Pharmaceutical compositions of nilotinibe

Description

1 / 28 Nilotinib Pharmaceutical Compositions Cross-Reference

[001] This application claims priority over Indian Patent Application No. 202341026974, filed on April 12, 2023. Field of Invention

[002] The present invention relates to an immediate-release pharmaceutical composition comprising amorphous solid dispersions of the protein kinase inhibitor or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to immediate-release pharmaceutical compositions of nilotinib, or a pharmaceutically acceptable salt thereof. A method of preparing said compositions is also disclosed. Background of the Invention

[003] Nilotinib is a kinase inhibitor with the following structure:

[004] The chemical name of Nilotinib is 4-methyl-N-[3-(4-methyl1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide. The molecular formula is C28H22F3N7O, which corresponds to a molecular weight of 529 q / mol (nilotinib base, anhydrous). Globally, Nilotinib is marketed under the trade name TASIGNA®, as an immediate-release formulation containing nilotinib monohydrochloride monohydrate and is used to treat certain types of chronic myeloid leukemia.

[005] Nilotinib monohydrochloride monohydrate is characterized as a Class IV (low / moderate) compound Petition 870250092921, dated 10 / 10 / 2025, page 11 / 44 2 / 28 aqueous solubility and low permeability) according to the Biopharmaceutical Classification System (BCS). The solubility of nilotinib in aqueous solutions decreases with increasing pH. The recommended dosage of TASIGNA® is 300 mg or 400 mg orally, twice daily. Based on reported data, the absorption of nilotinib after oral administration of TASIGNA® is approximately 30%.

[006] When TASIGNA® is administered with a high-fat meal, the maximum concentration (Cmax) and the area under the curve (AUC) increase by 112% and 82%, respectively.

[007] According to approved prescribing information, significant QT interval prolongation may occur when TASIGNA® is improperly taken with food and / or strong CYP3A4 inhibitors and / or medications with a known potential to prolong the QT interval. This effect on the QT interval is likely due to increased exposure (expressed as area under the curve, or AUC) and / or maximum plasma concentration (Cmax) that may occur when TASIGNA® is taken with food. This increase in serum levels may also exacerbate or increase the prevalence of common side effects such as nausea, diarrhea, rash, headache, muscle and joint pain, fatigue, vomiting, and fever; as well as more serious side effects such as low blood cell counts, decreased blood flow to the heart or brain, inflammation of the pancreas, liver problems, and bleeding problems.

[008] In addition, the solubility of nilotinib decreases significantly with increasing pH and therefore the absorption of nilotinib may be compromised if TASIGNA® is administered together with gastric acid-reducing agents. The use of TASIGNA® with common gastric acid-reducing agents is restricted, according to the prescribing information.

[009] Therefore, the current prescribing information for TASIGNA® instructs the patient to take TASIGNA® twice daily. Petition 870250092921, dated 10 / 10 / 2025, page 12 / 44 3 / 28 with an empty stomach and avoiding food 2 hours before and 1 hour after taking a dose, causing unnecessary burden to patients, which may lead to non-adherence to the treatment regimen. As a consequence of the above, few researchers are trying to develop an improved formulation of nilotinib and their proposed solutions are as follows: WO2013105894A1 provides a formulation of amorphous hybrid nanoparticles produced using nilotinib or a pharmaceutically acceptable salt thereof and a stabilizing and matrix-forming polymeric component. The method used in this disclosure for the preparation of amorphous hydride nanoparticles is supercritical fluid technology.

[010] The disclosures in document WO2021222739A1 provide a pharmaceutical composition in the form of an orally disintegrating tablet and comprise an amorphous solid dispersion of nilotinib. Orally disintegrating formulations are formulations that disintegrate or dissolve rapidly in the oral cavity without the use of water and are primarily targeted to geriatric patient populations.

[011] Document US20150273070A1 discloses solubilized modified-release solid dosage forms of nilotinib containing organic acids.

[012] Despite the efforts made in the technique to solve the aforementioned problems associated with TASIGNA®, there is still a need to develop an improved nilotinib formulation. Summary of the Invention

[013] The present inventors have discovered that a nilotinib formulation with enhanced properties could be developed by carefully selecting the excipients. According to the main aspect of the invention, an immediate-release formulation comprising a solid dispersion is provided. Petition 870250092921, dated 10 / 10 / 2025, page 13 / 44 4 / 28 amorphous nilotinib (ASD) or its pharmaceutically acceptable salts and a polymer wherein said polymer has a high glass transition temperature. Polymers with a glass transition temperature above 100°C are preferred.

[014] According to the preferred aspect of the present invention, an immediate-release formulation is provided comprising an amorphous solid dispersion of nilotinib or its pharmaceutically acceptable salts and a polymer with a high glass transition temperature and one or more excipients. The pharmaceutically acceptable excipients are selected from at least one filler and / or at least one binder and / or at least one disintegrant and / or at least one glidant and / or at least one lubricant and at least one solubilizer.

[015] In another aspect, the present immediate-release formulation provides enhanced solubility and absorption of nilotinib. Furthermore, the absorption of nilotinib from the present composition is minimally dependent on food intake and, therefore, in a preferred embodiment of the present invention, the immediate-release tablet for the present invention can be administered independently of food consumption. In another aspect, the present immediate-release formulation provides exceptionally large increases in aqueous concentration in a setting of use and therapeutic enhancement in oral bioavailability, thus enabling the administration of a reduced dose to achieve an effect similar to that obtained by the currently marketed TASIGNA® formulation.

[016] Another aspect of the disclosure relates to a method for increasing the bioavailability of nilotinib in a human subject, wherein the method comprises administering a pharmaceutical composition comprising an amorphous solid dispersion (ASD) of nilotinib to the human subject, and wherein the bioavailability is increased by at least 1.3 times, preferably by at least 1.5 times, and further Petition 870250092921, dated 10 / 10 / 2025, p. 14 / 44 5 / 28 preferably, at least 2 times, compared to the reference immediate-release crystalline nilotinib capsule TASIGNA®.

[017] Furthermore, in another aspect, the pharmaceutical compositions of the present disclosure unexpectedly provide a pharmacokinetic profile similar to that of TASIGNA®, even when the nilotinib dose administered by the pharmaceutical compositions is a fraction of the nilotinib dose normally administered when using TASIGNA®. Therefore, the disclosure provides pharmaceutical compositions that can be administered at a lower dose than TASIGNA®, but are bioequivalent to TASIGNA® and are therefore expected to provide a comparable therapeutic effect.

[018] Another aspect of the disclosure relates to a method of preparing an immediate-release pharmaceutical composition comprising an amorphous solid dispersion comprising nilotinib by solvent-controlled precipitation using a suitable polymer with a high glass transition temperature (over 100°C).

[019] In another aspect, the disclosure provides a method for manufacturing amorphous solid dispersions of nilotinib, wherein the method comprises: (i) preparing a solution comprising nilotinib and one or more polymers and (ii) mixing the solutions with at least one antisolvent to obtain a suspension of amorphous particles by coprecipitation.

[020] Another aspect of the revelation relates to a method of treating a disease that responds to an inhibition of protein kinase activity, such as a proliferative disorder.

[021] In another aspect, the present disclosure relates to a method of treating a proliferative disorder in a patient who needs it, the method comprising administering a therapeutically effective amount of a pharmaceutical composition of the present disclosure to the patient, regardless of food intake. Petition 870250092921, dated 10 / 10 / 2025, page 15 / 44 6 / 28

[022] In another aspect, the present disclosure relates to a method of treating a proliferative disorder in a patient who needs it, the method comprising administering an ASD or pharmaceutical composition of the present disclosure to a patient, regardless of whether the patient is fasting or fed. Brief Description of the Drawings

[023] Figure 1: XRD diffractogram of the amorphous solid dispersion of Nilotinib. Description of the Invention

[024] The present invention relates to an immediate-release pharmaceutical composition comprising an amorphous solid dispersion (ASD) of nilotinib that provides specific advantages and offers a safer, yet equally effective, nilotinib composition compared with currently available conventional immediate-release nilotinib formulations, such as TASIGNA®.

[025] The term amorphous solid dispersion, as used herein, refers to the dispersion of at least one drug in a matrix, in the amorphous state. The matrix may comprise polymers, optionally solubilizers or mixtures thereof. The term 'nilotinib' used herein refers broadly to nilotinib freebase, nilotinib salts, anhydrous nilotinib (or salts thereof), nilotinib hydrates or solvates, and nilotinib salt hydrates or solvates as suitable alternatives, unless otherwise specified.

[026] As used herein, TASIGNA® refers to the commercially available TASIGNA® immediate-release capsules, available in 50 mg, 150 mg and 200 mg dosages, marketed by Novartis.

[027] As used herein, the term immediate release refers to the rapid release of most of the therapeutic compound, for example, greater than about 50%, about 55%, Petition 870250092921, dated 10 / 10 / 2025, p. 16 / 44 7 / 28 approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, or approximately 90% in a relatively short time, for example, within 1 hour, 40 minutes, 30 minutes, or 20 minutes after oral ingestion. Particularly useful conditions for immediate release are the release of at least or equal to approximately 80% of the therapeutic compound within 45 minutes after oral ingestion. The particular conditions for immediate release for a specific therapeutic compound will be recognized or known by someone skilled in the art.

[028] The term 'pharmaceutical composition' used here means solid oral form, i.e., a tablet, capsule or granule, most preferably the solid pharmaceutical form is in the form of tablets, suitable for oral administration.

[029] An object of the present invention is to provide an immediate-release pharmaceutical composition comprising an amorphous solid dispersion comprising nilotinib. The ASD comprises nilotinib and one or more suitable polymers and, optionally, a solubilizer.

[030] Yet another objective of the present invention is that the polymer employed in the preparation of ASD has a high glass transition temperature, preferably more than 75°C, more preferably more than 100°C.

[031] The glass transition temperature (Tg), as used herein, is the characteristic temperature at which a glassy material, after gradual heating, undergoes a relatively rapid physical change (e.g., 10 to 100 seconds) from a glassy state to a rubbery state.

[032] The present invention provides an amorphous solid dispersion of nilotinib with a suitable polymer having a glass transition point in the range of 100°C to 180°C; preferably from 110°C to 160°C. The glass transition temperature can be measured by Differential Heat Flow Scanning calorimetry or Differential Compensation Scanning calorimetry. Petition 870250092921, dated 10 / 10 / 2025, page 17 / 44 8 / 28 Power.

[033] In some embodiments, the suitable polymer with a glass transition temperature of 110°C to 160°C is selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, Eudragit L100-55, modified HPMCs such as hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and hydroxypropyl methylcellulose phthalate (HPMCP), or mixtures thereof. In some embodiments, the nilotinib:polymer ratio is in the range of 1:0.5 to 1:5, preferably 1:1 to 1:3 and more preferably 1:1 to 1:2.

[034] This descriptive report further discloses a process in which coprecipitated particles of nilotinib and polymer are obtained by solvent-controlled precipitation, a technique in which a drug and a polymer are dissolved in a solvent, and this solution is then added to an antisolvent. The drug and the polymer then precipitate simultaneously in the antisolvent.

[035] According to one aspect of the present invention, a method is provided for manufacturing amorphous solid dispersions of nilotinib, wherein the method comprises: (i) preparing a solution comprising nilotinib and a solution comprising one or more polymers and stabilizing agents, wherein each solution is prepared using a first solvent, and (ii) mixing the solutions with a second solvent comprising at least one antisolvent to obtain a suspension of amorphous particles by coprecipitation.

[036] In one embodiment, the solution comprising the pharmaceutically active compound and the solution comprising at least one polymer are combined to form a first stream, before mixing with the second solvent, an antisolvent of the pharmaceutically active ingredient and the polymer. Preferably, the first stream solution comprising the polymer and the active compound is combined with the second solvent. Petition 870250092921, dated 10 / 10 / 2025, page 18 / 44 9 / 28 to form a second stream, which second stream comprises an antisolvent of the pharmaceutically active compound.

[037] The term solvent is used here to describe a solvent or a mixture of solvents, which is any substance, usually liquid, that is capable of dissolving nilotinib or its salt and the polymer.

[038] The first and / or second solvent is selected from: water, acetone, methyl chloride, dimethylformamide, methanol, ethanoldimethyl sulfoxide, methyl ethyl ketone, dimethylacetamide, lactic acid, isopropanol, 3-pentanol, n-propanol, glycerol, butylene glycol, ethylene glycol, propylene glycol, dimethyl isosorbide, tetrahydrofuran, 1,4-dioxanepolyethylene glycol, polyethylene glycol esters, polyethylene glycol sorbitans, polyethylene glycol monoalkyl ethers, polypropylene glycol, polypropylene alginate, butanediol and mixtures thereof.

[039] The term antisolvent is used here to describe a solvent, which is any substance, usually liquid, that has very low solubility for nilotinib and its pharmaceutically acceptable salt. When a solution containing nilotinib or its pharmaceutically acceptable salt is mixed with the common antisolvent, the nilotinib or its pharmaceutically acceptable salt precipitates within the antisolvent instead of dissolving in it, preferentially forming compound particles made of different substances. The antisolvent is preferably acidified water with a pH of 1.0–5.0.

[040] The antisolvent, according to the present invention, may be miscible or immiscible with solvent and has low solubility for Nilotinib. The preferred antisolvent is, but not exclusively, an aqueous solution that may be provided with one or more surface modifiers, such as an anionic surfactant, a cationic surfactant or a nonionic surfactant mixed with it. Preferably, the aqueous solution comprises Petition 870250092921, dated 10 / 10 / 2025, p. 19 / 44 10 / 28 deionized water.

[041] In one embodiment of the present invention, an amorphous solid dispersion of Nilotinib is manufactured by a method comprising: (i) preparing a solution comprising nilotinib and one or more suitable polymers with a high glass transition temperature using dimethylacetamide as a solvent; (ii) mixing the solution obtained in step (i) with cooled acidified water (pH 1-5) to precipitate the drug and the polymer; (iii) filtering and washing the solid mass obtained in step (ii) with fresh antisolvent and water, and drying to obtain the amorphous solid dispersion of the present invention.

[042] Another objective of the present invention is to provide pharmaceutical compositions comprising ASDs. In particular, the present invention provides a pharmaceutical composition comprising a nilotinib ASD and one or more solubilizers.

[043] Solubilizers that may be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (SOLUPLUS), polyethylene glycol dD-tocopherol (PEG) 1000 acid succinate (TPGS), PEG-40 hydrogenated castor oil (CREMOPHOR RH40), PEG35 castor oil (CREMOPHOR EL), PEG-40 stearate (MYRJ 540), hard fat (as GELUCIRE 33 / 01), polyoxylglycerides (as GELUCIRE 44 / 14), stearoyl polyoxylglycerides (as GELUCIRE 50 / 13), PEG-8 caprylic / capric glycerides (as LABRASOL) and poloxamers (as PLURONIC, KOLLIPHOR).

[044] Pharmaceutical compositions in the form of solid oral dosage forms may also include other pharmaceutically acceptable excipient(s) selected from a group comprising one or more fillers, one or more binders, one or more lubricants, one or more disintegrants and / or other conventional excipients, such as one or more glidants, one or more buffering agents, a Petition 870250092921, dated 10 / 10 / 2025, page 20 / 44 11 / 28 or more pH adjusting agents, one or more surfactants, one or more antioxidants, one or more precipitation inhibitors and / or one or more carriers, for example.

[045] Suitable fillers include acacia, calcium carbonate, calcium sulfate, calcium sulfate dihydrate, compressible sugar, anhydrous dibasic calcium phosphate (e.g., FUJICALIN, EMCOMPRESS), dibasic calcium phosphate dihydrate, tribasic calcium phosphate, monobasic sodium phosphate, dibasic sodium phosphate, lactose monohydrate, anhydrous lactose, magnesium oxide, magnesium carbonate, silicon dioxide, aluminum magnesium silicate, maltodextrin, mannitol, methylcellulose, microcrystalline cellulose (e.g., AVICEL PH-101, AVICEL PH-102), powdered cellulose, starches, sorbitol, dextrose, dextrates, dextrin, sucrose, xylitol and mixtures thereof.

[046] Suitable binders include various celluloses (e.g., HPMC, HPC, starch, etc.), povidone, cross-linked polyvinylpyrrolidone, microcrystalline cellulose (e.g., AVICEL PH101, AVICEL PH-102, AVICEL PH-105) or silicified microcrystalline cellulose (e.g., PROSOLV SMCC), for example.

[047] One or more lubricants may be included to reduce friction and adhesion to processing equipment during processing. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, stearic acid, stearyl alcohol, glyceryl monostearate, sodium stearyl fumarate, talc, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, and the like. When included, the one or more lubricant(s) is / are generally present in the range of 0.1% to 5% by weight of the pharmaceutical composition. In some embodiments, the one or more lubricant(s) is / are generally present in the range of 0.25% to 2% by weight of the pharmaceutical composition. In certain embodiments, the lubricant is magnesium stearate. Petition 870250092921, dated 10 / 10 / 2025, page 21 / 44 12 / 28

[048] Suitable disintegrants in the practice of developing include natural, modified or pregelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpolypyrrolidone (PVPP) and mixtures thereof.

[049] Slip agents are employed to improve the flow properties of a powder or granule mixture prior to further processing (such as tablet compression, for example). Suitable slip agents that may be employed in the compositions of the present disclosure include, but are not limited to, fumed silica (e.g., CAB-OSIL), colloidal silica, hydrophobic colloidal silica (e.g., AEROSIL R972), hydrophilic colloidal silica (e.g., AEROSIL 200 PHARMA), silica gel, precipitated silica and the like. When included, one or more slip agent(s) is / are generally present in the range of 0.1% to 5% by weight of the pharmaceutical composition. In some embodiments, one or more slip agent(s) is / are present in the range of 0.25% to 2% by weight of the pharmaceutical composition.

[050] Buffering agents that may be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, triethylamine, meglumine, diethanolamine, ammonium acetate, arginine, lysine, histidine, a phosphate buffer (e.g., tribasic sodium phosphate, dibasic sodium phosphate, monobasic sodium phosphate or phosphoric acid), sodium bicarbonate, a Britton-Robinson buffer, a Tris buffer (containing Tris(hydroxymethyl)-aminomethane), a HEPES buffer (containing N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid), acetate, a citrate buffer (e.g., citric acid, anhydrous citric acid, monobasic citrate, dibasic citrate, tribasic citrate, citrate salt), ascorbate, glycine, glutamate, lactate, malate, formate, sulfate and mixtures Petition 870250092921, dated 10 / 10 / 2025, page 22 / 44 13 / 28 of the same.

[051] In addition, pH adjusting agents that may be used in the pharmaceutical compositions of the present disclosure include pharmaceutically acceptable acids or bases. For example, acids may include, but are not limited to, one or more inorganic mineral acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric and the like; or one or more organic acids, such as acetic, succinic, tartaric, ascorbic, citric, glutamic, benzoic, methanesulfonic, ethanesulfonic, trifluoroacetic and the like. Bases may be one or more inorganic bases or organic bases including, but not limited to, alkaline carbonate, alkaline bicarbonate, alkaline earth metal carbonate, alkaline hydroxide, alkaline earth metal hydroxide or amine.For example, the inorganic or organic base could be an alkaline hydroxide, such as lithium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydroxide, or similar; an alkaline carbonate, such as calcium carbonate, sodium carbonate, or similar; or an alkaline bicarbonate, such as sodium bicarbonate or similar; the organic base could also be sodium acetate.

[052] Surfactants that may be used in the pharmaceutical compositions of the present disclosure may include, but are not limited to, sodium lauryl sulfate, sodium docusate, sodium dioctyl sulfosuccinate, sodium dioctyl sulfonate, benzalkonium chloride, benzethonium chloride, lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene hydrogenated castor oil 10, 50 or 60), glyceryl monostearate, polysorbate (e.g., polysorbate 40, 60, 65 or 80), sucrose fatty acid ester, methylcellulose, polyalcohols and ethoxylated polyalcohols, thiols (e.g., mercaptans) and derivatives, poloxamers, polyethylene glycol fatty acid esters (e.g., KOLLIPHOR RH40, KOLLIPHOR EL), lecithins and mixtures thereof. Petition 870250092921, dated 10 / 10 / 2025, page 23 / 44 14 / 28

[053] Antioxidants that may be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, acetylcysteine, ascorbyl palmitate, BHA, BHT, monothioglycerol, potassium nitrate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, EDTA (e.g., disodium edetate), DTPA, bismuth and sodium triglycolate, or a combination thereof. Antioxidants may also comprise amino acids such as methionine, histidine, cysteine, and those carrying a charged side chain, such as arginine, lysine, aspartic acid, and glutamic acid.Any stereoisomer (e.g., l-, d-, or a combination thereof) of any specific amino acid (e.g., methionine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine, and combinations thereof) or combinations of these stereoisomers may be present, provided that the amino acid is present in its free base form or in its salt form.

[054] In some cases, a single excipient can provide more than one function. For example, microcrystalline cellulose (when present) can function as both a filler and a binder. Alternatively, such multifunctional excipients can be used in combination with other functional excipients. (For example, microcrystalline cellulose can be used with other fillers and / or other binders.)

[055] The pharmaceutical compositions of the present disclosure may be in a dosage form 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 the formation of another oral dosage form, such as tablets, granules or pellets. In some embodiments, the pharmaceutical compositions may be in a Petition 870250092921, dated 10 / 10 / 2025, p. 24 / 44 15 / 28 solid dosage form for oral administration, such as capsule, tablet, granules or pellet.

[056] The pharmaceutical compositions of the disclosure in tablet form may be prepared using methods known in the art. For example, nilotinib ASD and one or more pharmaceutically acceptable additives may be mixed to provide a tablet mixture by manual mixing or in sachets, or using a suitable device. Suitable tablet mixtures may then be compressed into tablets with a target weight of 50 to 1000 mg using, for example, a manual tablet press or a conventional mechanical tablet press.

[057] In some embodiments, it may be desirable to form granules as an intermediate step in the formation of a tablet mixture. Granules typically exhibit improved flow, handling, mixing, and compression properties compared to non-granulated materials. Granules can be prepared from ASD particles by processes known in the art, including wet granulation and dry granulation.

[058] In certain embodiments, the granulation mixture may comprise ASD in an amount of 20% to 80%, or in an amount of 25% to 75% by weight. In specific embodiments, the granulation mixture comprises 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or 50%, or 55%, or 60%, or 65%, or 70%, 75% or 80% of ASD by weight. When a higher proportion of extragranular excipients is employed, the granulation mixture would contain a relatively high proportion of ASD; if a lower proportion of extragranular excipients is employed, the granulation mixture may contain a relatively lower proportion of ASD.

[059] In one embodiment, the granulation mixture is formed by dry mixing the granule components and then the granulation mixture is densified using a compactor. Petition 870250092921, dated 10 / 10 / 2025, page 25 / 44 16 / 28 rolls that normally form ribbons of material. The ribbons are then reduced in size by grinding to form granules. Enhanced wetting, disintegration, dispersion and dissolution properties are obtained by the inclusion of suitable excipients, as described above. After granulation, the granules can be included in a tablet mix and compacted into tablets.

[060] In one embodiment, the pharmaceutical compositions are in the form of a tablet.

[061] In one embodiment of the present invention, the immediate-release pharmaceutical composition is a tablet, and wherein the tablet is prepared by a method comprising: (i) Mix nilotinib amorphous solid dispersion (ASD), filler, solubilizer, disintegrant, glidant and, optionally, other excipients, (ii) Add the mixture from step (i) to the roller compaction and form granules, (iii) Add disintegrant and lubricant to the granules from step (ii), (iv) Compress the mixture from step (iii) into the tablet, and (v) Optionally coat the tablet.

[062] In certain embodiments, the tablet may comprise ASD in an amount of 20% to 50% by weight of the tablet; one or more solubilizers (such as polyvinyl caprolactam acetate-polyethylene glycol copolymer) in an amount of 20% to 40% by weight of the tablet; one or more fillers (such as mannitol and / or microcrystalline cellulose); one or more disintegrants (such as croscarmellose sodium and crospovidone); one or more lubricants and / or glidants (such as hydrophobic colloidal silica and / or magnesium stearate); and one or more binders (such as crospovidone).

[063] In some embodiments, the tablets are additionally film-coated. Preferably, the Petition 870250092921, dated 10 / 10 / 2025, page 26 / 44 17 / 28 film may be a hydrophilic / hydrophobic polymer selected from the group consisting of hydroxypropylcellulose, ethylcellulose, PVA or combinations thereof.

[064] In another aspect, the disclosure provides pharmaceutical compositions that are effectively bioequivalent to a suitable reference composition when administered to healthy human subjects in a fasted state, but at a lower molar dose of the active ingredient compared to the reference composition.

[065] The present invention provides a method for increasing bioavailability by administering the composition or pharmaceutical composition of the invention, respectively, to an animal or a patient, wherein the increase in bioavailability is determined by comparing the Cmax value or the AUC value of the composition or pharmaceutical composition of the invention with the composition disclosed in the present invention. Preferably, the method increases the bioavailability of a drug in the administered animal or patient by at least 1.3 times, preferably at least 1.5 times, even more preferably at least twice, relative to the commercially available TASIGNA® hard gelatin capsule.

[066] In some embodiments, where the pharmaceutical composition when administered to a human subject in a fed state provides a nilotinib Cmax value not exceeding 30%, preferably not exceeding 20%, preferably not exceeding 10%, preferably not exceeding 5% and most preferably not exceeding 1% compared to the nilotinib Cmax value resulting from administration of the pharmaceutical composition to a human subject in a fasted state.

[067] In some embodiments, where the pharmaceutical composition when administered to a fed human subject provides an AUC value not exceeding 45%, preferably not exceeding 40%, preferably not exceeding 30%, preferably not exceeding 10% and more Petition 870250092921, dated 10 / 10 / 2025, page 27 / 44 18 / 28 preferably not exceeding 5% compared to the AUC value resulting from administering the pharmaceutical composition to a fasting human subject.

[068] Bioavailability can be measured by a person skilled in the art using conventional methods. For example, tablets, capsules, liquids, powders, etc., are administered orally to humans or animals and blood levels are measured.

[069] For example, in some embodiments, administration of an ASD or pharmaceutical composition of the present disclosure may result in a pharmacokinetic profile comparable to the pharmacokinetic profile obtained by oral administration of a conventional immediate-release nilotinib formulation, but administered at a fraction of the dosage. For this comparison, administration should be done on an empty stomach, since TASIGNA® should only be administered on an empty stomach.

[070] By comparable, it is understood that administration of the ASD or the pharmaceutical composition of the disclosure to the individual may provide AUC0-t (such as AUC0-24h or AUC0-inf) or Cmax in the individual's plasma that are within the bioequivalence criteria of 80% to 125% compared with administration of the immediate-release crystalline nilotinib formulation to the same individual, dosed according to the label instructions.

[071] As used herein, fractional dosage may mean that the nilotinib dose in the ASD or pharmaceutical composition of the present disclosure may be 80% lower, or 75% lower, or 70% lower, or 65% lower, or 60% lower, or 55% lower, or 50% lower, or 45% lower, or 40% lower, or 35% lower, or 30% lower, or 25% lower, or 20% lower compared with the dosage indicated in the immediate-release nilotinib formulation.

[072] In some embodiments, the nilotinib dose in the ASD or in the pharmaceutical composition of the present disclosure is at least 80% lower, or 75% lower, or 70% lower, or 65% lower, or 60% lower, or 55% lower, or 50% lower compared to the dosage Petition 870250092921, dated 10 / 10 / 2025, page 28 / 44 19 / 28 indicated in the immediate-release crystalline nilotinib formulation.

[073] In a preferred embodiment of the present invention, a pharmaceutical composition of the present disclosure containing approximately 100 mg of nilotinib provides a pharmacokinetic profile that is comparable to the pharmacokinetic profile obtained by oral administration of an immediate-release crystalline nilotinib formulation labeled to contain 150 mg of nilotinib (such as 150 mg of TASIGNA®).

[074] In another preferred embodiment of the present invention, a pharmaceutical composition of the present disclosure containing approximately 135 mg of nilotinib provides a pharmacokinetic profile comparable to the pharmacokinetic profile obtained by oral administration of an immediate-release crystalline nilotinib formulation labeled to contain 200 mg of nilotinib (such as 200 mg of TASIGNA®).

[075] In another preferred embodiment of the present invention, a pharmaceutical composition of the present disclosure containing approximately 95 mg of nilotinib provides a pharmacokinetic profile comparable to the pharmacokinetic profile obtained by oral administration of an immediate-release crystalline nilotinib formulation labeled to contain 200 mg of nilotinib (such as 200 mg of TASIGNA®).

[076] By lowering the required dosage, but still providing effective exposure to the patient, the risks of overexposure are reduced. Overexposure to nilotinib is associated with the risk of QT prolongation discussed above, which is currently the subject of a black box warning on the TASIGNA® label.

[077] The risk of overexposure affects the entire population of patients treated with nilotinib. In addition to reducing the overall risk of overexposure, breakthrough formulations can limit the risk associated with an undesirably high Cmax. Petition 870250092921, dated 10 / 10 / 2025, page 29 / 44 20 / 28

[078] Yet another aspect of the disclosure relates to a method of preparing a pharmaceutical composition comprising a nilotinib ASD.

[079] Yet another objective of the present invention is to provide a method of treating a disease that responds to inhibition of protein kinase activity, such as a proliferative disorder.

[080] Some embodiments refer to a method of treating a proliferative disorder, the method comprising administering a nilotinib ASD of the present disclosure, or a pharmaceutical composition of the present disclosure, to a patient in need.

[081] Some embodiments relate to the use of an ASD of nilotinib, or pharmaceutical composition of the present disclosure, in the manufacture of a medicament for the treatment of a proliferative disorder, such as cancer.

[082] In some modalities, a therapeutically effective amount may be 50 mg / m2 to 250 mg / m2 of nilotinib, or 50 mg / m2 to 150 mg / m2 of nilotinib, or 60 to 120 mg / m2 of nilotinib.

[083] As generally interpreted, food effect refers broadly to all aspects of food interactions in drug dissolution, absorption, distribution, metabolism, and elimination. Implications of the food effect include alterations in bioavailability, rate of onset, duration of therapeutic effect, and incidence and severity of side effects. The magnitude of a food effect is generally greater when the drug is administered shortly after a meal.

[084] An example of a drug that exhibits a food-related effect is TASIGNA®, which can produce an increase in AUC and Cmax of 82% and 112%, respectively, when taken orally 30 minutes after a high-fat meal, compared to levels Petition 870250092921, dated 10 / 10 / 2025, page 30 / 44 21 / 28 obtained while fasting.

[085] In assessing the feeding effect, data obtained from fasted and fed studies are processed using conventional pharmacokinetic statistical analyses and methods. Fasted and fed studies may be single-dose studies or steady-state studies, as appropriate. Using pooled data from an adequate number of subjects, the absence of a feeding effect is indicated when the 90% confidence interval for the ratio of population geometric means between fed and fasted administrations, based on logarithmically transformed data, is contained within the equivalence limits of 80% to 125% for AUC0-inf (or AUC0-t when appropriate) and Cmax.On the other hand, the absence of a feeding effect is not established if the 90% confidence interval for the ratio of population geometric means between fed and fasting administrations, based on logarithmically transformed data, is not contained within the 80% to 125% equivalence limits for AUC0-inf (or AUC0-t when appropriate) or Cmax.

[086] In the methods of the present disclosure, no food effect means that the relative difference is not substantially large, for example, less than 20%, or less than 15%, or less than 10%, for AUC (which may be, for example, AUC0-24h, AUC0-last or AUC0-inf) and / or Cmax, for nilotinib when the ASD or pharmaceutical composition of the present disclosure is administered orally, concomitantly with food or in a fed state, compared with the value measured for the same parameter when the same ASD or pharmaceutical composition is administered in a fasted state.

[087] In the methods of the present disclosure, regardless of food consumption means that no consideration needs to be given to whether the ASD or pharmaceutical composition of the present disclosure is being administered to the individual or patient. Petition 870250092921, dated 10 / 10 / 2025, page 31 / 44 22 / 28 concomitantly with food, or if the patient or individual is in a fed or fasting state.

[088] In preferred embodiments of the present invention, administration of ASD or the pharmaceutical composition to a fed individual provides nilotinib exposure similar to the exposure resulting from administration of the pharmaceutical composition to a fasting individual. Exposure can be expressed as AUC0-12h, AUC0-24h, AUC0-last or AUC0-inf, for example; exposure can be for an individual individual or a geometric mean of several individuals.

[089] In certain preferred embodiments of the present invention, administration of the pharmaceutical composition to a fed individual provides a plasma Cmax of nilotinib similar to the plasma Cmax resulting from administration of the pharmaceutical composition to a fasting individual. The plasma Cmax may be for one individual or a geometric mean of several individuals. As used in this context, similar exposure means a relative difference in plasma nilotinib exposure between the fed and fasting states of less than 25%, or less than 20%, or less than 15%, or less than 10%, or less than 5%.

[090] Although the invention has been described with reference to specific embodiments, these descriptions are not intended to be constructive in a limiting sense. Various modifications of the disclosed embodiments, as well as alternative embodiments of the invention, will become apparent to a person skilled in the art by reference to the description of the invention. Therefore, it is anticipated that such modifications may be made without departing from the spirit or scope of the present invention, as defined. Examples

[091] The following examples are presented for illustration purposes only and are not intended to limit the scope of the invention or the appended claims. Petition 870250092921, dated 10 / 10 / 2025, pp. 32 / 44 23 / 28 Example 1: Amorphous solid dispersion of nilotinib Table 1: Formula for Example 1 Ingredient Weight (mg) Weight (mg) Nilotinib 135.00 100.00 Hypromellose-55 Phthalate (HP-55) 202.50 150.00 N,N-Dimethylacetamide q.s. q.s. Acidified water (pH 1.0-5.0) q.s. q.s. Purified water q.s. q.s.

[092] Manufacturing process: i. prepare a solution comprising nilotinib and hypromellose phthalate, using dimethylacetamide; ii. mix the solution obtained in step (i) with cooled acidified water (pH 1.0-5.0) to precipitate the drug and the polymer; and iii. filter and wash the solid mass obtained in step (ii) with fresh antisolvent and water, and dry to obtain the amorphous solid dispersion of the present invention. Example 2: Amorphous solid dispersion of nilotinib Table 2: Formula for Example 2 Ingredient Weight (mg) Weight (mg) Nilotinib 135.00 100.00 Hypromellose acetate succinate 202.500 150.00 N,N-Dimethylacetamide q.s. q.s. Acidified water (pH 1.0-5.0) q.s. q.s. Purified water q.s. q.s.

[093] The manufacturing process was similar to that described above in Example -1. Example 3: Nilotinib ASD tablet compositions Example 1 [T2] and Example 2 [T1] Table 3: Formula for Example 3 Nilotinib 100 mg and 135 mg Tablets Product No. Ingredients T1 T2 135 mg 100 mg 135 mg 100 mg % w / w % w / w % w / w % w / w Petition 870250092921, dated 10 / 10 / 2025, pp. 33 / 44 24 / 28 Solid Dispersion 1 Nilotinib 15.66 15.66 21.84 21.73 2 Hypromellose-55 Phthalate (HP-55) ^^^B ^^^B 32.76 32.60 3 Hypromellose ASMG 23.49 23.49 ^^^B ^^^B 4 N,N-Dimethylacetamide qs qs qs qs 5 Purified water pH 1-5 qs qs qs qs 6 Purified water qs qs qs qs Roller Compaction 7 Mannitol (Perlitol SD 200) 17.69 17.69 24.67 24.55 8 Soluplus 27.14 27.14 ^^^B ^^^B 9 Croscarmellose sodium 3, 82 3, 82 5, 33 5, 31 10 Crospovidone 3, 82 3, 82 5, 33 5, 31 11 Colloidal Silicon Dioxide (Aerosil 200) 0.29 0.29 0.40 0.40 12 Magnesium Stearate 0.52 0.52 0.48 0.72 Extragranular Materials 13 Crospovidone 3, 82 3, 82 5, 33 5, 31 14 Colloidal Silicon Dioxide (Aerosil 200) 0.29 0.29 0.40 0.40 15 Magnesium Stearate 0.52 0.52 0.48 0.72 Film Coating 16 Opadry (PVA-based) 2.90 2.90 2.91 2.91 17 Purified water qs qs qs qs Total weight of the tablet 100.00 100.00 100.00 100.00

[094] Manufacturing process: 1. Nilotinib ASD, Soluplus, and a portion of mannitol, croscarmellose sodium, crospovidone, colloidal silicon dioxide, and magnesium stearate are sieved and mixed; Petition 870250092921, dated 10 / 10 / 2025, pages 34 / 44 25 / 28 2. The granulation mixture obtained in step (1) was compacted with a roller and granulated; 3. Strips of compacted material obtained in step (2) were then ground; 4. The nilotinib ASD granules obtained in step (3) were mixed with the remaining portion of crospovidone, colloidal silicon dioxide and magnesium stearate; and the resulting tablet-forming mixture was then compressed into tablets. 5. The tablets were coated with Opadry using purified water as a solvent. Example 4: Comparative study of dissolution [0 95] Nilotinib T1 and T2 tablets prepared according to Example 3 (Test Formulation) were evaluated for in vitro dissolution, in comparison with TASIGNA® 200 mg tablets (Reference Formulation). [0 96] Dissolution was performed using a two-stage dissolution procedure, in which the acidic medium was transferred to the basic medium in order to simulate the in vivo condition and verify the rate of precipitation inhibition in alkaline medium. [0 97] Initially, dissolution was performed in 250 mL of Simulated Gastric Fluid (SGF) for up to 30 minutes using a USP type II (Paddle) apparatus at 50 rpm and transferred to an alkaline medium containing Fasting Stimulated Intestinal Fluid (FaSSIF) pH 6.5, 500 mL at 8 mL / min using a peristaltic pump, maintaining dissolution conditions similar to those of the acidic medium. The total volume of the FaSSIF medium becomes 750 mL after the addition of the acidic medium (250 mL of 0.01 N HCl + 500 mL of phosphate buffer pH 6.8). Sampling was performed simultaneously at different time points while the acidic medium was added and dissolution continued for up to 240 minutes. [0 98] The dissolution profiles of the test formulation and the reference formulation are shown in Table 4 below: Petition 870250092921, dated 10 / 10 / 2025, pages 35 / 44 26 / 28 TASIGNA® 200 mg T1 T2 1:1.5 1:1.5 Acid stage Peristaltic pump Disso: Acid stage - SGF, 250 mL, Paddle, 50 rpm Time (min) %DR %DR %DR 10 18 77 53 20 24 82 57 30 30 87 62 Buffer stage Buffer stage: FaSSIF pH 6.5, 750 mL, Paddle, 50 RPM 10 13 42 24 15 22 63 27 20 31 58 33 30 44 68 27 45 34 59 14 60 13 52 11 90 13 41 6 120 12 31 5 150 14 26 5 180 9 22 5 210 12 24 5 240 13 21 5 [09 9] The results above demonstrate that the test formulations T1 and T2 (nilotinib 135 mg tablets) provide better dissolution than the Reference formulation (TASIGNA® 200 mg tablets). Other T1 formulations showed better results compared to the T2 formulations. It is also clear that the Test formulation does not precipitate in buffer medium, unlike the Reference formulation. Based on the dissolution results shown in Example 4, formulations T1 and T2 were further tested for in vivo PK assays in humans against TASIGNA® 200 mg tablets (Reference Formulation). Example 5: Comparative In vivo Pharmacokinetic (PK) Study in Humans

[100] A PK study was conducted. This is an open-label, randomized, three-treatment, four-period, four- Petition 870250092921, dated 10 / 10 / 2025, pp. 36 / 44 27 / 28 sequences, single-dose, crossover, oral bioavailability of nilotinib 135 mg tablets (135 mg x 2 tablets) from Dr. Reddy's Laboratories Limited, India, compared with the reference formulation TASIGNA® (Nilotinib) 200 mg capsules (200 mg x 2 capsules) from Novartis Biosciences SA Indústria Brasileira in normal, healthy adult human subjects, both fasted and fed. The four-way crossover PK study was conducted to obtain the following comparative data: Fasting (TFa / RFa fasting): Reference (2 x 200 mg) vs. T1 and T2 (2 x 135 mg) Fed (TFe / TFa): Test (2 x 135 mg) vs. Test (2 x 135 mg)

[101] The results of the Example 5 study are summarized in Tables 5 and 6 provided below: Table 5: Statistical Summary for the Fasting Study with 135 mg Nilotinib Tablets (TFa / RFa) Test Dose of 270 mg vs. 400 mg RLD Dose Parameter Geometric Least Squares Mean Ratio (TFa / RFa) % 90% Confidence Limits (%) Potency (%) ISCV (%) Test Reference Lower Upper Fasting - Formulation T1 Cmax (ng / mL) 952.221 625.419 152.25 130.73 177.32 78.30 32.48 AUC0-t (ng.h / mL) 17106.577 13023.396 131.35 115.95 148.81 90.53 26.36 AUC0-inf (ng.h / mL) 17566.730 13991.00 125.56 109.98 143.34 87.39 28.05 Fasting - T2 Formulation Cmax (ng / mL) 944.039 623.648 151.37 135.24 169.43 94.67 23.98 AUC0-t (ng.h / mL) 16293.012 12978.635 125.54 111.63 141.17 93.19 24.91 AUC0-inf (ng.h / mL) 17402.546 13976.673 124.51 112.17 139.21 96.84 22.07

[102] From the data shown in Table 5, it is evident that improved bioavailability was observed considering the test dose of 270 mg versus the RLD dose of 400 mg. Table 6: Statistical Summary for the Nilotinib 135 mg Tablet-Fed Study (T1Fe / T1Fa) Test dose of 270 mg Petition 870250092921, dated 10 / 10 / 2025, pp. 37 / 44 28 / 28 Parameter Mean of Geometric Least Squares Ratio (T1Fe / T1Fa) % 90% Confidence Limits (%) Power (%) ISCV (%) Test (T1Fe) Test (T1Fa) Lower Upper Fasting - ASD with HPMC ASMG (T1) (N=27) Cmax (ng / mL) 1222.529 963.848 126.84 109.09 147.48 79.03 33.19 AUCc-t (ng.h / mL) 23934.017 17250.019 138.75 123.25 156.19 92.83 25.81 AUC0-inf (ng.h / mL) 24901.761 17690.490 140.76 124.93 158.61 92.51 26.02

[103] From the data shown in Table 6, it is evident that the feeding effect was observed with a 27% increase in Cmax in the test formulation (compared to a 112% increase in Cmax in the case of TASIGNA® RLD, based on data reported in the literature) and a 40% increase in AUC in the test formulation (compared to an 82% increase in AUC in TASIGNA® RLD, based on data reported in the literature). Therefore, the reduction of the positive feeding effect is achieved.

[104] Based on the results of the in vivo Pharmacokinetic (PK) study of example 5, it is possible to further reduce the dose to obtain bioavailability comparable to the reference formulation TASIGNA® (Nilotinib) 200 mg capsules. Another PK study is planned with reduced doses of 90 mg, 95 mg and 100 mg, administered twice daily, of the Test formulation against the TASIGNA®RLD 200 mg formulation. Petition 870250092921, dated 10 / 10 / 2025, pp. 38 / 44

Claims

1 / 3 CLAIMS 1. Immediate-release pharmaceutical composition, characterized in that the composition comprises: a) an amorphous solid dispersion comprising: i. Nilotinib or a pharmaceutically acceptable salt thereof, ii. one or more suitable polymers with a glass transition temperature between 100°C and 180°C, iii. optionally, one or more solubilizers b) one or more pharmaceutically acceptable excipients.

2. Immediate-release pharmaceutical composition according to claim 1, characterized in that nilotinib and the polymer are present in a ratio of 1:0.5 to 1:

5.

3. Immediate-release pharmaceutical composition according to claim 1, characterized in that the polymer is selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, Eudragit L100-55, modified HPMCs such as hydroxypropylmethylcellulose acetate succinate and hydroxypropylmethylcellulose phthalate, or mixtures thereof.

4. Immediate-release pharmaceutical composition according to claim 1, characterized in that the solubilizer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, polyethylene glycol succinate dD-tocopherol 1000 acid, PEG-40 hydrogenated castor oil, PEG-35 castor oil, PEG-40 stearate, hard fat, polyoxylglycerides, stearoyl polyoxylglycerides, PEG-8 caprylic / capric glycerides and poloxamers.

5. Immediate-release pharmaceutical composition, according to claim 1, characterized in that the composition comprises an amorphous solid dispersion in an amount of 20% to 50% by weight of the tablet and one or more solubilizers in an amount of 20% to 40% by weight of the tablet.

6. Immediate-release pharmaceutical composition according to claim 1, characterized in that a pharmaceutically acceptable excipient is selected from at least one solubilizer, at least one bulking agent, at least one disintegrant, at least one glidant and at least one lubricant.

7. Immediate-release pharmaceutical composition according to claim 1, characterized in that the composition is a tablet, and the tablet is prepared by a method comprising: (i) mixing the amorphous solid dispersion (ASD) of nilotinib, solubilizer, filler, disintegrant, lubricant and glidant, (ii) adding the mixture from step (i) to roller compaction and forming granules, (iii) adding disintegrant and lubricant to the granules from step (ii), (iv) compressing the mixture from step (iii) into a tablet, and (v) optionally coating the tablet.

8. Immediate-release pharmaceutical composition according to claim 1, characterized in that the composition can be administered independently of food consumption.

9. Immediate-release pharmaceutical composition according to claim 1, characterized in that the amorphous solid dispersion of nilotinib is prepared using a method comprising: (i) preparing a solution comprising nilotinib and a solution comprising one or more polymers, wherein each solution is prepared using a first solvent, and (ii) mixing the solutions with a second solvent comprising at least one antisolvent to obtain a suspension of amorphous particles by coprecipitation.

10. Method for manufacturing the amorphous solid dispersion of nilotinib, as defined in claim 1, characterized in that the first and / or second solvents are selected from the group consisting of water, acetone, methyl chloride, dimethylformamide, methanol, ethanol dimethyl sulfoxide, methyl ethyl ketone, dimethylacetamide, lactic acid, isopropanol, 3-pentanol, n-propanol, glycerol, butylene glycol, ethylene glycol, propylene glycol, 1,4-dioxane polyethylene glycol, polyethylene glycol sorbitans, polyethylene glycol monoalkyl ethers, polypropylene glycol, butanediol and mixtures thereof, and the antisolvent is acidified water (pH 1.0-5.0). Petition 870250092921, dated 10 / 10 / 2025, pp. 41 / 44

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