WO2023285981A1

WO2023285981A1 - Stable pharmaceutical liquid composition of nilotinib

Info

Publication number: WO2023285981A1
Application number: PCT/IB2022/056447
Authority: WO
Inventors: Amol Kulkarni; Yogesh Patel; Abhijeet Upadhye; Savitri SINGH
Original assignee: Torrent Pharmaceuticals Ltd
Current assignee: Torrent Pharmaceuticals Ltd
Priority date: 2021-07-15
Filing date: 2022-07-13
Publication date: 2023-01-19
Anticipated expiration: 2024-01-15

Abstract

The present invention relates to the pharmaceutical composition of Nilotinib or its pharmaceutically acceptable salts and process for preparation thereof. More particularly, the present invention relates to the liquid dosage form of Nilotinib or its pharmaceutically acceptable salts with improved solubility and stability. Said Nilotinib or its pharmaceutically acceptable salts provide high drug load of oral suspension.

Description

STABLE PHARMACEUTICAL LIQUID COMPOSITION OF NILOTINIB

FIELD OF INVENTION

BACKGROUND AND PRIOR ART OF THE INVENTION Nilotinib belongs to pharmacologic class of drugs known as kinase inhibitors. Chemically nilotinib is 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(Triflouro methyl)phenyl]-3-[[4-(3- pyridinyl)-2-pyrimidinyl]amino]-Benzamide having the following structural formula:

Nilotinib hydrochloride marketed as 150 mg and 200 mg oral capsules in United States under the trade name, TASIGNA® by Novartis. It is prescribed as 300 mg twice daily (600 mg daily dose) for treatment of newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia and 400 mg twice daily (800 mg daily dose) for treatment resistant or intolerant Philadelphia chromosome positive chronic myelogenous leukemia.

U.S. Patent No. 7,169,791 relates to nilotinib or its pharmaceutically acceptable salts thereof and specifically claims the compound. U.S. Patent No. 8163904 relates to salt of nilotinib monohy drochl oride .

U.S. Patent No. 8,293,756 and 8,501,760 disclose solid pharmaceutical composition, especially capsules, comprising granules containing nilotinib or a salt thereof with at least one pharmaceutically acceptable excipient. The granules may be produced by a wet granulation process.

WO2019/162756 discloses a liquid composition comprising an anticancer drug and one or more pharmaceutically acceptable excipients. A liquid composition is selected from the group comprising of liquids, liquid dispersions, suspensions, solutions, emulsions, sprays, spot-on, syrups, elixirs or concentrates.

W02020/039264 discloses a pharmaceutical composition in the form of a suspension for oral delivery. Some embodiments provide a pharmaceutical composition in the form of a suspension for oral delivery comprising an anti-cancer active pharmaceutical ingredient; water; a suspending agent; a buffering agent; and one or more of a wetting agent and a binder/filler.

“Hari Krishna Ananthula, “Pharmacokinetic Evaluation and Modeling of Tyrosine Kinase Inhibitors nilotinib and Imatinib in Preclinical Species to Aid their Repurposing As Anti- Viral Agents” University of Cincinnati, 2017” discloses the suspension of nilotinib with Avicel/HPMC and nilotinib was grinded manually in a mortar using a pestle to reduce the particle size. This resulted in an 18 mg/Ml nilotinib suspension which was stored at 4°C for use in next 24 hours. It also discloses nilotinib/NMP (2mg/mL) in PEG 300 oral formulation.

Tsu-han Lin et al., Biopharm. Drug Dispos. 33: 536 549 (2012) discloses nilotinib suspension (2.5 mg/mL), prepared in a 0.5% (w/v) of hydroxypropyl methylcellulose (HPMC) aqueous solution.

Armando Gabrielli et al, Arthritis & Rheumatology, 68, (9), September 2016, 2263-2273, discloses suspension of nilotinib at a concentration of 8 mg/mL was prepared daily by adding, as vehicle, an aqueous solution composed of 0.5% hydroxypropyl methylcellulose and 0.05% Tween 80.

SUMMARY OF PRIOR ARTS

Nilotinib or its salts are poorly water-soluble compounds and are difficult to formulate and deliver (due to its low bioavailable when ingested orally). Nilotinib or its pharmaceutically acceptable salts administered as solid oral dosage forms, which results a challenge when administered to paediatric and geriatric patients or for the patients having swallowing difficulties. Nilotinib is not available in any other dosage form. Administration of capsule by sprinkle the contents of each capsule in applesauce may not administer correct and consistent dose every time. Additionally, such vehicles are intended only for short-term use and opening capsules would expose parents, care givers and the environment to cytotoxic drug particles.

Oral liquid formulations are known for ease of administration for paediatric and geriatric patients or for the patients having swallowing difficulties. However, suspension are uncommon for the purpose of attaining high dose formulation of poorly water soluble drug.

It is very challenging to prepare liquid dosage forms, with high drug load oral formulation for nilotinib or its pharmaceutically acceptable salts. None of the prior art discloses the high drug load system and high stability. Therefore, the prior patent application unable to achieve high drug load system and high stability for liquid dosage form of nilotinib or its pharmaceutically acceptable salts.

Considering very low solubility, and higher dosage requirements, formulating nilotinib into a liquid dosage form is often challenging particularly while maintaining dosage requirements, stability and other concerns.

The present invention therefore describes liquid compositions of nilotinib or its pharmaceutically acceptable salts that are palatable and acceptable to all types of patients' population.

Therefore, it is desirable to have dosage forms in liquid forms, with high drug load oral formulation for nilotinib or its pharmaceutically acceptable salts, particularly in view of the relatively high daily dose required for administration. OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a stable liquid dosage form of nilotinib or its pharmaceutically acceptable salts and process for preparation thereof.

Another objective of the present invention is to provide a liquid dosage form of nilotinib or its pharmaceutically acceptable salts with improved solubility in pharmaceutical composition. Yet another objective of the present invention is to provide a high drug load of oral suspension of nilotinib or its pharmaceutically acceptable salts.

Yet another objective of the present invention is to provide a high drug load of oral suspension of nilotinib or its pharmaceutically acceptable salts with improved stability. Yet another objective of the present invention is to provide a stable pharmaceutical suspension composition of nilotinib or its pharmaceutically acceptable salts in the range of about40 mg/mL to about lOOmg/mL, preferably about 80 mg/mL to about 100 mg/mL.

Yet another objective of the present invention is to provide an oral suspension of nilotinib or its pharmaceutically acceptable salt with the composition containing suspending agent and wetting agent.

Yet another objective of the present invention is to provide a pharmaceutical composition of nilotinib or its pharmaceutically acceptable salts having pH range of about 3.0 to about 9.0, more preferably about 3.0 to about 5.0, and most preferably about 3.0 to about 4.0.

Yet another objective of the present invention is to provide a pharmaceutical composition of nilotinib or its pharmaceutically acceptable salts with process for preparing the liquid dosage form.

Yet another objective of the present invention is to provide uniform dispersion of particles upon thereby better absorption of the suspension dosage form of nilotinib or its pharmaceutically acceptable salts.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Mean plasma concentration of Nilotinib in male Beagle Dogs at oral dose 200mg

DETAILED DESCRIPTION OF THE INVENTION

The following paragraphs detail various embodiments of the invention. For the avoidance of doubt, it is specifically intended that any particular feature(s) described individually in any one of these paragraphs (or part thereof) may be combined with one or more other features described in one or more of the remaining paragraphs (or part thereof). In other words, it is explicitly intended that the features described below individually in each paragraph (or part thereof) represent important aspects of the invention that may be taken in isolation and combined with other important aspects of the invention described elsewhere within this specification as a whole, and including the examples and figures. The skilled person will appreciate that the invention extends to such combinations of features and that these have not been recited in detail here in the interests of brevity.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

The term "nilotinib" as used herein includes nilotinib in the form of freebase, a pharmaceutically acceptable salts thereof, amorphous nilotinib, crystalline nilotinib or any isomer, complex, co-crystals, derivative, esters, hydrate, solvate, or prodrug or combinations thereof. "Salts" or "pharmaceutically acceptable salt(s)", as used herein, include but not limited to inorganic or organic salts, hydrates and solvates of nilotinib known to person skilled in the art. In particular, the salt of nilotinib is nilotinib hydrochloride, and more particular nilotinib hydrochloride monohydrate.

The term "excipient" means a pharmacologically inactive component such as a wetting agent, a suspending agent, a co-solvent, a sweetener, a flavouring agent, a preservative, a pH modifier, a stabilizer, a buffering agent, a solubilizer and other ingredients of a pharmaceutical product. The excipients which are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient.

The term "composition" or "pharmaceutical composition" as used herein synonymously include dosage forms such as emulsion, solution, suspension, pellets/spheres for suspension, or granules/powders for suspension which meant for oral administration.

The term “stable,” as used herein, refers to chemical stability, wherein not more than 5% % w/w of total degradation products are formed on storage at 40 ±2°C and 75 ±5% relative humidity (R.H.) or at 25 ±2°C and 60±5% R.H. for a period of at least one month, particularly for a period of two months, and more particularly for a period of at least three months.

The term “resuspendable or resuspendability” as used herein refers to where the amount of nilotinib throughout the composition is about 100% label content (l.c.) i.e., 100±10% within about 30 seconds of shaking.

The term "high drug load" as used herein refers to about 40 mg/mL drug or more e.g. 40 mg/mL to 100 mg/mL. Nilotinib or its pharmaceutically acceptable salts are poorly water-soluble compounds and is non-achievable to formulate stable high drug load dosage form.

The present invention provides a pharmaceutical suspension composition of nilotinib or its pharmaceutically acceptable salts with improved solubility and stability. Said suspension dosage form produces a uniform dispersion with uniform or better absorption. Based on the above to improve solubility of nilotinib or its pharmaceutically acceptable salts with oral suspension dosage form proposed with improve stability and the high drug load of nilotinib with great economic benefits as well as patient compliance.

As shown in table 1, the solubility of nilotinib or its pharmaceutically acceptable salts in water is 0.0 to 0.30 mg/mL; in acetate buffer, pH 4.5 and phosphate buffer, pH 6.8 the solubility is 0.00 mg/mLand in 0.1N HC1, pH 1.2 media, solubility is 1.5 to 2.21 mg/mL.

Table 1: Solubility of the nilotinib or its pharmaceutically acceptable salts

The first embodiment of the present invention provides stable liquid dosage form of nilotinib or its pharmaceutically acceptable salts with improved solubility in pharmaceutical composition.

Another embodiment of the present invention provides a high solubility in pharmaceutical suspension composition of nilotinib or its pharmaceutically acceptable salts. Another embodiment of the present invention provides a high drug load of nilotinib or its pharmaceutical acceptable salt in oral suspension.

Another embodiment of the present invention provides a pharmaceutical composition of nilotinib or its pharmaceutically acceptable salts with high drug load of nilotinib with improve the stability of the dosage form.

Another embodiment of the present invention provides a stable pharmaceutical suspension composition of nilotinib or its pharmaceutically acceptable salts which is room temperature stable.

Another embodiment of the present invention provides a stable pharmaceutical suspension composition of nilotinib or its pharmaceutically acceptable salts in the range of about 20 mg/mL to about lOOmg/mL, about 40 mg/mL to about lOOmg/mL, about 50mg/mL to about lOOmg/mL, about 60mg/mL to about lOOmg/mL, about 70mg/mL to about lOOmg/mL, about 80mg/mL to about lOOmg/mL, about 90mg/mL to about lOOmg/mL. Other embodiments of the present invention provides a stable pharmaceutical suspension composition of nilotinib or its pharmaceutically acceptable salts in the range of about 40mg/mL to about lOOmg/mL, about 40mg/mL to about 90mg/mL, about 40mg/mL to about 80mg/mL, about 40mg/mL to about 70mg/mL, about 40mg/mL to about 60mg/mL, about 40mg/mL to about 50mg/mL. Preferred embodiments of the present invention provides a stable pharmaceutical suspension composition of nilotinib or its pharmaceutically acceptable salts in the range of about 40mg/mL to about 80mg/mL, more preferably about 80mg/mL to about lOOmg/mL.

Another embodiment of the present invention provides a pharmaceutical composition of nilotinib or its pharmaceutically acceptable salts have the pH range within about 3.0 to about 9.0, preferably pH range within about3.0 to about 5.0, more preferably pH range within about 3.0 to about 4.0.

Another embodiment of the present invention provides compositions comprising nilotinib or its pharmaceutically acceptable salts and at least one excipient selected from a wetting agent, a suspending agent, a co-solvent, a sweetener, a flavouring agent, and a preservative.

Another embodiment of the present invention provides a compositions comprising nilotinib or its pharmaceutically acceptable salts and at least one excipient selected from a wetting agent, a suspending agent, a co-solvent, a sweetener, a flavouring agent, a preservative, a pH modifier, a stabilizer, a buffering agent, a solubilizer, an anti-foaming agent, an anticaking agent. Suitable wetting agents or surfactants includes, but are not limited to nonionic surfactants such as polyethylene glycol tert-octylphenyl ether (Triton™ X-100), nonoxynol- 9,polysorbate,sorbitanmonooleate(Span®80), poloxamerpoloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407, secondary alcohol ethoxylates (Tergitol™), ethoxylatedpolyoxypropylene block copolymers (Antarox®); anionic surfactant such as Dioctyl sodium sulfosuccinate (DOSS), perfluorooctanesulfonate (PFOS), linear alkylbenzene sulfonates, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate, lignosulfonate, sodium stearate, and others such as polyoxyethylenesorbitanmonooleate (Tween® 80), docusate sodium or mixtures thereof. Preferred wetting agents or surfactants include polyoxyethylenesorbitanmonooleate (Tween® 80), poloxamer 188, or mixtures thereof.

The wetting agent or surfactant may be used in a concentration range of about 0.01% to about 10% weight/ weight(w/w) (about O.lmg/mL to about lOOmg/mL), preferably about 0.1% to about 3% w/w (about lmg/mL to about 30mg/mL), more preferably about 0.1% to about 1.5% w/w(about lmg/mL to about 15mg/mL) and most preferably about 0.3% to about 1.5% w/w (about 3mg/mL to about 15mg/mL).

The suspending agent or thickening agents or viscosity agents includes but are not limited to aqueous biological polymers, including methylcellulose (MC), sodium carboxymethylcellulose (CMC), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose (HPMC), acacia, tragacanth, starch, alginate, xanthan gum, magnesium aluminum silicate (Veegum®), Sodium carboxymethyl starch, carboxymethyl cellulose and its salts/derivatives, sodium carboxymethyl cellulose, microcrystalline cellulose, co-processed microcrystalline cellulose and carboxymethyl cellulose sodium (such as Avicel® RC-501, Avicel® RC-581, Avicel® RC-591, and Avicel® 5 CL-611),carbomers; arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; propylene glycol alginate, dextran; gelatin; polyethylene glycols; polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols such as xylitol and mannitol bentonite, carboxypolymethylene, colloidal silicon dioxide or mixtures thereof. Preferred suspending agent is magnesium aluminum silicate. Another embodiment of the present invention provide compositions comprising nilotinib or its pharmaceutically acceptable salts and suspending agent is selected from magnesium aluminum silicate, hydroxypropyl cellulose, or mixtures thereof.

Particular embodiment of the present invention provide compositions comprising nilotinib or its pharmaceutically acceptable salts and suspending agent is selected from magnesium aluminum silicate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, or mixtures thereof.

Other embodiments of the present invention provide compositions comprising a combination of magnesium aluminum silicate and at least one other suspending agent selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, or mixtures thereof.

The suspending agents may be used in a concentration range of about 0.5% to about 10% weight/ weight (w/w) (about 5 mg/mL to about 100 mg/mL), preferably about 1% to about 4% w/w (about lOmg/mL to about 40mg/mL), more preferably about about 1% to about 3% w/w (about 10 mg/mL to about 30mg/mL).

The co-solvent include but are not limited to Sorbitol, glycerin, ethanol, propylene glycol, water, polyethylene glycol, or mixtures thereof. Preferred co-solvent is propylene glycol.

The co-solvent may be used in a concentration range of about 1% to about 25%weight/ weight(w/w) (about 10 mg/mL to about 250 mg/mL), preferably, about 10% to about 25% w/w (about 100 mg/mL to about 250 mg/mL), more preferably from about 15% to about 25% w/w (about 150 mg/mL to about 250 mg/mL), and most preferably about 15% to 20% w/w (about 150 mg/mL to about 200 mg/mL).

Surprisingly, it has been found that nilotinib hydrochloride in the presence of the co-solvent glycerine leads to cake formation. Hence, one embodiment of the present invention provides a pharmaceutical composition of nilotinib or its pharmaceutically acceptable salts that is free from glycerin.

Surprisingly, this phenomena is not observed when nilotinib base is used.

The sweetener provides the sweetness to the dosage form and include but are not limited to sorbitol, dextrose, sodium saccharin, glucose, sucralose, trehalose, fructose, xylose, dextrose, mannitol, xylitol, aspartameor mixtures thereof. Preferred sweeteners are sodium saccharin or sorbitol. The sweetener may be used in a concentration range of about 0% to about 10% (weight/ weight(w/w) (about 0 mg/mL to about 100 mg mL).

The flavouring agent enhance and modify the taste and the aroma in dosage form and are thereof included for taste-masking purposes. Flavouring agents for use in particular embodiments include but are not limited to peppermint, lemon oils, butterscotch, tutti-frutti, vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, flavour or mixtures thereof.

The flavouring agent may be used in a concentration range of about 0% to about 2.5% weight/ weight (w/w) (about 0 mg/mL to about 25 mg/mL).

The preservative used for preserving or retarding spoilage caused by chemical changes to increase the stability of the dosage form. Preservatives for use in particular embodiments include but are not limited to benzyl alcohol, sorbic acid, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, methyl hydroxybenzoate, ethyl parahydroxybenzoate, parabens such as methylparaben, propylparaben, butyl paraben and their salts, chloroform, sucrose, benzalkonium chloride, alcohol, ethanol, sodium citrate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol or mixture thereof. Preferred preservative is benzyl alcohol, methyl paraben, propyl paraben, or mixtures thereof.

The preservative may be used in a concentration range of about 0.01% to about 2.5% weight/ weight(w/w) (about 0.1 mg/mL to about 25 mg/mL), and preferably, about 0.05% to about 0.5% w/w (about 0.5 mg/mL to about 5 mg/mL).

Antioxidants may be included in particular embodiments. Preferred antioxidants include, but are not limited to, a-tocopherol, ascorbic acid, butylated hydroxy anisole, butylated hydroxytoluene, propyl gallate, sodium pyrosulfite, sodium bisulfite, sodium sulfite, cysteine, ascorbyl palmitate, acetylcysteine, sodium metabisulfite, thiourea, sodium thiosulfate or mixture thereof.

Antifoaming agents used to prevent or counter the foam generation in the formulation. It includes but are not limited to alcohols (cetostearyl alcohol), insoluble oils (castor oil), stearates, polydimethylsiloxanes and other silicones derivatives, ether and glycols, simethicone or mixtures thereof. Preferred Antifoaming agents is simethicone. Anticaking agents may be included in particular embodiments to improve the re- suspendability of the formulation. Preferred anticaking agents include, but are not limited to, colloidal silica and/or colloidal silicon dioxide, magnesium oxide, magnesium silicate, calcium silicate, calcium phosphate tribasic, or mixtures thereof. The anticaking agents may be used in a concentration range of about 0.1% to about 10% weight/ weight(w/w) (about lmg/mL to about 100 mg/mL).

In particular embodiments, a pH modifier or buffering agent may be included. The pH modifier include but are not limited to adipic acid, L(+)-tartaric acid, sodium hydrogen carbonate, tri-potassium citrate monohydrate, sodium hydroxide, hydrochloric acid (HC1), acid/base, phosphate buffer, citric acid, sodium phosphate dibasic, sodium citrate, acetic acid, diethanolamine, potassium bicarbonate, potassium chloride, potassium citrate, potassium metaphosphate, potassium phosphate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium chloride, sodium phosphate, succinic acid, tartaric acid, tri ethyl amine, triethanolamine, tromethamine, trolamine, meglumineor mixture thereof. The buffering agent include but are not limited to carbonates, bicarbonates, hydrogen phosphates and mixture thereof.

It has been surprisingly found that nilotinib hydrochloride in the presence of pH modifier and/or buffering agent leads to cake formation. Hence, in one of the embodiment of the present invention provides a pharmaceutical composition of nilotinib or its pharmaceutically acceptable salts that is free from pH modifiers and buffering agents.

Surprisingly, this phenomena is not observed when nilotinib base is used.

The solubilizer increases the solubility of the nilotinib or its pharmaceutically acceptable salts. The solubilizer include but are not limited to propylene glycol/ polyethylene glycol, sorbitol, glycerin, ethanol, propylene glycol and mixtures thereof. The solubilizer may be used in a concentration range of about 1% to about 25% (weight/ weight (w/w) (about 10 mg/mL to about 250 mg/mL), preferably, about 10% to about 25% w/w (about 100 mg/mL to about 250 mg/mL), more preferably about 15% to about 25% w/w (about 150 mg/mL to about 250 mg/mL), and most preferably about 15% to 20% w/w (about 150 mg/mL to about 200 mg/mL). Another embodiment of the present invention provides a pharmaceutical composition of nilotinib or its pharmaceutically acceptable salts which can be packaged in a suitable package such as an amber colored polyethylene terephthalate (PETE) bottle, a polypropylene (PP) bottle, a high density polyethylene (HDPE) bottle, a low density polyethylene (LDPE) bottle, or a glass bottle.

Certain embodiments of the present invention provide a stable liquid composition comprising: a) more than 40 mg/mL of nilotinib hydrochloride monohydrate; b) a suspending agent selected from the group comprising of magnesium aluminum silicate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulouse, and mixtures thereof; c) a co-solvent propylene glycol; d) a surfactant selected from the group comprising of polaxamer 188 and polyoxyethylenesorbitanmonooleate; e) a preservative; and f) a sufficient amount of water vehicle.

Certain embodiments of the present invention provide a stable liquid composition comprising: a) more than 40 mg/mL of nilotinib hydrochloride monohydrate; b) a suspending agent selected from the group comprising of magnesium aluminum silicate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulouse, and mixtures thereof; c) a co-solvent propylene glycol; d) a surfactant selected from the group comprising of polaxamer 188 and polyoxyethylenesorbitanmonooleate; e) a preservative; f) optionally a sweetener; g) optionally a flavouring agent; and h) a sufficient amount of water vehicle.

Certain embodiments of the present invention provide a stable liquid composition comprising: a) more than 40 mg/mL of nilotinib hydrochloride monohydrate; b) a suspending agent selected from the group comprising of magnesium aluminum silicate and hydroxypropyl cellulose; c) a co-solvent propylene glycol; d) a surfactant selected from the group comprising of polaxamer 188 and polyoxyethylenesorbitanmonooleate; e) a preservative; f) optionally a sweetener; g) optionally a flavouring agent; and h) a sufficient amount of water vehicle.

Certain embodiments of the present invention provide a stable liquid composition comprising: a) more than 40 mg/mL of nilotinib hydrochloride monohydrate; b) a suspending agent selected from the group comprising of magnesium aluminum silicate, and hydroxypropyl methylcellulose; c) a co-solvent propylene glycol; d) a surfactant selected from the group comprising of polaxamer 188 and polyoxyethylenesorbitanmonooleate; e) a preservative; f) optionally a sweetener; g) optionally a flavouring agent; and h) a sufficient amount of water vehicle.

Certain embodiments of the present invention provide a stable liquid composition comprising: a) more than 40 mg/mL of nilotinib hydrochloride monohydrate; b) a suspending agent selected from the group comprising of magnesium aluminum silicate, microcrystalline cellulose, sodium carboxymethylcellulouse, and mixtures thereof; c) a co-solvent propylene glycol; d) a surfactant selected from the group comprising of polaxamer 188 and polyoxyethylenesorbitanmonooleate; e) a preservative; f) optionally a sweetener; g) optionally a flavouring agent; and h) a sufficient amount of water vehicle. Certain embodiments of the present invention provide a stable liquid composition comprising: a) more than 40 mg/mL of nilotinib base; b) a suspending agent selected from the group comprising of methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, acacia, tragacanth, starch, alginate, xanthan gum, magnesium aluminum silicate, Sodium carboxymethyl starch, carboxymethyl cellulose and its salts/derivatives, sodium carboxymethyl cellulose, microcrystalline cellulose, co-processed microcrystalline cellulose and carboxymethyl cellulose sodium, carbomers; arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; propylene glycol alginate, dextran; gelatin; polyethylene glycols; polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols such as xylitol and mannitol bentonite, carboxypolymethylene, colloidal silicon dioxide, and mixtures thereof; c) a co-solvent; d) a surfactant selected from the group comprising of polyethylene glycol tert-octylphenyl ether, nonoxynol-9, polysorbate, sorbitanmonooleate, poloxamer, secondary alcohol ethoxylates, ethoxylatedpolyoxypropylene block copolymers, anionic surfactant such as Dioctyl sodium sulfosuccinate, perfluorooctanesulfonate, linear alkylbenzene sulfonates, sodium lauryl sulfate, sodium lauryl ether sulfate, lignosulfonate, sodium stearate, and others such as polyoxyethylenesorbitanmonooleate, docusate sodium, and mixtures thereof; e) a preservative; f) optionally a sweetener; g) optionally a flavouring agent; and h) a sufficient amount of water vehicle.

Another embodiment of the present invention provides a stable liquid composition comprising: a) about 80 mg/mL to about 100 mg/mLnilotinib hydrochloride monohydrate; b) about 10 mg/mL to about 30 mg/mL a suspending agent selected from the group comprising of magnesium aluminum silicate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulouse, and mixtures thereof; c) about 150 mg/mL to about 250 mg/mL of a co-solvent propylene glycol; d) about 3 mg/mL to about 15 mg/mL of a surfactant; e) about 0.5 mg/mL to about 5 mg/mL preservative; and f) a sufficient amount of water vehicle.

Another embodiment of the present invention provides a process for preparing pharmaceutical suspension composition of nilotinib or its pharmaceutically acceptable salts. The present invention further provides process for preparing compositions of nilotinib or its pharmaceutically acceptable salts by mixing with one or more excipients and preparing the stable suspension dosage form, wherein the process comprises:

Step 1 : Adding wetting agent, water, co-solvent and stir for clear solution,

Step 2: Mixing of nilotinib or its pharmaceutically acceptable salts and optionally adjust the pH through pH modifier,

Step 3: Homogenising the solution at pressure 500-2000 bar,

Step 4: Adding the suspending agent to the homogenized solution of step 3 and stirring until it forms a homogenous suspension,

Step 5: Adding additional excipients to the homogenous suspension of step 4.

Another embodiment of the present invention provides a process for preparation of a stable pharmaceutical suspension composition of nilotinib or its pharmaceutically acceptable salts, wherein process comprises following steps:

I. dissolving wetting agent in the water;

II. dispersing nilotinib or its pharmaceutically acceptable salts in the solution of step (I) to form a dispersion

III. dissolving preservative in co-solvent and adding to dispersion of step (II)

IV. dissolving suspending agent, flavouring agent in the solution of step (III) with optionally homogenization;

V. mixing of suspending agent, and water with stirring;

VI. adding suspension of step (V) to the suspension of step (IV) with stirring.

The invention will be further illustrated by the following examples, however, without restricting its scope to these embodiments.

EXAMPLE 1:

Manufacturing Process for preparing suspension of the nilotinib or its pharmaceutically acceptable salts: The wetting agent, nilotinib or its pharmaceutically acceptable salts, suspending agent, pH modifier were weighed suitability. The wetting agent, water, co-solvent were added and stirred until clear solution formed. The nilotinib or its pharmaceutically acceptable salts and pH modifier added to the above solution. Homogenization of the solution at pressure 500- 2000 bar for at least 3 cycle. Further suspending agent were added to the above solution until it form homogenous suspension. Thus, prepared the oral suspension of nilotinib or its pharmaceutically acceptable salts.

Examples 2 and 3 were prepared by manufacturing process of example 1.

EXAMPLE 2: Specific Composition of nilotinib or its pharmaceutically acceptable salts Table 2: Nilotinib hydrochloride monohydrate for oral suspension

The pharmaceutical composition of Table 2, was prepared as per manufacturing process of Example 1 and was subjected to physical stability studies. The results are shown in Table 3. Redispersibility was studied for one month. Redispersibilityis defined as the ease of resuspendibility, where the suspension sediment should be loosely packed such that after minimal hand shaking the sediment redisperse and reform the original suspension.

Table 3

The results shown in Table 3 indicate that there was no change in redispersibility in the composition of the present invention for a period of one month.

EXAMPLE 3: Composition of nilotinib or its pharmaceutically acceptable salts

Table 4: Nilotinib hydrochloride monohydrate for oral suspension

The pharmace utical compositi on of Table 4, was prepared as per manufactu ring process of Example 1 and was subjected

to physical stability studies and the results are shown in Table 5. Redispersibility was studied for one month.

Table 5

The results shown in Table 5 indicate that there was no change in redispersibility in the composition of the present invention for a period of one month.

EXAMPLE 4:

Manufacturing Process for preparing suspension of the nilotinib or its pharmaceutically acceptable salts: Part A Suspension: Wetting agent, and water added and stirred until clear solution formed. The nilotinib or its pharmaceutically acceptable salts added to the above solution and stirred until dispersed completely. Dissolved preservative in co-solvent and added to the above solution and stirred. Homogenization of the solution for about 10 minutes at 10,000rpm (model DCA 25). Further suspending agent, flavouring agent were added to the above solution and again homogenized for about 5 minutes at 10,000 rpm (model DCA T25).

Part B Suspension: The suspending agent, and water added and stirred until clear solution formed.

Part B suspension added to the part A suspension under stirring and further stirred for 10 minutes. Sorbitol solution, added and continue stirred for 5 minutes.

Thus, prepared the oral suspension of nilotinib or its pharmaceutically acceptable salts.

Examples 5 to 12were prepared by manufacturing process of Example 4.

EXAMPLE 5-8: Composition of nilotinib or its pharmaceutically acceptable salts Table 6: Nilotinib Base for oral suspension

EXAMPLE 9-12: Composition of nilotinib or its pharmaceutically acceptable salts Table 7: Nilotinib hydrochloride monohydrate for oral suspension

EXAMPLE 13: Assay for Nilotinib

The suspension for examples 5 to 12 were analysed for drug content by HPLC using Inertsil ODS-3, 250 X4.6 mm, 3 pm or equivalent column using Buffer and Acetonitrile in the ratio of 55:45 v/v and the results are shown in the table 8. Table 8: Assay of Nilotinib

EXAMPLE 14: Dissolution Test

The suspension for examples 5 to 12were evaluated for in-vitro Nilotinib release according to:

Apparatus: USP Type-II (Paddle)

Volume: 1000 ml

Media (OGD): 0.1 N HC1 Stirrer speed: 50 rpm Temperature: 37°C ± 0.5°C

Measurement method: HPLC (Inertsil ODS 3,250 x 4.6mm, 3 pm (or) Equivalent, column) by UV detector at 260 nm, using Buffer and Acetonitrile in the ratio of 55:45 v/v.

The results for for in-vitro Nilotinib release shown in Table 9.

Table 9: Percentage (%) of nilotinib release in the USP Type-II (Paddle) apparatus

EXAMPLE 15: Stability

The stability study was performed at condition such as:

Temperature: 40±2° C and Relative humidity (RH): 75%±5% RH.

The composition of suspension was analyzed and total degradation product was determined using HPLC. The suspensions for examples 5, 6, 9, and 10 were analysed for stability studies and the results shown in table 10.

Table 10: The stability study data

EXAMPLE 16: Pharmacokinetics study of nilotinib hydrochloride monohydrate formulations in Beagle dog The suspension for examples 11 was subjected to Pharmacokinetics study in the male Beagle dogs. To compare nilotinib oral suspension with Nilotinib oral capsule (Tasigna®, Batch Number AANA309)Study design was:

Animals: Male Beagle dogs, fasted overnight. Two dose groups (Reference, and suspension composition of example 11), with group contains five dogs. Dose: Parallel dose administration of oral reference capsule 200 mg or 2.5 mL of suspension (400mg/5mL) formulations to respective dose groups.

Sampling: Blood samples were collected over a period of 24 hr post dose.

Bioanalysis: Plasma samples were cleaned with solid phase extraction and the processed sample analysed with LC-MS/MS method for nilotinib. Pharmacokinetic evaluation: Non-compartmental analysis.

Results of Pharmacokinetics study shown in table 11 and figure 1 : Table 11: Plasma concentration (ng/mL) comparison of Tasigna® (nilotinib Capsule,

200mg) and nilotinib oral suspension of example 11 in Beagle dogs

Claims

We Claim:

1. A stable liquid composition comprising: a) about 40 mg/mL to about 100 mg/mL nilotinib or its pharmaceutically acceptable salts; b) a suspending agent selected from the group consisting of magnesium aluminum silicate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, and mixtures thereof; c) a co-solvent; and d) a surfactant.

2. The liquid composition of claim 1, wherein the composition is in the form of an oral suspension.

3. The liquid composition of claim 1, wherein nilotinib or its pharmaceutically acceptable salts is nilotinib hydrochloride monohydrate.

4. The liquid composition of claim 1, wherein the composition comprises about 80 mg/mL to about 100 mg/mL of Nilotinib or its pharmaceutically acceptable salts.

5. The liquid composition of claim 1, further comprising: a preservative; a flavoring agent; a sweetener; and a sufficient amount of water vehicle.

6. The liquid composition of claim 1, wherein the suspending agent is a mixture of magnesium aluminum silicate and hydroxypropyl cellulose

7. The liquid composition of claim 1, wherein the composition comprises suspending agent in a range of about 10 mg/mL to about 30 mg/mL.

8. The liquid composition of claim 1, wherein the composition comprises surfactant in a range of about 3 mg/mL to about 15 mg/mL.

9. The liquid composition of claim 1, wherein the surfactant is selected from the group consisting of polyoxyethylenesorbitanmonooleate, poloxamer, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407, t- octylphenoxypolyethoxyethanol, polyethylene glycol tert-octylphenyl ether, nonoxynol-9, polysorbate, sorbitanmonooleate, secondary alcohol ethoxylates, ethoxylatedpolyoxypropylene block copolymers, dioctyl sodium sulfosuccinate (DOSS), perfluorooctanesulfonate (PFOS), linear alkylbenzene sulfonates, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate, lignosulfonate, sodium stearate, and mixtures thereof.

10. The liquid composition of claim 9, wherein the surfactant is selected from the group consisting of polyoxyethylenesorbitanmonooleate, poloxamerl88, and mixtures thereof.

11. The liquid composition of claim 1, wherein the composition comprises co-solvent in a range of about 150 mg/mL to about 250 mg/mL.

12. The liquid composition of claim 11, wherein the co-solvent is selected from the group consisting of sorbitol, ethanol, propylene glycol, water and polyethylene glycol.

13. The liquid composition of claim 12, wherein the co-solvent is propylene glycol.

14. The liquid composition of claim 1, wherein the composition further comprises an anti foaming agent.

15. The liquid composition of claim 1, wherein the pH of composition is between about 3 to about 5.

16. The liquid composition of claim 1, wherein the composition exhibits an in-vitro dissolution profile of about 90% to about 100% released after 5 minutes, when said dosage form is placed in a dissolution vessel filled with 1000 ml of 0.1 N HC1 media maintained at 37°C + 0.5°C and stirred at a paddle speed of 50 rpm using a USP Type II apparatus.

17. A liquid composition comprising: a) about 80 mg/mL to about 100 mg/mL nilotinib hydrochloride monohydrate; b) about 10 mg/mL to about 30 mg/mL a suspending agent selected from the group comprising of magnesium aluminum silicate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulouse, and mixtures thereof; c) about 150 mg/mL to about 250 mg/mL of a co-solvent; d) about 3 mg/mL to about 15 mg/mL of a surfactant; e) about 0.5 mg/mL to about 5 mg/mL preservative; and f) a sufficient amount of water vehicle.

18. A process for the preparation of stable liquid composition of claim 1, wherein the composition is prepared by the process comprising following steps:

I. dissolving wetting agent in the water;

II. dispersing nilotinib or its pharmaceutically acceptable salts in the solution of step (I) to form a dispersion;

ITT. dissolving preservative in co-solvent and adding to dispersion of step (II);

V. mixing of suspending agent, and water with stirring;

VI. adding suspension of step (V) to the suspension of step (IV) with stirring.