Claims:WE CLAIM:
1. A bilayer tablet comprising of:
a) immediate release layer comprising 13-14% of ticagrelor of the total weight of the tablet, mannitol, lactose, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, magnesium stearate and optionally hydroxypropyl methyl cellulose;

b) extended release layer comprising 31-32 % by weight of ticagrelor of the total weight of the tablet, hydroxypropyl methyl cellulose, mannitol, lactose, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate and optionally microcrystalline cellulose;

wherein total weight of tablet is selected from 267 mg and 400 mg.

2. The bilayer tablet as claimed in claim 1, wherein amount of hydroxypropyl methyl cellulose in ticagrelor extended release layer is between 12-21% of the total weight of the tablet.
3. The bilayer tablet as claimed in claim 2, wherein hydroxypropyl methyl cellulose in ticagrelor extended release layer is selected from hydroxypropylmethyl cellulose K 100 LV and mixture of hydroxypropylmethyl cellulose K 100 LV and hydroxypropylmethyl cellulose K4M.
4. The bilayer tablet as claimed in claim 1, wherein immediate release layer comprises 0.1%-4% of mannitol of the total weight of the tablet; 4%-5% of lactose of the total weight of the tablet; 6%-9% of microcrystalline cellulose of the total weight of the tablet; 0.1% - 1% of hydroxypropyl cellulose of the total weight of the tablet, 0.1% - 0.5% of magnesium stearate of the total weight of the tablet and 1% - 2% of croscarmellose sodium of the total weight of the tablet and optionally 1% to 2% hydroxypropylmethyl cellulose of the total weight of the tablet.

5. The bilayer tablet as claimed in claim 4, wherein immediate release layer comprises 0.3% or 3.75% of mannitol of the total weight of the tablet; 4.65 % of lactose monohydrate of the total weight of the tablet; 6.8% or 8.5% of microcrystalline cellulose of the total weight of the tablet; 1.6% of croscarmellose sodium of the total weight of the tablet, 0.6% of hydroxypropyl cellulose of the total weight of the tablet, 0.3% of magnesium stearate of the total weight of the tablet and optionally 1.7% of hydroxypropylmethyl cellulose of the total weight of the tablet.

6. The bilayer tablet as claimed in claim 1 wherein extended release layer comprises 12%-21% of hydroxypropyl methyl cellulose of the total weight of the tablet; 2%-11% of mannitol of the total weight of the tablet; 9%-11% of lactose of the total weight of the tablet; 3%-4% of hydroxypropyl cellulose of the total weight of the tablet; 0.1%-0.2% of colloidal silicon dioxide of the total weight of the tablet and 0.6%-0.7% of magnesium stearate of the total weight of the tablet and optionally 1% - 2% of microcrystalline cellulose of the total weight of the tablet.
7. The bilayer tablet as claimed in claim 6 wherein extended release layer comprises 12% or 20.6% of hydroxypropyl methyl cellulose of the total weight of the tablet; 10.5% or 2.5% of mannitol of the total weight of the tablet; 10.8% or 9% of lactose monohydrate of the total weight of the tablet; 3.2% of hydroxypropyl cellulose of the total weight of the tablet; 0.14% of colloidal silicon dioxide of the total weight of the tablet; 0.7% of magnesium stearate of the total weight of the tablet and optionally 1% of microcrystalline cellulose of the total weight of the tablet.

8. A process of preparation of a bilayer tablet comprising
a) Granulating 13-14% of ticagrelor of the total weight of the tablet, mannitol, lactose, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and optionally hydroxypropyl methyl cellulose for preparation of immediate release layer;
b) Granulating 31-32 % by weight of ticagrelor of the total weight of the tablet, hydroxypropyl methyl cellulose, mannitol, lactose, hydroxypropyl cellulose and optionally microcrystalline cellulose for preparation of extended release layer;
c) Adding magnesium stearate and/or colloidal silicon dioxide to the granules of immediate release layer and extended release layer of step (a) and (b) to form the blend;
d) Compressing the blend of immediate release layer and extended release layer of step c) to form bilayer tablet; wherein total weight of tablet is selected from 267 mg and 400 mg.

Dated this 07th day of Oct, 2021

-----------------------------------
for Torrent Pharmaceuticals Limited
Dr. Rajiv Ghanshyam Shah [IN/PA-992]
Torrent Pharmaceuticals Limited,
Torrent Research Centre
P.O. Bhat – 382428, Gandhinagar
Gujarat, India
, Description:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
TITLE OF THE INVENTION:
A BILAYER TABLET OF TICAGRELOR
APPLICANT(S):
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Address: Torrent House, Off Ashram Road, Near Dinesh Hall, Ahmedabad
380 009, Gujarat, India

PREAMBLE OF THE DESCRIPTION:
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

A BILAYER TABLET OF TICAGRELOR

FIELD OF THE INVENTION:
The present invention relates to a bilayer tablet of ticagrelor. More particularly, the present invention relates to a bilayer tablet of ticagrelor for once daily administration comprising immediate release layer and extended release layer that provides the release of ticagrelor upto 24 hrs.

BACKGROUND OF THE INVENTION:
Ticagrelor is an antithrombotic agent that acts as a platelet aggregation inhibitor by antagonising the P2Y12 receptor, used in the patients with acute coronary syndromes, optionally in combination with aspirin. Chemically it is (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. The empirical formula of ticagrelor is C23H28F2N6O4S and its molecular weight is 522.57. The chemical structure of ticagrelor is:

It is effective in reducing the incidence of thrombotic cardiovascular events (death due to cardiovascular abnormalities, myocardial infarction, stroke). It is useful in reducing the risk of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome or a history of myocardial infarction.
In case of patients with acute coronary syndrome or in the patient with the history of myocardial infraction, the treatment is initiated with 180 mg of oral loading dose of BRILINTA® then followed by administration of 90 mg twice daily during the first year. After one year 60 mg is administer twice daily.
Due to short half-life, the drug is administering twice a day to maintain the therapeutic drug concentration that results in poor patient compliance. Thereby to enhance the patient compliance there is a need to reduce the multiple administration of doses. Moreover, to reduce the risk of myocardial infarction or stroke caused by acute thrombosis, there is a need to formulate a dosage form that maintains the concentration of drug for prolong period of time by administering the dose only once a day.
There are inventions in the prior arts which tried to solve the above mentioned problem.
The Chinese patent application CN103520164 discloses extended -release preparation comprising of ticagrelor, a pharmaceutically acceptable extended -release material, and other pharmaceutically acceptable auxiliary materials. The sustained-release preparation has an immediate-release part and a sustained-release part; wherein the sustained release portion showed the drug release profile of about 40% in the first 1 hour and then at constant rate released 90% at 20 hours.
The Korean patent publication KR2020077956 discloses a composition with an immediate-release unit and a sustained release unit, where the active ingredient of immediate-release unit and the sustained release unit is selected from ticagrelor or its pharmaceutically acceptable salt. The immediate release portion comprises 20 to 45% by weight of the total weight of ticagrelor and sustained release part comprises 55 to 80% by weight of the total weight of the ticagrelor or pharmaceutically acceptable salt thereof.
The patent application CN105998026 aimed to provide a pharmaceutical composition which comprised of one immediate release layer and two slow release layers containing ticagrelor, which could achieve quick effect after 1 administration for 1 day and ensure continuous effectiveness within 24 hours.
Inventors of the present invention have developed an alternate composition of ticagrelor in the form of bilayer tablet for once daily administration that aims for extending the drug release continuously up to 24 hours and hence patient compliance is achieved.

SUMMARY OF THE PRESENT INVENTION:
One aspect of present invention provides a bilayer tablet comprising
a) immediate release layer comprising 13-14% of ticagrelor of the total weight of the tablet, mannitol, lactose, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and magnesium stearate;

b) extended release layer comprising 31-32 % by weight of ticagrelor of the total weight of the tablet, hydroxypropyl methyl cellulose, mannitol, lactose, hydroxypropyl cellulose, colloidal silicon dioxide and magnesium stearate; wherein total weight of tablet is selected from 267 mg and 400 mg.
Another aspect of present invention provides process of preparation of a bilayer tablet comprising
a) Granulating 13-14% of ticagrelor of the total weight of the tablet, mannitol, lactose, microcrystalline cellulose, hydroxypropyl cellulose and croscarmellose sodium for preparation of immediate release layer;
b) Granulating 31-32 % by weight of ticagrelor of the total weight of the tablet, hydroxypropyl methyl cellulose, mannitol, lactose and hydroxypropyl cellulose for preparation of extended release layer;
c) Adding magnesium stearate and/or colloidal silicon dioxide to the granules of immediate release layer and extended release layer obtained in step (a) and (b) to prepare blend;
d) Compressing the blend of immediate release layer and extended release layer of step c) to form bilayer tablet; wherein total weight of tablet is selected from 267 mg and 400 mg.

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 references 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 "ticagrelor" as used herein includes ticagrelor in the form of freebase, amorphous ticagrelor, crystalline ticagrelor or any isomer, derivative, hydrate, solvate, or prodrug or combinations thereof.
The term “Immediate release layer” as used herein means a layer of bilayer tablet which releases more than 80% Ticagrelor within 60 minutes, when dissolved in media with 0.1 N HCl.
The term “Extended release layer” as used herein means a layer of bilayer tablet which releases more than 90% of Ticagrelor within 24 hours, when dissolved in media with acetate buffer + 0.2% Tween 80.
The amount of Ticagrelor or any of the excipient or total weight of tablet as described in this application refer to the specified value, including its variations upto 10% of the mentioned value.
The present invention provides a bilayer tablet of ticagrelor comprising immediate release layer of ticagrelor and extended release layer of ticagrelor which releases the ticagrelor upto 24 hrs, thereby tablet can be administered once daily.
One embodiment of the present invention provides a bilayer tablet comprising
a) immediate release layer comprising 13-14% of ticagrelor of the total weight of the tablet, mannitol, lactose, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and magnesium stearate;

b) extended release layer comprising 31%-32 % by weight of ticagrelor of the total weight of the tablet, hydroxypropyl methyl cellulose, mannitol, lactose, hydroxypropyl cellulose, colloidal silicon dioxide and magnesium stearate; wherein total weight of tablet is selected from 267 mg and 400 mg.

Bilayer tablet of invention optionally contains hydroxypropyl methyl cellulose in immediate release layer a) and microcrystalline cellulose in extended release layer b).
Therefore, another embodiment of present invention provides a bilayer tablet comprising of
a) immediate release layer comprising 13%-14% of ticagrelor of the total weight of the tablet, mannitol, lactose, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, hydroxypropyl methyl cellulose and magnesium stearate;

b) extended release layer comprising 31%-32 % by weight of ticagrelor of the total weight of the tablet, microcrystalline cellulose, hydroxypropyl methyl cellulose, mannitol, lactose, hydroxypropyl cellulose, colloidal silicon dioxide and magnesium stearate; wherein total weight of tablet is selected from 267 mg and 400 mg.
The hydroxypropylmethyl cellulose used in extended release layer is preferably selected from hydroxypropylmethyl cellulose K 100 LV, hydroxypropylmethyl cellulose K4M or mixture thereof which controls the release of Ticagrelor.
Hydroxypropylmethyl cellulose K 100 LV is a low molecular weight hydroxypropyl methylcellulose (HPMC) which yields a viscosity of 100 cP at a 2% addition rate in water. Hydroxypropylmethyl cellulose K4M is a medium molecular weight hydroxypropyl methylcellulose (HPMC), which yield a viscosity of 4,000 cP at 2% in water.
The hydroxypropylmethyl cellulose used in immediate release layer is preferably hydroxypropylmethyl cellulose K 100 LV.
The bilayer tablet according to present invention comprises 120 mg or 180 mg of ticagrelor per tablet which is administered once a day and that is bioequivalent to ticagrelor tablet 60 mg and 90 mg bid respectively.
In another embodiment, immediate release layer of bilayer tablet of the present invention comprises 0.1%-4% of mannitol of the total weight of the tablet, preferably 0.3% or 3.75% of mannitol of the total weight of the tablet; 4%-5% of lactose of the total weight of the tablet, preferably 4.65 % of lactose monohydrate of the total weight of the tablet; 6%-9% of microcrystalline cellulose of the total weight of the tablet, preferably 6.8% or 8.5% of microcrystalline cellulose of the total weight of the tablet; 1%-2% of croscarmellose sodium of the total weight of the tablet, preferably 1.6% of croscarmellose sodium of the total weight of the tablet; 0.1% - 1% of hydroxypropyl cellulose of the total weight of the tablet, preferably 0.6% of hydroxypropyl cellulose of the total weight of the tablet and 0.1% - 0.5% of magnesium stearate of the total weight of the tablet, preferably 0.3% of magnesium stearate of the total weight of the tablet.

Immediate release layer optionally comprises colorant such as ferric oxide yellow and hydroxypropylmethyl cellulose K 100 LV. Hydroxypropylmethyl cellulose K 100 LV, if present in immediate release layer, ranges from 1% - 2% of the total weight of the tablet, preferably, 1.7% of the total weight of the tablet.

In another embodiment, extended release layer of bilayer tablet of the present invention comprises 12%-21% of hydroxypropyl methyl cellulose of the total weight of the tablet, preferably 12% or 20.6% of hydroxypropyl methyl cellulose of the total weight of the tablet; 2%-11% of mannitol of the total weight of the tablet, preferably 10.5% or 2.5% of mannitol of the total weight of the tablet; 9%-11% of lactose of the total weight of the tablet, preferably 10.8% or 9% of lactose monohydrate of the total weight of the tablet; 3%-4% of hydroxypropyl cellulose of the total weight of the tablet, preferably 3.2% of hydroxypropyl cellulose of the total weight of the tablet; 0.1%-0.2% of colloidal silicon dioxide of the total weight of the tablet, preferably 0.14% of colloidal silicon dioxide of the total weight of the tablet and 0.6%-0.7% of magnesium stearate of the total weight of the tablet, preferably 0.7% of magnesium stearate of the total weight of the tablet.

The hydroxypropyl methyl cellulose present in the extended release layer of the composition according to present invention can be selected from hydroxypropylmethyl cellulose K 100 LV, hydroxypropylmethyl cellulose K4M or mixture thereof. More preferably, extended release layer of the composition of present invention comprises either mixture of 8.6% of hydroxypropylmethyl cellulose K4M and 3.4% hydroxypropylmethyl cellulose K 100 LV or comprises 20.6% of hydroxypropylmethyl cellulose K 100 LV.

Extended release layer optionally comprises Microcrystalline cellulose. Microcrystalline cellulose, if present in extended release layer, ranges from 1% - 2% of the total weight of the tablet, preferably, 1% of the total weight of the tablet.

Another embodiment of present invention provides a bilayer tablet comprising 180 mg of Ticagrelor wherein total weight of immediate release layer is 125 mg and total weight of extended release layer is 275 mg.

Another embodiment of present invention provides a bilayer tablet comprising 120 mg of Ticagrelor wherein total weight of immediate release layer is 83.33 mg and total weight of extended release layer is 183.34 mg.

Another embodiment of the present invention provides process of preparation of a bilayer tablet comprising
a) Granulating 13-14% of ticagrelor of the total weight of the tablet, mannitol, lactose, microcrystalline cellulose, hydroxypropyl cellulose and croscarmellose sodium for preparation of immediate release layer;
b) Granulating 31-32 % by weight of ticagrelor of the total weight of the tablet, hydroxypropyl methyl cellulose, mannitol, lactose and hydroxypropyl cellulose for preparation of extended release layer;
c) Adding magnesium stearate and/or colloidal silicon dioxide to the granules of immediate release layer and extended release layer of step (a) and (b) to form the blend;
d) Compressing the blend of immediate release layer and extended release layer of step c) to form bilayer tablet; wherein total weight of tablet is selected from 267 mg and 400 mg.

Step a) of the process may optionally comprise hydroxypropyl methyl cellulose. The granulation of step a) preferably involves dry mixing ticagrelor, mannitol, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and optionally hydroxypropyl methyl cellulose K 100 LV in FBP followed by granulation using aqueous solution of hydroxyl propyl cellulose.
Step b) of the process may optionally comprise microcrystalline cellulose. The granulation of step b) preferably involves dry mixing ticagrelor, hydroxypropyl methyl cellulose, mannitol, lactose and optionally microcrystalline cellulose in FBP followed by granulation using aqueous solution of hydroxyl propyl cellulose.
Granules of step a) and (b) are dried and optionally sized and sifted.
In the granules of immediate release layer magnesium stearate is added to form the blend while in the granules of extended release layer magnesium stearate and colloidal silicon dioxide are added to form the blend.
Blend of immediate release layer and extended release layer are compressed to form a bilayer tablet. Such tablet may optionally be coated with film forming agent comprising hydroxyl propyl methyl cellulose or polyvinyl alcohol.
Bilayer tablet of present invention can be combined with aspirin or enteric coated aspirin in a dosage form such as capsule.
The invention will be further illustrated by the following examples, however, without restricting the scope to these embodiments.
Example 1: Composition of Ticagrelor Extended Release Tablet 180 mg
Sr. No Ingredients Example 1 (a) Example 1 (b)
% w/w % w/w
Immediate release Layer
1 Ticagrelor 13.5 13.5
2 Mannitol 0.31 3.75
3 Lactose Monohydrate 4.65 4.65
4 Microcrystalline Cellulose 8.5 6.78
5 Ferric oxide yellow 0.10 0.10
6 Croscarmellose Sodium 1.56 1.56
7 HPMC K100 LV 1.72 -
8 HPC Klucel LF 0.6 0.6
9 Purified Water Q.S. Q.S.
10 Magnesium Stearate 0.31 0.31
Extended release Layer
1 Ticagrelor 31.5 31.5
2 Lactose Monohydrate 10.77 9.055
3 HPMC K4M 8.6 -
4 HPMC K100LV 3.44 20.62
5 Mannitol 10.43 2.5
6 Microcrystalline Cellulose - 1.06
7 HPC Klucel LF 3.19 3.19
8 Purified Water Q.S. Q.S.
9 Colloidal silicon dioxide 0.14 0.14
10 Magnesium Stearate 0.69 0.69
Lubricated Blend of Immediate Release Layer 125 mg 125 mg
Lubricated Blend of Extended Release Layer 275 mg 275mg
Total weight of tablet 400 mg 400 mg

Immediate release layer: Specified amount of Ticagrelor, Mannitol, Lactose monohydrate, Microcrystalline cellulose, ferric oxide yellow, Croscarmellose sodium and hydroxypropylmethyl cellulose (In example 1(a)) were mechanical sifted, dry mixed and granulated in FBP using hydroxypropyl cellulose solution prepared using water. Obtained granules were dried, sized and sifted followed by lubrication using magnesium stearate to prepare lubricated blend.
Extended release layer: Specified amount of Ticagrelor, Mannitol, Lactose monohydrate, Microcrystalline cellulose (For Example2(b)) and hydroxypropylmethyl cellulose were mechanically sifted, dry mixed and granulated in FBP using hydroxypropyl cellulose solution prepared using water. Obtained granules were dried and sized using Quadro mill followed by blending with colloidal silicon dioxide and lubrication with magnesium stearate to prepare lubricated blend.
Lubricated blend of immediate release layer and extended release layer were compressed to form bilayer tablet.

Dissolution of the tablet of Example 1(a) and 1 (b) was checked at 37±0.5°C, in 900 ml of acetate buffer with 0.2% Tween 80 and at a paddle speed of 50 RPM using a USP Type II (paddle) apparatus.

Table 1
Time in Hrs 1 2 3 4 6 8 10 12 14 16 20 24
[Example 1(a)] 16.7 26.1 33 38.3 48.4 57.3 64.7 71 77.3 82.8 90.6 96.2
Example 1(b)] 26 35.6 44.5 52.3 63.5 71.7 78.2 84.8 86.8 88.4 89.6 90.3

Drug release of the bilayer tablet of ticagrelor of the present invention is shown in Table 1 wherein more than 15% of drug is released in first one hour followed by sustained release upto 24 hours.

Example 2: Composition of Ticagrelor Extended Release Tablet 120 mg
Sr. No Ingredients Example 2 (a) Example 2 (b)
% w/w % w/w
Immediate release Layer
1 Ticagrelor 13.5 13.5
2 Mannitol 0.31 3.75
3 Lactose Monohydrate 4.65 4.65
4 Microcrystalline Cellulose 8.5 6.78
5 Ferric oxide yellow 0.10 0.10
6 Croscarmellose Sodium 1.56 1.56
7 HPMC K100 LV 1.72 -
8 HPC Klucel LF 0.6 0.6
9 Purified Water Q.S. Q.S.
10 Magnesium Stearate 0.31 0.31
Extended release Layer
1 Ticagrelor 31.5 31.5
2 Lactose Monohydrate 10.77 9.055
3 HPMC K4M 8.6 -
4 HPMC K100LV 3.44 20.62
5 Mannitol 10.43 2.5
6 Microcrystalline Cellulose - 1.06
7 HPC Klucel LF 3.19 3.19
8 Purified Water Q.S. Q.S.
9 Colloidal silicon dioxide 0.14 0.14
10 Magnesium Stearate 0.69 0.69
Lubricated Blend of Immediate Release Layer 83.33 mg 83.33 mg
Lubricated Blend of Extended Release Layer 183.34 mg 183.34 mg
Total weight of tablet 267 mg 267 mg

Composition of Example 2 was prepared using process similar to Example 1.