DESC:FIELD OF THE INVENTION
The present invention relates to 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 preparation of the said compositions is also dislcosed.

BACKGROUND OF THE INVENTION
Nilotinib is a kinase inhibitor having the following structure:

The chemical name for Nilotinib is 4-methyl-N-[3-(4-methyl-1H-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 g/mol (nilotinib base, anhydrous). Globally, Nilotinib is marketed under the tradename TASIGNA®, as an immediate-release formulation containing nilotinib monohydrochloride monohydrate and is used to treat certain types of chronic myeloid leukemia.

Nilotinib monohydrochloride monohydrate is characterized as a Class IV compound (low/moderate 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 300mg or 400mg orally twice daily. Based on the reported data, the absorption of Nilotinib after oral administration of TASIGNA® is approximately 30%. When TASIGNA® is administered with high fat meal, maximum concentration (Cmax) and area under the curve (AUC) increases 112% and 82%, respectively.
According to the approved prescribing information, “[s]ignificant prolongation of the QT interval may occur when TASIGNA® is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT.” This effect on the QT interval is likely due to the increase in exposure (expressed as area-under- the-curve, or AUC) and/or maximum plasma concentration (Cmax) that can occur when TASIGNA® is taken with food. Such an 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, tiredness, vomiting, and fever; as well as more serious side effects such as low blood cell counts, decreased blood flow to the heart or brain, pancreas inflammation, liver problems, and bleeding problems.

In addition, the solubility of nilotinib significantly decreases with increasing pH, and therefore nilotinib absorption may be compromised if TASIGNA® is administered along with gastric acid-reducing agents. Use of TASIGNA® with common gastric acid-reducing agents is restricted in accordance with prescribing information.

Therefore, the current prescribing information for TASIGNA® instructs the patient to take TASIGNA® twice daily on an empty stomach, and avoid food 2 hours before and 1 hour after taking a dose causing unnecessary burden to patients, which may lead to patient non-compliance with the treatment regiment. As a conquence of the above, few reaserchers are trying to develop an improved formulation of nilotinib and their proposed solutions are as follows:

WO2013105894A1 provides an amorphous hybrid nanoparticle formulation produced by using Nilotinib or pharmaceutically acceptable salt thereof and a polymeric stabilizing and matrix-forming component. The method used in this disclosure, for the preparation of amorphous hydrid nanoparticle is supercritical fluid technology.

The disclosures in WO2021222739A1 provides pharmaceutical composition in the form of orally disintegrating tablet and comprises of an amorphous solid dispersion of nilotinib orally disintegrating formulations are the formulations which rapidly disintegrates or dissolves in the oral cavity without using water and mainly targeted for geriatric patient polulations.

US20150273070A1 discloses nilotinib solubilized modified release solid dosage forms containing organic acids.

In spite of the efforts made in art to solve the aforementioned issues associated with TASIGNA®, there still remains a need to develop an improved nilotinib formulation.

SUMMARY OF THE INVENTION
The present inventors have found that a nilotinib formulation with improved properties could be developed by carefully selecting the excipinets. According to the main aspect of the invention, there is provided an immediate release formulation comprising amorphous solid dispersion (ASD) of nilotinib or it’s pharmaceutically acceptable salts and a polymer wherein the said polymer has a high glass transition temperature. The polmyers having glass transition temperature of more than 100 ° C are preferred.

According to preferred aspect of the present invention, there is provided an immediate release formulation comprising amorphous solid dispersion of nilotinib or it’s pharmaceutically acceptable salts and a polymer having high glass transition temperature and one or more excipinets. The pharmaceutically acceptable excipient 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 solublizer.

In another aspect, the present immediate release formulation provides improved solubility and abosprtion of nilotinib. Additionally, the absorption of nilotinib from the present composition is minimally dependent on the food intake and thus, in preferred embodiment of the present invention, the immediate release tablet for the present invention can be administered independent of the food consumption. In another aspect, the present immediate release formulation provides unusually large enhancements in aqueous concentration in an environment of use and theraby improvement in the oral bioavalability and thus possibility of administering a reduced dose to achieve a similar effect which is achieved by currently marketed TASIGNA® formulation.

Yet another aspect of the disclosure relates to a method of increasing bioavailability of nilotinib in a human subject, wherein the method comprises administration of a pharmaceutical composition comprising an amorphous solid dispersion (“ASD”) of nilotinib to the human subject, and wherein the bioavailability is increased by least 1.3 fold, preferably at least 1.5 fold, and more preferably by at least 2 fold, as compared to reference immediate-release crystalline nilotinib capsule TASIGNA®.

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

Yet another aspect of the disclosure relates to a method of preparation of immediate release pharmaceutical composition comprising an amorphous solid dispersion comprising nilotinib by solvent controlled precipitation technique using a suitable polymer having a high glass transition temperature (more than 100 ° C).

In another aspect, the disclosure provides a method of manufacturing amorphous solid dispersions 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 anti-solvent to obtain a suspension of amorphous particles by co-precipitation.

Yet another aspect of the disclosure relates to a method of treating a disease which responds to an inhibition of protein kinase activity, such as a proliferative disorder.

In another aspect, the present disclosure relates to a method of treating a proliferative disorder in a patient in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition of the present disclosure to the patient without regard to consumption of food.

In another aspect, the present disclosure relates to a method of treating a proliferative disorder in a patient in need thereof, the method comprising administration of an ASD or pharmaceutical composition of the present disclosure to a patient without regard to whether the patient is in a fasted state or a fed state.

BRIEF DESCRIPTION OF DRAWINGS
Figure 1: XRD diffractogram of Nilotinb amorphous solid dispersion.

DESCRIPTION OF THE INVENTION
The present invention relates to immediate release pharmaceutical composition comprising amorphous solid dispersion (“ASD”) of nilotinib that provide particular advantages, and offer a safer but equally effective composition of nilotinib as compared to the currently available conventional immediate-release nilotinib formulations, such as TASIGNA®.

The term “amorphous solid dispersion” as used herein, refers to dispersion of at least one drug in a matrix, in the amorphous state. The matrix may comprise polymers, optionally solubilizer or mixtures thereof. The term 'nilotinib' used herein refers broadly to nilotinib free base, salts of nilotinib, anhydrous nilotinib (or salts thereof), hydrates or solvates of nilotinib, and hydrates or solvates of nilotinib salts as suitable alternatives, unless specified.

As used herein, “TASIGNA®” refers to commercially available TASIGNA® immediate-release capsules, available in strengths of 50mg, 150mg and 200mg, marketed by Novartis.

As used herein the term “immediate-release” refers to the rapid release of the majority of the therapeutic compound, e.g., greater than about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, or about 90% within a relatively short time, e.g., within 1 hour, 40 minutes, 30 minutes or 20 minutes after oral ingestion. Particularly useful conditions for immediate-release are release of at least or equal to about 80% of the therapeutic compound within forty-five minutes after oral ingestion. The particular immediate-release conditions for a specific therapeutic compound will be recognized or known by one of ordinary skill in the art.

The term 'pharmaceutical composition' used herein, means solid oral form i.e., either a tablet or capsules or granules, more preferably the solid dosage form is present in the form of tablets, suitable for oral administration.

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

Yet another object of the present invention the polymer employed in preparation of ASD has a high glass transition temperature, preferably more than 750C, more preferably more than 100 ° C.

Glass transition temperature (Tg) as used herein is the characteristic temperature where a glassy material, upon gradual heating, undergoes a relatively rapid (e.g., 10 to 100 seconds) physical change from a glass state to a rubber state.

The present invention provides an amorphous solid dispersion of nilotinib with a suitable polymer having a glass transition point in the range of from 100 °C to 180 °C; preferably from 110 °C to 160 °C. The glass transition temperature may be measured by Heat Flux Differential Scanning calorimetry or Power Compensation Differential Scanning calorimetry.

In some embodiments, the suitable polymer having a glass transition temperature of from 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 from 1:1 to 1:2.

The present specification further discloses a process wherein co-precipitated particles of nilotinib and polymer are obtained through solvent controlled precipitation, a technique in which a drug and polymer are dissolved in a solvent, and this solution is then added to an antisolvent. The drug and polymer then precipitate out simultaneously in the antisolvent.

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

In an embodiment, the solution comprising the pharmaceutically active compound and the solution comprising at least one polymer are combined to form a first stream, prior to mixing with the second solvent, an anti-solvent of both the pharmaceutically active ingredient and the polymer. Preferably, the first stream solution comprising the polymer and active compound is combined with the second solvent to form a second stream, which second stream comprises an anti-solvent of the pharmaceutically active compound.

The term "solvent" is used herein to describe a solvent or a mixture of solvents, which is any substance, usually liquid, which is capable of dissolving nilotinib or it’s salt and the polymer. .

The first and/or the second solvent is selected from: water, acetone, methylchloride, dimethylformamide, methanol, ethanoldimethyl sulfoxide, methylethylketone, 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.

The term "anti-solvent" is used herein to describe a solvent, which is any substance, usually liquid, and has a very poor solublity for nilotinib and pharmaceutically acceptable salt. When solution containing Nilotinib or pharmaceutically acceptable salt is mixed with the common anti-solvent, the Nilotinib or pharmaceutically acceptable salt precipitate within the anti-solvent as opposed to dissolving within in, preferably forming composite particles made of the different substances. The anti-solvent is preferably acidified water with a pH 1.0-5.0.

The anti-solvent, according to the present invention, may be miscible or immiscible with the solvent and has low solubility for Nilotinib. The preferred anti-solvent is, but not exclusively, an aqueous solution which may be provided with one or more surface modifiers such as an anionic surfactant, a cationic surfactant or a nonionic surfactant mixed in it. Preferably, the aqueous solution comprises deionized water.

In an 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 having a high glass transition temperature using dimethylacetamide as the solvent; (i) mixing the solution obtained in step (i) to cooled acidified water (pH 1-5) to precipitate out both the drug and the polymer; (iii) filtering and washing the solid mass obtained in step (ii) with fresh antisolvent and water, and dried to obtain amorphous solid dispersion of the present invention.

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

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), d-D-tocopherol acid polyethylene glycol (PEG) 1000 succinate (TPGS), PEG-40 hydrogenated castor oil (CREMOPHOR RH40), PEG-35 castor oil (CREMOPHOR EL), PEG-40 stearate (MYRJ 540), hard fat (such as GELUCIRE 33/01), polyoxylglycerides (such as GELUCIRE 44/14), stearoyl polyoxylglycerides (such as GELUCIRE 50/13), PEG-8 caprylic/capric glycerides (such as LABRASOL) and poloxamers (such as PLURONIC, KOLLIPHOR).

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 agent(s), one 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.

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

Suitable binders include various celluloses (e.g. HPMC, HPC, starch, ect.), povidone, cross-linked polyvinylpyrrolidone, microcrystalline cellulose (e.g., AVICEL PH-101, AVICEL PH-102, AVICEL PH-105), or silicified microcrystalline cellulose (e.g., PROSOLV SMCC), for example.

One or more lubricants may be included to reduce friction with and adherence 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 is generally present in the range of 0.1% to 5%, by weight of the pharmaceutical composition. In some embodiments, the one or more lubricant is generally present in the range of 0.25% to 2%, by weight of the pharmaceutical composition. In certain embodiments, the lubricant is magnesium stearate.

Suitable disintegrants in the practice of the disclosure include natural, modified or pre- gelatinized starch, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpolypyrrolidone (“PVPP”), and mixtures thereof.

Glidants are employed to improve flow properties of a powder or granule mixture prior to further processing (such as tablet compression, for example). Suitable glidants that may be employed in the compositions of the present disclosure include, but are not limited to, fumed silica (e.g., CAB-O-SIL), 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, the one or more glidant is generally present in the range of 0.1% to 5%, by weight of the pharmaceutical composition. In some embodiments, the one or more glidant is present in the range of 0.25% to 2%, by weight of the pharmaceutical composition.

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., sodium phosphate tribasic, sodium phosphate dibasic, sodium phosphate monobasic, or o-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, citric acid anhydrous, citrate monobasic, citrate dibasic, citrate tribasic, citrate salt), ascorbate, glycine, glutamate, lactate, malate, formate, sulfate, and mixtures thereof.

Further, 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. The 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 may be an alkaline hydroxide such as lithium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydroxide, or the like; an alkaline carbonate such as calcium carbonate, sodium carbonate, or the like; or an alkaline bicarbonate such as sodium bicarbonate, or the like; the organic base may also be sodium acetate.

Surfactants that may be used in the pharmaceutical compositions of the present disclosure may include, but are not limited to, sodium lauryl sulfate, docusate sodium, dioctyl sodium sulfosuccinate, dioctyl sodium sulfonate, benzalkonium chloride, benzethonium chloride, lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene hydrogenated castor oil 10, 50, or 60), glycerol monostearate, polysorbate (e.g., polysorbate 40, 60, 65, or 80), sucrose fatty acid ester, methyl cellulose, 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.

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 sodium triglycollamate, 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 particular amino acid (e.g., methionine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine and combinations thereof) or combinations of these stereoisomers, may be present so long as the amino acid is present either in its free base form or its salt form.

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

The pharmaceutical compositions of the present disclosure may be in a dosage form appropriate 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 to forming another oral dosage form, such as tablets, sprinkles, or pellets. In some embodiments, the pharmaceutical compositions may be in a solid dosage form for oral administration, such as a capsule, tablet, sprinkle, or pellet.

Pharmaceutical compositions of the disclosure in the form of a tablet may be prepared using methods known in the art. For example, the nilotinib ASD and the one or more pharmaceutically acceptable additives may be blended to provide a tableting blend by hand or bag blending, or using a suitable device. Suitable tableting blends may then be compressed into tablets having a target weight from 50 to 1000 mg using, for example, a manual tablet press or a conventional mechanical tablet press.

In some embodiments, it may be desirable to form granules as an intermediate step to forming a tableting blend. Granules typically have improved flow, handling, blending, and compression properties relative to ungranulated materials. The granules may be prepared from the ASD particles by processes known in the art, including wet granulation and dry granulation.

In certain embodiments, the granulation blend may comprise the ASD in an amount of 20% to 80%, or in an amount of 25% to 75%, by weight. In particular embodiments, the granulation blend comprises 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or 50%, or 55%, or 60%, or 65%, or 70%, or 75%, or 80% of the ASD, by weight. When a higher proportion of extra-granular excipients is employed, then the granulation blend accordingly would contain a relatively high proportion of the ASD; if a lower proportion of extra-granular excipients is employed, then the granulation blend can contain a relatively lower proportion of the ASD.
In an embodiment, the granulation blend is formed by dry-blending granule components, and then the granulation blend is densified using a roller compactor which typically forms ribbons of material. The ribbons are then reduced in size by milling to form granules. Improved wetting, disintegrating, dispersing and dissolution properties is obtained by the inclusion of suitable excipients, as described above. After granulation, the granules can be included into a tableting blend and compressed into tablets.

In an embodiment, the pharmaceutical compositions are in the form of a tablet.

In an embodiment of the present invention, immediate release pharmaceutical composition is a tablet, and wherein the tablet is prepared by a method comprising:
(i) blending amorphous solid dispersion (“ASD”) of nilotinib, filler, solubilizer, disintegrant, glidant and optionally other excipients,
(ii) adding the blend of step (i) into roller compaction, and forming granules,
(iii) adding disintegrant and lubricant to the granules of step (ii)
(iv) compressing the blend of step (iii) into tablet, and
(v) optionally coating the tablet.

In certain embodiments, the tablet may comprise the ASD in an amount of 20% to 50% by weight of the tablet; one or more solubilizer (such as polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer) in an amount 20% to 40% by weight of the tablet; one or more fillers (such a 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).

In some embodiments, the tablets are further film coated. Preferably, the film may be a hydrophilic/hydrophobic polymer selected from the group consisting of hydroxypropyl cellulose, ethyl cellulose, PVA or combinations thereof.

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 as compared to the reference composition.

The present invention provides a method of increasing bioavailability by administering the composition or the pharmaceutical composition of the invention, respectively, to an animal or to a patient, wherein the increased bioavailability is determined by comparing the Cmax value or the AUC value of the composition or the pharmaceutical composition of the invention with the composition disclosed in the present invention. Preferably the method increases bioavailability of a drug in administered animal or patient by least 1.3 fold, preferably at least 1.5 fold, even more preferably by at least two fold, over marketed TASIGNA® hard-gelatin capsule.

In some embodiments, wherein the pharmaceutical composition when administered to a human subject in fed state provides a Cmax value of nilotinib not more than 30%, preferably not more than 20%, preferably not more than 10%, preferably not more than 5% and more preferably not more than 1% as compared to the Cmax value of nilotinib resulting from administration of the pharmaceutical composition to the human subject in fasted state.

In some embodiments, wherein the pharmaceutical composition when administered to a human subject in fed state provides an AUC value not more than 45%, preferably not more than 40%, preferably not more than 30%, preferably not more than 10%, and more preferably not more than 5% as compared to the AUC value resulting from administration of the pharmaceutical composition to the human subject in fasted state.

Bioavailability can be measured by skilled artisan by conventional methods. For example, tablets, capsules, liquids, powders, etc., are given orally to humans or animals and blood levels are measured.

For instance, in some embodiments, administration of an ASD or pharmaceutical composition of the present disclosure may result in a pharmacokinetic profile that is comparable to the pharmacokinetic profile obtained by orally administering a conventional immediate- release nilotinib formulation, but administered at a fraction of the dosage. For this comparison, administration must be done in a fasted state, since TASIGNA® should only be administered in a fasted state.

By “comparable,” it is meant that the administration of the ASD or the pharmaceutical composition of the disclosure to the subject may provide AUC0-t (such as AUC0-24h or AUC0-inf) or Cmax in the subject’s plasma that are within the 80% to 125% bioequivalence criteria compared to administration of the immediate-release crystalline nilotinib formulation to the same subject, dosed according to its labeled instructions.

As used herein, “fraction of the dosage” may mean that the dose of nilotinib in the ASD or pharmaceutical composition of the present disclosure may be 80% less, or 75% less, or 70% less, or 65% less, or 60% less, or 55% less, or 50% less, or 45% less, or 40% less, or 35% less, or 30% less, or 25% less, or 20% less, as compared to the labeled dosage of the immediate- release nilotinib formulation.

In some embodiments, the dose of nilotinib in the ASD or pharmaceutical composition of the present disclosure is at least 80% less, or 75% less, or 70% less, or 65% less, or 60% less, or 55% less, or 50% less, as compared to the labeled dosage of the immediate-release crystalline nilotinib formulation.

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

In another preferred embodiment of the present invention, a pharmaceutical composition of the present disclosure containing approximately 135 mg nilotinib provide a pharmacokinetic profile that is comparable to the pharmacokinetic profile obtained by orally administering an immediate- release crystalline nilotinib formulation labeled to contain 200 mg of nilotinib (such as 200 mg TASIGNA®).

In another preferred embodiment of the present invention, a pharmaceutical composition of the present disclosure containing approximately 95 mg nilotinib provide a pharmacokinetic profile that is comparable to the pharmacokinetic profile obtained by orally administering an immediate- release crystalline nilotinib formulation labeled to contain 200 mg of nilotinib (such as 200 mg TASIGNA®).

By decreasing the required dosage while still providing an efficacious 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.

The risk of overexposure affects the entire patient population treated with nilotinib.In addition to reducing the overall risk of overexposure, the formulations of the disclosure may limit risk associated with an undesirably high Cmax.

Yet another aspect of the disclosure relates to a method of preparation of pharmaceutical composition comprising an ASD of nilotinib.

Yet another object of the present invention is to provide a method of treating a disease which responds to an inhibition of protein kinase activity, such as a proliferative disorder.

Some embodiments relate 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 thereof.
Some embodiments relate to a use of a nilotinib ASD or pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a proliferative disorder such as cancer.

In some embodiments, a therapeutically effective amount may be from 50 mg/m2 to 250 mg/m2 of nilotinib, or from 50 mg/m2 to 150 mg/m2 of nilotinib, or from 60 to 120 mg/m2 of nilotinib.

As generally interpreted, “food effect” broadly refers to all aspects of interactions of food on drug dissolution, absorption, distribution, metabolism and elimination. The implications of food effect include changes in bioavailability, rate of on-set, duration of therapeutic effect and incidence and seriousness of side effects. The magnitude of a food effect is generally greatest when the drug product is administered shortly after a meal is ingested.

An example of a drug product exhibiting a food effect is TASIGNA®, which can produce an increase of AUC and Cmax by 82% and 112%, respectively, when orally taken 30 minutes after a high-fat meal as compared to levels obtained under fasting conditions.

In assessing food effect, data obtained from fasted and fed studies is 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 a suitable number of subjects, an absence of food effect is indicated when the 90% confidence interval for the ratio of population geometric means between fed and fasted administrations, based on log- transformed data, is contained in the equivalence limits of 80% to 125% for AUC0-inf (or AUC0-t when appropriate) and Cmax. On the other hand, an absence of food effect is not established if the 90% confidence interval for the ratio of population geometric means between fed and fasted administrations, based on log-transformed data, is not contained in the equivalence limits of 80% to 125% for either AUC0-inf (or AUC0-t when appropriate) or Cmax.

In the methods of the present disclosure, “without a food effect” means that the relative difference is not substantially large, e.g., less than 20%, or less than 15%, or less than 10%, for AUC (which can 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, as compared to the measured value for the same parameter when the same ASD or pharmaceutical composition is administered in a fasted state.

In the methods of the present disclosure, “without regard to consumption of food” means that no consideration has to be made whether the ASD or pharmaceutical composition of the present disclosure is being administered to the subject or patient concomitantly with food, or whether the patient or subject is in a fed state or fasted state.

In preferred embodiments of the present invention, administration of the ASD or pharmaceutical composition to a subject in a fed state provides an exposure of nilotinib that is similar to the exposure resulting from administration of the pharmaceutical composition to the subject in a fasted state. Exposure may be expressed as AUC0-12h, AUC0-24h, AUC0-last, or AUC0-inf, for example; exposure can be for an individual subject, or a geometric mean from a number of subjects.

In certain preferred embodiments of the present invention, pharmaceutical composition administration to a subject in a fed state provides a plasma Cmax of nilotinib that is similar to the plasma Cmax resulting from administration of pharmaceutical composition to the subject in a fasted state. Plasma Cmax can be for an individual subject, or a geometric mean from a number of subjects. As used herein in this context, “similar” exposure means a relative difference in the plasma exposure of nilotinib between the fed state and the fasted state of less than 25%, or less than 20%, or less than 15%, or less than 10%, or less than 5%.

Although the invention has been described with reference to specific embodiments, these descriptions are not meant to be constructed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to person skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.
EXAMPLES
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.

Example-1: Amorphous solid dispersion of nilotinib
Table 1: Formula of Example-1
Ingredient Weight (mg) Weight (mg)
Nilotinib 135.00 100.00
Hypromellose Phthalate-55 (HP-55) 202.50 150.00
N,N-Dimethyl acetamide q.s q.s
Acidified water (pH 1.0-5.0) q.s q.s
Purified water q.s q.s

Manufacturing process:
i. preparing a solution comprising nilotinib and hypromellose pthalate, using dimethylacetamide
ii. mixing the solution obtained in step (i) to cooled acidified water (pH 1.0-5.0) to precipitate out both the drug and the polymer; and
iii. filtering and washing the solid mass obtained in step (ii) with fresh antisolvent and water, and dried to obtain amorphous solid dispersion of the present invention.

Example-2: Amorphous solid dispersion of nilotinib
Table 2: Formula of Example-2
Ingredient Weight (mg) Weight (mg)
Nilotinib 135.00 100.00
Hypromellose acetate-succinate 202.500 150.00
N,N-Dimethyl acetamide q.s q.s
Acidified water (pH 1.0-5.0) q.s q.s
Purified water q.s q.s

Manufacturing process was similar to that described above in Example -1.

Example 3: Tablet compositions of Nilotinib ASD from Example 1 [T2] and Example 2 [T1]
Table 3: Formula of Example 3
Nilotinib Tablet 100mg and 135mg
S.No Ingredients T1 T2
135mg 100mg 135mg 100mg
% wt/wt % wt/wt % wt/wt % wt/wt
Solid dispersion
1 Nilotinib 15.66 15.66 21.84 21.73
2 Hypromellose Pthalate-55 (HP-55) - - 32.76 32.60
3 Hypromellose ASMG 23.49 23.49 - -
4 N,N-Dimethyl acetamide qs qs qs qs
5 pH 1-5 Purified water 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 - -
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 (Aerosil200) 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 (Aerosil200) 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 tablet weight 100.00 100.00 100.00 100.00

Manufacturing process:
1. Nilotinib ASD, soluplus, and a portion of mannitol, croscarmellose sodium, crospovidone, colloidal silicon dioxide and magnesium stearate are sifted and mixed;
2. The granulation blend obtained in step (1) was roller-compacted and granulated;
3. Ribbons of compacted material obtained in step (2) were then milled;
4. Nilotinib ASD granules obtained in step (3) were mixed with remaing portion of crospovidone, colloidal silicon dioxide and magnesium stearate; and the tabletting blend obtained was then compressed into tablets.
5. Tablets were coated with opadry using purified water as solvent

Example 4: Comparative dissolution study

Nilotinib tablets T1 & T2 prepared according to Example 3 (Test formulation) were evaluated for in vitro dissolution, against TASIGNA® 200mg tablets (Reference Formualtion).
The dissolution was performed using two stage dissolution procedure where acid media was transferred to base media inorder to mimic the invivo condition and to check the rate of precipitation inhibition in alkline media.

Initially the dissolution was performed in Simulated Gastric Fluid (SGF) media 250mL up to 30mins using USP type II apparatus (Paddle) at 50 rpm and transferred to alkaline media containing Fasted State Stimulated Intestinal Fluid (FaSSIF) pH 6.5, 500mL at 8mL/min using peristaltic pump while maintaining the dissolution conditions similar to acid media. The total volume of FaSSIF media becomes 750mL after addition of acid media (250mL 0.01N HCl + 500mL pH 6.8 Phosphate buffer). The sampling was done simultaneously at different time points while addition of acid media and continued dissolution up to 240mins.

The dissolution profiles of the Test formulation and the Reference formulation are shown in Table-4 below:
Tasigna® 200mg T1 T2
1:1.5 1:1.5
Acid stage Peristaltic pump Disso: Acid stage - SGF , 250mL, Paddle, 50 rpm
Time (mins) %DR %DR %DR
10 18 77 53
20 24 82 57
30 30 87 62
Buffer stage Buffer stage: FaSSIF pH 6.5, 750mL, 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

The above results demonstrate that the Test formulations T1 and T2 (Nilotinib tablets 135mg) furnishes a better dissolution than that of the Reference formulation (TASIGNA® 200mg tablets). Further T1 formulation has shown better results as compared to T2 formulations. It is also clear that the Test formulation does not undergo precipitation in buffer media contrary to that of the Reference formulation. Based on the dissolution results as shown in Example 4, the T1 and T2 formulations were further tested for in-vivo PK testing in human subjects against TASIGNA® 200mg tablets (Reference Formulation).

Example 5: Comparative in-vivo Pharmacokinetic (PK) study in human subjects
One PK study was conducted. This study is an open label, randomized, three-treatment, Four-period, Four Sequence, Single dose, crossover, oral bioavailability study of nilotinib Tablets 135mg (135mg × 2 tablets) of Dr. Reddy’s Laboratories Limited, India comparing with that of reference formulation TASIGNA® (Nilotinib) capsules 200mg (200 mg x 2 capsule) of Novartis Biosciences SA Brazilian Industry in normal, healthy, adult, human subjects under fasting and fed conditions. The Four-way crossover PK study was conducted to get following comparison data:
Fasting (TFa/RFa in 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)

Results of the study of Example 5 are summarized in Table 5 and Table 6 provided below:
Table 5: Statistical Summary for nilotinib tablets 135 mg Fasting Study (TFa/RFa)
270 mg Test dose Vs 400 mg RLD dose
Parameter Geometric Least Square Mean Ratio (TFa/RFa)
% 90% Confidence Limits (%) Power (%) ISCV (%)
Test Reference Lower Upper
Fasting - T1 Formulation
Cmax (ng/mL) 952.221 625.419 152.25 130.73 177.32 78.30 32.48
AUC0-t (ng.hr/mL) 17106.577 13023.396 131.35 115.95 148.81 90.53 26.36
AUC0-inf (ng.hr/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 23.89
AUC0-t (ng.hr/mL) 16293.012 12978.635 125.54 111.63 141.17 93.19 24.91
AUC0-inf (ng.hr/mL) 17402.546 13976.673 124.51 112.17 139.21 96.84 22.07

From the data shown in Table 5, it is apparent that, improved Bioavailability observed considering 270mg test dose vs 400mg RLD dose.

Table 6: Statistical Summary for nilotinib tablets 135 mg Fed Study (T1Fe/T1Fa)
270 mg Test dose
Parameter Geometric Least Square Mean Ratio (T1Fe/ T1Fa)
% 90% Confidence Limits (%) Power (%) ISCV (%)
Test (T1Fe) Test (T1 Fa) 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
AUC0-t (ng.hr/mL) 23934.017 17250.019 138.75 123.25 156.19 92.83 25.81
AUC0-inf (ng.hr/mL) 24901.761 17690.490 140.76 124.93 158.61 92.51 26.02

From the data shown in Table 6, it is apparent that, food effect was observed with 27% increase in Cmax in test formulation (compared to 112% increase of Cmax in case of RLD TASIGNA®, based on the reported literature data) and 40% increase in AUC in test formulation (compared 82% if AUC in RLD TASIGNA® based on the reported literature data). Hence, reduction of positive food effect is achieved.

Based on the results of in-vivo Pharmacokinetic (PK) study of example 5, it is possible to reduce the dose further to get bioavailability comparable to reference formulation TASIGNA® (Nilotinib) capsules 200mg. Another PK study is planned with reduced dose of 90 mg, 95 mg, and 100 mg twice a day administration of Test formulation againt 200mg RLD TASIGNA® formulation.
,CLAIMS:1. An immediate release pharmaceutical composition, wherein the composition comprises:
a) an amorphous solid dispersion that comprises:
i. Nilotinib or a pharmaceutically acceptable salt thereof,
ii. one or more suitable polymer having a glass transition temperature between 100 °C and 180 °C,
iii. optionally, one or more solubilizers
b) one or more pharmaceutically acceptable excipient(s).

2. The immediate release pharmaceutical composition according to claim 1, wherein the Nilotinib and the polymer are present in a ratio of from 1:0.5 to 1:5.

3. The immediate release pharmaceutical composition according to claim 1, wherein polymer is selected from the group consisting of Cellulose acetate phthalate, Polyvinyl acetate phthalate, Eudragit L100-55, modified HPMCs, such as hydroxypropyl methylcellulose acetate-succinate and hydroxypropyl methylcellulose phthalate, or mixtures thereof.

4. The immediate release pharmaceutical composition according to claim 1, wherein the solubilizer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, d-D-tocopherol acid polyethylene glycol 1000 succinate, PEG-40 hydrogenated castor oil, PEG-35 castor oil, PEG-40 25 stearate, hard fat, polyoxylglycerides, stearoyl polyoxylglycerides, PEG-8 caprylic/capric glycerides and poloxamers.

5. The immediate release pharmaceutical composition according to claim 1, wherein composition comprise the amorphous solid dispersion in an amount of 20% to 50% by weight of the tablet and one or more solubilizer in an amount 20% to 40% by weight of the tablet.

6. The immediate release pharmaceutical composition according to claim 1, wherein a pharmaceutically acceptable excipient selected from at least one solubilizer, at least one filler, at least one disintegrant, at least one glidant, and at least one lubricant.

7. The immediate release pharmaceutical composition according to claim 1, wherein composition is a tablet, and the tablet is prepared by a method comprising:
(i) blending amorphous solid dispersion (“ASD”) of nilotinib, solubilizer, filler, disintegrant, lubricant and glidant,
(ii) adding the blend of step (i) into roller compaction, and forming granules,
(iii) adding disintegrant and lubricant to the granules of step (ii)
(iv) compressing the blend of step (iii) into tablet, and
(v) optionally coating the tablet.

8. The immediate release pharmaceutical composition according to claim 1, wherein composition can be administered without regard to food consumption.

9. The immediate release pharmaceutical composition according to claim 1, wherein amorphous solid dispersion of nilotinib is prepared by using a method comprises: (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 which comprises at least one anti-solvent to obtain a suspension of amorphous particles by co-precipitation.

10. A method of manufacturing amorphous solid dispersion of nilotinib according to claim 10, wherein first and/or the second solvent is selected from the group consisting of water, acetone, methylchloride, dimethylformamide, methanol, ethanoldimethyl sulfoxide, methylethylketone, dimethylacetamide, lactic acid, isopropanol, 3-pentanol, n-propanol, glycerol, butylene glycol, ethylene glycol, propylene glycol, 1,4-dioxanepolyethylene glycol, polyethylene glycol sorbitans, polyethylene glycol monoalkyl ethers, polypropylene glycol, butanediol, and mixtures thereof and anti-solvent is acidified water (pH 1.0-5.0).