions. In the methods and uses of the present disclosure, a therapeutically effective amount of the 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 a clinician.

[0065] <00(00631>In some embodiments, the therapeutically effective amount may be 50 mg / m 2 ~250 mg / m 2 of nilotinib, or 50 mg / m 2 ~150 mg / m 2 of nilotinib, or 60 - 120 mg / m 2 of nilotinib. In other embodiments, the therapeutically effective amount may be a fixed dose. For example, the fixed dose may be 20 mg to 400 mg per day, or 30 mg to 300 mg per day, or 40 mg to 200 mg per day of nilotinib. In one embodiment, the fixed dose may be 50 mg, or 55 mg, or 60 mg, or 65 mg, or 70 mg, or 75 mg, or 80 mg, or 85 mg, or 90 mg, or 95 mg, or 100 mg, or 110 mg, or 120 mg, or 125 mg, or 130 mg, or 140 mg, or 150 mg, or 160 mg, or 170 mg, or 175 mg, or 180 mg, or 190 mg, or 2(00 mg, or 210 mg, or 220 mg, or 225 mg, or 230 mg, or 240 mg, or 250 mg, or 260 mg, or 270 mg, or 275 mg, or 280 mg, or 290 mg, or 300 mg of nilotinib. Depending on the treatment plan, the amount of nilotinib administered daily may be twice daily or once daily, based on the label guidelines or the physician's recommendation. In some embodiments, administration is twice daily, approximately 12 hours apart.

[0066] As further described below, the pharmaceutical compositions of this disclosure may provide enhanced or otherwise desirable bioavailability under a variety of administration conditions. The term “bioavailability” refers to the rate and extent to which the active ingredient is absorbed from the pharmaceutical composition and becomes available at the site of action. For orally administered pharmaceuticals, bioavailability is generally assessed by monitoring the plasma of the subject over time and evaluating the pharmacokinetic profile for the presence of the active ingredient (or a suitable substitute, e.g., a metabolite) after administration of the pharmaceutical composition. From the pharmacokinetic profile, certain relevant pharmacokinetic parameters can be established. Such pharmacokinetic parameters include, for example, C max , T max , and / or AUC can be cited. max This indicates the highest plasma concentration observed over the observable period. max This indicates the point in time when the peak plasma concentration was observed.

[0067] AUC represents the area under the curve ("AUC") of a concentration-time curve, expressed numerically. 0-t It is expressed as (or AUC) t AUC can be evaluated over a specific time interval of 0-t (expressed as ). 0-t Generally, this is obtained by numerically integrating the concentration-time curve over the period from t=0 to time "t" (e.g., AUC). 0-24h or AUC 24h (This shows the integral over the period from t=0 to t=24 hours). AUC 0-last (Or, AUC last The expression AUC represents the integral from t=0 to the last time a sample was taken during the observed period. 0-inf(Or, AUC inf The integral (expressed as ) represents the integral from t=0 to t="infinity", determined by extrapolation of data obtained using commonly used pharmacokinetic statistical modeling techniques. Typically, plasma concentration data are logarithmically transformed for analysis. For most pharmacokinetic analyses, data from many subjects are pooled for analysis. Once the data is pooled, relevant pharmacokinetic parameters can be expressed as population geometric means, according to conventional pharmacokinetic statistical analysis and methods. The administration of the ASD or pharmaceutical composition of this disclosure is characterized by the pharmacokinetic profile or by the observed or calculated pharmacokinetic parameters obtained by the administration of a specific dose of the ASD or pharmaceutical composition to a subject or patient under defined administration conditions. As merely an example (as further described below), the administration of the ASD or pharmaceutical composition of this disclosure in a fasted state or under fasting conditions is characterized by the pharmacokinetic profile obtained by the administration or by the observed pharmacokinetic parameters.

[0068] Method of administration with meals Aspects of the present disclosure relate to a method for treating a proliferative disorder in a patient requiring treatment for a proliferative disorder, the method comprising the step of administering a therapeutically effective amount of the pharmaceutical composition of the present disclosure to a patient who is not affected by food. In another embodiment, the Disclosure relates to a method for treating a proliferative disorder in a patient requiring treatment for a proliferative disorder, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of the Disclosure, regardless of food consumption. In another embodiment, the Disclosure relates to a method for treating a proliferative disorder in a patient requiring treatment for a proliferative disorder, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of the Disclosure, regardless of whether the patient is fasting or feeding.

[0069] In yet another embodiment, the Disclosure relates to a method for safely delivering nilotinib to a patient who requires safe delivery of nilotinib, the method comprising step (a) administering a therapeutically effective amount of the pharmaceutical composition of the Disclosure to the patient and step (b) giving the patient a meal. In some embodiments, step (b) occurs before step (a). In other embodiments, step (a) occurs before step (b). In some embodiments, steps (a) and (b) occur within two hours of each other. In some embodiments, steps (a) and (b) occur within ninety minutes of each other. In some embodiments, steps (a) and (b) occur within one hour of each other. In some embodiments, steps (a) and (b) occur within thirty minutes of each other. In some embodiments, steps (a) and (b) occur within fifteen minutes of each other. In some embodiments, step (b) occurs less than one hour after step (a). In some embodiments, step (b) occurs less than 30 minutes after step (a). In some embodiments, step (b) occurs less than 15 minutes after step (a). In some embodiments, process (a) occurs less than 2 hours after process (b). In some embodiments, process (a) occurs less than 90 minutes after process (b). In some embodiments, process (a) occurs less than 1 hour after process (b). In some embodiments, process (a) occurs less than 30 minutes after process (b). In some embodiments, process (a) occurs less than 15 minutes after process (b).

[0070] In some embodiments, “meal” is any solid food that, when consumed, provides a patient or subject with at least 200 calories. In other embodiments, meal is any solid food that, when consumed, provides a patient or subject with at least 400 calories. In yet another embodiment, meal is any solid food that, when consumed, provides a patient or subject with at least 600 calories. In some embodiments, meal is the high-fat test meal described below. In other embodiments, meal is the low-fat test meal described below. In another embodiment, the Disclosure relates to a method for delivering a therapeutically effective dose of nilotinib to a patient regardless of the effects of food, the method comprising the step of administering a therapeutically effective dose of the pharmaceutical composition of the Disclosure to the patient. In a further embodiment, the Disclosure relates to a method for delivering a therapeutically effective dose of nilotinib to a patient, regardless of food consumption, the method comprising the step of administering a therapeutically effective dose of the pharmaceutical composition of the Disclosure to the patient. In another embodiment, the Disclosure relates to a method for delivering a therapeutically effective dose of nilotinib to a patient, regardless of whether the patient is fasting or feeding, the method comprising the step of administering a therapeutically effective dose of the pharmaceutical composition of the Disclosure to the patient.

[0071] As is commonly interpreted, "food effect" broadly refers to all aspects of the interaction between food and the dissolution, absorption, distribution, metabolism, and excretion of a drug. The meaning of food effect includes changes in bioavailability, morbidity, duration of therapeutic effect, and incidence and severity of side effects. The magnitude of the food effect is generally greatest when the drug is administered immediately after a meal. An example of a drug affected by food is Tasigna, which, as mentioned above, exhibits the same AUC and C as obtained under fasting conditions when taken orally 30 minutes after a high-fat meal. max Compared to the previous levels, AUC and C are 82% and 112%, respectively. max This could lead to an increase. In practice, the effect of food is generally assessed by measuring standard pharmacokinetic parameters observed after administration of a drug to a fasted subject and comparing them to the same measurements observed after administration to the same subject in a fed state. Relevant pharmacokinetic parameters include AUC and C15. max , and / or T max It can include AUC, which is calculated over a specific time interval (for example, AUC 0-12h or AUC 0-24h Evaluate the following, or AUC 0-last or AUC 0-inf It can be evaluated as follows. Typically, data on many subjects is pooled for analysis.

[0072] For further information on studies of the effects of food, see "Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies" (Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), December 2002). Its entire contents are incorporated herein by reference. See also "Guidance for Industry: Assessing the Effects of Food on Drugs in INDs and NDAs - Clinical Pharmacology Considerations (Draft Guidance)" (CDER, FDA, February 2019), which its entire contents are also incorporated herein by reference. As used in relation to the methods of this disclosure, the phrase “effect of food” means that when an active substance or a preparation thereof (e.g., a solid dispersion or a pharmaceutical composition) is orally administered to a human subject together with food, or orally administered to a human subject in a feeding state, one or more AUCs, Cs of the active substance. max , and / or T max This refers to the relative difference when comparing the measured values ​​for the same parameter when the same formulation is administered to the same subject in a fasted state. The effect of food F is given by F = (Y 摂食 -Y 絶食 ) / Y絶食 It is calculated as Y 摂食 and Y 絶食 These are AUC and C in the feeding and fasting states, respectively. max or T max This is a measured value. The phrase "positive diet effect" means that when a drug is administered orally while eating, the AUC and / or C values ​​are higher than when the drug is administered orally while fasting. max This refers to the effect of diet that increases AUC and / or C. The phrase "negative diet effect" means that when a drug is administered orally while eating, AUC and / or C are higher than when the drug is administered orally while fasting. max This refers to the effect of diet on lowering [a certain level of health].

[0073] In evaluating the effects of diet, conventional pharmacokinetic statistical analysis and methods are used, and data obtained from fasting and feeding studies are processed. If necessary, fasting and feeding studies may be single-dose studies or steady-state studies. Using pooled data from an appropriate number of subjects, the 90% confidence interval ("CI") for the ratio of the population geometric mean between administration in a fed state and administration in a fasted state, based on logarithmically transformed data, is calculated using the AUC. 0-inf (where appropriate, or AUC) 0-t ) and C max If the equivalence limit falls between 80% and 125%, it indicates that there is no effect from food. On the other hand, the 90% confidence interval for the ratio of the population geometric mean between administration during feeding and administration during fasting, based on logarithmically transformed data, is the AUC. 0-inf (where appropriate, or AUC) 0-t ) or C max If the result falls below 80% to 125% of the equivalence limit, it cannot be proven that there is no dietary influence.

[0074] In the methods of this disclosure, "not affected by food" means that when the ASD or pharmaceutical composition of this disclosure is administered orally with food or while eating, the AUC (e.g., AUC) of nilotinib is not affected by food. 0-24h AUC 0-last or AUC 0-inf (possibly) and / or Cmax With respect to the same parameters when administering the same ASD or pharmaceutical composition in a fasting state, it means that the relative difference is substantially large compared to the measured values, for example, less than 20%, or less than 15%, or less than 10%. (As used herein, for the relative difference shown as %, each range described relates to the absolute value of the relative difference, that is, "less than 20%" means that the relative difference F falls within the range of -20% < F < +20%. In the method of the present disclosure, "regardless of food consumption" means that it is not necessary to consider whether the ASD or pharmaceutical composition of the present disclosure is administered to a subject or patient together with food, or whether the patient or subject is in a fed state or a fasting state. Administration is expected to provide a therapeutically appropriate exposure regardless of whether the patient or subject is in a fed state or a fasting state, and is not expected to result in an excessive exposure that is not safe.

[0075] As used herein, "therapeutically appropriate exposure" is the AUC in the plasma of a subject expected to produce the desired therapeutic effect 0-t (e.g., AUC 0-24h ) and / or C max means an exposure that provides. One way to determine a similar therapeutic effect is whether the AUC 0-t or C max is within the biological equivalence criteria of 80% - 125% compared to when an immediate-release composition of conventional nilotinib of appropriate strength (determined by referring to the product label) is administered to the same subject according to the instructions of its label. As used herein, the phrase "conventional immediate-release composition of nilotinib" generally refers to a commercially available composition containing nilotinib monohydrochloride monohydrate in crystalline form. The conventional immediate-release composition of nilotinib can be in capsule form. One suitable conventional immediate-release composition of nilotinib is Tasigna IR capsules (sold in the United States in New Drug Application 22-068). Tasigna is understood to be nilotinib monohydrochloride monohydrate crystals contained in an immediate-release capsule formulation. As used herein, the phrase “with food” refers to administration to the subject from 30 minutes to 1 hour after the subject has ingested food. As used herein, the phrase “administration in a feeding state” (or “administration under feeding conditions” is synonymous) refers to administration to the subject from 30 minutes after the subject has started eating a meal until 1 hour after the subject has completely consumed the meal. Similarly, “feeding state” or “feeding conditions” refers to the conditions under which the subject has started eating a meal until 1 hour after the subject has completely consumed the meal.

[0076] In some embodiments, the meal is a “high-fat test meal” (or, instead, a “high-fat diet”), which is a high-fat and high-calorie (approximately 800–1000 calorie) meal containing approximately 150 calories from protein, 250 calories from carbohydrates, and 500–600 calories from fat, in accordance with the FDA Guidance for Industry (December 2002) referenced above. In other embodiments, the meal is a “low-fat test meal”, which is a low-calorie (approximately 400–500 calorie) meal containing approximately 11–14 grams of fat and approximately 25% of the calories from fat (the remainder from protein and carbohydrates), in accordance with the FDA Draft Guidance for Industry (February 2019) referenced above. As used herein, the phrase “administration in a fasted state” (synonymous with “administration under fasting conditions”) refers to administration to the subject at least two hours, more preferably at least four hours, or more preferably at least eight hours, from the subject’s last meal. Preferably, administration in a fasted state or under fasting conditions is followed by at least 10 hours of overnight fasting. Similarly, “fasted state” or “fasting conditions” refers, as used herein, to conditions in which the subject has not consumed food for at least two hours, more preferably at least four hours, or more preferably at least eight hours; or conditions in which the subject has been fasted for at least 10 hours overnight. Furthermore, administration in a fasted state or under fasting conditions may require at least one hour, more preferably at least two hours, or more preferably at least four hours of continuous fasting after administration.

[0077] In one embodiment, the ASD or pharmaceutical composition is administered regardless of whether the subject is fasting or not. In one embodiment, the ASD or pharmaceutical composition is administered regardless of whether the subject is eating or not. In one embodiment, the ASD or pharmaceutical composition is administered regardless of whether the subject is fasting or eating. In one embodiment, the ASD or pharmaceutical composition is administered regardless of the effect of food. In one embodiment, the ASD or pharmaceutical composition is administered together with food. Some embodiments relate to methods for delivering nilotinib to a subject regardless of whether the subject is fasted or not, and such methods include the step of administering the ASD or pharmaceutical composition of the present disclosure to the subject. Some embodiments relate to methods for delivering nilotinib to a subject regardless of whether the subject is feeding or not, and such methods include the step of administering the ASD or pharmaceutical composition of the present disclosure to the subject. Some embodiments relate to methods for delivering nilotinib to a subject regardless of whether the subject is fasted or fed, and such methods include the step of administering the ASD or pharmaceutical composition of the present disclosure to the subject.

[0078] Administration of the ASD or pharmaceutical composition of this disclosure is determined by the pharmacokinetic profile obtained by administering the ASD or pharmaceutical composition at a certain dose to a subject in a fasted or fed state, or by the pharmacokinetic parameters (C) calculated accordingly. max and / or AUC 0-t For example, AUC 0-24h AUC 0-last or AUC 0-inf Characterized by (possibly). For example, in some embodiments, administering the ASD or pharmaceutical composition of this disclosure at a dose of 40 mg to 80 mg of nilotinib to healthy human subjects in a fasted state results in plasma C2 levels of 501 ng / mL to 621 ng / mL of nilotinib. max Plasma AUC of nilotinib between 3790 ng·h / mL and 4820 ng·h / mL 0-12h Plasma AUC of nilotinib between 5590 ng·h / mL and 7340 ng·h / mL 0-24h Plasma AUC of nilotinib between 7610 ng·h / mL and 10600 ng·h / mL 0-last ; and / or plasma AUC of nilotinib in the range of 7760 ng·h / mL to 11000 ng·h / mL 0-inf It can bring about. In some embodiments, administering the ASD or pharmaceutical composition of this disclosure at a dose of 40 mg to 80 mg to healthy human subjects in a feeding state resulted in a plasma C2 concentration of 456 ng / mL to 525 ng / mL of nilotinib. max Plasma AUC of nilotinib between 3770 ng·h / mL and 4320 ng·h / mL 0-12h Plasma AUC of nilotinib between 6310 ng·h / mL and 7130 ng·h / mL 0-24h Plasma AUC of nilotinib in the range of 9490 ng·h / mL to 11000 ng·h / mL 0-last ; and / or plasma AUC of nilotinib in the range of 9840 ng·h / mL to 11300 ng·h / mL 0-inf It can bring about.

[0079] The administration of the ASD or pharmaceutical composition of this disclosure can also be characterized by how the pharmacokinetic profile obtained by administration of the ASD or pharmaceutical composition to a fed subject compares to the pharmacokinetic profile obtained by administration of the ASD or pharmaceutical composition to a fasted subject. For example, in some embodiments, administration of the ASD or pharmaceutical composition of this disclosure to a fasted subject and administration of the ASD or pharmaceutical composition to a fasted subject can result in a relative difference in plasma exposure of nilotinib between a fed and a fasted state of less than 50%, or less than 40%, or less than 35%, or less than 30%, or less than 25%, or less than 20%, or less than 15%, or less than 10%, or 5%. Exposure can be measured, for example, by AUC. 0-12h AUC 0-24h AUC 0-last , or AUC 0-inf This can be expressed as follows: Exposure can be determined for individual subjects or, instead, for an appropriate number of subjects (n>1). When comparing a pool of data from many subjects, exposure can be expressed as a population geometric mean, according to conventional pharmacokinetic statistical analysis and methods.

[0080] In one embodiment, administration of the ASD or pharmaceutical composition of this disclosure to a subject in a feeding state is equivalent to the plasma AUC of nilotinib obtained by administration of the pharmaceutical composition to a subject in a fasting state. 0-12h Lower plasma AUC of nilotinib 0-12h In one embodiment, administration of the ASD or pharmaceutical composition of this disclosure to a subject in a feeding state can result in the plasma AUC of nilotinib that can be obtained by administration of the pharmaceutical composition to a subject in a fasting state. 0-12h Plasma AUC of nilotinib within 25% or within 20% 0-12h This can result in plasma AUC. 0-12h This can be a geometric mean of individual objects or a geometric mean of many objects. In one embodiment, administration of the ASD or pharmaceutical composition of this disclosure to a subject in a feeding state is equivalent to the plasma AUC of nilotinib obtained by administration of the pharmaceutical composition to a subject in a fasting state. 0-24hresult in a lower plasma AUC of nilotinib 0-24h In certain embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fed state results in a plasma AUC of nilotinib that is 0-24h within 50% or within 40% or within 35% or within 30% or within 25% or within 20% or within 15% or within 10% of the plasma AUC of nilotinib that can be obtained by administration of the pharmaceutical composition to a subject in a fasted state 0-24h The plasma AUC 0-24h can be for an individual subject or the geometric mean from multiple subjects.

[0081] In certain embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fed state results in a plasma AUC of nilotinib that is 0-last lower than the plasma AUC of nilotinib 0-last In certain embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fed state results in a plasma AUC of nilotinib that is 0-last within 50% or within 40% or within 35% or within 30% or within 25% or within 20% or within 15% or within 10% of the plasma AUC of nilotinib that can be obtained by administration of the pharmaceutical composition to a subject in a fasted state 0-last The plasma AUC 0-last can be for an individual subject or the geometric mean from multiple subjects. In certain embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fed state results in a plasma AUC of nilotinib that is 0-inf lower than the plasma AUC of nilotinib 0-inf In certain embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fed state results in a plasma AUC of nilotinib that is 0-infresulting in a plasma AUC of nilotinib within 50% or within 40% or within 35% or within 30% or within 25% or within 20% or within 15% or within 10% 0-inf The plasma AUC 0-inf may be for an individual subject or a geometric mean from multiple subjects.

[0082] For some embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in the fed state and to a subject in the fasted state results in a relative difference in plasma C of nilotinib between the fed and fasted states of less than 50% or less than 30% or less than 25% or less than 20% or less than 15% or less than 10% or less than 5%. max In one embodiment, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in the fed state results in a lower plasma C of nilotinib than can be obtained by administration of the ASD or pharmaceutical composition of the present disclosure to a subject in the fasted state. max C of nilotinib max can be determined for an individual subject or alternatively for a suitable number of subjects (n>1). When comparing many subjects with pooled data, C max can be expressed as a population geometric mean according to conventional pharmacokinetic statistical analyses and methods. max In yet other embodiments, administration of the ASD or pharmaceutical composition to a subject in the fed state provides an exposure similar to the exposure of nilotinib obtained by administration of the pharmaceutical composition to a subject in the fasted state. The exposure can be represented, for example, as AUC 0-12h 0-24h 0-last 0-inf Cmax Cmax Cmax Cmax and the exposure may be for an individual subject or a geometric mean from multiple subjects.

[0083] In some embodiments, administration of the ASD or pharmaceutical composition to a subject in the fed state results in a plasma of nilotinib similar to the plasma of nilotinib obtained by administration of the ASD or pharmaceutical composition to a subject in the fasted state. Cmax of nilotinibCmax is provided. Plasma Cmax may be for an individual subject or a geometric mean from multiple subjects. As used herein, in this context, "similar" exposure means a relative difference in nilotinib plasma exposure between fed and fasted states of less than 25%, or less than 20%, or less than 15%, or less than 10%, or less than 5%; "similar" Cmax similarly means a relative difference in nilotinib plasma Cmax exposure between fed and fasted states of less than 25%, or less than 20%, or less than 15%, or less than 10%, or less than 5% (each % described is understood as an absolute value. That is, "less than 20%" means that the relative difference F falls within the range of -20% < F < +20%). In some embodiments, the pharmaceutical composition of the present disclosure can provide a nilotinib plasma C of 501 ng / mL to 621 ng / mL obtained by administering a dose of 40 mg to 80 mg of nilotinib to a healthy human subject in a fasted state max and can provide a nilotinib plasma C of 456 ng / mL to 525 ng / mL obtained by administering a dose of 40 mg to 80 mg of nilotinib to a healthy human subject in a fed state max .

[0084] In some embodiments, the pharmaceutical composition of the present disclosure can provide a nilotinib plasma AUC of 3790 ng·h / mL to 4820 ng·h / mL obtained by administering a dose of 40 mg to 80 mg of nilotinib to a healthy human subject in a fasted state 0-12h and can provide a nilotinib plasma AUC of 3770 ng·h / mL to 4320 ng·h / mL obtained by administering a dose of 40 mg to 80 mg of nilotinib to a healthy human subject in a fed state 0-12h . In some embodiments, the pharmaceutical composition of the present disclosure can provide a nilotinib plasma AUC of 5590 ng·h / mL to 7340 ng·h / mL obtained by administering a dose of 40 mg to 80 mg of nilotinib to a healthy human subject in a fasted state0-24h This can provide the plasma AUC of nilotinib ranging from 6310 ng·h / mL to 7130 ng·h / mL obtained by administering 40 mg to 80 mg of nilotinib to healthy human subjects in a feeding state. 0-24h We can provide this. In some embodiments, the pharmaceutical compositions of this disclosure are used to obtain a plasma AUC of 7610 ng·h / mL to 10600 ng·h / mL of nilotinib obtained by administering a dose of 40 mg to 80 mg of nilotinib to healthy human subjects in a fasted state. 0-last This can provide the plasma AUC of nilotinib ranging from 9490 ng·h / mL to 11000 ng·h / mL, obtained by administering 40 mg to 80 mg of nilotinib to healthy human subjects in a feeding state. 0-last We can provide this.

[0085] In some embodiments, the pharmaceutical compositions of the present disclosure are used to obtain a plasma AUC of 7760 ng·h / mL to 11000 ng·h / mL of nilotinib obtained by administering a dose of 40 mg to 80 mg of nilotinib to healthy human subjects in a fasted state. 0-inf This can provide the plasma AUC of nilotinib ranging from 9840 ng·h / mL to 11300 ng·h / mL, obtained by administering 40 mg to 80 mg of nilotinib to healthy human subjects in a feeding state. 0-inf We can provide this. As used herein, the phrase “food-insensitive composition” refers to a pharmaceutical composition of the present disclosure that can be administered regardless of whether the patient or subject is fasting or not. A food-insensitive composition provides therapeutically appropriate exposure to a patient or subject, regardless of whether the patient or subject has recently eaten, eats immediately after administration of the pharmaceutical composition, or is fasting at the time of administration and remains fasting for some time after administration.

[0086] Method of administering with a reduced dose In addition, the administration of the ASD or pharmaceutical composition of this disclosure can be characterized by a method in which the pharmacokinetic profile obtained by the administration of the ASD or pharmaceutical composition is compared to the pharmacokinetic profile obtained by the administration of a conventional immediate-release composition of nilotinib. For example, in some embodiments, administration of the ASD or pharmaceutical composition of this disclosure can result in a pharmacokinetic profile comparable to that obtained by oral administration of a conventional immediate-release formulation of nilotinib, but at a fraction of the dose. For this comparison, administration must be carried out under fasting conditions, since Tasigna should only be administered under fasting conditions. In embodiments of this disclosure, which allow administration at a fraction of the required dose compared to the conventional immediate-release composition of nilotinib, it can be inferred that the formulations of the present invention are inherently safer than the corresponding conventional immediate-release composition of nilotinib. By reducing the required dose while providing effective exposure to the patient, the risk of excessive exposure is reduced. Excessive exposure to nilotinib is associated with the risk of QT prolongation discussed above, which is currently subject to the “black box warning” on the Tasigna label. The risk of excessive exposure affects the entire patient population treated with nilotinib. Given that QT prolongation has been reported to cause sudden cardiac death in approximately 1 in 300 Tasigna patients, the reduced dose inherently reduces the risk of sudden death in the patient population.

[0087] In addition to reducing the overall risk of excessive exposure, the formulations of this disclosure have an undesirable high C max This may limit the associated risks. For risks such as QT extension, C max This may actually be a more relevant pharmacokinetic parameter, such as between fasting and feeding states. max A significant increase in C is highly undesirable and may be unsafe. In some embodiments, the formulations of the present disclosure result in undesirable high C max To reduce or eliminate the possibility of patients experiencing this condition. With respect to each pharmacokinetic profile, “comparable” means that the AUC in the subject’s plasma is within the bioequivalence criteria of 80% to 125% when administered to the same subject as an immediate-release formulation of nilotinib crystals, according to the instructions on its label. 0-t (For example, AUC 0-24h or AUC 0-inf ) or C max This means that it can provide. As used herein, “a fraction of a dose” may mean that the dose of nilotinib in the ASD or pharmaceutical composition of this disclosure may be 80% or 75% or 70% or 65% or 60% or 55% or 50% or 45% or 40% or 35% or 30% or 25% or 20% less than the labeled dose of the immediate-release formulation of nilotinib crystals.

[0088] As merely an example, a pharmaceutical composition of the present disclosure containing approximately 50 mg of nilotinib free base may provide a pharmacokinetic profile comparable to that obtained by orally administering an immediate-release formulation of nilotinib crystals labeled to contain 200 mg of nilotinib (e.g., 200 mg Tasigna IR capsules). In this example, the dose of nilotinib in the pharmaceutical composition of the present invention is 75% less than the dose of the immediate-release formulation of nilotinib crystals. In some embodiments, the dose of nilotinib in the ASD or pharmaceutical composition of the present disclosure is 80% or 75% or 70% or 65% or 60% less than the indicated dose on the label of the immediate-release formulation of nilotinib crystals.

[0089] In some embodiments, administration of the ASD or pharmaceutical composition of this disclosure to a fasted subject can result in a plasma exposure of nilotinib of up to 20%, 15%, or 10% of that obtained by administration of an immediate-release formulation of nilotinib crystals to a fasted subject, at a fraction of the dose. In some embodiments, administration of the ASD or pharmaceutical composition of this disclosure to a fasted subject can result in a higher plasma exposure of nilotinib at a fraction of the dose obtained by administration of an immediate-release formulation of nilotinib crystals to a fasted subject. The exposure is, for example, AUC 0-12h AUC 0-24h AUC 0-last , or AUC 0-inf It can be expressed as follows. The exposure may be for individual subjects or as a geometric mean from many subjects. In some embodiments, administration of the ASD or pharmaceutical composition of this disclosure to a fasted subject is equivalent to administering a rapid-release formulation of nilotinib crystals to a fasted subject, thereby obtaining plasma C of nilotinib. max Plasma C10% of nilotinib within 20%, or within 15%, or within 10%. max This can be achieved with a fraction of the dose. In one embodiment, administration of the ASD or pharmaceutical composition of this disclosure to a fasted subject is equivalent to the administration of an immediate-release formulation of nilotinib crystals to a fasted subject, which can result in plasma C of nilotinib. max A higher amount of nilotinib in plasma C max This can be achieved with a fraction of the dose. max This can be a geometric mean of individual objects or a geometric mean of many objects.

[0090] In some embodiments, the dose of the immediate-release formulation of nilotinib crystals is a multiple of the dose of nilotinib contained in the pharmaceutical composition of the Disclosure. In some embodiments, the immediate-release formulation of nilotinib crystals may contain at least twice, at least three times, at least four times, or at least five times the amount of nilotinib as present in the pharmaceutical composition of the Disclosure. In some embodiments, the immediate-release formulation of nilotinib crystals may contain two to five times the amount of nilotinib as present in the pharmaceutical composition of the Disclosure. In some embodiments, the immediate-release formulation of nilotinib crystals may contain two to four times the amount of nilotinib as present in the pharmaceutical composition of the Disclosure. In some embodiments, administration of the ASD or pharmaceutical composition of this disclosure to a fasted subject may result in the administration of an immediate-release formulation of nilotinib crystals containing four times, three times, or twice the amount of nilotinib as the ASD or pharmaceutical composition, thereby obtaining the plasma AUC of nilotinib. 0-12h Larger plasma AUC of nilotinib 0-12h This can result in plasma AUC. 0-12h This can be a geometric mean of individual objects or a geometric mean of many objects. In some embodiments, administration of the ASD or pharmaceutical composition of this disclosure to a fasted subject may result in the administration of an immediate-release formulation of nilotinib crystals containing four times, three times, or twice the amount of nilotinib as the ASD or pharmaceutical composition, thereby obtaining the plasma AUC of nilotinib. 0-12h Plasma AUC of nilotinib within 20% or 15% 0-12h This can result in plasma AUC. 0-12h This can be a geometric mean of individual objects or a geometric mean of many objects.

[0091] In some embodiments, administration of the ASD or pharmaceutical composition of this disclosure to a fasted subject may result in the administration of an immediate-release formulation of nilotinib crystals containing four times, three times, or twice the amount of nilotinib as the ASD or pharmaceutical composition, thereby obtaining the plasma AUC of nilotinib. 0-24h Larger plasma AUC of nilotinib 0-24h This can result in plasma AUC.0-24h This can be a geometric mean of individual objects or a geometric mean of many objects. In some embodiments, administration of the ASD or pharmaceutical composition of this disclosure to a fasted subject may result in the administration of an immediate-release formulation of nilotinib crystals containing four times, three times, or twice the amount of nilotinib as the ASD or pharmaceutical composition, thereby obtaining the plasma AUC of nilotinib. 0-24h Plasma AUC of nilotinib within 20% or 15% 0-24h This can result in plasma AUC. 0-24h This can be a geometric mean of individual objects or a geometric mean of many objects. In some embodiments, administration of the ASD or pharmaceutical composition of this disclosure to a fasted subject may result in the administration of an immediate-release formulation of nilotinib crystals containing four times, three times, or twice the amount of nilotinib as the ASD or pharmaceutical composition, thereby obtaining the plasma AUC of nilotinib. 0-last Plasma AUC of nilotinib within 20% or 15% 0-last This can result in plasma AUC. 0-last This can be a geometric mean of individual objects or a geometric mean of many objects.

[0092] In some embodiments, administration of the ASD or pharmaceutical composition of this disclosure to a fasted subject may result in the administration of an immediate-release formulation of nilotinib crystals containing four times, three times, or twice the amount of nilotinib as the ASD or pharmaceutical composition, thereby obtaining the plasma AUC of nilotinib. 0-inf Plasma AUC of nilotinib within 25% or within 20% 0-inf This can result in plasma AUC. 0-inf This can be a geometric mean of individual objects or a geometric mean of many objects. In some embodiments, administration of the ASD or pharmaceutical composition of this disclosure to a fasted subject can be performed by administering an immediate-release formulation of nilotinib crystals containing four times, three times, or twice the amount of nilotinib as the ASD or pharmaceutical composition, thereby obtaining plasma nilotinib C max A higher amount of nilotinib in plasma C maxPlasma C can bring about this. max This can be a geometric mean of individual objects or a geometric mean of many objects. In some embodiments, administration of the ASD or pharmaceutical composition of this disclosure to a fasted subject can be performed by administering an immediate-release formulation of nilotinib crystals containing four times, three times, or twice the amount of nilotinib as the ASD or pharmaceutical composition, thereby obtaining plasma nilotinib C max Plasma C2 of nilotinib within 25% or 20% max Plasma C can bring about this. max This can be a geometric mean of individual objects or a geometric mean of many objects.

[0093] In further embodiments, administration of the ASD or pharmaceutical composition of this disclosure to a fasted subject provides, at a fraction of a dose, an exposure to nilotinib similar to that obtained by administration of an immediate-release formulation of nilotinib crystals. The exposure is, for example, AUC 0-12h AUC 0-24h AUC 0-last , or AUC 0-inf It can be expressed as follows. The exposure may be for individual subjects or as a geometric mean from many subjects. In yet another embodiment, administration of the ASD or pharmaceutical composition of this disclosure to a fasted subject is performed at a fraction of the dose, and the plasma C of nilotinib obtained by administration of an immediate-release formulation of nilotinib crystals is further reduced. max Similar nilotinib plasma C max Provides plasma C max This can be a geometric mean of individual objects or a geometric mean of many objects. In further embodiments, administration of the ASD or pharmaceutical composition of this disclosure to a subject in a feeding state provides, at a fraction of a dose, an exposure to nilotinib similar to that obtained by administration of an immediate-release formulation of nilotinib crystals to a subject in a fasted state. The exposure is, for example, AUC 0-12h AUC 0-24h AUC 0-last , or AUC 0-infIt can be represented as. The exposure may be for an individual subject or the geometric mean from multiple subjects.

[0094] In yet other embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fed state at a fraction-of-dose results in plasma C of nilotinib obtained by administration of an immediate-release formulation of nilotinib crystals to a subject in a fasting state max similar to that of nilotinib max is provided. Plasma C max may be for an individual subject or the geometric mean from multiple subjects. As used herein, in this context, "similar" exposure means a relative difference in plasma exposure between administration of the pharmaceutical composition and administration of the immediate-release formulation of nilotinib crystals that is less than 25%, or less than 20%, or less than 15%, or less than 10%, or less than 5%; "similar C max " means a relative difference in plasma Cmax of nilotinib between administration of the pharmaceutical composition and administration of the immediate-release formulation of nilotinib crystals that is less than 25%, or less than 20%, or less than 15%, or less than 10%, or less than 5% (each % described is understood as an absolute value. That is, "less than 20%" means that the relative difference F falls within the range of -20% < F < +20%).

[0095] Effective biological equivalence to a reference composition In another embodiment, the present disclosure provides a pharmaceutical composition that is effectively biologically equivalent to an appropriate reference composition when administered to a healthy human subject in a fasting state, but has a lower molar dose of the active ingredient compared to the reference composition. In some embodiments, the reference composition is a conventional immediate-release composition of nilotinib containing nilotinib monohydrochloride monohydrate. In some embodiments, the reference composition is Tasigna IR capsules. Regarding bioequivalence studies, the FDA has published "Guidance for Industry: Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA (Draft Guideline)" (CDER, FDA, December 2013), the full contents of which are incorporated herein by reference. Regarding statistical methods for determining bioequivalence, the FDA has published "Guidance for Industry: Statistical Approaches to Establishing Bioequivalence" (CDER, FDA, January 2001), the full contents of which are incorporated herein by reference. According to FDA guidelines, a drug ("test composition") is bioequivalent to a reference drug ("reference composition") if the rate and extent of absorption of the active ingredient (i.e., the active component) from the test composition is not significantly different from the rate and extent of absorption of the active ingredient when administered using a reference composition under similar experimental conditions. For many orally bioavailable active ingredients, including nilotinib, the preferred method for assessing bioequivalence is to evaluate the pharmacokinetic profiles achieved when the test composition and the reference composition are administered orally.

[0096] The assessment of bioequivalence reflects pharmacokinetic endpoints, such as the rate and degree of absorption, respectively. max And often relies on AUC. Generally, using pooled data from a suitable number of subjects, the 90% confidence interval ("CI") for the ratio of the ensemble geometric mean between the test composition and the reference composition, based on logarithmically transformed data, is often used, compared to AUC. 0-inf (where appropriate, or AUC) 0-t ) and C max Bioequivalence between the test composition and the reference composition is established when the equivalence limit for both falls between 80% and 125%. On the other hand, the 90% confidence interval for the ratio of the ensemble geometric mean between the test composition and the reference composition, based on logarithmically transformed data, is the AUC. 0-inf(where appropriate, or AUC) 0-t ) or C max If the equivalence limit for the two items is not 80% to 125%, then bioequivalence is not established. As discussed above, the pharmacokinetic profile is evaluated by monitoring the plasma of the subject over time for the presence of the active ingredient (or a suitable alternative, e.g., a metabolite) after administration of the pharmaceutical composition of interest. According to the draft FDA guidelines for the nilotinib hydrochloride monohydrate composition, the plasma analyte of interest is nilotinib. Nilotinib is also a suitable plasma analyte for the pharmaceutical composition of this disclosure. Depending on the properties of the reference composition, test composition, and active pharmaceutical ingredient, essential labeling may require single-dose or multi-dose studies. The latest FDA guidance document (draft guideline, July 2014) regarding bioequivalence studies related to oral capsules (200 mg) of nilotinib hydrochloride monohydrate recommends a two-way crossover study with a single dose under fasting conditions.

[0097] According to FDA guidelines, a test composition may be bioequivalent only when administered at the same molar dose as the reference composition. However, as discussed above, administration of the ASD or pharmaceutical composition of this disclosure can yield a pharmacokinetic profile at a fraction of the dose that is comparable to the pharmacokinetic profile obtained by orally administering a conventional immediate-release formulation of nilotinib. For such embodiments, a more appropriate comparison is to evaluate the relative bioequivalence of the test composition when administered at a fraction of the corresponding molar dose of the selected reference composition. As used herein, the phrases “effectively bioequivalent” and “effective bioequivalence” refer to a situation in which the test composition and the reference composition meet the described bioequivalence criteria at different molar doses. In one embodiment, the disclosure provides a pharmaceutical composition comprising 100 mg nilotinib in an oral dosage form. Herein, when the oral dosage form is administered to healthy human subjects in a fasted state, the AUC achieved after administration of a reference composition is a conventional immediate-release nilotinib composition comprising 200 mg nilotinib monohydrochloride monohydrate. 0-inf and C max In comparison, AUC within the bioequivalence criteria of 80% to 125% 0-inf and C max Achieve. In another embodiment, the disclosure provides a pharmaceutical composition comprising an amorphous solid dispersion containing nilotinib and one or more polymers. The composition is an oral dosage form containing 100 mg of nilotinib, and when administered orally to healthy human subjects in a fasted state, the AUC achieved after administration of a reference composition which is a conventional immediate-release composition of nilotinib containing 200 mg of nilotinib monohydrochloride monohydrate. 0-inf and C max In comparison, AUC within the bioequivalence criteria of 80% to 125% 0-inf and C max Achieve.

[0098] In another embodiment, the Disclosure provides a pharmaceutical composition comprising 100 mg nilotinib in an oral dosage form, the pharmaceutical composition being effectively bioequivalent under fasting conditions to a reference composition which is a conventional immediate-release composition of nilotinib comprising 200 mg nilotinib monohydrochloride monohydrate, the effective bioequivalent being (a) a 90% confidence interval for AUC of 80% to 125%, and (b) a C of 80% to 125%. max This is established by a 90% confidence interval. In another embodiment, the Disclosure provides a pharmaceutical composition that satisfies one or more bioequivalence criteria when the active ingredient is administered to healthy human subjects in a fasted or fed state at a lower molar dose compared to a reference composition, compared to when a suitable reference composition is administered to healthy human subjects in a fasted state. In any of the embodiments described above, AUC may be used as needed, for example, AUC 0-24h AUC 0-last, or AUC 0-inf It is possible. In some embodiments, the reference composition is a conventional immediate-release nilotinib composition comprising nilotinib monohydrochloride monohydrate. In some embodiments, the reference composition comprises nilotinib monohydrochloride monohydrate crystals. In some embodiments, the reference composition is in capsule form. In some embodiments, the reference composition is Tasigna IR capsules.

[0099] Method of use in combination with gastric acid-reducing agents Other embodiments of this disclosure relate to the use of nilotinib ASD and pharmaceutical compositions of this disclosure with gastric acid-reducing agents. In one embodiment, the present disclosure relates to a method for delivering nilotinib together with an acid-reducing agent to a patient who requires delivery of nilotinib together with an acid-reducing agent, the method comprising administering to the patient together (a) a therapeutically effective amount of the pharmaceutical composition of the present disclosure and (b) a therapeutically effective amount of an acid-reducing agent. In another embodiment, the present disclosure relates to a method for treating a patient having a proliferative disorder and a condition caused by or aggravated by excessive gastric acid production, the method comprising administering to the patient (a) a therapeutically effective amount of the pharmaceutical composition of the present disclosure and (b) a therapeutically effective amount of a gastric acid-reducing agent. In yet another embodiment, the Disclosure relates to a method for delivering a therapeutically effective dose of nilotinib to a patient, regardless of whether the patient is concurrently receiving an acid-reducing agent, the method comprising the step of administering a therapeutically effective dose of the pharmaceutical composition of the Disclosure to the patient. As used herein, “acid-reducing agent” refers to any agent that acts to significantly reduce the amount of acid in the target stomach. Acid reduction may result from suppression or inhibition of acid secretion, or from neutralization of stomach acid. Examples of acid-reducing agents include, but are not limited to, proton pump inhibitors, histamine-2 receptor antagonists (or H2 antagonists), and antacids.

[0100] Proton pump inhibitors reduce gastric acid production by inhibiting the hydrogen / potassium adenosine triphosphatase enzyme (i.e., the gastric proton pump) in parietal cells, which are epithelial cells that secrete gastric acid. Examples of proton pump inhibitors include, but are not limited to, rabeprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and dexlansoprazole. H2 antagonists inhibit histamine from binding to H2 receptors on parietal cells, thereby suppressing both normal acid secretion by parietal cells and food-stimulated acid secretion. Examples of H2 antagonists include, but are not limited to, famotidine, cimetidine, nizatidine, and ranitidine. Antacids contain alkaline ions that chemically neutralize stomach acid. Examples of antacids include, but are not limited to, aluminum hydroxide, magnesium hydroxide, sodium citrate, sodium carbonate, sodium bicarbonate, calcium carbonate, and magnesium trisilicate.

[0101] Acid-reducing agents may be administered according to known medication information in the technical field relating to acid-reducing agents, or according to a physician's instructions. The “therapeutically effective dose” of an acid-reducing agent may be the amount described in known medication information in the technical field relating to acid-reducing agents, or the amount prescribed by a physician. The “standard dose” is the dose prescribed on the product label. In particular, standard doses are suitable for acid-reducing agents available over-the-counter (i.e., without a physician's instructions), such as most antacids, some H2 antagonists, and some proton pump inhibitors. As used herein, a condition resulting from or aggravated by excessive gastric acid production may be any condition that can be treated by reducing the amount or acidity of the acid in the stomach in question. Examples of such conditions include, but are not limited to, dyspepsia (i.e., indigestion), gastroesophageal reflux disease, duodenal or gastric ulcer, erosive esophagitis, stress-induced gastritis, Barrett's esophagus, and gastrinoma.

[0102] As used herein, “co-administration” (or “to be used in combination, to be administered together”) refers to the administration of two or more therapeutic agents within a suitable period of time (e.g., one day, or 12 hours, or 8 hours, or 6 hours) such that consideration must be given to whether the administration of one therapeutic agent may affect the absorption or efficacy of the other therapeutic agent. Such administration may be performed to treat two or more conditions simultaneously. For example, as mere example, a patient may need to treat a proliferative disorder as described herein with nilotinib as a therapeutic agent, while simultaneously receiving treatment for another condition such as acid reflux or ulcers with a second therapeutic agent, such as an acid-reducing agent (e.g., a proton pump inhibitor). Since both therapeutic agents are administered at least once a day, the two therapeutic agents are “used in combination, to be administered together,” and consideration must be given to whether the administration of one therapeutic agent affects the absorption and efficacy of the other therapeutic agent. In the context of this disclosure, the phrase “may be used in combination (administered together)” means that two (or more) therapeutic agents for a particular purpose may be used in combination without adverse reduction of exposure to nilotinib. “Without adverse reduction” means that the resulting exposure is comparable to the exposure that would occur without the concomitant use of the acid-reducing agent. Any difference in the resulting exposure is negligible and / or therapeutically insignificant. Conversely, if adverse reduction of exposure is achieved, concomitant use should be avoided. “Adverse reduction” means a substantial and significant reduction of the resulting exposure. For example, if the resulting exposure is below a level recognized as below therapeutic dose, concomitant use would result in adverse reduction of exposure.

[0103] 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 gastric pH of a patient or subject. A gastric acid-insensitive composition provides therapeutically appropriate exposure to a patient or subject across a range of gastric pH values. Therefore, a gastric acid-insensitive composition can be administered regardless of whether the patient or subject has taken an acid-reducing agent, or whether the patient has a condition that causes an increase in gastric pH (as further described below). Embodiments of the present disclosure relate to administering an acid-reducing agent immediately before, simultaneously with, or immediately after the administration of nilotinib ASD or the pharmaceutical composition of the present disclosure. As used herein, the term “immediately before” may mean administering the acid-reducing agent to a target within 10 hours, 8 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, or 15 minutes prior to the administration of the pharmaceutical composition of the present disclosure. As used herein, the terms “concurrently” or “concomitantly” may mean administering the acid-reducing agent to the target within 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, or simultaneously with the administration of the pharmaceutical composition. As used herein, the term “immediately after” may mean administering the acid-reducing agent to the target within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, or 15 minutes after the administration of the pharmaceutical composition.

[0104] In some embodiments, administration of the ASD or pharmaceutical composition of this disclosure to subjects simultaneously, immediately before, or immediately after administration of an acid-reducing agent exhibits a pharmacokinetic profile similar to that of nilotinib obtained by administration of the ASD or pharmaceutical composition to subjects not simultaneously, immediately before, or immediately after administration of an acid-reducing agent. In some embodiments, a single administration of the ASD or pharmaceutical composition to subjects simultaneously, immediately before, or immediately after administration of an acid-reducing agent results in an AUC of nilotinib within 50%, 40%, or 30% of that of nilotinib obtained by administration of the ASD or pharmaceutical composition to subjects not simultaneously, immediately before, or immediately after administration of an acid-reducing agent. In some embodiments, the AUC is 0-24h In other embodiments, AUC is AUC 0-inf That is the case. Aspects of the present disclosure further relate to a treatment plan including the administration of the pharmaceutical compositions and gastric acid-reducing agents of the present disclosure. Such a treatment plan may be for treating a proliferative disorder in a patient requiring treatment for a proliferative disorder, or for treating a proliferative disorder and a condition caused by or aggravated by gastric acid in a patient requiring treatment for a condition caused by or aggravated by gastric acid, resulting from both a proliferative disorder and gastric acid overproduction.

[0105] In some embodiments, a treatment plan may include (a) administering a first dose to a patient containing a therapeutically effective amount of a proton pump inhibitor; and (b) administering a second dose to a patient containing the pharmaceutical composition of the Disclosure within two hours following the first dose. In some embodiments, a treatment plan may include (a) administering a first dose to a patient containing a therapeutically effective amount of a proton pump inhibitor; and (b) simultaneously administering a second dose to a patient containing the pharmaceutical composition of the Disclosure. In some embodiments, a treatment plan may include (a) administering a first dose to a patient containing a therapeutically effective amount of an H2 antagonist; and (b) administering a second dose to a patient containing the pharmaceutical composition of the Disclosure within 10 hours following the first dose. In some embodiments, a treatment plan may include (a) administering a first dose to a patient containing a therapeutically effective amount of the pharmaceutical composition of the Disclosure; and (b) administering a second dose to a patient containing a therapeutically effective amount of an H2 antagonist within 2 hours following the first dose. In some embodiments, a treatment plan may include (a) administering a first dose to a patient containing a therapeutically effective amount of an antacid; and (b) administering a second dose to a patient containing the pharmaceutical composition of the Disclosure within two hours following the first dose.

[0106] How to treat patients with elevated stomach pH The pharmaceutical compositions of this disclosure can be suitably administered to subjects or patients in whom the pH of the stomach is elevated. Some aspects of this disclosure relate to the use of the nilotinib ASD or pharmaceutical composition of this disclosure for delivering nilotinib to subjects or patients with elevated gastric pH. Some embodiments relate to a method for delivering nilotinib to subjects with elevated gastric pH, the method comprising the step of administering the ASD or pharmaceutical composition of this disclosure to the subject or patient. Some embodiments relate to the use of the nilotinib ASD or pharmaceutical composition of this disclosure for delivering nilotinib to subjects or patients with elevated gastric pH, the use comprising administering the ASD or pharmaceutical composition to the subject or patient. Some embodiments relate to the nilotinib ASD or pharmaceutical composition of this disclosure for use in delivering nilotinib to subjects or patients with elevated gastric pH, the use comprising administering the ASD or pharmaceutical composition to the subject or patient. Some embodiments relate to the use of nilotinib ASD or pharmaceutical composition of this disclosure in the manufacture of a pharmaceutical for delivering nilotinib to a subject or patient with elevated gastric pH, wherein such delivery includes administering the ASD or pharmaceutical composition to the subject or patient.

[0107] As used herein, “gastric pH” refers to the internal pH of the stomach of a subject or patient. A gastric pH can be considered “elevated” if, under fasting conditions, it exceeds 3.5, 4, or 5. Gastric pH can be assessed using standard methods, or an elevated gastric pH can be inferred, for example, from the effects of treatment with acid-reducing agents or from known effects of identified conditions that typically cause a measurable elevated gastric pH. In implementing this disclosure, the gastric pH of a subject or patient may be elevated due to different causes, including, but not limited to, the administration of an acid-reducing agent to the subject or patient, or the subject or patient having a condition that causes an elevation of gastric pH. An elevation of gastric pH may be caused, for example, by conditions such as hypochlorhydria or achlorhydria, or infection by Helicobacter pylori. As used herein, with respect to gastric pH, the phrase “chronically elevated” means that the subject or patient experiences a persistent or recurrent elevation of gastric pH. Chronically elevated gastric pH may result from conditions such as hypochlorhydria or achlorhydria, or infections caused by Helicobacter pylori.

[0108] In some embodiments, the methods of the present disclosure may include a step of identifying a condition in which a patient's gastric pH is elevated (including a chronically elevated condition). Such a step may include a step of 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, nilotinib ASD or the pharmaceutical composition may be administered to a subject or patient regardless of the subject's or patient's gastric pH. Therefore, nilotinib ASD or the 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., less than 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 temporary use of acid-reducing agents, or when the subject or patient has hypochlorhydria (resulting in a gastric pH that may fluctuate depending on factors such as whether the subject or patient has recently eaten).

[0109] In some embodiments, administration of the ASD or pharmaceutical composition of this disclosure to subjects or patients with elevated gastric pH exhibits a pharmacokinetic profile similar to that of nilotinib obtained by administration of the ASD or pharmaceutical composition to subjects or patients with normal gastric pH. In some embodiments, a single dose of the ASD or pharmaceutical composition to subjects or patients with elevated gastric pH exhibits a pharmacokinetic profile similar to that of nilotinib obtained by a single dose of the ASD or pharmaceutical composition to subjects or patients with normal gastric pH. 0-t and / or C max AUC of nilotinib within 50%, 40%, or 30% of the total AUC 0-t (For example, AUC 0-24h AUC 0-last Alternatively, AUC 0-inf ) and / or C max This brings about AUC. In one embodiment, 0-t AUC 0-24h In other embodiments, AUC 0-t AUC 0-inf That is the case. In one embodiment, administration of the ASD or pharmaceutical composition of this disclosure to a subject or patient with elevated gastric pH results in an AUC in the plasma of the subject or patient within the bioequivalence criteria of 80% to 125% compared to administration of a conventional immediate-release composition of nilotinib administered to a subject or patient with normal gastric pH. 0-t (For example, AUC 0-24h AUC 0-last or AUC 0-inf ) and C max It may provide AUC. In one embodiment, AUC 0-t AUC 0-24h In other embodiments, AUC 0-t AUC 0-inf That is the case.

[0110] In implementing this disclosure, administration of ASD or pharmaceutical composition can provide enhanced exposure compared to standard immediate-release compositions. In some embodiments, a single dose of the ASD or pharmaceutical composition of this disclosure to subjects or patients with elevated gastric pH provides a greater AUC and / or C2 compared to a single dose of a conventional nilotinib immediate-release composition (e.g., Tasigna) to subjects or patients with elevated gastric pH. max This indicates (it should be understood that in each case, the same molar amount or "label claim" of nilotinib is administered). In one embodiment, AUC is 0-24h In other embodiments, AUC is AUC 0-inf In one embodiment, a single dose of ASD or the pharmaceutical composition to a subject or patient with elevated gastric pH is equivalent to the AUC of nilotinib obtained by administration of a conventional immediate-release composition of nilotinib to a subject or patient with elevated gastric pH. 0-t and / or C max The AUC of nilotinib is at least 80% higher, or at least 100% higher, or at least 150% higher, or at least 200% higher than that of [another product]. 0-t and / or C max This brings about AUC. In one embodiment, AUC 0-24h In other embodiments, AUC is AUC 0-inf That is the case.

[0111] Furthermore, certain embodiments of this disclosure relate to the use of the nilotinib ASD or pharmaceutical composition of this disclosure for delivering nilotinib to a target regardless of the pH of the target's stomach. Some embodiments relate to a method for delivering nilotinib to a target regardless of the pH of the target's stomach, the method comprising the step of administering the ASD or pharmaceutical composition of this disclosure to the target. Some embodiments relate to the use of the nilotinib ASD or pharmaceutical composition of this disclosure for delivering nilotinib to a target regardless of the pH of the target's stomach, the use comprising administering the ASD or pharmaceutical composition to the target. Some embodiments relate to the use of the nilotinib ASD or pharmaceutical composition of this disclosure for use in delivering nilotinib to a target regardless of the pH of the target's stomach, the use comprising administering the ASD or pharmaceutical composition to the target. Some embodiments relate to the use of the nilotinib ASD or pharmaceutical composition of this disclosure in the manufacture of a pharmaceutical for delivering nilotinib to a target regardless of the pH of the target's stomach, the delivery comprising administering the ASD or pharmaceutical composition to the target. According to this embodiment, nilotinib ASD or the pharmaceutical composition can be administered to the target regardless of whether the pH of the target stomach is normal or whether the pH of the target stomach is elevated as described herein.

[0112] Pharmaceutical composition with improved variability The pharmaceutical compositions of this disclosure may, in some embodiments, provide less variability in in vivo pharmacokinetic performance. As used herein, the phrase “improved variability composition” refers to a composition of this 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 conventional immediate-release formulation of nilotinib (e.g., Tasigna) is administered to a suitable set of healthy human subjects. For this evaluation, in accordance with standard practice and relevant FDA guidelines, the set of healthy human subjects should include an appropriate number of subjects so that the study has sufficient force to demonstrate bioequivalence.

[0113] In some embodiments, the improved variability compositions provide a coefficient of variation for at least one pharmacokinetic parameter that is 30%, 25%, 20%, 15%, 10%, or 5% lower than the coefficient of variation observed when a standard commercially available nilotinib immediate-release composition (e.g., Tasigna) is administered under similar conditions. The pharmacokinetic parameter is C max AUC last and AUC 0-inf It may be any of the following. In some embodiments, the composition with improved variability is C max , and AUC last and AUC 0-inf It provides an improvement with respect to at least one of the following. In other embodiments, the composition with improved variability is C max AUC last and AUC 0-inf We will provide improvements in all aspects of this. In particular, it has been observed that the compositions of this disclosure can provide a lower coefficient of variation for pharmacokinetic parameters when administered to healthy human subjects in a fasted state. As shown in Example 5 (Table 24), the test composition, under such conditions, max AUC last and AUC 0-inf It showed a lower coefficient of variation for C. The CV observed for the test composition was C compared to the reference composition. max It was at least 30% lower.

[0114] A kit containing a pharmaceutical composition and an accompanying leaflet. In some embodiments, the Disclosure provides a kit comprising a pharmaceutical composition and accompanying documentation as described above in the embodiments of the Disclosure. As used herein, “kit” is a trading unit of sale and may contain a fixed number of doses of the pharmaceutical composition. As merely an example, a kit may provide a 30-day supply of one or more fixed-strength dose units, including 30 dose units, 60 dose units, 90 dose units, 120 dose units, or other appropriate quantities as directed by a physician. As another example, a kit may provide a 90-day supply of dose units. As used herein, “Package Insert” means a document providing 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 Daily Med service of the National Library of Medicine, National Institutes of Health, which provides up-to-date prescription information (see https: / / dailymed.nlm.nih.gov / dailymed / index.cfm).

[0115] In some embodiments, the package insert informs the kit user that the pharmaceutical composition may be administered with food. In some embodiments, the package insert informs the kit user that the pharmaceutical composition may be administered with or without food. In some embodiments, the package insert does not include a warning that the pharmaceutical composition should not be administered with food. In some embodiments, the package insert informs the kit user that the pharmaceutical composition can be used in combination with an 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 kit user that the proton pump inhibitor can be used in combination with the pharmaceutical composition. In some embodiments, the package insert does not include a warning that the proton pump inhibitor should not be used in combination with the pharmaceutical composition. In some embodiments, the package insert informs the kit user that an H2 antagonist can be used in combination with the pharmaceutical composition. In some embodiments, the package insert does not inform the user to use the H2 antagonist approximately 10 hours before or approximately 2 hours after administering the pharmaceutical composition. In some embodiments, the package insert informs the user that an H2 antagonist can be used approximately 10 hours before or approximately 2 hours after administering the pharmaceutical composition.

[0116] In some embodiments, the package insert informs the kit user that the antacid and the pharmaceutical composition can be used in combination. In some embodiments, the package insert does not inform the user to use the antacid approximately two hours before or approximately two hours after administering the pharmaceutical composition. In some embodiments, the package insert informs the user that the antacid can be used within approximately two hours before or approximately two hours after administering the pharmaceutical composition. In some embodiments, the package insert informs the kit user that the pharmaceutical composition can be suitably administered to users with chronically elevated gastric pH. In some embodiments, the package insert informs the kit user that the pharmaceutical composition can be suitably administered to patients diagnosed with achlorhydria or hypochlorhydria, or patients suffering from achlorhydria or hypochlorhydria. In some embodiments, the package insert informs the kit user that the pharmaceutical composition can be suitably administered to patients diagnosed with Helicobacter pylori infection, or patients suffering from Helicobacter pylori infection. The following embodiments further illustrate and / or illustrate the present disclosure, and such embodiments are provided for illustrative / representational purposes only and are not intended to limit the present disclosure in any way.

[0117] This disclosure includes the following embodiments: Embodiment ASD1 is an amorphous solid dispersion containing nilotinib and one or more polymers. Embodiment ASD2 is an amorphous solid dispersion containing nilotinib and one or more polymers, where nilotinib and one or more polymers are present in the amorphous solid dispersion in a w / w ratio of 20:80 to 95:5 (nilotinib:polymer). Embodiment ASD3 is an amorphous solid dispersion containing nilotinib and one or more polymers, where nilotinib and one or more polymers are present in the amorphous solid dispersion in a w / w ratio of 40:60 to 70:30 (nilotinib:polymer). Embodiment ASD4 is an amorphous solid dispersion containing nilotinib and one or more polymers, where nilotinib and one or more polymers are present in the amorphous solid dispersion in a w / w ratio of 50:50 (nilotinib:polymer). Embodiment ASD5 is an amorphous solid dispersion according to any one of Embodiments ASD1 to ASD4, wherein one or more polymers exhibit pH-dependent solubility.

[0118] Embodiment ASD6 is an amorphous solid dispersion according to any one of Embodiments ASD1 to ASD5, wherein one or more polymers comprise hydroxypropyl methylcellulose acetate succinate. Embodiment ASD7 is an amorphous solid dispersion according to Embodiment ASD6, wherein one or more polymers essentially consist of hydroxypropyl methylcellulose acetate succinate. Embodiment ASD8 is an amorphous solid dispersion according to any one of Embodiments ASD6 to ASD7, wherein one or more polymers comprise hydroxypropyl methylcellulose acetate succinate characterized by 7-11% acetyl substitution and 10-14% succinyl substitution. Embodiment ASD9 is an amorphous solid dispersion according to any one of Embodiments ASD1 to ASD5, wherein one or more polymers comprise a copolymer of methacrylic acid and ethyl acrylate. Embodiment ASD10 is an amorphous solid dispersion according to Embodiment ASD9, wherein one or more polymers essentially consist of a copolymer of methacrylic acid and ethyl acrylate. Embodiment ASD11 is an amorphous solid dispersion according to any one of Embodiments ASD9 to ASD10, wherein one or more polymers comprise a copolymer of methacrylic acid and ethyl acrylate, and is insoluble in aqueous media with a pH of 5 or less, and soluble in aqueous media with a pH of 5.5 or more.

[0119] Embodiment ASD12 is an amorphous solid dispersion described in any of Embodiments ASD1 to ASD11, wherein the amorphous solid dispersion essentially consists of nilotinib and one or more polymers. Embodiment ASD13 is an amorphous solid dispersion according to any of Embodiments ASD1 to ASD12, wherein the amorphous solid dispersion contains one or more antioxidants. Embodiment ASD14 is an amorphous solid dispersion according to any of Embodiments ASD1 to ASD13, wherein the amorphous solid dispersion contains one or more antioxidants present in an amount of 0.001% to 2% by mass of the amorphous solid dispersion. Embodiment ASD15 is an amorphous solid dispersion according to any of Embodiments ASD1 to ASD14, wherein the amorphous solid dispersion contains one or more antioxidants present in an amount of 0.05% to 0.5% by mass of the amorphous solid dispersion. Embodiment ASD16 is an amorphous solid dispersion according to any of Embodiments ASD1 to ASD15, wherein the amorphous solid dispersion contains one or more antioxidants selected from butylated hydroxytoluene.

[0120] Embodiment ASD17 is an amorphous solid dispersion according to any of Embodiments ASD1 to ASD16, wherein the amorphous solid dispersion is manufactured by a process including electrospraying. Embodiment ASD18 is an amorphous solid dispersion according to any of Embodiments ASD1 to ASD16, wherein the amorphous solid dispersion is an electrosprayed amorphous solid dispersion. Embodiment ASD19 is an amorphous solid dispersion described in any of Embodiments ASD1 to ASD16, wherein the amorphous solid dispersion is manufactured by a process including spray drying. Embodiment ASD20 is an amorphous solid dispersion described in any of Embodiments ASD1 to ASD16, wherein the amorphous solid dispersion is a spray-dried amorphous solid dispersion. Embodiment ASD21 is an amorphous solid dispersion according to any of Embodiments ASD1 to ASD20, wherein the amorphous solid dispersion remains amorphous or essentially amorphous after storage at 40°C / 75% relative humidity for 6 months, as determined by powder X-ray diffraction. Embodiment ASD22 is an amorphous solid dispersion according to any of Embodiments ASD1 to ASD20, wherein the amorphous solid dispersion remains amorphous or essentially amorphous after storage at 25°C / 60% relative humidity for 6 months, as determined by powder X-ray diffraction.

[0121] Embodiment ASD23 is an amorphous solid dispersion according to any of Embodiments ASD1 to ASD20, wherein the amorphous solid dispersion contains a water content of 4% or less, as measured by Karl Fischer coulometric titration, after storage at 25°C / 60%RH for 12 months. Embodiment ASD24 is an amorphous solid dispersion according to any of Embodiments ASD1 to ASD20, wherein the water content contains 4% or less, as measured by Karl Fischer coulometric titration, after storage at 40°C / 75%RH for 6 months. Embodiment ASD25 is an amorphous solid dispersion according to any of Embodiments ASD1 to ASD20, characterized in that the amorphous solid dispersion has a quantitative level of at least 90% as measured by high-performance liquid chromatography (HPLC) after storage at 25°C / 60% relative humidity for 12 months. Embodiment ASD26 is an amorphous solid dispersion according to any of Embodiments ASD1 to ASD20, characterized in that the quantitative level of the amorphous solid dispersion after storage at 40°C / 75% relative humidity for 6 months is at least 90%.

[0122] Embodiment ASD27 is an amorphous solid dispersion as described in any one of Embodiments ASD1 to ASD20, and the amorphous solid dispersion contains 1% or less of all related substances measured by HPLC after storage at 25°C / 60%RH for 12 months. Embodiment ASD28 is an amorphous solid dispersion as described in any one of Embodiments ASD1 to ASD20, and the amorphous solid dispersion contains 1% or less of all related substances measured by HPLC after storage at 40°C / 75%RH for 6 months. Embodiment ASD29 is an amorphous solid dispersion as described in any one of Embodiments ASD1 to ASD20, and the amorphous solid dispersion contains a glass transition temperature measured by modulated differential scanning calorimetry that does not change by more than 5°C after storage at 25°C / 60%RH for 12 months. Embodiment ASD30 is an amorphous solid dispersion as described in any one of Embodiments ASD1 to ASD20, and the amorphous solid dispersion contains a glass transition temperature measured by modulated differential scanning calorimetry that does not change by more than 5°C after storage at 40°C / 75%RH for 6 months.

[0123] Embodiment PC1 is a pharmaceutical composition containing the amorphous solid dispersion as described in any one of Embodiments ASD1 to ASD30. Embodiment PC2 is a pharmaceutical composition containing the amorphous solid dispersion as described in any one of Embodiments ASD1 to ASD30 and one or more pharmaceutically acceptable additives. Embodiment PC3 is the pharmaceutical composition of Embodiment PC2, and the one or more pharmaceutically acceptable additives include one or more solubilizing agents, one or more buffering agents, one or more pH adjusting agents, one or more surfactants, one or more antioxidants, one or more carriers, or combinations thereof. Embodiment PC4 is the pharmaceutical composition of Embodiment PC2, and the one or more pharmaceutically acceptable additives include one or more fillers, one or more binders, one or more lubricants, one or more disintegrants, one or more fluidizing agents, or combinations thereof. Embodiment PC5 is the pharmaceutical composition of Embodiment PC4, and the pharmaceutical composition is a solid dosage form suitable for oral administration. Embodiment PC6 is the pharmaceutical composition of Embodiment PC4, and the pharmaceutical composition exists as a solid dosage form suitable for oral administration and contains 25 to 100 mg of nilotinib.

[0124] Embodiment PC7 is the pharmaceutical composition of Embodiment PC6. When the oral dosage form is administered to healthy human subjects in a fasting state, the AUC achieved after administration of a reference composition, which is an immediate-release composition of conventional nilotinib containing 200 mg of nilotinib monohydrochloride monohydrate 0-inf and C max Compared to, an AUC within the biological equivalence criteria of 80% to 125% 0-inf and C max is achieved. Embodiment PC8 is the pharmaceutical composition of Embodiment PC6. The pharmaceutical composition is effectively bioequivalent to a reference composition, which is an immediate-release composition of conventional nilotinib containing 200 mg of nilotinib monohydrochloride monohydrate, under fasting conditions. The effective bioequivalence is established by (a) a 90% confidence interval for AUC of 80% to 125%, and (b) a 90% confidence interval for C max is established by. Embodiment PC9 is the pharmaceutical composition of Embodiments PC1 - PC8. The pharmaceutical composition is a food-insensitive composition. Embodiment PC10 is the pharmaceutical composition of Embodiments PC1 - PC9. The pharmaceutical composition is an acid-insensitive composition. Embodiment PC11 is the pharmaceutical composition of Embodiments PC1 - PC10. The pharmaceutical composition is a composition with improved variability.

[0125] Embodiment MT1 is a method for treating a proliferative disorder in a patient who requires treatment for a proliferative disorder. The method includes the step of administering to the patient the pharmaceutical composition according to any one of Embodiments PC1 - PC11. Embodiment MT2 is a method for treating proliferative disorders in patients requiring treatment for proliferative disorders, the method comprising the step of administering a pharmaceutical composition described in any of Embodiments PC1 to PC11 to the patient, the pharmaceutical composition being administered regardless of food consumption. Embodiment MT3 is a method for treating proliferative disorders in patients requiring treatment for proliferative disorders, the method comprising the step of administering a pharmaceutical composition described in any of Embodiments PC1 to PC11 to the patient, the pharmaceutical composition being administered regardless of whether the patient is fasting or eating. Embodiment MT4 is a method for treating proliferative disorders in patients requiring treatment for proliferative disorders, the method comprising the step of administering a pharmaceutical composition described in any of Embodiments PC1 to PC11 to the patient without being affected by food. Embodiment MT5 is a method for safely delivering nilotinib to a patient who requires safe delivery of nilotinib, the method comprising (a) administering to the patient a therapeutically effective amount of a pharmaceutical composition described in any of Embodiments PC1 to PC11, and (b) providing the patient with a meal, wherein steps (a) and (b) occur within two hours of each other.

[0126] Embodiment MT6 is a method for delivering a therapeutically effective dose of nilotinib to a patient regardless of food consumption, and the method includes administering to the patient a pharmaceutical composition described in any of Embodiments PC1 to PC11. Embodiment MT7 is a method for delivering a therapeutically effective dose of nilotinib to a patient regardless of whether the patient is fasting or feeding, and the method includes administering to the patient a pharmaceutical composition described in any of Embodiments PC1 to PC11. Embodiment MT8 is a method according to any of Embodiments MT1 to MT7, wherein the administration of the pharmaceutical composition to a patient in a feeding state is compared to the administration of the pharmaceutical composition to a patient in a fasting state, resulting in the plasma C of nilotinib obtained by the administration of the pharmaceutical composition to a patient in a fasting state. max Lower plasma C levels of nilotinib max Embodiment MT9 is a method according to any of Embodiments MT1 to MT7, wherein administration of the pharmaceutical composition to a patient in a feeding state results in the same plasma C as nilotinib obtained by administration of the pharmaceutical composition to a patient in a fasting state. maxPlasma C of nilotinib within 30% max It brings about.

[0127] Embodiment MT10 is the method according to any of Embodiments MT1 to MT9, wherein administration of the pharmaceutical composition to a patient in a fed state results in a lower plasma AUC of nilotinib than that obtained by administration of the pharmaceutical composition to a patient in a fasted state. Embodiment MT11 is the method according to any of Embodiments MT1 to MT9, wherein administration of the pharmaceutical composition to a patient in a fed state results in a plasma AUC of nilotinib within 30% of that obtained by administration of the pharmaceutical composition to a patient in a fasted state. Embodiment MT12 is the method according to any of Embodiments MT1 to MT9, wherein administration of the pharmaceutical composition to a patient in a fed state results in a plasma AUC of nilotinib within 15% of that obtained by administration of the pharmaceutical composition to a patient in a fasted state. Embodiment MT13 is the method according to any of Embodiments MT10 to MT12, wherein the AUC is 0-12h Embodiment MT14 is a method according to any of Embodiments MT10 to MT12, and AUC is AUC 0-24h Embodiment MT15 is a method according to any of Embodiments MT10 to MT12, and AUC is AUC 0-last Embodiment MT16 is a method according to any of Embodiments MT10 to MT12, and AUC is AUC 0-inf That is the case.

[0128] Embodiment MT17 is a method according to any of Embodiments MT1 to MT7, wherein the administration of the pharmaceutical composition to a patient in a fasted state is performed by administering an immediate-release formulation of nilotinib crystals containing 2 to 4 times the amount of nilotinib as the pharmaceutical composition, thereby obtaining nilotinib in plasma C max Larger nilotinib plasma C maxEmbodiment MT18 is a method according to any of Embodiments MT1 to MT7, wherein administration of the pharmaceutical composition to a patient in a feeding state results in the administration of an immediate-release formulation of nilotinib crystals containing 2 to 4 times the amount of nilotinib as the pharmaceutical composition, resulting in plasma C max Plasma C of nilotinib within 25% max It brings about. Embodiment MT19 is the method according to any of Embodiments MT1 to MT7, wherein administration of the pharmaceutical composition to a fasted patient results in a plasma AUC of nilotinib greater than that obtained by administering an immediate-release formulation of nilotinib crystals containing 2 to 4 times the amount of nilotinib as in the pharmaceutical composition. Embodiment MT20 is the method according to any of Embodiments MT1 to MT7, wherein administration of the pharmaceutical composition to a fed patient results in a plasma AUC of nilotinib within 25% of that obtained by administering an immediate-release formulation of nilotinib crystals containing 2 to 4 times the amount of nilotinib as in the pharmaceutical composition. Embodiment MT21 is the method according to any of Embodiments MT1 to MT7, wherein administration of the pharmaceutical composition to a patient in a feeding state results in a plasma AUC of nilotinib that is within 20% of the plasma AUC of nilotinib obtained by administration of an immediate-release formulation of nilotinib crystals having 2 to 4 times the amount of nilotinib as in the pharmaceutical composition. Embodiment MT22 is the method according to any of Embodiments MT19 to MT21, wherein the AUC is 0-12h Embodiment MT23 is the method described in any of Embodiments MT19 to MT21, and AUC is AUC 0-24h Embodiment MT24 is the method described in any of Embodiments MT19 to MT21, and AUC is AUC 0-last Embodiment MT25 is the method described in any of Embodiments MT19 to MT21, and AUC is AUC 0-inf That is the case.

[0129] Embodiment MT26 is a method for treating a proliferative disorder in a patient requiring treatment for a proliferative disorder, the method comprising administering to the patient a pharmaceutical composition according to any of Embodiments PC1 to PC11, regardless of whether the patient is concomitantly taking a proton pump inhibitor. Embodiment MT27 is a method for delivering a therapeutically effective amount of nilotinib to a patient concomitantly taking a proton pump inhibitor, the method comprising administering to the patient (a) a pharmaceutical composition according to any of Embodiments PC1 to PC11 and (b) a proton pump inhibitor. Embodiment MT28 is the method according to any of Embodiments MT1 to MT27, where the proliferative disorder is cancer. Embodiment MT29 is the method according to any of Embodiments MT1 to MT27, where the proliferative disorder is Philadelphia chromosome-positive chronic myeloid leukemia. Embodiment MT30 is the method according to any of Embodiments MT1 to MT27, where the proliferative disorder is chronic-phase Philadelphia chromosome-positive chronic myeloid leukemia that is resistant to or intolerant to prior tyrosine kinase inhibitor treatment.

[0130] Embodiment MS1 is a method for delivering nilotinib to a subject with therapeutically appropriate exposure, regardless of whether the subject is fasted or fed, and the method includes the step of administering to a subject the pharmaceutical composition described in any of Embodiments PC1 to PC11. Embodiment MS2 is the method described in Embodiment MS1, wherein the administration of the pharmaceutical composition to a subject in a feeding state is compared to the administration of the pharmaceutical composition to a subject in a fasting state, which results in the plasma C of nilotinib obtained by the administration of the pharmaceutical composition to a subject in a fasting state. max Lower plasma C levels of nilotinib max Embodiment MS3 is the method described in Embodiment MS1, wherein administration of the pharmaceutical composition to a subject in a feeding state results in the plasma C of nilotinib obtained by administration of the pharmaceutical composition to a subject in a fasting state. max Plasma C of nilotinib within 30% max It brings about. Embodiment MS4 is the method described in Embodiment MS1, in which administration of the pharmaceutical composition to a fed subject results in a lower plasma AUC of nilotinib than that obtained by administration of the pharmaceutical composition to a fasted subject. Embodiment MS5 is the method described in Embodiment MS1, in which administration of the pharmaceutical composition to a fed subject results in a plasma AUC of nilotinib that is within 30% of the plasma AUC of nilotinib obtained by administration of the pharmaceutical composition to a fasted subject. Embodiment MS6 is the method described in Embodiment MS1, in which administration of the pharmaceutical composition to a fed subject results in a plasma AUC of nilotinib that is within 15% of the plasma AUC of nilotinib obtained by administration of the pharmaceutical composition to a fasted subject. Embodiment MS7 is the method described in any of Embodiments MS4 to MS6, in which the AUC is 0-12h Embodiment MS8 is the method described in any of Embodiments MS4 to MS6, and AUC is AUC 0-24h Embodiment MS9 is the method described in any of Embodiments MS4 to MS6, and AUC is AUC 0-last Embodiment MS10 is the method described in any of Embodiments MS4 to MS6, and AUC is AUC 0-inf That is the case.

[0131] Embodiment MS11 is the method described in Embodiment MS1, wherein the administration of the pharmaceutical composition to a subject in a fasted state is performed by administering an immediate-release formulation of nilotinib crystals containing 2 to 4 times the amount of nilotinib as the pharmaceutical composition, thereby obtaining plasma C of nilotinib. max Larger nilotinib plasma C max Embodiment MS12 is the method described in Embodiment MS1, wherein administration of the pharmaceutical composition to a subject in a feeding state results in the administration of an immediate-release formulation of nilotinib crystals containing 2 to 4 times the amount of nilotinib of the pharmaceutical composition to a fasted subject, resulting in plasma C max Plasma C of nilotinib within 25% max It brings about. Embodiment MS13 is the method described in Embodiment MS1, in which administration of the pharmaceutical composition to a fasted subject results in a plasma AUC of nilotinib greater than that obtained by administration of an immediate-release formulation of nilotinib crystals containing 2 to 4 times the amount of nilotinib as in the pharmaceutical composition. Embodiment MS14 is the method described in Embodiment MS1, in which administration of the pharmaceutical composition to a fed subject results in a plasma AUC of nilotinib within 25% of that obtained by administration of an immediate-release formulation of nilotinib crystals containing 2 to 4 times the amount of nilotinib as in the pharmaceutical composition to a fasted subject. Embodiment MS15 is the method described in Embodiment MS1, wherein administration of the pharmaceutical composition to a subject in a ingested state results in a plasma AUC of nilotinib that is within 20% of the plasma AUC of nilotinib obtained by administration of an immediate-release formulation of nilotinib crystals containing 2 to 4 times the amount of nilotinib in the pharmaceutical composition to a fasted state. Embodiment MS16 is the method described in any of Embodiments MS13 to MS15, wherein the AUC is 0-12h Embodiment MS17 is the method described in any of Embodiments MS13 to MS15, and AUC is AUC 0-24h Embodiment MS18 is the method described in any of Embodiments MS13 to MS15, and AUC is AUC 0-last Embodiment MS19 is the method described in any of Embodiments MS13 to MS15, and AUC is AUC 0-inf That is the case.

[0132] Embodiment TR1 is a treatment plan for treating a proliferative disorder in a patient requiring treatment for a proliferative disorder, the plan comprising (a) administering a first dose containing a proton pump inhibitor to the patient, and (b) administering a second dose containing a pharmaceutical composition according to any of Embodiments PC1 to PC11 to the patient within 12 hours of the first dose. Embodiment TR2 is a treatment plan for treating a proliferative disorder and a condition caused by excessive gastric acid production or a condition aggravated by gastric acid in a patient who requires treatment for a proliferative disorder and a condition caused by excessive gastric acid production or a condition aggravated by gastric acid, the plan comprising (a) administering to the patient a first dose containing a therapeutically effective amount of a proton pump inhibitor, and (b) administering to the patient a second dose containing a pharmaceutical composition according to any of Embodiments PC1 to PC11 within 12 hours after the first dose. Embodiment TR3 is a treatment plan according to any of Embodiments TR1 to TR2, wherein the first dose comprises a standard dose of a proton pump inhibitor selected from rabeprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, dexlansoprazole, and combinations thereof. Embodiment TR4 is a treatment plan according to any of Embodiments TR1 to TR2, wherein the first dose comprises a standard dose of omeprazole.

[0133] Embodiment TR5 is a treatment plan according to any of Embodiments TR1 to TR4, where step (a) occurs before step (b). Embodiment TR6 is a treatment plan according to any of Embodiments TR1 to TR4, where step (b) occurs before step (a). Embodiment TR7 is a treatment plan according to any of Embodiments TR1 to TR6, where the second dose is administered within 8 hours of the first dose. Embodiment TR8 is a treatment plan according to any of Embodiments TR1 to TR6, where the second dose is administered within 6 hours of the first dose. Embodiment TR9 is a treatment plan according to any of Embodiments TR1 to TR6, where the second dose is administered within 4 hours of the first dose. Embodiment TR10 is a treatment plan according to any of Embodiments TR1 to TR6, where the second dose is administered within 2 hours of the first dose. Embodiment TR11 is a treatment plan according to any of Embodiments TR1 to TR6, where the first and second doses are administered simultaneously.

[0134] Embodiment TR12 is a treatment plan for treating proliferative disorders in patients requiring treatment for proliferative disorders, the plan comprising (a) administering a first dose containing an H2 antagonist to the patient, and (b) administering a second dose containing the pharmaceutical composition described in any of Embodiments PC1 to PC11 to the patient within 10 hours after the first dose. Embodiment TR13 is a treatment plan for treating proliferative disorders and conditions caused by or aggravated by gastric acid in patients requiring treatment for proliferative disorders and conditions caused by or aggravated by gastric acid, the plan comprising (a) administering a first dose containing a therapeutically effective amount of an H2 antagonist to the patient, and (b) administering a second dose containing the pharmaceutical composition described in any of Embodiments PC1 to PC11 to the patient within 10 hours after the first dose. Embodiment TR14 is a treatment plan described in any of Embodiments TR12 to TR13, wherein the second dose is administered within 8 hours of the first dose. Embodiment TR15 is a treatment plan according to any of Embodiments TR12 to TR13, in which the second dose is administered within 6 hours of the first dose. Embodiment TR16 is a treatment plan according to any of Embodiments TR12 to TR13, in which the second dose is administered within 4 hours of the first dose. Embodiment TR17 is a treatment plan according to any of Embodiments TR12 to TR13, in which the second dose is administered within 2 hours of the first dose. Embodiment TR18 is a treatment plan according to any of Embodiments TR12 to TR13, in which the first and second doses are administered simultaneously.

[0135] Embodiment TR19 is a treatment plan for treating proliferative disorders in patients requiring treatment for proliferative disorders, the plan comprising (a) administering a first dose to the patient containing the pharmaceutical composition described in any of Embodiments PC1 to PC11, and (b) administering a second dose to the patient containing an H2 antagonist within two hours after the first dose. Embodiment TR20 is a treatment plan for treating proliferative disorders and conditions caused by or aggravated by gastric acid in patients requiring treatment for proliferative disorders and conditions caused by or aggravated by gastric acid, the plan comprising (a) administering a first dose to the patient containing the pharmaceutical composition described in any of Embodiments PC1 to PC11, and (b) administering a second dose to the patient containing a therapeutically effective amount of an H2 antagonist within two hours after the first dose. Embodiment TR21 is a treatment plan described in any of Embodiments TR19 to TR20, in which the first and second doses are administered simultaneously. Embodiment TR22 is a treatment plan according to any of Embodiments TR12 to TR21, where the H2 antagonist is selected from famotidine, cimetidine, nizatidine, ranitidine, and combinations thereof. Embodiment TR23 is a treatment plan according to any of Embodiments TR12 to TR21, where the H2 antagonist is famotidine.

[0136] Embodiment TR24 is a treatment plan for treating proliferative disorders in patients requiring treatment for proliferative disorders, the plan comprising (a) administering a first dose containing an antacid to the patient, and (b) administering a second dose containing the pharmaceutical composition described in any of Embodiments PC1 to PC11 to the patient within two hours of the first dose. Embodiment TR25 is a treatment plan for treating proliferative disorders and conditions caused by or aggravated by gastric acid in patients requiring treatment for proliferative disorders and conditions caused by or aggravated by gastric acid, the plan comprising (a) administering a first dose containing the pharmaceutical composition described in any of Embodiments PC1 to PC11 to the patient, and (b) administering a second dose containing a therapeutically effective amount of antacid to the patient within two hours of the first dose. Embodiment TR26 is a treatment plan according to any of Embodiments TR24 to TR25, in which the first dose and the second dose are administered simultaneously. Embodiment TR27 is a treatment plan described in any of Embodiments TR24 to TR26, wherein the antacid is selected from aluminum hydroxide, magnesium hydroxide, and combinations thereof.

[0137] Embodiment TR28 is a treatment plan according to any of Embodiments TR1 to TR27, where the proliferative disorder is cancer. Embodiment TR29 is a treatment plan according to any of Embodiments TR1 to TR27, where the proliferative disorder is Philadelphia chromosome-positive chronic myeloid leukemia. Embodiment TR30 is a treatment plan according to any of Embodiments TR1 to TR27, where the proliferative disorder is chronic-phase Philadelphia chromosome-positive chronic myeloid leukemia that is resistant to or intolerant to prior tyrosine kinase inhibitor treatment. Embodiment TR31 is a treatment plan described in any of Embodiments TR1 to TR30, wherein the administration of the pharmaceutical composition provides the patient with a therapeutically appropriate exposure to nilotinib.

[0138] Embodiment KT1 is a kit for sale to a user, which includes the pharmaceutical composition described in any of Embodiments PC1 to PC11 and a package insert, the package insert informing the user that the pharmaceutical composition can be administered with food. Embodiment KT2 is a kit for sale to a user, which includes the pharmaceutical composition described in any of Embodiments PC1 to PC11 and a package insert, the package insert informing the user that the pharmaceutical composition can be administered with or without food. Embodiment KT3 is a kit for sale to a user, which includes the pharmaceutical composition described in any of Embodiments PC1 to PC11 and a package insert, the package insert does not include a warning that the pharmaceutical composition should not be administered with food. Embodiment KT4 is a kit for sale to a user, which includes the pharmaceutical composition described in any of Embodiments PC1 to PC11 and a package insert, the package insert informing the user that the proton pump inhibitor and the pharmaceutical composition can be used in combination. Embodiment KT5 is a kit for sale to a user, which includes the pharmaceutical composition described in any of Embodiments PC1 to PC11 and a package insert, the package insert does not include a warning that the proton pump inhibitor and the pharmaceutical composition should be avoided in combination.

[0139] Embodiment KT6 ​​is a kit for sale to users, which includes a pharmaceutical composition and a package insert described in any of Embodiments PC1 to PC11, and the package insert informs the user that an H2 antagonist can be used in combination with the pharmaceutical composition. Embodiment KT7 is a kit for sale to users, which includes a pharmaceutical composition and a package insert described in any of Embodiments PC1 to PC11, and the package insert does not inform the user of the kit that the H2 antagonist should be used approximately 10 hours before or approximately 2 hours after administration of the pharmaceutical composition. Embodiment KT8 is a kit for sale to users, which includes a pharmaceutical composition and a package insert described in any of Embodiments PC1 to PC11, and the package insert informs the user of the kit that the H2 antagonist can be used approximately 10 hours before or approximately 2 hours after administration of the pharmaceutical composition. Embodiment KT9 is a kit for sale to users. The kit includes the pharmaceutical composition described in any one of Embodiments PC1 - PC11 and an accompanying document. The accompanying document informs the user that an antacid can be used in combination with the pharmaceutical composition. Embodiment KT10 is a kit for sale to users. The kit includes the pharmaceutical composition described in any one of Embodiments PC1 - PC11 and an accompanying document. The accompanying document does not inform the user of the kit that an antacid should be used approximately 2 hours before or approximately 2 hours after administration of the pharmaceutical composition. Embodiment KT11 is a kit for sale to users. The kit includes the pharmaceutical composition described in any one of Embodiments PC1 - PC11 and an accompanying document. The accompanying document informs the user of the kit that an antacid can be used within approximately 2 hours before or within approximately 2 hours after administration of the pharmaceutical composition.

[0140] Embodiment KT12 is a kit for sale to users. The kit includes the pharmaceutical composition described in any one of Embodiments PC1 - PC11 and an accompanying document. The accompanying document informs the user that the pharmaceutical composition can be suitably administered even when the user's gastric pH is chronically elevated. Embodiment KT13 is a kit for sale to users. The kit includes the pharmaceutical composition described in any one of Embodiments PC1 - PC11 and an accompanying document. The accompanying document informs the user that the pharmaceutical composition can be suitably administered even when the user is diagnosed with achlorhydria or hypochlorhydria, or when the user is suffering from achlorhydria or hypochlorhydria. Embodiment KT14 is a kit for sale to users. The kit includes the pharmaceutical composition described in any one of Embodiments PC1 - PC11 and an accompanying document. The accompanying document informs the user that the pharmaceutical composition can be suitably administered even when the user is diagnosed with Helicobacter pylori infection, or when the user is suffering from Helicobacter pylori infection.

Example

[0141] Example 1. Preparation of nilotinib ASD and stability under harsh conditions Nilotinib ASD was prepared according to embodiments of the present disclosure. Next, studies were conducted to evaluate the chemical and physical stability of nilotinib ASD under severe acceleration conditions. Nilotinib ASD was prepared using Eudragit L100-55 or HPMC-AS as the polymer in the ratios shown in Table 2. To prepare each composition, appropriate amounts of polymer and nilotinib were dissolved in a 50:50 (v / v) solvent mixture of tetrahydrofuran and methanol to provide liquid raw materials (a small amount of BHT was used as an antioxidant to stabilize the tetrahydrofuran. Therefore, the ASD prepared in this example contained a small amount of undetermined BHT along with the nilotinib and polymer).

[0142] Table 2. Composition of nilotinib ASD for Example 1 [Table 2]

[0143] The obtained raw material was sprayed using the Nanocopoeia ES ENS-P machine at a total solids concentration of 20 mg / mL. For each spray operation, the spray process parameters such as the extractor voltage and flow rate were adjusted to obtain an acceptable spray plume. Following the electrospraying process, each ASD (in powder form at the time) underwent a second drying process to reduce the levels of residual solvent and moisture. For the second drying, the ASD powder was placed in a suitable container and placed in an oven (Lindberg Blue M, model V01218A) heated to 80°C. The powder was dried under vacuum (-20”~28”Hg) for 6 hours. For compositions requiring multiple spray sub-batches to provide sufficient ASD material to support stability studies, the materials obtained from the sub-batches were combined into a single blend using a Resodyn LabRam II acoustic mixer. The sub-batches were placed in a single container and blended for 2 minutes at a force set to 40G. The obtained ASD was placed in a stable state in an open dish under harsh conditions of 50°C / 80%RH. The ASD powder was evaluated at t=0, 1 week, 2 weeks, and 4 weeks for amorphousness (XRD), water content (Karl Fischer), glass transition temperature (DSC), and quantification / related substances (HPLC).

[0144] Amorphous Amorphism (i.e., lack of crystallinity) of ASD was evaluated by XRD. Diffraction patterns were obtained by X-ray diffraction using a Rigaku MiniFlex600. The X-ray source was Cu Kα with a long anode. Samples were prepared by placing a small amount of ASD powder in a Rigaku zero-background sample holder with a 0.1 mm indentation. Next, a glass slide was used to firmly pack the powder so that the surface of the sample was level with the edge of the sample holder. Details of the apparatus and measurement conditions are specified in Table 3. Table 3. Rigaku MiniFlex device and measurement conditions [Table 3]

[0145] Amorphism after spraying (t=0) and after stabilization was evaluated using ASD. The presence of crystalline peaks was evaluated by scanning each XRD, and the results are shown in Table 4. Table 4. Summary of amorphous ASD data for ASD in Example 1 [Table 4]

[0146] As shown in Table 4, each ASD was amorphous after the electrospray process. After stabilization at 50°C / 80%RH for one week, ASDs with lower drug loads (50:50 and 60:40 nilotinib: Eudragit L100-55; 50:50, 60:40 and 70:30 nilotinib: HPMC-AS) remained amorphous, while ASDs with higher drug loads began to show signs of crystallization on XRD scanning. Only the ASD formulation with the lowest drug load (50:50 and 60:40 nilotinib: Eudragit L100-55; 50:50 nilotinib: HPMC-AS) remained amorphous at week 2 and remained amorphous throughout the entire 4-week study. All other ASDs showed the presence of crystalline peaks by week 2. Despite the fact that crystallinity was observed in many of these ASDs after some time, this result was considered promising due to the harsh accelerated conservation conditions (which do not reflect real-world conservation conditions).

[0147] water content The water content was determined by Karl Fischer coulometric titration using a Mettler-Toledo C30S Karl Fischer instrument equipped with a Stromboli oven sampler. Approximately 40-50 mg of ASD powder was weighed and placed in a glass Stromboli sample vial, which was immediately sealed. The vial was then placed on the instrument and analyzed using a nitrogen carrier gas. The instrument details and measurement conditions are specified in Table 5. Table 5. Karl Fischer apparatus and measurement conditions [Table 5]

[0148] As shown in Table 6, initial moisture levels were remarkably consistent for all eight ASDs. Similarly, all ASDs showed a sharp increase in moisture content after one week of exposure to high humidity, then leveled off and remained nearly constant (3.5%–5%) for the remainder of the study. Despite some variability in the data, ASDs containing either Eudragit L100-55 or HPMC-AS exhibited some degree of hygroscopicity. Table 6. Summary of ASD water content (KF) data for ASD in Example 1. [Table 6]

[0149] glass transition temperature Modulated differential scanning calorimetry (mDSC) was performed on a TA instrument model Q200 equipped with an RCS90 refrigerated cooling system to analyze the glass transition temperature. Typically, about 5-10 mg of ASD powder was used in the TA T zero Place on a low-mass aluminum plate, T zero The container was sealed with a lid. Details of the apparatus and measurement conditions are provided in Table 7. The results are provided in Table 8. Table 7. TA Q200 DSC device and measurement conditions [Table 7]

[0150] Table 8. Observed glass transition temperature (DSC) data for ASD in Example 1 (T g Summary of ) [Table 8] 1 A second T that may have been observed at around 60°C g ND = Not detected

[0151] As can be seen from the results in Table 8, ASD including Eudragit L100-55 showed that with increasing drug load, Tg The value decreased. For all four drug load levels, the T for stability decreased. g There was essentially no change. For ASDs including HPMC-AS, T g The values ​​were similar across the four drug load levels. ASD with a 60:40 ratio showed stable T in the first two weeks. g However, in 4 weeks T g No ASD was detected. The 70:30 ASD also showed stable T in the first two weeks. g It had a second T around 60°C. g A weak thermal event was observed that could indicate this. This suggests that while the sample was in a stable state, it may have undergone phase separation. Regarding the stability of the 80:20 ASD sample, T g Detection was not possible for such samples. g The absence of [this] suggests that some type of physical change may have occurred in the ASD of HPMC-AS under accelerated conditions during stability testing.

[0152] Quantitative determination / related substances The quantification and identification of related substances (e.g., impurities) were performed using an Agilent 1200 HPLC with an Agilent Poroshell C18 3.0 mm × 150 mm × 2.7 μm column. Sample solutions for each ASD were prepared by accurately weighing approximately 50 mg of ASD powder and placing it in a 50 mL volumetric flask. First, the ASD powder was dissolved in approximately 40 mL of methanol in the flask, followed by vortexing and sonication of the flask until the ASD powder was completely dissolved. Next, methanol was added to match the volume of the sample flask, and the mixture was thoroughly mixed. This sample solution was then diluted 10-fold with a diluent (50:50 acetonitrile (ACN):0.1% phosphoric acid aqueous solution). The final concentration of the analyte (nilotinib) in the sample was approximately 0.05 mg / mL. Details of the instrument and measurement conditions are shown in Table 9, while the gradient profile is shown in Table 10.

[0153] Table 9. HPLC equipment and measurement conditions [Table 9] TEA = Triethylamine AA = Acetic Acid

[0154] Table 10. Gradient profiles of HPLC instruments [Table 10]

[0155] The quantitative results are provided in Table 11. The quantitative values ​​for ASD containing Eudragit L100-55 (96.2%–98.4%) and ASD containing HPMC-AS (96.5%–97.9%) were as expected, considering the relatively high levels of all relevant substances observed in the as-supplied API (~2%) and the initial water content of the measured ASD samples (~1%). In general, all ASDs showed a decrease in quantitative stability over time. This decrease in ASD containing HPMC-AS was more pronounced compared to ASD containing Eudragit L100-55. Regarding Table 6, the increase in water content may be partly responsible for the measured loss of potency, as the ASDs for stability were found to contain 4%–5% water after one week, and the quantitative measurements for water content were not corrected. The nilotinib peak was sufficiently abundant, allowing us to determine the impurity percentage for each sample.

[0156] Table 11. Summary of quantitative (HPLC) data for ASD in Example 1. [Table 11] n / a - No relevant data found.

[0157] The results for related substances are shown in Table 12. At all time points, the levels of related substances were similar for all eight ASDs. Based on this data, the electrospray process does not appear to increase the levels of related substances, and all ASDs appeared to be chemically stable under accelerated stability conditions despite exposure to high levels of heat and humidity. Table 12. Summary of all related substance (HPLC) data for ASD in Example 1. [Table 12]

[0158] Example 2. Stability of nilotinib ASD under accelerated storage conditions We conducted studies to evaluate the stability of nilotinib ASD according to embodiments of the present disclosure under different accelerated storage conditions. ASD was prepared in the same manner as described in Example 1, except that the solvent mixture was tetrahydrofuran and methanol in a ratio of 60:40 (v / v) (a small amount of BHT was used as an antioxidant to stabilize the tetrahydrofuran. Therefore, the ASD prepared in this example contained a small amount of undetermined BHT along with the nilotinib and polymer). Equal amounts of nilotinib and HPMC-AS were dissolved in the solvent mixture to prepare a liquid raw material, and the ASD powder was provided by electrospraying. The obtained ASD powder contained nilotinib and HPMC-AS in a 50:50 (w / w) ratio. The obtained ASD powder was stored under accelerated conditions for 24 months at 25°C / 60%RH or 6 months at 40°C / 75%RH. The ASD powder was evaluated for amorphousness (XRD), water content (Karl Fischer), glass transition temperature (DSC), and quantification / related substances (HPLC) at t=0, 1 month, 2 months, 3 months, and 6 months for each storage condition. Samples stored at 25°C / 60%RH were further evaluated at later time points up to 24 months.

[0159] Amorphous Amorphous properties were evaluated in the same manner as in Example 1 described above. Under both storage conditions, ASD remained amorphous throughout the stability study. water content Except for the sample size being approximately 50-100 mg of ASD powder, the water content was measured by Karl Fischer coulometric titration, similar to Example 1. As shown in Table 13, the water content remained substantially constant throughout the stability period, and no unfavorable hygroscopicity was observed for ASD.

[0160] Table 13. Summary of water content (KF) data for ASD in Example 2. [Table 13]

[0161] glass transition temperature Similar to Example 1, the glass transition temperature (T) of the ASD stored under accelerated conditions was obtained. g We evaluated the following. The results are shown in Table 14. Table 14. Glass transition (mDSC) data for ASD in Example 2 (T g Summary of ) [Table 14] The results indicate that the glass transition temperature of ASD remained largely unchanged over time under each storage condition, demonstrating that ASD was physically stable.

[0162] Quantitative determination / related substances ASD was quantified and related substances (e.g., impurities) were evaluated by HPLC using an Agilent Poroshell HPH-C18 3.0 mm × 150 mm × 2.7 μm column. A sample solution was prepared by accurately weighing approximately 10 mg of ASD powder and placing it in a 100 mL volumetric flask. The ASD powder was dissolved in approximately 90 mL of methanol (MeOH):water (80:20). Next, the volume of the sample flask was adjusted with 80:20 MeOH:water, and the mixture was thoroughly mixed until the ASD powder was completely dissolved. The final concentration of the analyte (nilotinib) in the sample was approximately 0.1 mg / mL. Details of the instrument and measurement conditions are specified in Table 15, while the gradient profile is shown in Table 16.

[0163] Table 15. HPLC equipment and measurement conditions [Table 15]

[0164] Table 16. HPLC equipment and measurement conditions [Table 16]

[0165] Quantitative values ​​of ASD were determined for the period after spraying (t=0) and at the specified stability point under each storage condition. The measured quantitative values ​​of ASD for each storage condition are shown in Table 17. The reported quantitative values ​​have not been corrected for water content. Table 17. Summary of quantitative (HPLC) data for ASD in Example 2. [Table 17]

[0166] Table 18 shows the measured values ​​of all relevant substances for ASD under each storage condition. Table 18. Summary of all related substance (HPLC) data for ASD in Example 2. [Table 18] As shown in Tables 17 and 18, ASD exhibited moderately high quantitative values ​​and moderately low values ​​for related substances, which did not change significantly over time. This indicates that ASD was chemically stable.

[0167] Example 3. Stability of Nilotinib ASD Suspension Formulation A study was conducted to evaluate the stability of two pharmaceutical compositions of the embodiments of this disclosure in the form of suspensions. The components of the two pharmaceutical compositions, labeled "Composition 1" and "Composition 2," are shown in Table 19. Table 19. Components of the pharmaceutical composition for Example 3 [Table 19]

[0168] The ASD powder contained nilotinib free base (49.78% by mass of ASD), HPMC-AS (49.78%), and BHT (0.44%) (the amount of BHT was quantified by analysis of the as-prepared ASD). Composition 1 was prepared by mixing the ASD powder with 0.5% methylcellulose in 0.5 mM citrate buffer to form a suspension. Composition 2 was prepared by mixing ASD and Solplus (manufactured by BASF North America, commercially available) until blended, and then mixing with 0.5% methylcellulose in 0.5 mM citrate buffer to form a suspension. The nominal concentration of nilotinib in both compositions was 12.5 mg / mL. Throughout this study, each composition was stored in a sealed container on a laboratory bench at standard room temperature and humidity. As described in Example 2 above, the quantitative analysis of each pharmaceutical composition was performed by HPLC over a period of 4 hours. The measured quantitative values ​​for each pharmaceutical composition are provided in Table 20.

[0169] Table 20. Summary of data on the quantitative determination of the suspension over a 24-hour period for the composition of Example 3. [Table 20] As described in Example 1 above, the amorphous nature of each pharmaceutical composition was evaluated by XRD at T=0, 2, and 4. Both pharmaceutical compositions remained amorphous throughout this stability study, regardless of the presence or absence of Solplus.

[0170] Example 4. In vivo study of dogs To investigate the effects of gastric pH and food on in vivo exposure obtained using the pharmaceutical compositions of this disclosure (prepared as suspensions, capsules, and tablets) compared to in vivo exposure obtained by administering a conventional immediate-release formulation of nilotinib, such as Tasigna IR capsules, studies were conducted in beagle dogs. For the selected conditions, pretreatment was incorporated into this study to adjust the pH of the dogs' stomachs before administration. Based on the published protocol, pretreatment of dogs with pentagastriin would control the pH to a range of 1-2, while pretreatment with phosphate buffer would raise the pH to 2-3. The study design is provided in Table 21. For sections A1 and A3, a suspension at a concentration of 10 mg / mL of nilotinib ("Tasigna suspension") was prepared using the decanted contents of Tasigna IR capsules in a vehicle containing 0.5% methylcellulose in 0.5 mM citrate buffer (pH 4). For section B1, the amount of the decanted contents in powder form from the Tasigna IR capsules was weighed to accurately provide a dose of 5 mg / kg, and this weighed powder was then filled into conventional gelatin capsules for administration ("Tasigna capsules").

[0171] Sections B2, B3, B4, C2, and C3 used ASD (prepared as in Example 2 above) containing nilotinib and HPMC-AS in a 50:50 (w / w) nilotinib:HPMC-AS ratio in appropriate pharmaceutical compositions prepared as follows: For section B2, ASD was mixed with appropriate excipients and prepared into granules (15% nilotinib drug load) by slugging, and an appropriate amount of granules was then filled into conventional gelatin capsules for administration ("ASD capsules"). For sections B3 and C3, ASD suspensions were prepared according to Composition 1 of Example 3 (Table 19). For section B4, granules (for section B2) were combined with conventional excipients and manually compressed into slug tablets (7.7% nilotinib drug load) using a tablet press ("ASD tablets"). For section C2, an ASD suspension containing Solplus was prepared according to composition 2 of Example 3 (Table 19). For section C1, the ASD suspension was prepared according to composition 2 of Example 3 (Table 19), except that the nilotinib ASD contained nilotinib and eudragit L100-55 in a 50:50 (w / w) nilotinib:eudragit L100-55 ratio. This suspension was prepared by electrospraying from a methanol:THF solvent mixture (1:1 v / v).

[0172] Table 21. In vivo study design for dogs in Example 4 [Table 21]

[0173] All dogs were fasted for at least 10 hours before dose administration. The animals were allowed free access to water. Each study interval consisted of 10 dogs. This study employed a crossover design, in which the same dogs received each dose after a one-week rest period between each study interval. During the fasting period, feeding was withheld from the animals for at least 12 hours prior to administration. In addition, water was removed 2 hours before administration. For the feeding study section A3, the animals were adapted to a high-fat diet for 5 days prior to administration. The animals were fasted overnight (minimum 10 hours), followed by a pre-weighed portion (~50 grams) of puree consisting of a McDonald's Bacon Egg McMuffin. The animals consumed the food for 30 minutes, after which all remaining food was removed and the test articles were administered. Four hours after administration, the animals were given regular canine solid feed. Water was provided immediately after administration in all study segments. In study section A1, each dog was given an intramuscular injection of pentagastrin (6 μg / kg) approximately 30 minutes before administration to ensure that the stomach pH of the fasted animals was acidic (pH 1-2).

[0174] In the study group incorporating phosphate buffer pretreatment, each dog received 25 mL of 100 mM phosphate buffer (pH 2.5) via gastric tube feeding before administration. After administration, each dog received an additional 10 mL of buffer as a flush. For each study interval, at t=0, all dogs received the appropriate oral dose of the appropriate research product to deliver 5 mg / kg nilotinib. Blood samples were collected 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, and 24 hours after administration. Pharmacokinetic parameters were calculated from the time course of plasma concentration. Pharmacokinetic analysis was performed using Absorption Systems with a non-compartmental model using Phoenix WinNonlin (v7.0) software. From the data, post-administration C max and time to reach peak plasma drug concentration (T max We observed the following. Using the linear trapezoidal rule, we calculated the AUC by calculating up to the last quantifiable point in time and extrapolating to infinity. From the terminal elimination phase of 0.693 / slope, we calculated the plasma half-life (t1 / 2 The following was calculated: The mean residence time (MRT) was calculated by dividing the area under the moment curve (AUMC) by the AUC. All samples below the limit of quantification (0.5 ng / mL) were treated as zero for pharmacokinetic data analysis. Table 22 provides key pharmacokinetic parameters calculated from pooled data, and Figures 1–4 show comparisons between selected intervals in this study.

[0175] Table 22. Key pharmacokinetic parameters from in vivo studies of dogs in Example 4. [Table 22] *Average (SD)

[0176] As shown in Figure 1, exposure to Tasigna capsules under fasting conditions (section B1) was dramatically reduced compared to exposure to Tasigna IR suspension after pentagastrin pretreatment under fasting conditions (section A1). These results indicate that pentagastrin pretreatment increased the solubility of nilotinib in the canine stomach by lowering the gastric pH, thereby increasing exposure under fasting conditions. These results also indicate that pretreatment with 100 mM phosphate buffer (pH 2.5) was effective in creating a canine gastric condition that made Tasigna capsules more easily distinguishable under fasting conditions. Figure 2 compares exposure to Tasigna capsules under fasting conditions (interval B1) and exposure to Tasigna IR suspension under feeding conditions (interval A3). These results indicate that the protocol used in this study, which employs phosphate buffer pretreatment, successfully creates conditions that allow for the successful demonstration in the canine model of the large positive dietary effect known to be observed in humans for conventional immediate-release nilotinib. Statistical analysis of these results shows that C was observed after administration under feeding conditions compared to administration under fasting conditions. max The results show a significant improvement in both p-value (<0.0001) and AUC (p-value (<0.0019)).

[0177] Figure 3 shows the pharmacokinetic profiles of three nilotinib ASD compositions (ASD capsules - section B2; ASD suspension (HPMC-AS) - section B3; ASD tablets - section B4) under fasting conditions with a pH of ~2.5, along with the pharmacokinetic profile of Tasigna capsules (section B1). Under fasting conditions, all three ASD compositions resulted in increased exposure compared to Tasigna capsules. ASD tablets and ASD capsules showed increased C25 exposure compared to Tasigna capsules. max And AUC increased, but ASD suspension (HPMC-AS) C max Both AUC and metric increased significantly. Figure 4 shows the pharmacokinetic profiles of three nilotinib ASD suspension compositions (ASD suspension of nilotinib and Eudragit L100-55 with Solplus - section C1; ASD suspension of nilotinib and HPMC-AS with Solplus - section C2; ASD suspension of nilotinib and HPMC-AS - section C3) administered under fasting conditions at pH ~2.5, along with the pharmacokinetic profile of Tasigna capsules (section B1). Under fasting conditions, all three ASD suspension compositions resulted in increased exposure compared to Tasigna capsules. ASD suspensions without Solplus showed increased exposure compared to Tasigna capsules. max Although AUC increased, the two suspension formulations, including Solplus, showed a C max Both AUC and metric increased significantly. These results indicate that nilotinib ASD of this disclosure can increase nilotinib exposure in a fasted state, potentially facilitating lower dose delivery and an improved diet impact profile compared to Tasigna capsules.

[0178] Example 5. In vivo studies in humans Studies were conducted in human subjects to evaluate the pharmacokinetics observed after administration of compositions 1 and 2 of Example 3 compared to the pharmacokinetics observed after administration of conventional commercially available 200 mg Tasigna IR capsules, and to evaluate the effect of food on the pharmacokinetics observed after administration of the pharmaceutical compositions. Healthy subjects (n=26) were orally administered either Tasigna IR capsules (200 mg) or an appropriate amount of Composition 1 or Composition 2 of Example 3, according to the plan described in Table 23. This study employed a crossover study design in which each subject participated in each plan during each period of the study (note that Tasigna IR capsules cannot be administered under oral conditions, as indicated on the product label).

[0179] Table 23. Human in vivo administration plan for Example 5 [Table 23]

[0180] Subjects were screened for inclusion in this study up to 28 days prior to administration. Each study period followed the same design. Subjects were admitted to a clinical unit on the morning of the day before administration of the study product (day 1), where their eligibility was assessed and confirmed. After a minimum of 10 hours of overnight fasting, subjects were administered the product on the morning of day 1 of each period, and they were required to fast for approximately 4 hours after administration. In the feeding plan, subjects were administered the product 30 minutes after the start of a high-fat breakfast. Plasma samples were collected at the following time points after oral administration to assess plasma concentrations of nilotinib: 0 (before administration), 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 ​​hours, and 72 hours. For the first 48 hours after administration, subjects remained at the site, and at 72 hours post-administration, they returned to the clinical unit for pharmacokinetic plasma sampling and safety evaluation. There was a minimum of 7 days of drug-free rest between each study period. A subject was deemed evaluable for pharmacokinetic evaluation if, while fasted, they received Tasigna IR capsules and at least one of test compositions 1 and 2, and pharmacokinetic and safety data were obtained up to 72 hours after administration. A subject was deemed evaluable for evaluation of the effect of food if, while both fed and fasted, they received at least one of test compositions 1 and 2 (i.e., the same composition in both states) at the same dosage level, and pharmacokinetic and safety data were obtained up to 72 hours after administration.

[0181] Using pooled data from evaluable subjects (n=24-26), key pharmacokinetic parameters were calculated. Table 24 provides the geometric mean of key pharmacokinetic parameters, and Table 25 shows the dose-unadjusted relative bioavailability (F) in subjects after administration for each plan. rel The geometric mean of ) is shown. A comparison of plans A to C (see Figure 5) shows that although Tasigna IR capsules (plan A) contained 200 mg of nilotinib, and composition 1 (plan B) and composition 2 (plan C) contained only 50 mg of nilotinib, composition 1 and composition 2 showed the same AUC and C as 200 mg Tasigna IR capsules. max Equivalent to or better than AUC and C max This indicates that it showed the following values. In addition, composition 1 (plan B), which did not contain Solplus, had higher AUC and C than composition 2 (plan C). max The value was shown. A comparison between plans B and D (see Figure 6) shows that administration of the nilotinib pharmaceutical composition under fed conditions did not result in a significant increase in plasma concentrations of nilotinib compared to administration under fasting conditions. This is because the concentration levels and key pharmacokinetic parameters obtained with plan D (composition 1 at 50 mg administered under fed conditions) were not significantly improved compared to those obtained with plan B (composition 1 at 50 mg administered under fasting conditions) (see Figure 6, Tables 24 and 25). Similar results are evident in the comparison of plans E and F (see Figure 7). This is because the plasma concentration levels and key pharmacokinetic parameters of nilotinib obtained with plan F (composition 1 of 65 mg administered under food conditions) were equivalent to or lower than those obtained with plan E (composition 2 of 65 mg administered under food conditions) (see Tables 24 and 25). These results are surprising in light of the effects of food associated with conventional, commercially available immediate-release compositions of nilotinib known in the art (e.g., Tasigna IR capsules).

[0182] Table 24. Geometric mean (coefficient of variation, or CV%) of key pharmacokinetic parameters of nilotinib in healthy volunteers after oral administration of Tasigna IR capsules and nilotinib ASD compositions of selected embodiments of the present disclosure. [Table 24]

[0183] Table 25. Relative bioavailability (F) of nilotinib doses in healthy volunteers after oral administration of the nilotinib ASD composition of this disclosure. rel Geometric mean (CV%) of ) [Table 25] * * * * *

[0184] The foregoing statements are provided solely for the purpose of clear understanding, and no unwarranted limitations should be assumed from them. Various modifications and changes to this disclosure will be apparent to those skilled in the art without deviating from the scope and spirit of this disclosure. This disclosure is not intended to be unduly limited by the exemplary embodiments and examples described herein, and it should be understood that such embodiments and examples are presented merely as examples. Throughout this specification, references to "one embodiment," "an embodiment," "certain embodiments," etc., mean that a particular feature, configuration, composition, or characteristic described in relation to an embodiment is included in at least one embodiment of this disclosure. Therefore, the appearance of such phrases in various places throughout this specification does not necessarily refer to the same embodiment of this disclosure. Furthermore, such particular features, configurations, compositions, or characteristics may be combined in any preferred manner in one or more embodiments. Throughout this specification, if a composition is described as containing an ingredient or material, unless otherwise stated, it is intended that the composition may also essentially consist of any combination of the ingredients or materials described, or may consist of any combination of the ingredients or materials described. Similarly, if a method is described as containing a particular step, unless otherwise stated, it is intended that the method may also essentially consist of any combination of the steps described, or may consist of any combination of the steps described.

[0185] The methods disclosed herein, and the individual steps of such methods, can be carried out manually and / or with the help of electronic devices, or automated by electronic devices. While the processes have been described with reference to specific embodiments, those skilled in the art will readily understand that other methods can be used to perform the actions associated with such methods. Unless otherwise noted, the order of various steps can be changed, for example, without deviating from the scope or spirit of such methods. In addition, some of the individual steps can be combined, omitted, or further subdivided into additional steps. The term "comprises," and variations such as "comprises" and "comprising," are not restrictive when they appear in the description and claims of the specification. Such terms are understood to indicate the inclusion of the described process or element, or group of described processes or elements, but not to imply the exclusion of other processes or elements, or groups of other processes or elements.

[0186] "Consists of" means that the phrase includes and is limited to everything that precedes it. Thus, the phrase "consists of" indicates that the element indicated is necessary or essential, and that no other elements are present. "Consists essentially of" means that it includes and is limited to all elements that precede it, and that no other elements interfere with or contribute to the activity or action of the element indicated as specified in this disclosure. Thus, the phrase "consists essentially of" indicates that the element indicated is necessary or essential, but the other elements are optional and may or may not be present, depending on whether they substantially affect the activity or action of the element indicated. The words “preferred” and “preferred” refer to embodiments of the disclosure that, under certain circumstances, may provide a certain benefit. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the description of one or more preferred embodiments does not imply that other embodiments are useless, nor is it intended to exclude other embodiments from the scope of the disclosure.

[0187] In this application, terms such as “1 (a, an)” and “the” are not intended to refer only to singular entities, but also to a general class of specific examples that may be used for illustrative purposes. The terms “1” and “the” are used interchangeably with the term “at least one.” Where there are lists before or after the phrases “at least one” and “including at least one,” they refer to any one item in the list, and any combination of two or more items in the list. As used herein, the terms “or,” “or,” and “or” are generally used in their ordinary sense, including “and / or,” unless otherwise specified in the context. The terms “and / or” mean one or all of the elements shown, or any combination of two or more of the elements shown (for example, “preventing and / or treating pain” means preventing pain, treating pain, or treating and preventing pain).

[0188] Furthermore, in this specification, all numbers are assumed to be modified by the term “approximately,” preferably the term “exactly.” As used herein with respect to measured quantities, the term “approximately” refers to the variation in the measured quantity that a person skilled in the art would expect, given that the measurement is performed and with a level of care commensurate with the purpose of the measurement and the precision of the measuring instrument used. In this specification, “up to” a number (e.g., up to 50) includes that number (e.g., 50). Also in this specification, a numerical range description by endpoint includes all numbers and endpoints contained within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.), as well as any partial range (e.g., 1 to 5 includes 1 to 4, 1 to 3, 2 to 4, etc.).

[0189] The complete disclosures of patents, patent gazettes, and publications cited herein are included herein by reference in their entirety, as if each were included individually. In the event of any inconsistency or conflict between this disclosure and any other document included herein by reference, the description herein shall prevail.

Claims

1. A pharmaceutical composition comprising an amorphous solid dispersion, wherein the amorphous solid dispersion comprises nilotinib and one or more polymers, One or more polymers include a polymer that exhibits pH-dependent solubility. The pharmaceutical composition comprising nilotinib and one or more polymers present in an amorphous solid dispersion in a w / w ratio of 20:80 to 95:5 (nilotinib:polymer).

2. The pharmaceutical composition according to claim 1, wherein one or more polymers include hydroxypropyl methylcellulose acetate succinate.

3. The pharmaceutical composition according to claim 1, wherein one or more polymers comprises hydroxypropyl methylcellulose acetate succinate characterized by 7 to 11% acetyl substitution and 10 to 14% succinyl substitution.

4. A pharmaceutical composition according to any one of claims 1 to 3, wherein one or more polymers essentially consist of hydroxypropyl methylcellulose acetate succinate.

5. The pharmaceutical composition according to claim 1, wherein one or more polymers include a copolymer of methacrylic acid and ethyl acrylate that exhibits pH-dependent solubility.

6. The pharmaceutical composition according to claim 1, wherein one or more polymers comprise a copolymer of methacrylic acid and ethyl acrylate, and the copolymer is insoluble in aqueous media with a pH of 5 or less and soluble in aqueous media with a pH of 5.5 or more.

7. The pharmaceutical composition according to claim 5 or 6, wherein one or more polymers essentially consist of a copolymer of methacrylic acid and ethyl acrylate that exhibits pH-dependent solubility.

8. The pharmaceutical composition according to claim 1, wherein one or more polymers essentially consist of polymers that exhibit pH-dependent solubility.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the amorphous solid dispersion contains one or more antioxidants including butylated hydroxytoluene.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the amorphous solid dispersion contains one or more antioxidants present in an amount of 0.001% to 2% by mass of the amorphous solid dispersion.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the amorphous solid dispersion essentially consists of nilotinib and one or more polymers.

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

13. The pharmaceutical composition according to any one of claims 1 to 11, wherein nilotinib and one or more polymers are present in an amorphous solid dispersion in a w / w ratio of 50:50 (nilotinib:polymer).

14. A pharmaceutical composition according to any one of claims 1 to 13, comprising an amorphous solid dispersion and one or more pharmaceutically acceptable additives.

15. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is a solid dosage form suitable for oral administration.

16. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition exists as a solid dosage form suitable for oral administration and contains 25 to 100 mg of nilotinib.

17. A method for treating a proliferative disorder in a patient who requires treatment for a proliferative disorder, comprising the step of administering to the patient a pharmaceutical composition according to any one of claims 1 to 16, The method wherein the pharmaceutical composition is administered regardless of food consumption.

18. A method for treating a proliferative disorder in a patient who requires treatment for a proliferative disorder, comprising the step of administering to the patient a pharmaceutical composition according to any one of claims 1 to 16, The method wherein the pharmaceutical composition is administered regardless of whether the patient is fasting or feeding.

19. The method according to claim 17 or 18, wherein the proliferative disorder is cancer.

20. The method according to claim 17 or 18, wherein the proliferative disorder is Philadelphia chromosome-positive chronic myeloid leukemia.

21. The method according to claim 17 or 18, wherein the proliferative disorder is chronic-phase Philadelphia chromosome-positive chronic myeloid leukemia that is resistant to or intolerant to prior tyrosine kinase inhibitor treatment.

22. A method for safely delivering nilotinib to patients who require safe delivery of nilotinib, (a) The step of administering to a patient a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 16, (b) including the process of feeding the patient, The method wherein process (a) and process (b) occur within two hours of each other.

23. A method for delivering a therapeutically appropriate exposure dose of nilotinib to a subject, regardless of whether the subject is fasting or feeding, the method comprising the step of administering a pharmaceutical composition according to any one of claims 1 to 16 to the patient.

24. Administration of the pharmaceutical composition to a subject in a feeding state compared to administration of the pharmaceutical composition to a subject in a fasting state, resulting in a higher plasma C content of nilotinib. max Plasma C of nilotinib within 30% max The method according to claim 23, which brings about the following.

25. The method according to claim 23, wherein administration of the pharmaceutical composition to a subject in a feeding state results in a plasma AUC of nilotinib that is no more than 30% of the plasma AUC of nilotinib obtained by administration of the pharmaceutical composition to a subject in a fasting state.

26. The administration of the pharmaceutical composition to a subject in a feeding state yielded plasma C12 of nilotinib obtained by administering a nilotinib crystal immediate-release formulation containing 2 to 4 times the amount of nilotinib in the pharmaceutical composition to a fasted subject. max Plasma C of nilotinib within 25% max The method according to claim 23, which brings about the following.

27. The method according to claim 23, wherein administration of the pharmaceutical composition to a subject in a feeding state results in a plasma AUC of nilotinib that is no more than 25% of the plasma AUC of nilotinib obtained by administration of a nilotinib crystal immediate-release formulation having 2 to 4 times the amount of nilotinib of the pharmaceutical composition in a fasting state.

28. A kit for sale to users, comprising the pharmaceutical composition described in any one of claims 1 to 16 and an accompanying document, The kit, wherein the accompanying leaflet informs the user that the pharmaceutical composition can be administered together with food.

29. A kit for sale to users, comprising the pharmaceutical composition described in any one of claims 1 to 16 and an accompanying document, The kit, wherein the accompanying leaflet informs the user that the pharmaceutical composition can be administered with or without food.

30. A kit for sale to users, comprising the pharmaceutical composition described in any one of claims 1 to 16 and an accompanying document, The kit, wherein the accompanying leaflet does not include a warning that the pharmaceutical composition should not be administered with food.

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