Claims:We Claim:
1. A pharmaceutical composition comprising dasatinib propylene glycol solvate, hydroxypropyl cellulose and one or more pharmaceutically acceptable excipient.
2. The pharmaceutical composition according to claim 1, wherein hydroxypropyl cellulose is about 3.5 to 16.0%w/w, preferably about 5.5 to 10.0 %w/w, most preferably about 8.0% w/w of the total composition.
3. The pharmaceutical composition according to any of the preceding claims, wherein particle size distribution (D90) of dasatinib propylene glycol solvate is 50 microns to 300 microns, preferably 150 microns to 200 microns, most preferably about 190 microns.
4. The pharmaceutical composition according to any of the preceding claims wherein the pharmaceutically acceptable excipient is selected from diluent, disintegrant, binder and lubricant.
5. The pharmaceutical composition according to claim 4, wherein diluent is selected from lactose, sucrose, microcrystalline cellulose, dicalcium carbonate, mannitol, starch and mixture thereof, disintegrant is selected from croscarmellose sodium, sodium starch glycolate, crospovidone and mixture thereof, binder is hydroxyl propyl cellulose and lubricant is selected from magnesium stearate, sodium stearyl fumarate and mixture thereof.
6. The pharmaceutical composition according to any of the preceding claims, wherein composition further comprises a coating which is devoid of polyethylene glycol.
7. A pharmaceutical composition comprising dasatinib propylene glycol solvate and one or more pharmaceutically acceptable excipients, wherein the composition is prepared by dry manufacturing processes.
8. The pharmaceutical composition according to claim 7, wherein the dry manufacturing processes is selected from direct compression and dry granulation.
9. A process of preparation of pharmaceutical composition comprising dasatinib propylene glycol solvate comprising of steps:
a. Mixing dasatinib propylene glycol solvate and hydroxypropyl cellulose optionally with diluent and disintegrant.
b. Optionally, granulating the blend of step a
c. Mixing blend of step a. or b. with lubricant
d. Compressing the blend of step c. into tablets
e. Coating the tablet obtained in step d.
10. The process of preparation of pharmaceutical composition according to claim 9, comprising:
a. Mixing dasatinib propylene glycol solvate, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and hydroxypropyl cellulose
b. Mixing blend of step a. with magnesium stearate
c. Compressing the blend of step b. into tablets
d. Coating the tablets obtained in step c.
, Description:Pharmaceutical composition of Dasatinib

FIELD OF INVENTION
Present invention relates to a stable pharmaceutical composition comprising Dasatinib propylene glycol solvate, hydroxyl propyl cellulose and one or more suitable pharmaceutically acceptable excipients; and its process of preparation.

BACKGROUND
Dasatinib, N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide a compound having the following chemical structure:

is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel®. Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinases inhibitor and is useful in the treatment of oncological diseases. It is approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

US6596746 discloses Dasatinib and its preparation. Several crystalline forms are described in the literature, these were designated forms H1-7, BU-2, E2-1, N-6, T1H1-7, and T1E2-1. Crystalline dasatinib monohydrate (H1-7) and butanol solvate (BU-2) along with the processes for their preparation are described in WO2005077945. In addition, it also describes two ethanol solvates (E2-1; T1E2-1) and two anhydrous forms (N-6; T1H1-7). All known forms of dasatinib have different characteristic properties. Marketed formulation of dasatinib (Sprycel®) uses dasatinib monohydrate, which has very low rate of dissolution.
US20060251723 and US20130122093 discloses formulation of Dasatinib, specifically monohydrate form and PEG is incorporated into coating to avoid decomposition of dasatinib.

WO2017002131 discloses propylene glycol solvates of Dasatinib. Rate of dissolution of dasatinib propylene glycol solvate is very high as compared to monohydrate form. Therefore, composition and process of prior art for dasatinib monohydrate or other dasatinib forms may not give bioequivalent product with dasatinib propylene glycol solvate. Further, maintaining propylene glycol solvate of dasatinib in the formulation is difficult as solvates of active agent may get dissociated during its formulation, which shows impact on efficacy of the product.
Therefore, there remains challenge to prepare a stable formulation of a form of dasatinib which has higher rate of dissolution, while making a bioequivalent product to marketed composition.

Present invention provides a bioequivalent and stable composition of dasatinib propylene glycol solvate which resolves the mentioned issues and is produced using robust, reproducible and easily scalable process.

SUMMARY OF THE INVENTION
One aspect of the present invention is to provide a pharmaceutical composition comprising dasatinib propylene glycol solvate, hydroxypropyl cellulose and one or more pharmaceutically acceptable excipient.

Another aspect of the present invention is to provide a pharmaceutical composition comprising dasatinib propylene glycol solvate, hydroxypropyl cellulose, one or more pharmaceutically acceptable excipient and coating wherein coating is devoid of polyethylene glycol (PEG).

Another aspect of the present invention is to provide process of preparation of pharmaceutical compositions according to present invention.
DETAILED DESCRIPTION OF THE INVENTION
Present invention relates to pharmaceutical composition of dasatinib propylene glycol solvate wherein said composition provides a stable product with desired dissolution profile. Present invention provides the composition comprising dasatinib propylene glycol solvate bioequivalent to Sprycel®.

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. 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 “added” or “mixed” as used herein are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply mixing or addition of one of the excipient/mixture of excipients with other excipients.

Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have” and "include" and variations such as "comprises", "comprising", “having” "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

The term “dasatinib propylene glycol solvate” as used herein includes dasatinib propylene glycol solvates comprising 10 to 16% of propylene glycol measured by Gas Chromatography. Preferably, dasatinib propylene glycol solvate is anhydrous, comprising less than 1% of water by KF.
The term "D90" as used herein means at least 90% of the particles have volume diameter in the specified range when measured by a suitable method for example laser diffraction using a Malvern Mastersizer® laser diffraction instrument.
The term “dry manufacturing processes” as used herein includes processes of dry granulation and direct compression. Dry granulation processes encompass slugging as well as roller compaction. The therapeutic agents and pharmaceutically acceptable excipients are made into slugs (as in slugging) or ribbons (as in roller compaction). Direct compression process involves directly compressing the therapeutic agent and pharmaceutically acceptable excipients into a pharmaceutical formulation, without changing the physical and chemical properties of the therapeutic agent.

The term “coating” as used herein refers to functional or non-functional coating layer devoid of polyethylene glycol (PEG). It may comprise a film forming polymer and one or more excipients suitable for said coating such as film former, glidant, opacifier or colorant and plasticizer – except PEG. Preferably, coating is non-functional coating.

Therefore, another embodiment of present invention provides a pharmaceutical composition comprising dasatinib propylene glycol solvate, hydroxypropyl cellulose and one or more pharmaceutically acceptable excipients.

Surprisingly, the inventors found hydroxypropyl cellulose lends the required adhesion and desired dissolution. The effective range of hydroxypropyl cellulose in the composition is about 3.5 to 16.0% w/w, preferably about 5.5 to 10.0% w/w, most preferably about 8.0 %w/w, of the total composition. Viscosity of hydroxypropyl cellulose used according to present invention ranges from 150 to 600 cps w/w, preferably 300-600 cps w/w, most preferably 450 cps w/w, measured using Brookfield Viscometer LVF at 25°C; and molecular weight of hydroxypropyl cellulose not less than 80,000 Da (weight average molecular weight determined by size-exclusion chromatography).

Another preferred embodiment of present invention provides a pharmaceutical composition comprising dasatinib propylene glycol solvate, hydroxypropyl cellulose and one or more pharmaceutically acceptable excipients, wherein hydroxypropyl cellulose is about 3.5 to 16.0%w/w, preferably about 5.5 to 10.0 %w/w, most preferably about 8.0%w/w of the total composition.

It was surprisingly noted that present invention provides a stable product without incorporating PEG in the coating. Another embodiment of present invention provides a pharmaceutical composition comprising dasatinib propylene glycol solvate, hydroxypropyl cellulose, one or more pharmaceutically acceptable excipients and coating wherein coating is devoid of polyethylene glycol (PEG).
Commercially available product Sprycel® comprises Dasatinib monohydrate, which has low rate of dissolution and thus lower particle size is required. It was found by inventors that composition of present invention comprising dasatinib propylene glycol solvate provides bioequivalent product without need of reduction of particle size of active ingredient. In one embodiment, particle size distribution (PSD-D90) of dasatinib propylene glycol solvate is from 50 microns to 300 microns, preferably D90 is 150 microns to 200 microns, most preferably D90 is about 190 microns.
A preferred embodiment of the present invention provides a pharmaceutical composition comprising dasatinib propylene glycol solvate and one or more pharmaceutical excipients selected from diluent, disintegrant, binder and lubricant, preferably the diluent is selected from lactose, sucrose, microcrystalline cellulose, dicalcium carbonate, mannitol, starch and mixture thereof, preferably the disintegrant is selected from croscarmellose sodium, sodium starch glycolate, crospovidone and mixture thereof, preferably the binder is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pregelatinized starch and povidone and preferably the lubricant is selected from magnesium stearate, sodium stearyl fumarate and mixture thereof. The composition further comprises a coating devoid of polyethylene glycol.

Pharmaceutical composition according to present invention can be prepared according to any of the known process such as wet or dry manufacturing process. Preferably, dry manufacturing is used, which can be selected from direct compression and dry granulation.

Another embodiment of present invention provides pharmaceutical composition comprising dasatinib propylene glycol solvate and one or more pharmaceutically acceptable excipients, wherein the composition is prepared by dry manufacturing processes.

A generalized embodiment of present invention provides process of preparing compositions according to present invention.

An embodiment of present invention provides a process of preparing pharmaceutical composition comprising dasatinib propylene glycol solvate comprising
a. Mixing dasatinib propylene glycol solvate and hydroxypropyl cellulose optionally with diluent and disintegrant.
b. Optionally, granulating the blend of step a.
c. Mixing blend of step a. or b. with lubricant
d. Compressing the blend of step c. into tablets
e. Coating the tablet obtained in step d.

Another embodiment of present invention provides direct compression process of preparing pharmaceutical composition of the present invention comprising
a. Mixing dasatinib propylene glycol solvate, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and hydroxypropyl cellulose
b. Mixing blend of step a. with magnesium stearate
c. Compressing the blend of step b. into tablets
d. Coating the tablets obtained in step c.
Yet another embodiment of present invention provides dry granulation process of preparing pharmaceutical composition of the present invention comprising
a. Mixing dasatinib propylene glycol solvate, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and hydroxypropyl cellulose
b. Granulating the blend obtained in step a.
c. Mixing granules of step b. with magnesium stearate
d. Compressing the blend of step c. into tablets
e. Coating the tablets obtained in step c.

Pharmaceutically acceptable excipients according to any of the embodiment of present invention comprises diluent, disintegrant, binder and lubricant. Pharmaceutical composition may optionally comprise coating.

Compositions according to present invention may optionally further comprises one or more surfactant, glidant, coloring agent, flavoring agent, preservatives, antioxidants and the like. Example and suitable amount of said optional excipient is known to a skilled person or as given in Handbook of pharmaceutical excipients (sixth edition, 2009).

A diluent according to present invention includes powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, dicalcium carbonate, dibasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, calcium silicate, precipitated calcium carbonate; sugars such as dextrose, lactose or sucrose; sugar alcohols such as mannitol, sorbitol, xylitol, isomalt or erythritol; or mixture thereof. Preferably, the diluents are lactose monohydrate and microcrystalline cellulose. Pharmaceutical composition comprises diluent in the amount of about 50.0 to 98.0% w/w, preferably about 55.0 to 65.0% w/w, most preferably about 61.5 %w/w of the total composition.

A disintegrant according to present invention includes calcium carboxymethyl cellulose and its salt including sodium or calcium salt, cross-linked carboxymethyl cellulose sodium (Croscarmellose sodium), cross-linked carboxymethyl cellulose calcium, cross-linked polyvinylpyrrolidone (crospovidone), sodium starch glycolate, pregelatinized starch; low substituted hydroxypropyl cellulose; or mixture thereof. Preferably, the disintegrant is croscarmellose sodium. Pharmaceutical composition comprises disintegrant in the amount of about 0.5 to 8.0 % w/w, preferably about 1.0% w/w of the total composition.

A binder according to present invention includes polyvinyl alcohol, polyvinyl pyrrolidone (povidone), copovidone, starch, pregelatinized starch; cellulose derivatives such as cellulose powder, microcrystalline cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, zein, polymethacrylates, sodium alginate, gums, synthetic resins or mixture thereof. Preferably, the binder is hydroxypropyl cellulose. Pharmaceutical composition comprises binder in the amount of about 3.5 to 16.0%w/w, preferably about 5.5 to 10.0% w/w, most preferably about 8.0%w/w, of the total composition.

A lubricant according to present invention includes magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate, magnesium lauryl sulfate, L-leucine, fumaric acid, adipic acid, boric acid, sodium benzoate, potassium benzoate, sodium propionate or mixture thereof. Preferably, the lubricant is magnesium stearate. Pharmaceutical composition comprises lubricant in the amount of about 0.5 to 4.0%w/w, more preferably about 0.5%w/w of the total composition.

A coating according to present invention can be functional or non-function, and is devoid of polyethylene glycol. Non-functional coating includes a film forming polymer such as hydroxypropyl methyl cellulose, polyvinyl alcohol and one or more excipients suitable for said coating such as film former, non-aqueous solvent, glidant, opacifier or colorant and plasticizer - except PEG. Example and suitable amount of said excipient is known to a skilled person or as given in Handbook of pharmaceutical excipients (sixth edition, 2009). More specifically, the preferred non-aqueous based coating solution is Opadry® White (Colorcon®) and whose composition is about 59.0% hydroxypropyl methyl cellulose, about 32.0% titanium dioxide and about 9.0% triacetin. Pharmaceutical composition comprises coating in the amount of about 2.0 to 4.0%w/w, more preferably about 3.0%w/w of the total composition.

Pharmaceutical compositions prepared according to present invention, comprises dasatinib as propylene glycol solvate in the amount of about 1.0 to 50.0%w/w, preferably about 29.0%w/w of the total composition.

A pharmaceutical composition according to present invention is a solid composition for immediate release for oral administration and it can be in the form of tablet, powder or capsule. Preferably, said composition is in the form of tablet for oral administration.

The invention will be further illustrated by the following examples, however, without restricting its scope to these embodiments.
Example 1
No Ingredient % w/w
1 Dasatinib propylene glycol solvate 29.053
2 Lactose monohydrate 25.055
3 Microcrystalline cellulose 36.398
4 Croscarmellose sodium 1.000
5 Hydroxypropyl cellulose 7.995
6 Magnesium stearate 0.50
Total 100.00
7 Opadry® White (without PEG) 3.00

Dasatinib propylene glycol solvate was mixed with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and hydroxypropyl cellulose and screened through a 40# sieve. The blend was homogenized in blender for 5-15 minutes. Magnesium stearate, screened through a 60# sieve, was added to the above blend. The final blend was homogenized further in a blender. The lubricated blend was then compressed into tablets. The tablets so obtained, were coated using a perforated pan coater with an Opadry® non-aqueous suspension.

The dissolution performance for the composition of Example 1 in USP type IV (Flow through cell ) apparatus at Flow rate: 8.0ml, OGD: PH 4.0 acetate buffer with 1.0% triton, Time (Min.) % drug release at 0.25, 0.5, 0.75, 1.01.5, 2, 2.5, 3, 4, 5, 6, 7, 8 hours is presented in table 1 below.

Table 1: Dissolution data
Sprycel® Example 1
Time (Hrs.) % Release % Release
0.25 24 23
0.5 36 39
0.75 44 48
1 50 55
2 58 63
3 66 67
4 74 71
5 81 77
6 82 82
7 85 84
8 86 87

Example 2:
Intrinsic Dissolution Rate of dasatinib monohydrate and dasatinib propylene glycol solvate was checked using USP-II apparatus: Results are:
Intrinsic Dissolution
Condition: USP-II, 500 mL, OGD: PH 4.0 acetate buffer with 1.0% triton x, RPM: 60
% Dissolution Rate
Time (min) Dasatinib propylene glycol solvate
Dasatinib Monohydrate

5 24 3
10 25 5
15 26 5
20 27 6
30 29 8
45 33 10
60 34 13
90 44 18
120 52 25

Particle Size distribution of dasatinib propylene glycol solvate
D (volume) Dasatinib propylene glycol solvate
Micron
D10 22.3
D50 82.7
D90 193.6

Example 3:
No Ingredient % w/w
1 Dasatinib propylene glycol solvate 29.053
2 Lactose monohydrate 26.198
3 Microcrystalline cellulose 35.750
4 Croscarmellose sodium 2.000
5 Hydroxypropyl cellulose 6.5
6 Magnesium stearate 0.50
7 Methanol q.s.
Total 100.00

Dasatinib propylene glycol, a portion of microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and a portion of hydroxypropyl cellulose were mixed and granulated using solution of hydroxypropyl cellulose in methanol. Granules were dried, milled and mixed with microcrystalline cellulose and Magnesium stearate. Obtained blend was compressed to form tablets and coated similar to Example 1.