NILOTINIB

BACKGROUND OF THE PRESENT INVENTION

Nilotinib, chemically 4-methyl-N-[3-(4-methyl-l-H-imidazol-l-yl)- 5- (trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino ]benzamide of formula (I),

is a pharmaceutically active compound used for the treatment of Philadelphia-chromosome- positive chronic myelogenous leukaemia.

The compound was discovered by Novartis and was first described in WO2004005281. The compound may form acid addition salts, for instance Nilotinib hydrochloride, which is the active ingredient in the medicinal product sold under the brand name Tasigna ^® 150 and 200 mg capsules by Novartis. Nilotinib monohydrochloride monohydrate is described in WO2007015871.

Nilotinib hydrochloride shows a complex solid state behaviour with numerous forms (anhydrates, hydrate, solvates) and with a very low aqueous solubility leading to a poor bioavailability. Several patent applications provide salts and polymorphs of Nilotinib aiming to improve its solubility. WO2007015870 describes several polymorphs of Nilotinib hydrochloride, their process of preparation and compositions comprising them. Crystalline form B of the hydrochloride salt is a monohydrate which has a theoretical moisture content of 3.1% and was described as showing superior crystalline and physical stability with respect to form A of the hydrochloride salt. WO2007015870 additionally describes amorphous Nilotinib hydrochloride. However, it is described that the amorphous form spontaneously converts to the form A hydrochloride salt after storage at various relative humidities. We have observed in our laboratory that amorphous Nilotinib hydrochloride as such is unstable, hygroscopic and not suitable for use on pharmaceutical production scale.

Moreover, it was experienced in our laboratory that polymorphic transitions of Nilotinib hydrochloride take place rather easily, especially in the pharmaceutical

compositions.

In view of the prior art cited above, there is the need for a solid form of Nilotinib, showing an appropriate solubility/dissolution rate and which is simple to prepare, suitable for use on a commercial scale stable in time also within the pharmaceutical composition.

BRIEF DESCRIPTION OF THE PRESENT INVENTION

The present invention provides a pharmaceutical composition comprising an inclusion complex of Nilotinib, or a pharmaceutically acceptable salt thereof, in amorphous form in a cyclodextrin and one or more pharmaceutically acceptable excipients.

It also provides a process for preparing said inclusion complex by dissolving Nilotinib, or a pharmaceutically acceptable salt thereof, and a cyclodextrin in a suitable solvent or solvent mixture, followed by evaporation of the solvent(s), and the pharmaceutical composition obtainable by such process.

Said pharmaceutical composition may be used as a medicament, particularly in the treatment of Philadelphia-chromosome-positive chronic myelogenous leukaemia. DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to a pharmaceutical composition comprising an inclusion complex of Nilotinib, or a pharmaceutically acceptable salt thereof, in amorphous form in cyclodextrin and one or more pharmaceutically acceptable excipients.

Cyclodextrins are compounds made up of sugar molecules bound together in a ring and are composed of 5 or more a-D-glucopyranoside units linked 1→4. Cyclodextrins are produced from starch by means of enzymatic conversion. Three major non-substituted cyclodextrins are known, containing each a different number of glucose monomers ranging from six to eight in a ring, creating a conical shape. The so-called a-cyclodextrin is a six- membered sugar ring molecule, β-cyclodextrin is a seven- membered sugar ring molecule and γ-cyclodextrin is an eight-membered sugar ring molecule.

Among all the natural cyclodextrins, β-cyclodextrins exhibits poor water solubility. However, various semi synthetic derivatives with enhanced aqueous solubility have been developed. Well known examples are Sulfobutylether β-cyclodextrin sodium salt, which is a partially substituted β-cyclodextrin. Its aqueous solubility is high, exceeding 500 mg/ml and 2 hydro xypropyl^-cyclodextrin with a solubility exceeding 600 mg/ml.

Cyclodextrins may form complexes with various chemicals (guest molecules), in which the chemical is encapsulated inside the cyclodextrin ring and forms a so called inclusion complex. Thereby, original properties of the compound vis-a-vis the cyclodextrin-complexed compound may be modified (Arthur H. Kibbe (Ed.), Handbook of Pharmaceutical Excipients, Third Edition 2000, p. 165-168).

Drugs that can exist in either amorphous or crystalline form tend to crystallize over time when present in amorphous state because the crystalline form of the drug is a lower- energy state than the amorphous form. Active Pharmaceutical Ingredients (APIs) may form inclusion complexes in cyclodextrins wherein the API in the inclusion complex is kept in amorphous form (Thorstein Loftsson at al., Pharmaceutical Sciences, 85(10), 1996, 1017- 1025). It is however not self-evident that a given drug will form an inclusion complex with just any cyclodextrin, and that, even in the event the complex is formed, it will be stable over time. Factors playing a role herein are the physicochemical properties of both API and cyclodextrin, the ratio of API to cyclodextrin used, the technique used to prepare the complex and in the solvent evaporation techniques, the speed of solvent evaporation where a higher evaporation speed leads to a higher probability of isolating amorphous material. Although cyclodextrin complexation procedures are relatively simple processes, these techniques often require very specific conditions for each guest molecule (John L. Koontz et al., J. Agric. Food Chem., 57(4), 2009, p. 1162-1171).

It has been found that the inclusion complex of the current invention is very stable at such weight ratios of nilotinib or its salt thereof in relation to cyclodextrin such that nilotinib or its salt thereof, is present in clear molecular excess. Even at a weight ratio of nilotinib, or a pharmaceutically acceptable salt thereof, to cyclodextrin as low as 1: 1 the stability of the pharmaceutical composition is not decreasing. During stability studies no conversion into any crystalline form was observed for such compositions, even under stress conditions. With regard to impurity levels, also no significant differences have been observed. The

composition shows sufficient long term stability.

The excellent stability of the inclusion complex of the present invention of nilotinib, or a pharmaceutically acceptable salt thereof, in amorphous form in a cyclodextrin, wherein nilotinib, or a pharmaceutically acceptable salt thereof, is present in such molecular excess, can not only be explained for by (partial) encapsulation of nilotinib, or a pharmaceutically acceptable salt thereof, in the cyclodextrin cavity. Nilotinib, or a pharmaceutical acceptable salt thereof, is also accommodated in the intermolecular cavities formed or sandwich-like between layers of cyclodextrin. As described by Jozsef Szejtli (Cyclodextrin Technology, 1988, p. 81), the "intercalation" enhances the molar ratio in favour of the guest molecule, which could account for that, although nilotinib, or a pharmaceutically acceptable salt thereof, is present in molar excess amounts over the cyclodextrin, the stability of the pharmaceutical compositions is still excellent.

The pharmaceutical compositions prepared with the inclusion complex display dissolution behaviour typical for immediate-release formulations. The compositions of the present invention exhibit a dissolution rate of at least 80% in 30 minutes when tested in 1000 ml of 0.1 N HC1 in a USP apparatus I (basket) at 100 rpm.

The pharmaceutical compositions of the present invention behaved similar to Tasigna ^® in the above mentioned dissolution test.

The weight ratio of nilotinib, or a pharmaceutically acceptable salt thereof, to cyclodextrin in the inclusion complex ranges from about 1: 1 to about 1:4 and is preferably 1:2.5.

β-Cyclodextrin is the cheapest cyclodextrin, regarded as a safe compound and is widely applied in food and pharmaceutical industry.

At least a major portion of nilotinib, or a pharmaceutically acceptable salt thereof, in the inclusion complex is amorphous. The term "a major portion" of nilotinib, or a

pharmaceutically acceptable salt thereof, means that at least 90% as measured by powder X- ray diffraction or any other standard quantitative measurement. Preferably, nilotinib, or a pharmaceutically acceptable salt thereof, in the inclusion complex is in a completely amorphous form within the detection limits of the techniques used for characterization.

The inclusion complex in accordance with the present invention advantageously is in the form of a free-flowing powder, with excellent handling properties and stable morphology. The inclusion complex is very suitable to be used for the preparation of pharmaceutical compositions. The pharmaceutical compositions of the present invention comprise the inclusion complex of nilotinib, or a pharmaceutically acceptable salt thereof, in cyclodextrin and one or more pharmaceutically acceptable excipients. The excipients to be used in accordance with the present invention are well-known and are those excipients which are conventionally used by the person skilled in the art. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients. Preferably, the dosage form is a capsule or an immediate release tablet and the pharmaceutically acceptable excipients are chosen from one or more binders, diluents, disintegrants, glidants, lubricants, stabilizers, surface active agents or pH-adjusting agents. More preferably, the composition of the present invention comprises a diluent, a disintegrant and a lubricant.

The diluent to be used in accordance with the present invention may be any diluent known to a person of ordinary skill in the art. Particularly, the diluent to be used in accordance with the present invention is an inorganic diluent, polysaccharide, mono- or disaccharide or sugar alcohol. Microcrystalline cellulose is a particularly preferred diluent.

The disintegrant to be used in accordance with the present invention may be any disintegrant known to a person of ordinary skill in the art. Suitable disintegrants to be used in accordance with the present invention are selected from the group consisting of

croscarmellose sodium, crospovidone or sodium starch glycolate. Croscarmellose sodium is a particularly preferred disintegrant.

The lubricant to be used in accordance with the present invention may be any lubricant known to a person of ordinary skill in the art. Magnesium stearate is a particularly preferred lubricant.

In another embodiment of the present invention, at least one of the pharmaceutically acceptable excipients is an intragranular excipient. Preferably, the intragranular excipient to be used in accordance with the present invention is a diluent. Microcrystalline cellulose is a particularly preferred diluent.

In yet another embodiment of the present invention, at least one of the pharmaceutically acceptable excipients is an extragranular excipient. Preferably, the extragranular excipient is chosen from one or more diluents, disintegrants and lubricants. More preferably, the extragranular excipient to be used in accordance with the present invention is a disintegrant. Croscarmellose sodium is a particularly preferred disintegrant. In addition to croscarmellose sodium, the diluent microcrystalline cellulose and the lubricant magnesium stearate may be used as extragranular excipients.

In an advantageous variant of the current invention, the intragranular excipient is microcrystalline cellulose and the extragranular excipients are microcrystalline cellulose, croscarmellose sodium and magnesium stearate.

The pharmaceutical compositions of the present invention display dissolution behaviour typical for immediate-release formulations, exhibiting a dissolution rate of at least 80% in 30 minutes when tested in 1000 ml of 0.1 N HC1 in a USP apparatus I (basket) at 100 rpm.

During preparation and storage of the pharmaceutical compositions of the present invention, nilotinib, or a pharmaceutically acceptable salt thereof, remains in the amorphous form.

The present invention further provides a process to prepare an inclusion complex of nilotinib, or a pharmaceutically acceptable salt thereof, in cyclodextrin, comprising dissolving the cyclodextrin and nilotinib, or a pharmaceutically acceptable salt thereof, in a suitable solvent or solvent mixture, followed by evaporation of the solvent(s), using equipment and methods well-known in the art.

Preferably, the solvent or solvent mixture is water, a dilute aqueous acid, a polar organic solvent or a mixture of water/dilute aqueous acid and a polar organic solvent. Since some of the cyclodextrins exhibit a lower solubility compared to other cyclodextrins such as the various semi- synthetic derivatives like 2-hydroxypropyl-P-cyclodextrin, the process of the current invention may be performed at elevated temperatures in order to dissolve the cyclodextrin completely. Typically, the mixture of β-cyclodextrin and solvent(s) is heated to temperatures ranging from 40°C to reflux.

In an advantageous variant of the process of the present invention, the cyclodextrin is dissolved in water or a mixture of water and a polar organic solvent by heating and nilotinib, or a pharmaceutically acceptable salt thereof, is added to this solution. Preferred polar organic solvents are alcohols, particularly ethanol or methanol, ethers, particularly

tetrahydrofuran, ketones, particularly acetone and acetonitrile. Preferably, water or a mixture of an alcohol and water is used. Advantageously, the inclusion complex is prepared by dissolving cyclodextrin in water by heating, followed by the addition of nilotinib

hydrochloride and subsequent evaporation of the solvent.

The present invention further provides an inclusion complex of nilotinib, or a pharmaceutically acceptable salt thereof, in cyclodextrin, exhibiting a dissolution rate of at least 80% in 30 minutes when tested in 1000 ml of 0.1 N HCl in a USP apparatus I (basket) at 100 rpm., obtainable by:

a) Dissolving, by heating, the cyclodextrin in water or a mixture of an aqueous and a polar organic solvent;

b) Adding nilotinib, or a pharmaceutically acceptable salt thereof;

c) Evaporation of solvent(s).

Preferably, the pharmaceutically acceptable salt of nilotinib herein is the hydrochloric acid salt and the solvent is water/ethanol or dilute aqueous acid/ethanol.

The present invention still further provides a process to prepare pharmaceutical compositions comprising an inclusion complex of nilotinib, or a pharmaceutically acceptable salt thereof, in cyclodextrin and one or more pharmaceutically acceptable excipients. The process comprises mixing or granulating the inclusion complex with one or more

pharmaceutically acceptable excipients, followed by filling into capsules, using equipment and methods well-known to the skilled artisan. In an advantageous variant of the process of the present invention, a solution of nilotinib, or a pharmaceutically acceptable salt thereof, and the cyclodextrin was sprayed over a diluent in a fluidized bed and the resulting granulate/blend was mixed with one or more pharmaceutically acceptable extragranular excipients, followed by encapsulation. Preferably, HPMC or gelatin capsules are used.

Preferably, a solution of nilotinib hydrochloride and cyclodextrin in water/acetone was sprayed over lactose in a fluidized bed, after which the granulate/powder blend was mixed with microcrystalline cellulose and magnesium stearate, followed by filling into capsules.

The pharmaceutical compositions of the present invention are packaged in blister pack material. The blister pack materials to be used in accordance with the present invention may be any blister pack material known to a person of ordinary skill in the art. Suitable blister pack materials to be used in accordance with the present invention are selected from the group of PVC/Alu, Duplex/ Alu, Trip lex/ Alu and Alu/Alu. To ensure protection of the compositions of the present invention from e.g. moisture and thereby preventing polymorphic conversions, Triplex/ Alu and Alu/Alu are particularly preferred blister pack materials. After storage of the pharmaceutical compositions in these blister pack materials for 6 months at 40°C/75 RH, XRPD analysis showed no reflections in accordance with crystalline nilotinib hydrochloride.

The pharmaceutical composition in accordance with the present invention may be used as a medicament. The pharmaceutical composition typically may be used in the treatment of Philadelphia-chromosome-positive chronic myelogenous leukaemia. The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.

EXAMPLES

Example 1, inclusion complex of amorphous nilotinib hydrochloride : sulfo butyl ether β-cyclodextrin (weight ratio 1:3)

0.5 g Nilotinib HC1 and 1.5 g of sulfo butyl ether β-cyclodextrine Na is suspended in a mixture containing water and ethanol (3:2 V/V). The suspension was heated until a clear solution was obtained. The mixture was concentrated in vacuo. The residue was dried over night at 40°C under vacuum.

The XRPD pattern of the isolated inclusion complex does not show any reflections in accordance with crystalline nilotinib hydrochloride. XRPD analysis performed 4 weeks after storing the powder in an alu bag at 55°C/90 RH and 6 months at 40°C/75 RH showed still no reflections in accordance with crystalline nilotinib hydrochloride.

Example 2, composition comprising an inclusion complex of amorphous nilotinib hydrochloride : hydro xypropyl-p.cyclodextrin (weight ratio 1:2).

5.7 grams of hydroxypropyl-p.cyclodextrin (HPpCD, Kleptose HP®) was dissolved in 29 mL of ethanol: 1M HC1 (60:40 v/v) solution under heating (40°C) and magnetic stirring conditions. Once the HPpCD was completely dissolved 2.9 grams of Nilotinib hydrochloride monohydrate (NLN.hcl) were added to the previous solution at the same heating and magnetic stirring conditions. Once NLN.hcl was dissolved, the resulting solution was placed in an oven at 50°C under vacuum.

The resulting dried product was milled in a mortar and sieved through 0.71 mm mesh, obtaining a yellowish, fine powder (1). 1 gram of microcrystalline cellulose and 0.3 gram of croscarmellose sodium were added to the previous powder (1) and were mixed for 10 minutes in a turbula at 72 rpm, obtaining a preliminary blend (2). 0.1 grams of magnesium stearate were sieved though 0.5 mm mesh and mixed with the previous blend (2) for 3 minutes, obtaining the final blend (3). 577 milligrams of the final blend (3) was encapsulated in capsule size 0. XRPD analysis showed that NLN in the final blend as encapsulated was amorphous.

Example 3. composition comprising an inclusion complex of amorphous nilotinib hydrochloride : yxyclodextrin (weight ratio 1: 1).

2.2 grams of γ-cyclodextrin (yCD, Cavamax W8®) was dissolved in 123 mL of ethanoh lM HC1 (40:60 v/v) solution under heating (40°C) and magnetic stirring conditions. Once the yCD was completely dissolved 2.2 grams of Nilotinib hydrochloride monohydrate (NLN.hcl) were added to the previous solution at the same heating and magnetic stirring conditions. Once NLN.hcl was dissolved, the resulting solution was placed in an oven at 50°C under vacuum.

The resulting dried product was milled in a mortar and sieved through 0.71 mm mesh, obtaining a yellowish, fine powder (1). 0.5 gram of microcrystalline cellulose and 0.2 gram of croscarmellose sodium were added to the previous powder (1) and were mixed for 10 minutes in a turbula at 72 rpm, obtaining a preliminary blend (2). 0.05 grams of magnesium stearate were sieved though 0.5 mm mesh and mixed with the previous blend (2) for 3 minutes, obtaining the final blend (3). 385 milligrams of the final blend (3) were encapsulated in capsule size 1. XRPD analysis showed that NLN in the final blend as encapsulated was amorphous. Example 4. inclusion complex of amorphous nilotinib hydrochloride : hydroxypropyl- p.cyclodextrin (weight ratio 1: 1) using fluid bed technology.

18 grams of hydro xypropyl-β. eye lodextrin (HPpCD, Kleptose HP®) was dissolved in 180 mL of ethanoh lM HCl (60:40 v/v) solution solution under heating (40°C) and magnetic stirring conditions. Once the HPpCD was completely dissolved 18 grams of Nilotinib hydrochloride monohydrate (NLN.hcl) were added to the previous solution at the same heating and magnetic stirring conditions.

84 grams of microcrystalline cellulose were placed in Mini Glatt fluid bed and preheated up to 35°C. Once the NLN.hcl was completely dissolved in the previous solution, the solution was sprayed over the microcrystalline cellulose to obtain a granulate (1). Once the spraying of the solution was finished the granulate (1) was dried in the fluid bed. XRPD analysis of the resulting granulate (1) showed that NLN was amorphous.