The present invention relates to an oral dosage form comprising dasatinib, or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to an oral dosage form comprising dasatinib, or a pharmaceutically acceptable salt thereof, wherein the amount of disintegrant present is controlled so as to provide desirable dissolution and / or pharmacokinetic profiles.

Dasatinib is commercially available under the trade mark Sprycel and is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia (C L) in the chronic phase; chronic, accelerated or blast phase CM L with resistance or intolerance to prior therapy including imatinib mesylate; and Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy.

Dasatinib was first described as a compound in the patent family that includes EP 1169038B. EP 1169038B generically and specifically claims dasatinib. Compositions forthe compounds of EP 1169038B are generally described in paragraphs [0075] to [0080], but no specific compositions for dasatinib are disclosed.

Later patent specifications do disclose specific compositions for dasatinib. For example, WO 2006/121742 describes specific film coated tablets of dasatinib. In particular, the film coating is selected so as to be non-reactive and not to cause decomposition of dasatinib. WO 2006/121742 describes the various other excipients that could be used in the compositions thereof, and specific Examples are also provided. Specifically, the Examples describe tablets of varying strengths of dasatinib (from 5 to 150 mg). The excipients used in each tablet are lactose monohydrate, microcrystalline cellulose, hydroxypropylcellulose, croscarmellose sodium and magnesium stearate, and Opadry white is provided as the film coating.

Given the differing strengths of the dasatinib tablets as used in the Examples of WO 2006/121742, different amounts of excipients were also used. As disintegrant, croscarmellose sodium was used, and this was present at the following amounts - 4.0 mg (Examples I to III), 3.2 mg (Example IV), 8.0 mg (Example V), 11.2 mg (Example VI), and 24.0 mg (Example VII). Based on the amount of dasatinib present, the above disintegrant amounts are present at the following ratios to the amount of dasatinib - 0.8 : 1.0 (Example I), 0.08 : 1.0 (Example II), 0.16 : 1.0 (Examples III to VII).

WO 2006/121742 also describes the impact of dasatinib particle size and / or intra / extra granular location thereof, on compressibility. More specifically, page 8 of WO 2006/121742 describes that a formulation using larger particle size of dasatinib (D90 - 120 microns) was found to have poor compression properties when all of microcrystalline cellulose was added intragranularly. Conversely according to WO 2006/121742, the formulation using a particle size of dasatinib with D90 up to about 130 microns was found to have acceptable compression properties when a portion of the microcrystalline cellulose was added in the extragranular phase. Alternatively according to WO 2006/121742, the particle size of dasatinib may be up to or equal to 150 microns. To some extent however, this information is not particularly helpful, given no disclosure was provided as to the particle size measuring techniques employed. As a skilled person will immediately realize, different particle size measurements are obtained for any given sample, depending on the measurement technique that is used. Still further, no meaningful analysis can be performed of the dissolution properties and as such associated bioavailability of the specific tablets of the Examples of WO 2006/121742, because there is no disclosure whatsoever in these Examples as to the particle size of the specific Form of dasatinib that was used and the associated measurement technique.

A skilled reader would also be aware that the presence and associated amounts of specific excipients has an effect on the dissolution of an active pharmaceutical ingredient as present in a dosage form. Furthermore, the skilled reader would also be aware that particle size of an active pharmaceutical ingredient would also have an effect on the dissolution of an active pharmaceutical ingredient as present in a dosage form. For excipients, for example an increase in an amount of disintegrant present would be expected to enhance dissolution of an active pharmaceutical ingredient as present in the dosage form. For particle size, it would be expected that a decrease in particle size would also enhance dissolution of an active pharmaceutical ingredient as present in the dosage form. We have however now found that contrary to general understanding, that when the disintegrant content of an oral dosage form of dasatinib is increased within a specific range, then the dissolution of dasatinib from the dosage form generally decreases and as such disintegrant content can be used in an unexpected manner to control the dissolution rate of dasatinib from the dosage form.

According to the present invention therefore, there is provided an oral dosage form comprising dasatinib, or a pharmaceutically acceptable salt thereof, together with at least one disintegrant, wherein the ratio of the amount of disintegrant to the amount of dasatinib, or a pharmaceutically acceptable salt thereof, is in the range of 0.3 : 1.0 to 0.5 : 1.0, based on the amount of dasatinib free base as present in the dosage form.

It is further preferred that the dasatinib as present in an oral dosage form according to the present invention as described above has a particle size distribution, wherein D90 is preferably not more than 100 microns. More preferably, dasatinib as present in an oral dosage form according to the present invention as described above has a particle size distribution, wherein D90 is in the range of 5 to 100 microns, still more preferably 50 to 100 microns, still more preferably 50 to 90 microns, still more preferably 50 to 80 microns, still more preferably 50 to 70 microns, still more preferably 50 to 60 microns, and even more preferably a D90 of about 55 microns. The particle size distribution was measured by laser diffraction techniques typically employing a mastersizer 2000 laser particle size analyzer.

There is also provided by the present invention an oral dosage form comprising dasatinib, or a pharmaceutically acceptable salt thereof, together with at least one disintegrant, wherein the ratio of the amount of disintegrant to the amount of dasatinib, or a pharmaceutically acceptable salt thereof, is in the range of 0.3 : 1.0 to 1.0 : 1.0 based on the amount of dasatinib free base as present in the dosage form, and wherein said dasatinib has a D90 of not more than 100 microns when measured by laser diffraction techniques. More preferred D90 ranges are as described above.

Furthermore, an oral dosage form according to the present invention has a dissolution profile wherein about 45 to 70% of dasatinib is released in 60 minutes, when tested in a USP Type-ll Paddle apparatus, wherein the dissolution medium comprises 900 mL of an acetate buffer having a pH of 4.5, at 50 rpm, at a temperature of 37°C ± o.5°C. The acetate buffer is preferably prepared by dissolving an acetate salt, such as sodium acetate, in water, and the resulting solution is either added to, or to which solution is added, acetic acid.

Furthermore, it is preferred that an oral dosage form according to the present invention provides a maximum measured plasma dasatinib concentration over time (Cmax) ratio with respect to the reference product Sprycel in the range of 0.80 to 1.25. It is also preferred that an oral dosage form according to the present invention provides an AUC ratio with respect to the reference product Sprycel in the range of 0.80 to 1.25 as calculated by the linear trapezoidal method, up to the last observed value. As referenced herein, the reference product Sprycel is a film coated dasatinib (140 mg) tablet, having the following excipients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose and magnesium stearate. The film coating comprises hypromellose, titanium dioxide and acrogol 400. As a skilled reader will be aware, the Sprycel product is a commercially available product.

There is also provided by the present invention an oral dosage form comprising dasatinib, or a pharmaceutically acceptable salt thereof, together with at least one disintegrant, wherein the ratio of the amount of disintegrant to the amount of dasatinib, or a pharmaceutically acceptable salt thereof, is in the range of 0.3 : 1.0 to 1.0 : 1.0 based on the amount of dasatinib free base as present in the dosage form, and wherein said dissolution profile and / or said Cmax and / or said AUC is as hereinbefore described. Furthermore, the dosage form preferably includes dasatinib having a D90 of not more than 100 microns when measured by laser diffraction techniques as herein before described. More preferred D90 ranges are also as described above.

A particularly preferred ratio of disintegrant to dasatinib to be used in an oral dosage form according to the present invention is in the range of 0.3 : 1.0 to 0.5 : 1.0, based on the amount of dasatinib free base as present in the dosage form.

A disintegrant for use according to the present invention can be any one of the typically used disintegrants in the pharmaceutical field. For example, the disintegrant can be selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, maize starch, sodium carboxymethyl cellulose, other cellulose derivatives with disintegrant properties and the like. A preferred disintegrant to be used in accordance with the present invention is croscarmellose sodium.

Dasatinib as used in the present invention can be dasatinib free base or a pharmaceutically acceptable salt thereof. The dasatinib can be anhydrous or present as a hydrated Form, such as dasatinib monohydrate. Typically the dasatinib is present as an anhydrous free base Form, and even more preferably dasatinib anhydrous N6 polymorph can be a preferred polymorphic Form for use in the present invention. As already documented in the patent literature, for example WO 2005/077945, dasatinib anhydrous N6 polymorph can be characterized by the following representative 2theta values: 6.8, 11.1, 12.3, 13.2, 13.7, 16.7, 21.0, 24.3 and 24.8 ± 0.2° 2theta. Such X PD measurement can be carried out based on the skill and common general knowledge of one of ordinary skill in the art and indeed above referenced WO 2005/077945 provides teaching as to the techniques and apparatus used.

Compositions intended for oral use according to the present invention may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Oral dosage forms to be used in the present invention can contain the active ingredient dasatinib in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as microcrystalline cellulose, lactose, calcium carbonate, sodium carbonate, calcium phosphate or sodium phosphate; binding agents, for example hydroxypropyl cellulose, starch, gelatin, polyvinylpyrrolidone and polyethylene glycol; and lubricating agents, for example, magnesium stearate, stearic acid or talc. A disintegrant to be used in an oral dosage form according to the present invention is as hereinbefore described.

More preferably according to the present invention, croscarmellose sodium is used as a disintegrant; microcrystalline cellulose and lactose monohydrate are used as inert diluents or "fillers"; hydroxypropyl cellulose is used as a binder; and magnesium stearate is used as a lubricant. Preferred specific compositions according to the present invention and employing the above excipients are hereinafter described in the specific Examples.

The oral dosage forms of the present invention can be tablets or capsules, preferably tablets are employed.

The tablets may be uncoated or they may be coated by known techniques. Preferably the tablets are film coated. More preferably, the coating material used is a polyethylene glycol (PEC) free moisture protective coating material (for example, Opadry 200). For example, an Opadry coating as illustrated in the Examples is used for an oral dosage form according to the present invention.

Capsules can be hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. Such capsules include a disintegrant and API having properties as hereinbefore described.

An oral dosage form according to the present invention exhibits chemical and polymorphic stability after 6 months of storage under accelerated conditions 40°C/75% H when packed in aluminium-aluminium blisters or high density polyethylene bottles. Such stability is further illustrated herein by the accompanying Examples and Figures and in particular as illustrated herein when tablets according to the present invention are subjected to 6 months of storage under accelerated conditions 40°C/75%RH when packed in high density polyethylene bottles then substantially no polymorphic interconversion was observed.

In a particularly preferred embodiment, an oral dosage form according to the present invention is prepared by a wet granulation process. More preferably, the coating material used is a PEC free moisture protective coating material (for example, Opadry 200).

There is also provided by the present invention a method of providing a dasatinib oral dosage form having a dissolution profile and / or a pharmacokinetic profile as hereinbefore described, which method comprises including a disintegrant in an amount in the oral dosage form whereby the ratio of the amount of disintegrant to the amount of dasatinib, or a pharmaceutically acceptable salt thereof, is in the range of 0.3 : 1.0 to 1.0 : 1.0 based on the amount of dasatinib free base as present in the dosage form. There is also provided use of a disintegrant for controlling (lowering) a dissolution profile and / or a pharmacokinetic profile of an oral dosage form comprising dasatinib as hereinbefore described, wherein said disintegrant is present in an amount in the oral dosage form whereby the ratio of the amount of disintegrant to the amount of dasatinib, or a pharmaceutically acceptable salt thereof, is in the range of 0.3 : 1.0 to 1.0 : 1.0 based on the amount of dasatinib free base as present in the dosage form. More preferred ratios for the above methods and uses, are wherein the ratio of the amount of disintegrant to the amount of dasatinib, or a pharmaceutically acceptable salt thereof, is in the range of 0.3 : 1.0 to 0.5 : 1.0, based on the amount of dasatinib free base as present in the dosage form.

The present invention also provides an oral dosage form as herein before described, for use in the treatment of leukemia, and specifically for use in the treatment of newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia (CM L) in the chronic phase; chronic, accelerated or blast phase CM L with resistance or intolerance to prior therapy including imatinib mesylate; and Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast C L with resistance or intolerance to prior therapy.

The present invention is now illustrated by the following Examples, which do not limit the scope of the invention in any way.

Example 1:

A tablet was prepared with a disintegrant : API ratio of 0.5 : 1.0 based on the following recipe:

Weight of core tablet (mg) 560.0 100.0

Coating

Opadry 200 white 22.4 4.0 Coating material

Purified water - Coating solvent

Weight of coated tablet (mg) 582.4

Manu acturing process steps:

1) Materials were loaded and dry mixed together in a high shear mixer granulator.

2) Hydroxy Propyl Cellulose (binder solution) was dissolved in purified water by stirring.

3) The solution of Step 2 was added in the dry mixed material. Kneading of the mass takes place, until a desired consistency of wet mass was achieved.

4) The wet mass of Step 3, was wet-sized through screen.

5) The sized, wet granules of Step 4 were dried, until %LOD settles between 1.5 and 3 w/w.

6) The dried granules of Step 5 were further dry-sized.

7) The sized granules of Step 6 were blended with croscarmellose sodium and lubricated with magnesium stearate.

8) The blend of Step 7 was compressed into round shaped, concave tablets.

9) The obtained core tablets of Step 8, were film coated using Opadry 200, white.

Example 2

A tablet was prepared with a disintegrant : API ratio of 0.2 : 1.0 based on the following recipe:

Weight of core tablet (mg) 560.00 100.0

Coating

Opadry 200 white 22.4 4.0 Coating material

Purified water - Coating solvent

Weight of coated tablet (mg) 582-4

Manufacturing process steps:

These were carried out in accordance with the above described process of Example 1. Example 3: Dissolution results:

The following dissolution results were obtained for tablets with excipients as described in Examples 1 and 2, but with the following disintegrant / API ratios. Furthermore, the Cmax and AUC values that are referenced are ratios of the respective values for such tablets according to the present invention versus the Cmax and AUC values for the Sprycel product similarly including 140 mg of dasatinib.

Dissolution method:

Dissolution parameters:

Apparatus USP Type-l l, Paddle Dissolution medium pH 4.5 acetate buffer

Volume 900 ml_

Rotations Per Minute 50

Temperature 37°C ± o.5°C

Sampling Intervals 5, 10, 15, 20,30,45, 60 min and recovery (10 minutes at

200rpm)

Dissolution medium Dissolve 2.99 g of Sodium acetate trihydrate in 8oomL preparation: water. Add i4.oml_ of 2 M acetic acid and dilute to 1000 mL

Acetate Buffer pH 4.5 with water, mix.

Example 4: Stability on storage

140 mg tablets according to the present invention were prepared, packaged in HDPE bottles and chemical and polymorphic stability was investigated further to 6 month storage at 40°C ± 2°C / 75% RH ± 5% RH. From the above results, it can be seen that both chemical and polymorphic stability was retained during such 6 month storage. Figures 1 and 2 also show in further detail the observed polymorphic stability.