DESC:[001] FIELD OF THE INVENTION

[002] The present invention relates to the oral pharmaceutical compositions of nilotinib that provide high solubility, stability and patient compliance. The present invention specifically relates to the oral pharmaceutical composition comprising nilotinib free base and the process for preparation thereof.

[003] BACKGROUND OF THE INVENTION

[004] Nilotinib belongs to the pharmacological class of drugs known as kinase inhibitors. Chemically nilotinib is 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide and is represented as below.

[005] Nilotinib is indicated for the treatment of adult and pediatric patients greater than or equal to one year of age with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+CML) in chronic phase, adult patients with chronic phase (CP) and accelerated phase (AP) Ph+CML resistant to or intolerant to prior therapy that included imatinib and pediatric patients greater than or equal to one year of age with Ph+CML-CP resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy.

[006] Nilotinib is currently marketed as 50, 150 and 200 mg oral capsules in United States with the brand name Tasigna® by Novartis. Tasigna® capsules contain active ingredient Nilotinib Hydrochloride monohydrate salt and inactive ingredients colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, and poloxamer 188. The capsules contain gelatin, iron oxide (red), iron oxide (yellow), iron oxide (black), and titanium dioxide.

[007] The package insert of Tasigna® instructs the patients to take capsules twice daily at approximately 12 hours intervals. Tasigna® is prescribed as 300 mg twice daily (600 mg total daily dose) for treatment of newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia and 400 mg twice daily (800 mg total daily dose) for treatment resistant or intolerant Philadelphia chromosome positive chronic myelogenous leukemia.

[008] US Patent No. 7,169,791 discloses the nilotinib drug substance and its use for the treatment of leukemia by inhibition of protein kinase activity.

[009] US Patent No. 8,163,904 discloses the salts of nilotinib selected from group consisting of mono hydrochloride, mono phosphate, diphosphate, sulfate, methane sulfonate, ethane sulfonate, benzene sulfonate and p-toluene sulfonate. US Patent No. ‘904 further discloses the solubility of nilotinib free base in comparison with the various salts of nilotinib like hydrochloride, monophosphate, sulfate, methane sulfonate, ethane sulfonate, benzene sulfonate, p-toluene sulfonate at pH 6.8, pH 3.0 and pH 1.0 aqueous solutions depicting that solubility of nilotinib and its salts decreases strongly with increasing pH and it is practically insoluble at pH 4.5 and higher. This decrease in the solubility of nilotinib in environments with a pH of more than 1.0 leads to a decrease in absorption of nilotinib. At pH 1.0, the nilotinib free base form has the lowest solubility when compared to the all other salt forms of nilotinib disclosed in US ‘904 Patent. Further nilotinib hydrochloride salt has the advantage of 13-fold higher bioavailability when compared to the nilotinib free base form.

[010] US Patent No. US 8,501,760 discloses the pharmaceutical composition comprising granules of nilotinib hydrochloride, surfactant and a lubricant, wherein said lubricant does not exceed 1% by weight of the pharmaceutical composition. US Patent No. ‘760 further discloses the nilotinib hydrochloride granules prepared by the wet massing process.

[011] PCT Publication No. WO 2012164578A1 discloses the pharmaceutical composition comprising nilotinib hydrochloride and at least one pharmaceutically acceptable excipient, wherein the composition is prepared by dry granulation process.

[012] PCT Publication No. WO 2012174082A1 discloses the solubilized or amorphous pharmaceutical compositions of nilotinib or a pharmaceutically acceptable salt thereof using one or more organic acids that function as a solubilizing agent, increasing the bioavailability of nilotinib. PCT Publication No. ‘082 further exemplifies the formulations of nilotinib free base and nilotinib hydrochloride salt with an organic acid.

PCT Publication No. WO 2020101597A1 discloses the capsules comprising nilotinib hydrochloride, wherein the composition is free of lactose monohydrate and binder.

[013] All the above prior art publications disclose the nilotinib hydrochloride or other salt compositions with various combination of excipients that have increased bioavailability of nilotinib base. Further prior arts disclose that Nilotinib free base compositions have 13-fold less bioavailability than nilotinib hydrochloride compositions and therefore there exists a need to develop the pharmaceutical compositions of nilotinib free base that are bioequivalent to pharmaceutical compositions comprising nilotinib hydrochloride (Tasigna®).

[014] SUMMARY OF THE INVENTION

[015] In one aspect the present invention relates to a pharmaceutical composition comprising nilotinib free base.

[016] In one specific aspect the present invention relates to a capsule composition comprising nilotinib free base.

[017] In another aspect the present invention relates to a pharmaceutical composition comprising
(a) nilotinib free base,
(b) at least one filler selected from group consisting of lactose monohydrate, microcrystalline cellulose and mannitol,
(c) at least one disintegrant selected from group consisting of crospovidone, croscarmellose sodium and sodium starch glycolate,
(d) a solublizer, wherein solubilizer is a mixture of surfactant and porous mineral carrier,
(e) colloidal silicon dioxide as a glidant and
(f) magnesium stearate as the lubricant.
[018] In a further specific aspect, the present invention relates to a pharmaceutical composition comprising
(a) nilotinib free base,
(b) lactose monohydrate as a filler,
(c) crospovidone as a disintegrant,
(d) mixture of polysorbate 80 and magnesium aluminometasilicate as a solubilizer,
(e) colloidal silicon dioxide as a glidant and
(f) magnesium stearate as the lubricant.

[019] DETAILED DESCRIPTION OF THE INVENTION

[020] The present invention provides a pharmaceutical composition comprising nilotinib free base and a pharmaceutically acceptable excipient.

[021] In one embodiment the present invention provides a capsule composition comprising nilotinib free base and a pharmaceutically acceptable excipient.

[022] In another embodiment, the composition of the present invention is free of binder.

[023] In a preferred embodiment, the composition comprising nilotinib free base in either crystalline or amorphous polymorphic forms.

[024] In one embodiment, the amount of nilotinib free base present in the composition is about 10% w/w to 90% w/w based on the total weight of the composition, preferably of about 20% w/w to about 80% w/w based on the total weight of the composition and more preferably about 40% w/w to about 60% w/w based on the total weight of the composition.

[025] In one embodiment, the composition of present invention further comprises pharmaceutically acceptable excipients selected from group consisting of fillers, disintegrants, solubilizers, glidants and lubricants.

[026] According to one embodiment of the invention, the composition comprises at least one filler selected from the group consisting of lactose monohydrate, microcrystalline cellulose, mannitol, spray dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol and dicalcium phosphate. The most preferably used filler in the present invention is lactose monohydrate.

[027] In one embodiment, the amount of filler present in the composition is of about 10% w/w to 70% w/w based on the total weight of the composition, more preferably about 20% w/w to 60% w/w based on the total weight of the composition and most preferably of about 30% w/w to about 50% w/w based on the total weight of the composition. Filler, preferably lactose monohydrate is present in both the intragranular and extragranular portion of the composition. Lactose monohydrate present in the intragranular portion is of about 10% w/w to 50% w/w based on the total weight of the composition, preferably about 15% w/w to 45% w/w based on the total weight of the composition and most preferably about 20% w/w to about 40% w/w based on the total weight of the composition. Lactose monohydrate present in the extragranular portion of the composition is of about 1% w/w to 20% w/w based on the total weight of the composition, preferably about 2% w/w to about 15% w/w based on the total weight of the composition and most preferably about 5% w/w to about 10% w/w based on the total weight of the composition.

[028] In another embodiment, the composition comprises at least one disintegrant selected from group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, and low substituted hydroxypropyl cellulose. The most preferably used disintegrant in the present composition is crospovidone. The amount of disintegrant present in the composition is of about 0.5% w/w to 20% w/w based on the total weight of the composition, more preferably about 1% w/w to 15% w/w based on the total weight of the composition and most preferably of about 1.5% w/w to about 10% w/w based on the total weight of the composition.

[029] In one embodiment of the invention, the composition comprises a solubilizer. The solubilizer used in the present invention is a mixture of surfactant and a porous mineral carrier. The most preferably used surfactant is polysorbate 80 and the porous mineral carrier is magnesium aluminometasilicate. The solubilizer with mixture of polysorbate 80 and magnesium aluminometasilicate contains about 45% w/w to about 65% w/w of polysorbate 80 and about 35% w/w to about 55% w/w of magnesium aluminometasilicate based on the total weight of the solubilizer. The solubilizer with mixture of polysorbate 80 and magnesium aluminometasilicate is commercially available as SEPITRAPTM 80. Solubilizer which is a mixture of polysorbate 80 and magnesium aluminometasilicate is present in the composition in an amount of about 0.1% w/w to about 10% w/w based on the total weight of the composition, preferably about 0.2% w/w to about 8% w/w based on the total weight of the composition and more preferably about 0.5% w/w to about 5% w/w based on the total weight of the composition.

[030] In one embodiment of the invention, the present invention comprises colloidal silicon dioxide as a glidant. Colloidal silicon dioxide is present in amount of about 0.1% w/w to about 5% w/w based on the total weight of the composition, and more preferably of about 0.2% w/w to about 2% w/w based on the total weight of the composition.

[031] In further embodiment of the invention, the present invention comprises magnesium stearate as a lubricant. Magnesium stearate is present in an amount of more than 1% w/w based on the total weight of the composition, more preferably of about 1.05% w/w to about 2% w/w based on the total weight of the composition. In the more preferred embodiment, magnesium stearate is present in both the intragranular and extragranular portion of the composition. Magnesium stearate present in the intragranular portion is of about 0.1% w/w to about 0.5% w/w based on the total weight of the composition. Magnesium stearate present in the extragranular portion is of about 0.5% w/w to about 1.5% w/w based on the total weight of the composition.

[032] In one embodiment of the invention, the present invention provides a pharmaceutical composition comprising
(a) nilotinib free base,
(b) at least one filler selected from group consisting of lactose monohydrate, microcrystalline cellulose and mannitol,
(c) at least one disintegrant selected from group consisting of crospovidone, croscarmellose sodium and sodium starch glycolate,
(d) a solublizer, wherein solubilizer is a mixture of surfactant and porous mineral carrier,
(e) colloidal silicon dioxide as a glidant and
(f) magnesium stearate as the lubricant.

[033] In another embodiment of the invention, the present invention provides a pharmaceutical composition comprising
(a) nilotinib free base,
(b) lactose monohydrate as a filler,
(c) crospovidone as a disintegrant,
(d) mixture of polysorbate 80 and magnesium aluminometasilicate as a solubilizer,
(e) colloidal silicon dioxide as a glidant and
(f) magnesium stearate as the lubricant.

[034] In further embodiment the present invention relates to a pharmaceutical composition comprising
(a) about 40% w/w to about 60% w/w nilotinib free base,
(b) about 30% w/w to about 50% w/w lactose monohydrate,
(c) about 1.5% w/w to about 10% w/w crospovidone,
(d) about 0.5% w/w to about 5% w/w of solubilizer, wherein solublizer is a mixture of polysorbate 80 and magnesium aluminometasilicate,
(e) about 0.2% w/w to about 2% w/w colloidal silicon dioxide and
(f) about 1.05% w/w to about 2% w/w of magnesium stearate based on the total weight of the composition.

[035] In another embodiment the present invention relates to a pharmaceutical composition comprising
(a) about 40% w/w to about 60% w/w nilotinib free base,
(b) about 30% w/w to about 50% w/w lactose monohydrate,
(c) about 1.5% w/w to about 10% w/w crospovidone,
(d) about 0.5% w/w to about 5% w/w of solubilizer, wherein solublizer is a mixture of 45% w/w to about 65% w/w polysorbate 80 and about 35% w/w to about 55% w/w based on the total weight of the solubilizer,
(e) about 0.2% w/w to about 2% w/w colloidal silicon dioxide and
(f) about 1.05% w/w to about 2% w/w of magnesium stearate based on the total weight of the composition.

[036] In the preferred embodiment of the invention, the compositions disclosed in any of the above embodiments are filled into capsules. According to this embodiment, said capsules comprise gelatin. In one embodiment, capsule further comprises titanium dioxide, shellac and iron oxide colorants.

[037] The inventors of the present inventors have surprisingly found that the present capsule formulation with the nilotinib free base as an active ingredient is bioequivalent to the capsule dosage form comprising nilotinib hydrochloride monohydrate as an active ingredient.

[038] According to all these embodiments, the following formulation can be used in the capsule dosage form of the invention.

[039] The following examples are provided to illustrate the present invention. It is understood, however, that the invention is not limited to the specific conditions or details described in the examples below. The examples should not be construed as limiting the invention as the examples merely provide specific methodology useful in the understanding and practice of the invention and its various aspects. While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modification to the disclosed embodiments can occur to those who are skilled in the art.
[040] EXAMPLE 1
[041] Capsule formulation of Nilotinib free base
S. No Components % w/w
1. Nilotinib free base 40% - 60%
2. Lactose monohydrate 30% - 50%
3. Crospovidone 1.5% - 10%
4. SEPITRAPTM 80
(Polysorbate 80 + Magnesium aluminometasilicate) 0.5% - 5%
5. Colloidal silicon dioxide 0.2 – 2%
6. Magnesium Stearate 1.05% – 2%

[042] EXAMPLE 2 to 4:
[043] Capsule formulation of Nilotinib free base

S.No Components Example 2 Example 3 Example 4
mg/Cap mg/Cap mg/Cap
Intragranular Portion
1 Nilotinib free base 50 150 200
2 Lactose Monohydrate 35.6 106.8 142.4
3 Crospovidone 4 12 16
4 SEPITRAPTM 80
(Polysorbate 80 + Magnesium aluminometasilicate) 1 3 4
5 Magnesium Stearate 0.275 0.825 1.1
Extragranular Portion
6 Lactose Monohydrate 7.8 23.4 31.2
7 Colloidal Silicon Dioxide 0.5 1.5 2
8 Magnesium Stearate 0.825 2.475 3.3
Total 100 300 400

[044] Process for Preparation:

1. Dispense nilotinib free base and excipients.
2. Sift nilotinib free base, required quantity of intragranular lactose monohydrate, crospovidone, polysorbate 80 + Magnesium aluminometasilicate (SEPITRAPTM 80) and intragranular magnesium stearate together through suitable sieve and blended up to 10 minutes.
3. Sift extra granular lactose monohydrate, colloidal silicon dioxide through sieve and collect separately.
4. Sift extra granular magnesium stearate through sieve and collect separately.
5. Material of Step 2 shall be compacted using roll compactor to form flakes.
6. Flakes of Step 5 shall be passed through appropriate screen and collected separately in IBC bin.
7. Add pre-sifted extragranular lactose monohydrate and colloidal silicon dioxide of Step 3 into bin blender of step 6 and mix
8. Add pre-sifted extragranular magnesium stearate of Step 4 into bin blender of step 7 and lubricate at 15 rpm up to 5 minutes.
9. Capsule filling of lubricated blend of Step 8.
10. Pack the capsules
,CLAIMS:1. A pharmaceutical composition comprising nilotinib free base and a pharmaceutically acceptable excipient.

2. The pharmaceutical composition as claimed in claim 1, wherein the dosage form is a capsule.

3. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from the group consisting of fillers, disintegrants, solubilizers, glidants and lubricants.

4. The pharmaceutical composition as claimed in claim 1, wherein the composition is free of binder.

5. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises
(a) at least one filler selected from group consisting of lactose monohydrate, microcrystalline cellulose and mannitol,
(b) at least one disintegrant selected from group consisting of crospovidone, croscarmellose sodium and sodium starch glycolate,
(c) a solublizer, wherein solubilizer is a mixture of surfactant and porous mineral carrier,
(d) colloidal silicon dioxide as a glidant and
(e) magnesium stearate as the lubricant.

6. The pharmaceutical composition as claimed in claim 5, wherein the surfactant is polysorbate 80.

7. The pharmaceutical composition as claimed in claim 6, wherein the porous miner carrier is magnesium aluminometasilicate.

8. The pharmaceutical composition as claimed in 5, wherein the composition comprises
(a) nilotinib free base,
(b) lactose monohydrate as a filler,
(c) crospovidone as a disintegrant,
(d) mixture of polysorbate 80 and magnesium aluminometasilicate as a solubilizer,
(e) colloidal silicon dioxide as a glidant and
(f) magnesium stearate as the lubricant.