WO2023139243A1

WO2023139243A1 - A process for preparation of tartaric acid cores for dabigatran pellets and the pellets containing dabigatran

Info

Publication number: WO2023139243A1
Application number: PCT/EP2023/051449
Authority: WO
Inventors: Lukasz WOZNIAK
Original assignee: Adamed Pharma S.A
Priority date: 2022-01-21
Filing date: 2023-01-20
Publication date: 2023-07-27

Abstract

The invention relates to a process for the preparation of pharmaceutical oral dosage form of the active substance dabigatran etexilate and the pharmacologically acceptable salts thereof, in particular dabigatran etexilate methanesulfonate, the pharmaceutical composition obtainable by said process, to the said pharmaceutical composition obtainable by the said process packed into hard capsules, and to tartaric acid cores as an intermediate for active coats, such as dabigatran etexilate methanesulfonate coat.

Description

A process for preparation of tartaric acid cores for dabigatran pellets and the pellets containing dabigatran.

Description

Field of the invention

Technological background

The reference drug product containing dabigatran Pradaxa is marketed in the form of pellets in hard HPMC capsules. These pellets are prepared by the powder layering method described in W003/074056, W02009/118321, W02009/118322, and WO2010/007016. In these methods, a tartaric acid particles are sprayed with a solution of tartaric acid and a binder, preferably acacia gum. Thereafter, fine tartaric acid powder is sprinkled on the moist tartaric acid particles. The material is then dried, and sprayed with the binder solution again. The spraying of the tartaric acid solution and the sprinkling with the powder are repeated a number of times until a spherical particle is formed.

The steps of powder-coating are not only energy and time-consuming, but also difficult to be validated. As a result, repeatability of the resulting product and in-process losses are not acceptable for pharmaceutical production.

In these disclosures no pointer is provided that the process may be successfully performed with only selected steps of the whole sequence. Namely, that one of the steps - repeated powder layering, can be omitted without quality losses of the final dabigatran-pellet.

In EP2588090 powder-coating steps are omitted and ready to use of spherical cores made of sugar or tartaric acid. However, in case of neutral cores of sugar there is unnecessarily introduced an amount of an excipient without a function and consequently the total weight of the dabigatran- pellet is increased. This results in bigger size of the finished dosage form and negatively influences patients compliance and quality of life in the aspect of swallowing. In case of tartaric acid pellets, the core influences dabigatran solubility. However it is unknown how to prepare such core itself and whether the process finally will be economically more preferable than the powder-coating process. Tartaric acid spheres disclosed in EP2588090 (Examples A10 and A13) are coated with waterbased ethanolic solution of tartaric acid. The coating solution is free from a binder substance. EP2588090 doesn’t present any data as to the characteristic or quality of the pellets. Also dabigatran stability in these pellets is unknown. Due to the lack of dissolution or bioequivalency data, it is also unknown whether the inventive pellets can be applied in practice of pharmaceutical production to solve the existing problems connected with dabigatran-pellets uneconomical, timeconsuming powder-layering. Additionally, removal of the binder results in losses during spraying onto starter beads due to the lowered viscosity of the coating solution. The obtained coating is prone to cracking, and such cores must be rejected.

W02009097156 teaches that tartaric acid crystals may be used as starters for tartaric acid cores, on which farther layers, including active substance layer, are deposited. However, this document is related to compositions of an active substance which is chemically unrelated to dabigatran and is foreseen for an extended release. Additionally, coating of the crystal is performed with the use of tartaric acid dispersion and the description (p. 13, 1.5-12) teaches that the use of tartaric acid in form of a solution for coating should be avoided because of the high solubility in water of the tartaric acid crystal.

Problem to be solved

Therefore there still remain a need for more economical process of preparation of a tartaric acid cores which may be further utilized for preparation of dabigatran pellets.

There is also a need for provision of a complete manufacturing process of the chemically stable and bioequivalent to the referent drug dabigatran pellets which may be performed starting from raw materials. Such a process will be independent from the accessibility and quality of the intermediate materials, such as the cores utilized in EP2588090.

Summary of the Invention

It is an object of the present invention to provide:

- a process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate,

- the pharmaceutical composition obtainable by said process,

- the said pharmaceutical composition obtainable by the said process packed into hard capsules, and

- a tartaric acid core as an intermediate for active coats, such as dabigatran etexilate methanesulfonate coat, that separately or in combination reduce or overcome at least some or all of the above-mentioned problems. The object is solved by the process for preparation of a pharmaceutical composition and the pharmaceutical composition in form of pellets obtainable by said process and further packed into hard capsules, and by tartaric acid cores as an intermediate for active coats, in particular active coat comprising dabigatran etexilate methanesulfonate, according to the appended claims.

In particular, the present invention relates to the following aspects:

(1) According to an aspect the present invention relates to a process for the preparation of solid oral pellets comprising dabigatran etexilate methanesulfonate, wherein

(a) the non-spherical tartaric acid in form of an irregular crystal is coated with a solution comprising tartaric acid and a binder and optionally further pharmaceutical excipients in water,

(b) the coated core of step (a) is coated with an isolating layer, and

(c) the insulated core of step (b) is coated with a layer comprising dabigatran etexilate methanesulfonate. wherein a powder coating is not used at any step of the process.

(2) The process according to (1), wherein Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of0.3-0.7 mm± 5 wt.%.

(3) The process according to (1) or (2), wherein Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of 0.4- 0.6 mm ± 5 wt.% and < 20 wt.% of the tartaric acid crystals is in the size of not more than 0.4 mm.

(4) The process according to (3), wherein 25 - 60 wt.% of the tartaric acid crystals is in a range of 0.5- 0.63 mm.

(5) The process according to (1) to (4), wherein the solution comprising tartaric acid and a binder and optionally further pharmaceutical excipients in step a) is a homogenous solution, without any undissolved particles.

(6) The process according to any of (1) to (5), wherein the tartaric acid amount in the pellet is in a range of 40.0-45.0 wt.%, preferably 42.83 wt.% calculated on the total mass of the pellet.

(7) The process according to any of (1) to (6), wherein the crystals in step a) are coated with the use of fluid bed coating method.

(8) The process according to any of (1) to (7), wherein the binder in step a) is acacia or Hypromellose, preferably spray-dried acacia or Hypromellose 2910.

(9) The process according to any of (1) to (8), wherein the core in step b) is coated with an ethanolic HPMC-talk suspension.

(10) The process according to (9), wherein the HPMC has molecular weight of approximately 20000 -60000 g/mol, and viscosity in a range of 12-18 mPa-s (2wt.% in water at 20°C), preferably 15 mPa-s (2wt.% in water at 20°C). (11) The process according to (10), wherein the amount of HPMC in the insulation coat of step b) is in a range of 1.3- 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet.

(12) The process according to any of (9) to (11), wherein the amount of talk in the insulation coat of step b) is in a range of 1.0- 2.0 wt.%, most preferably 1.4 wt.% calculated on the total mass of the pellet, and 2,5 -3,5wt.%, preferably 3,0 wt.% calculated on the total mass of the isolated core obtained in step b).

(13) The process according to (9) to (12), wherein the insulating coat further comprises dimethicone, preferably in the form of an 35% aqueous emulsion, preferably dimethicone is present in the insulation coat of step b) in a range of 0.01- 0.03 wt.%, most preferably 0.02 wt.% calculated on the total mass of the pellet.

(14) The process according to (9) to (13), wherein the insulating coat is coated as a suspension in a mixture of ethanol 96% v/v and water.

(15) The process according to any of (1) to (14), wherein the layer in step c) comprises dabigatran etexilate methanesulfonate in an amount in a range of 35-45%, most preferably 41.85 wt.%, calculated on the total mass of the pellet.

(16) The process according to (15), wherein the layer in step c) is coated as a HPC-talk suspension in isopropanol.

(17) The process according to (16), wherein the HPC in the layer in step c), has molecular weight of approximately 80 000 Da, and its 10% aqueous solution has viscosity of 300 - 600 mPa-s in 25 °C.

(18) The process according to (16) or (17), wherein the amount of HPC in the layer of step c) is in a range of 3.7- 4.3 wt.%, preferably 4.0-4.2, most preferably 4.17 wt.% calculated on the total mass of the pellet.

(19) The process according to any of (15) to (18), wherein in the layer of step c) the weight ratio of HPC to the active substance is in a range of 2: 10 to 1 : 10, preferably 1 : 10.

(20) The process according to any of (9) to (11), wherein the layer comprising dabigatran etexilate in step c) further comprises talk, preferably the amount of talk is in a range of 5.0 - 7.0 wt.%, most preferably 6.05 wt.% calculated on the total mass of the pellet.

(21) According to a further aspect, the present invention relates to the pharmaceutical composition in the form of pellets obtainable by the process according to any of (1) to (20).

In particular, the obtained pellets have the following qualitative and quantitative composition: Table 1 Qualitative and quantitative composition obtainable according to the most preferred embodiment of the aspect (20)

(22) According to a further aspect, the present invention relates to a pharmaceutical composition as defined in (21) packed into a hard capsule, preferably a HPMC capsule.

(23) The capsule as defined in (22) contains 75mg, HOmg, or 150mg of Dabigatran active substance, which corresponds to 86.48mg, 126.83mg, and 172.95mg, respectively, of Dabigatran etexilate methanesulfonate.

(24) According to a further aspect, the present invention relates to a tartaric acid core as an intermediate for active coats, such as dabigatran etexilate methanesulfonate coat, the core being obtainable by subsequent steps a) and b) of the process as described in any of (1) to (5) and (7) to (10), (12) to (14) to the extent that these aspects relate to steps a) and b), wherein step c) is omitted.

According to a preferred aspect of the present invention, the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1) and (3). Thus, a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal, wherein Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of 0.4- 0.6 mm ± 5 wt.% and < 20 wt.% of the tartaric acid crystals is in the size of not more than 0.4 mm, measured by Ph. Eur. sieve analysis method, with a solution comprising tartaric acid and a binder and optionally further pharmaceutical excipients in water, the obtained coated core is further coated with an isolating layer, and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate, wherein powder coating is not used at any step of the process. The process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2) and (4) to (20).

According to a preferred aspect of the present invention, the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1) and (4). Thus, a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal, wherein Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of 0.4- 0.6 mm ± 5 wt.% and < 20 wt.% of the tartaric acid crystals is in the size of not more than 0.4 mm measured by Ph. Eur. sieve analysis method, and 25 - 60 wt.% of the tartaric acid crystals is in a range of 0.5 - 0.63 mm with a solution comprising tartaric acid and a binder and optionally further pharmaceutical excipients in water, the obtained coated core is further coated with an isolating layer, and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate, wherein powder coating is not used at any step of the process. The process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2) and (5) to (20).

According to another preferred aspect of the present invention, the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3) and (6). Thus, a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal fraction wherein Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of 0.4- 0.6 mm ± 5 wt.% and < 20 wt.% of the tartaric acid crystals is in the size of not more than 0.4 mm, measured by Ph. Eur. sieve analysis method, with a solution comprising tartaric acid and a binder and optionally further pharmaceutical excipients in water, the obtained coated core is further coated with an isolating layer, and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate, wherein powder coating is not used at any step of the process and wherein the tartaric acid amount in the pellet is in a range of 40.0-45.0 wt.%, preferably 42.83 wt.%. calculated on the total mass of the pellet. The process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (5), and (7) to (20). According to yet another preferred aspect of the present invention, the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (6) and (8). Thus, a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal fraction Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of 0.4- 0.6 mm ± 5 wt.% and < 20 wt.% of the tartaric acid crystals is in the size of not more than 0.4 mm, measured by Ph. Eur. sieve analysis method, with a solution comprising tartaric acid and a binder being acacia or Hypromellose, preferably spray-dried acacia or Hypromellose 2910 and optionally further pharmaceutical excipients in water, the obtained coated core is further coated with an isolating layer, and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate, wherein powder coating is not used at any step of the process and wherein the tartaric acid amount in the pellet is in a range of 40.0-45.0 wt.%, preferably 42.83 wt.%. calculated on the total mass of the pellet. The process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (5), (7) and (9) to (20)

According to yet another preferred aspect of the present invention, the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (6), (8) and (10). Thus, a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal fraction Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of 0.4- 0.6 mm ± 5 wt.% and < 20 wt.% of the tartaric acid crystals is in the size of not more than 0.4 mm, measured by Ph. Eur. sieve analysis method, with a solution comprising tartaric acid and a binder being acacia or Hypromellose, preferably spray-dried acacia or Hypromellose 2910 and optionally further pharmaceutical excipients in water, the obtained coated core is further coated with an isolating layer comprising HPMC, said HPMC has molecular weight of approximately 20000 -60000 g/mol, and viscosity in a range of 12-18 mPa-s (2wt.% in water at 20°C), preferably 15 mPa-s (2wt.% in water at 20°C), and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate, wherein powder coating is not used at any step of the process. The process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (5), (7), (9) and (11) to (20). According to yet another preferred aspect of the present invention, the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (6), (8), (10) and (11). Thus, a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal fraction Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of 0.4- 0.6 mm ± 5 wt.% and < 20 wt.% of the tartaric acid crystals is in the size of not more than 0.4 mm measured by Ph. Eur. sieve analysis method, with a solution comprising tartaric acid and a binder being acacia or Hypromellose, preferably spray-dried acacia or Hypromellose 2910 and optionally further pharmaceutical excipients in water, the obtained coated core is further coated with an isolating layer comprising HPMC in a range of 1.3- 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet, said HPMC has molecular weight of approximately 20000 -60000 g/mol, and viscosity in a range of 12-18 mPa-s (2wt.% in water at 20°C), preferably 15 mPa-s (2wt.% in water at 20°C), and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate, wherein powder coating is not used at any step of the process. The process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (5), (7), (9) and (12) to (20).

According to yet another preferred aspect of the present invention, the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (6), (8), (10), (11) and (15). Thus, a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal fraction Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of 0.4- 0.6 mm ± 5 wt.% and < 20 wt.% of the tartaric acid crystals is in the size of not more than 0.4 mm, measured by Ph. Eur. sieve analysis method, with a solution comprising tartaric acid and a binder being acacia or Hypromellose, preferably spray-dried acacia or Hypromellose 2910 and optionally further pharmaceutical excipients in water, the obtained coated core is further coated with an isolating layer comprising HPMC in a range of 1.3- 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet, said HPMC has molecular weight of approximately 20000 -60000 g/mol, and viscosity in a range of 12-18 mPa-s (2wt.% in water at 20°C), preferably 15 mPa-s (2wt.% in water at 20°C), and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate in an amount in a range of 35-45%, most preferably 41.85 wt.%, calculated on the total mass of the pellet, wherein powder coating is not used at any step of the process. The process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (5), (7), (9), (12) to (14) and (16) to (20).

According to yet another preferred aspect of the present invention, the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (4), (6), (10), (11), (15) and (16). Thus, a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal fraction Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of 0.4- 0.6 mm ± 5 wt.% and < 20 wt.% of the tartaric acid crystals is in the size of not more than 0.4 mm measured by Ph. Eur. sieve analysis method, with a solution comprising tartaric acid and a binder being acacia or Hypromellose, preferably spray-dried acacia or Hypromellose 2910 and optionally further pharmaceutical excipients in water, the obtained coated core is further coated with an isolating layer comprising HPMC in a range of 1.3- 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet, said HPMC has molecular weight of approximately 20000 -60000 g/mol, and viscosity in a range of 12-18 mPa-s (2wt.% in water at 20°C), preferably 15 mPa-s (2wt.% in water at 20°C), and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate in an amount in a range of 35- 45%, most preferably 41.85 wt.%, calculated on the total mass of the pellet. The layer in step c) is coated as a HPC-talk suspension in isopropanol and wherein powder coating is not used at any step of the process. The process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (5), (7), (9), (12) to (14) and (17) to (20).

According to yet another preferred aspect of the present invention, the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (6), (8), (10), (11), (15), (16) and (17). Thus, a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal fraction Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of 0.4- 0.6 mm ± 5 wt.% and < 20 wt.% of the tartaric acid crystals is in the size of not more than 0.4 mm measured by Ph. Eur. sieve analysis method, with a solution comprising tartaric acid and a binder being acacia or Hypromellose, preferably spray-dried acacia or Hypromellose 2910 and optionally further pharmaceutical excipients in water, the obtained coated core is further coated with an isolating layer comprising HPMC in a range of 1.3- 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet, said HPMC has molecular weight of approximately 20000 -60000 g/mol, and viscosity in a range of 12-18 mPa-s (2wt.% in water at 20°C), preferably 15 mPa-s (2wt.% in water at 20°C), and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate in an amount in a range of 35- 45%, most preferably 41.85 wt.%, calculated on the total mass of the pellet. The layer in step c) is coated as aHPC-talk suspension of dabigatran etexilate methanesulfonate in isopropanol. HPC in the layer in step c), has molecular weight of approximately 80 000 Da, and its 10% aqueous solution has viscosity of 300 - 600 mPa-s in 25 °C, and wherein powder coating is not used at any step of the process. The process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (5), (7), (9), (12) to (14) and (18) to (20).

According to yet another preferred aspect of the present invention, the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (6), (8), (10), (11), (15), (16), (17) and (19). Thus, a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal fraction Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of 0.4- 0.6 mm ± 5 wt.% and < 20 wt.% of the tartaric acid crystals is in the size of not more than 0.4 mm measured by Ph. Eur. sieve analysis method, with a solution comprising tartaric acid and a binder being acacia or Hypromellose, preferably spray-dried acacia or Hypromellose 2910 and optionally further pharmaceutical excipients in water, the obtained coated core is further coated with an isolating layer comprising HPMC in a range of 1.3- 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet, said HPMC has molecular weight of approximately 20000 -60000 g/mol, and viscosity in a range of 12-18 mPa-s (2wt.% in water at 20°C), preferably 15 mPa-s., and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate in an amount in a range of 35-45%, most preferably 41.85 wt.%, calculated on the total mass of the pellet. The layer in step c) is coated as a HPC-talk suspension in isopropanol. HPC in the layer in step c), has molecular weight of approximately 80 000 Da, and its 10% aqueous solution has viscosity of 300 - 600 mPa-s in 25 °C, and wherein powder coating is not used at any step of the process. The weight ratio of HPC to the active substance in the layer of step c) is in a range of 2: 10 to 1 : 10, preferably 1 : 10. The process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (5), (7), (9), (12) to (14), (18) and (20).

According to yet another preferred aspect of the present invention, the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (6), (8), (10), (15) and (18). Thus, a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal fraction Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of 0.4- 0.6 mm ± 5 wt.% and < 20 wt.% of the tartaric acid crystals is in the size of not more than 0.4 mm measured by Ph. Eur. sieve analysis method, with a solution comprising tartaric acid and a binder being acacia or Hypromellose, preferably spray-dried acacia or Hypromellose 2910 and optionally further pharmaceutical excipients in water, the obtained coated core is further coated with an isolating layer comprising HPMC, said HPMC has molecular weight of approximately 20000 - 60000 g/mol, and viscosity in a range of 12-18 mPa-s (2wt.% in water at 20°C), preferably 15 mPa’s., and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate in an amount in a range of 35-45%, most preferably 41.85 wt.%, calculated on the total mass of the pellet. The amount of HPC in the dabigatran layer of step c) is in a range of 3.7- 4.3 wt.%, preferably 4.0-4.2, most preferably 4.17 wt.% calculated on the total mass of the pellet. Powder coating is not used at any step of the process. The process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (5), (7), (9) and (11) to (14)., (16), (17), 19) and (20).

Further, it is preferred in all the above aspects and preferred variants of the present invention that the active substance dabigatran etexilate methanesulfonate is present in polymorphic form I. No change of polymorphic form I of dabigatran etexilate methanesulfonate is observed during any steps of the process according to the invention as well as during stability studies in accelerated conditions.

It is also preferred that the dabigatran etexilate methanesulfonate has a d90 particle size of less than 150 um, more preferably less than 80 um and most preferably less than 40 um.

The d90 or d50 particle size mentioned herein refers to the size of at least 90 or 50 wt.% by volume of the particles. It is measured by using light scattering methods and in particular using a Malvern Mastersizer and standard measurement methods recommended by the manufacturer of the instrument and well known in the art.

In a preferred embodiments the starting tartaric acid crystals contain water in a range of 0.4wt.% or less, more preferably in a range of 0.3% , in a most preferred embodiment in a range of 0.2%, calculated on the mass of the crystals.

In a preferred embodiments the final dabigatran pellets contain water in a range of 0.5 wt.% or less, more preferably in a range of 0.3wt.%, in a most preferred embodiment in a range of 0.2wt.%, calculated on the total mass of the final pellet. In the most preferred embodiment the process step a) utilizes 42.83wt.% of tartaric acid in form of non-spherical crystals, 2.18% of acacia suspended in purified water; process step b) utilizes 0.02wt% of dimethicone, 1.45wt% of HPMC, 1.45wt% of talc suspended in 96 v/v% of EtOH and process step c) utilizes 41.85wt% of Dabigatran etexilate methanesulfonate, 4.17wt% of HPC, 6.05wt% of talc suspended in iPrOH, wherein all wt.% are calculated on the total mass of the final pellet, and wherein the amount of solvents is determined as quantum satis (abbreviation q.s. or Q.S.) is a Latin term meaning the amount which is enough to perform the operations of process step a), b) and c), respectively. All the solvent evaporate during the process operations.

Detailed description of the present invention

According to an aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate, the pharmaceutical composition obtainable by said process, the said pharmaceutical composition obtainable by the said process packed into hard capsules, and the tartaric acid core as an intermediate for active coats, such as dabigatran etexilate methanesulfonate coat.

The process enables the production of the pharmaceutical composition using simple, non- expensive and widely available starting ingredients, conventional tools and well-known technologies, while significantly simplifying the manufacturing process, and reducing its costs comparing to manufacturing standards known in the art. The pharmaceutical composition can be prepared by coating methods, such as film coating with water-based solutions or water/organic solvent suspensions. Preferably, the coating agent comprises binder.

The inventors have found that stable dabigatran etexilate methanesulfonate composition in form of pellets, bioequivalent to the referent dabigatran etexilate methanesulfonate composition Pradaxa, can be obtained when non-spherical tartaric acid in form of an irregular crystal is coated with a solution comprising tartaric acid and a binder and optionally further pharmaceutical excipients in water, the obtained coated core is further coated with an isolating layer, and the insulated core of step is coated with a layer comprising dabigatran etexilate methanesulfonate. According to an embodiment, the process starts from non-spherical irregular tartaric acid crystals which have the diameter in a range of 0.3 - 0.7 mm± 5 wt.%, It is preferrable that Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of 0.4- 0.6 mm ± 5 wt.% and < 20 wt.% of the tartaric acid crystals is in the size of not more than 0.4 mm. It is further preferable that 25 - 60 wt.% of the tartaric acid crystals is in a range of 0.5 - 0.63 mm, < 15 wt.% of the tartaric acid crystals is in the size of not more than 0.4 mm and 25 - 60 wt.% of the tartaric acid crystals is in a range of 0.5 - 0.63 mm, measured by Ph. Eur. sieve analysis method. Such non-spherical tartaric acid crystals are coated with a water solution comprising tartaric acid and a binder and optionally further pharmaceutical excipients. Most preferably acacia or Hypromellose, preferably spray-dried acacia or Hypromellose 2910, even more preferably spray-dried acacia is used as the binder and the coating solution is homogenous solution, without any undissolved particles. The solution can be subsequently filtered via filtration mesh of the size of 0.5 - 0.8 mm The said solution is mixed by a low-shear equipment, preferably by a propeller. So more sophisticated equipment is not needed in the operation of coating (process step a)) and as a result the composition can be produced economically. The total amount of tartaric acid in the resulting pellet can be in a range of 40.0-45.0 wt.%, however most preferably is equal to 42.83 wt.% calculated on the total mass of the pellet. The crystals in step a) are coated with the use of any known coating method, however fluid bed coating method is preferred. Powder coating is not necessary to achieve tartaric acid cores suitable for application of insulating coat and active coat during process steps b) and c), respectively. Coating in process step a) is performed with the use of water solution. Thus, difficult for validation and technically demanding powdering and the use of organic solvents is avoided, and this process step a) is more economic and environmentally friendly comparing to prior art.

The tartaric acid cores obtained in process step a) are further coated in step b) with an ethanolic HPMC-talk suspension. This coating insulates the acidic environment of tartaric acid form the active coating. Such layer is necessary as the tartaric acid degrades dabigatran etexilate methanesulfonate when in contact. The insulation can be provided by any non-functional polymer suitable to be used as a coating, HPMC with molecular weight of approximately 20000 -60000 g/mol, and viscosity in a range of 12-18 mPa-s, preferably 15 mPa-s (2wt.% in water at 20°C) is particularly preferrable. Best insulation performance is achieved when the amount of HPMC in the insulation coat of step b) is in a range of 1.3- 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the final pellet. Other excipients can be used in insulating layer as to improve the performance of coating and characteristic of this coat. Best performance is achieved when the amount of talk in the insulation coat of step b) is in a range of 1.3- 1.5 wt.%, most preferably 1.45 wt.% calculated on the total mass of the final pellet. The insulating coat can further comprise dimethicone, preferably used in the form of an 35% aqueous emulsion, preferably in a range of 0.01- 0.03 wt.%, most preferably 0.02 wt.% calculated on the total mass of the pellet. As a suspending agent any liquid suitable for coating can be used, however, a suspension in a mixture of ethanol 96% v/v and water is particularly preferred.

The active layer in step c) comprises dabigatran etexilate methanesulfonate in an amount in a range of 35-45wt.%, most preferably 41.85 wt.%, calculated on the total mass of the pellet. As a suspending agent in process step c) any liquid suitable for coating can be used, however, a HPC- talk suspension in isopropanol is particularly preferred. Best performance is achieved when the HPC in the layer in step c), has molecular weight of approximately 80 000 Da, and its 10% aqueous solution has viscosity of 300 - 600 mPa-s in 25 °C. The amount of HPC in the layer of step c) can be in a range of 3.7- 4.3 wt.%, preferably 4.0-4.2, most preferably 4.17 wt.% calculated on the total mass of the pellet. In the coat-layer of step c) the weight ratio of HPC to the active substance is in a range of 2: 10 to 1 : 10, preferably 1 : 10.

The layer comprising dabigatran etexilate in step c) can further comprises talk, preferably the amount of talk is in a range of 5.0 - 7.0 wt.%, most preferably 6.05 wt.% calculated on the total mass of the final pellet.

According to an embodiment, the present invention relates to the pharmaceutical composition in the form of pellets obtainable by the manufacturing process comprising subsequently performed process step a), b) and c). In the most preferred embodiment the final pellet composition comprises 41.85 wt.% of Dabigatran etexilate methanesulfonate, 42.83 wt.% of tartaric acid, 2.18 wt.% of acacia, spray-dried

1.45 wt.% of Hypromellose 15cP, 7.50 wt.% of talc, 0.02 wt.% of dimethicone (as 35% aqueous emulsion) and 4.17 wt.% of hydroxypropylcellulose (molecular weight approx. 80 000).

According to a further embodiment, pharmaceutical composition obtainable by the manufacturing process comprising subsequently performed process step a), b) and c) can be packed into a hard capsule, preferably a HPMC capsule, and thus providing capsules with different strengths of the active substance, 150mg, 110 mg and 75 mg. Most preferably, the qualitative composition of these respective strengths is as follows:

Table 2

The capsules contain 75mg, llOmg, or 150mg ofDabigatran active substance, which corresponds to 86.48mg, 126.83mg, and 172.95mg, respectively, ofDabigatran etexilate methanesulfonate.

The present invention also provides tartaric acid core as an intermediate for active coats, in case when the acidic environment is required to achieve expected dissolution of the active substance, such as achieved in the case of dabigatran etexilate methanesulfonate. The core can be obtained by subsequent process steps a) and b) as described above.

Technical effects of the invention

According to the process of first aspect of the invention, the pellet of dabigatran etexilate methanesulfonate can be prepared from non-expensive and commercially available substrates starting from crude tartaric acid crystals.

Use of neutral cores is omitted therefore final drug form is smaller and thus easier to swallow for patients, which results also with better compliance to the dosing regimen.

The process according to the first aspect of the invention is economically less demanding than powder layering of tartaric acid crystals, since several repeated steps of powder-layering are omitted.

The obtained dabigatran etexilate methanesulfonate pellets are stable in intermediate and enhanced aging conditions for 6M and during 3 years shelf life as well as bioequivalent to the referent drug-product, which makes them ready to be applied in medicinal uses.

The coated pellets obtained according to the second aspect of the invention are of narrow size distribution and reveal a smooth surface. Satellites of tartaric acid crystals don’t protrude into the isolating layer and subsequently the layer comprising the active pharmaceutical ingredient thus degradation of dabigatran etexilate methanesulfonate is not observed.

Spherical shapes of the starting core are not essential for performance of the further /non- spherical shapes of the core doesn’t influence stability of dabigatran etexilate and stable, bioequivalent product is obtained, which not shown in any of the prior art documents.

No satellites protrude into the isolating layer and subsequently the dabigatran-layer.

Measurements methods'.

Sieve analysis method for measurement of Crystal diameters are measured according to the sieve analysis method using screens of aperture 0.7; 0.6; 0.5; 0.4 mm and receiver. They are placed on the automatic vibratory sieve shaker. 100 g sample of measured material is then placed on the top of the screens set. The apparatus setup is: interval: 10 s, amplitude 1,5 mm, analysis time: 5 minutes. The outcome is presented as a percentage of the fractions. Water content was measured according to the LOD method Loss on drying according to Ph Eur monography 2.2.32.

Dabigatran content in the final pellet and in BEQ samples: as specified in Experimental section. Dissolution', as specified in Experimental section.

Definitions:

Tartaric acid crystals: Ph Eur: Tartaric Acid, colourless monoclinic crystals of Acidum tartaricum; [R-(R*,R*)]-2,3-Dihydroxybutanedioic acid CAS Registry Number [87-69-4], Non-spherical tartaric acid crystals', starting tartaric acid crystals, as a product of direct crystallization without any further processing influencing the uniformity of the obtained crystals shape. These crystals are of prism shape with the diameter of the circle circumscribed on the smallest dimension is withing 0,4 - 0,6 mm range.

Dabigatran active substance', dabigatran etexilate, CAS Registry Number : 211914-51-1, Ethyl -[(2-[ [(4-[A-[(hexyloxy)carbonyl]carbamimidoyl [phenyl )amino]methyl }- l -methyl - 17/- benzimidazol-5-yl)carbonyl]-A-2-pyridinyl-P-alaninate

Dabigatran etexilate me thane sulfonate'. CAS Registry Number : 872728-81-9, Ethyl N-[(2-{[(4- {N-[(hexyloxy)carbonyl] carbamimidoyl}phenyl)amino]methyl}-l -methyl- lH-benzimidazol-5- yl)carbonyl]-N-2-pyridinyl-P-alaninate methanesulfonate

Acacia'. Acacia gum, arabic gum; E414; CAS Registry Number [9000-01-5]

Dimethicone'. a-(Trimethylsilyl)-o-methylpoly[oxy(dimethylsilylene)] [9006-65-9]

Water content', determined according to LOD method

Active coat', a coat comprising a pharmaceutically active substance of Dabigatran etexilate methanesulfonate

Particle Size Distribution (PSD) - range of particles size as measured by Sieve analysis method as described above.

Experimental part

Description of the Manufacturing Process

Dabigatran etexilate, capsules hard, 75mg, HOmg, 150mg are manufactured with standard technologies of sieving, three steps fluid bed granulation (coating) and drying and encapsulation. Table 2. Types of manufacturing equipment for production of Dabigatran etexilate, capsules hard, 75mg, HOmg, 150mg Table 3

The manufacturing process of Dabigatran etexilate, capsules hard, 75mg, HOmg, 150mg is described below with three process main stages appearing in the following order:

Process stage a) - Tartaric acid core crystals: non-spherical tartaric acid crystals are coated with tartaric acid water solution with acacia.

Process stage b) - Insulated tartaric acid pellets: tartaric acid cores obtained in process step a) are coated with an insulating coat.

Process stage c) - Dabigatran Pellets/ active coating: insulated tartaric acid cores are coated with an active coat.

Encapsulation: capsules with finished pellets

Packaging: capsules packed into blisters

The manufacturing process was performed on the following batch formulas:

Table 4. Qualitative and quantitative compositions of the Dabigatran etexilate methanesulfonate batch formulas, capsules hard, proportional for all strengths.

* Other strengths are calculated proportionally

1. Process stage a) - Tartaric acid core crystals: a. l. Sieving 1 - Weight and sieve the specified amount of Tartaric acid through two screens od specified sizes. Measure the Particle Size Distribution (PSD) of the fraction 0.4 - 0.6 mm and determine percentage of fraction NMT 0.4 mm. Repeat sieving and analyzing step until required PSD is fulfilled.

Additionally measure PSD of the fraction 0.4 - 0.6 mm. If the numeric result of the measurement is within limit for Tartaric acid core crystals. Tartaric acid fractions below 0.4 mm and above 0.6 mm combine and weigh specific amount to be dissolved. a.2. Sieving 2 - Fraction 0.4 - 0.6 mm, obtained from the previous step, sieve again achieving product fractions 0.4 - 0.5 and 0.5 - 0.6 mm. Measure the Particle Size Distribution (PSD) of the product fraction 0.5 - 0.6 mm and determine percentage of fractions according to PSD. The sieving step can be repeated until specified requirements are achieved. Table 5. Decision tree for Sieving 2 step.

a.3. Weighing and combining fractions - if required, calculate and weigh based on the PSD measurement, amounts of product fractions 0.4 - 0.5 and 0.5 - 0.6 mm in the way to achieve appropriate proportion of the fraction 0.5 - 0.63 mm in the final Tartaric acid core crystals mass. Weight the calculated amounts and combine them. a.4. Coating of the tartaric acid cores with water solution of tartaric acid with acacia binder. Preparation of Coating solution: Dissolve Acacia in the water (q.s.). After its complete dissolution add specified amount of Tartaric acid to be dissolved. Mix until solution is clear. Formula used for coating of tartaric acid core crystals. Table 6

a.5. Fluid bed coating of the Tartaric acid starter crystals - achieving Tartaric acid cores - Loac

Tartaric acid core crystals to the fluid bed granulator. Spray coating solution 1 using pump onto the surface of the core crystals in temperature higher than 40°C achieving Tartaric acid cores (pellets). a.6. Drying of the Tartaric acid cores - After coating process is finished, elevate the temperature of the bed (in temperature higher than 40°C) and dry the pellets to eliminate exceeding water from it. . . Sieving of Tartaric acid cores, weighing - Dry Tartaric acid pellets are unloaded and screened to eliminate under-, and over - sized particles as well as agglomerates. Ready pellets can be used as a substrate to another batches of Dabigatran etexilate pellets.

Water content, Method of measurement

Weigh out 5 g (± 5%) of the mass of the pellets for measurement. Carry out heating at 90°C and a constant time of 20 minutes.

Process stage b) - Insulated tartaric acid pellets b.1. Preparation of Coating suspension 2: Mix together Ethanol, water purified and dimethicone to the attained solution dose specified amount of Hypromellose. After its complete dissolution add specified amount of Talc. Mix until solution is free of lumps. b.2. Fluid bed coating of the Tartaric acid cores: Load specific amount of Tartaric acid cores obtained in step a) to the fluid bed granulator. Spray coating suspension 2 using pump onto the surface of the cores achieving Insulated tartaric acid pellets. b.3. Drying of the Insulated tartaric acid cores: after coating process is finished, elevate the temperature of the bed and dry the pellets to eliminate exceed of the solvents from it. b.4. Sieving of the Insulated tartaric acid cores, weighing: dry Insulated tartaric acid pellets are unloaded and screened to eliminate under-, and over - sized particles as well as agglomerates.

Table 7.

Process stage c) - Dabigatran Pellets/ active coating c. l. Preparation of Coating suspension 3 - Add specified amount of isopropyl alcohol to the mixer. Dose defined amount of Hydroxypropylcellulose and mix until all component is dissolved. Afterward add Dabigatran etexilate methanesulfonate and Talc to the liquid and mix until solution is free of lumps. c.2. Fluid bed coating of the Insulated Tartaric acid cores - Load Insulated tartaric acid cores to the fluid bed granulator. Spray coating suspension 3 using pump onto the surface of the cores, achieving ready Dabigatran pellets. c.3. Drying of the Dabigatran pellets - After coating process is finished, elevate the temperature of the bed and dry the pellets to eliminate exceed of the solvents from it. c.4. Sieving of the Dabigatran pellets, weighing - Dry pellets are unloaded and screened to eliminate under-, and over - sized particles as well as agglomerates.

Table 8.

Encapsulation - Encapsulate Dabigatran pellets into the HPMC capsules of the size appropriate to the strengths.

Table 9 Description of capsule shells

Packaging:

Bulk: Pack capsules into the PE bag placed in outer PET/PE bag with desiccant and plastic container.

Blisters: Pack Dabigatran etexilate, capsules hard, 75mg, HOmg, 150mg into Foil: Polyamide- Aluminium-PVC (laminate), Lidding foil: Aluminium. Pack the obtained blisters into carton boxes.

The pellets obtained according to the process of the invention have the following compositions respectively for 75, 110 and 150 mg of Dabigatran etexilate methanesulfonate: Table 10.

Determination of water content in the non-spherical tartaric acid cores vs commercial spherical tartaric acid cores: Dabigatran is sensitive to acid hydrolysis in an aqueous medium, therefore to maintain the stability, maximally dry tartaric acid cores should be used as a starting material. The use of standard tartaric acid crystals according to the invention is advantageous because such material has much lower water content compared to spherical tartaric acid pellets, i.e. no more than 0.2 wt.% vs up to 0.5 wt.% Table 11

Optimization of tartaric acid crystals size

Table 12

Different sizes of the starting crystals, in the size ranges given in the Table above, can be used to obtain a similar size end result after insulation coating in process step b). Particle Size Distribution (PSD) of the irregular tartaric acid crystal entering in step a) is acceptable in a range of 0.3- 0.7 mm Particle Size Distribution (PSD) of the insulated pellets resulting from step b) is acceptable in a range of 0.63- 0.80 mm. The use of larger tartaric acid crystals, i.e. in a range 0.5-0.7 mm and subsequent coating with smaller amount of tartaric acid-binder Solution (comparing to crystals in a range 0.4-0.6 mm) results in insulated pellets of similar mass and size. Table 13

Size of the pellets

Relative standard deviation of the size of the pellets obtained according to the step a) (process stage a), described above in details is obtained in a narrower range comparing to the comparative pellets prepared in an analogous way but stating from spherical commercial tartaric acid cores. Additionally spherical pellets are more susceptible to accidental undesirable falling out during encapsulation process, causing higher content mass variation compared to enclosed composition.

Table 14

Tartaric acid non-spherical crystals and spherical cores presented in the Table 14 above were covered with tartaric acid and acacia solution according to process stage a), described above in details. Subsequently, the obtained coated cores were dried. Insulating layer and active substance were applied on the tartaric acid cores coated with acacia, according to process step b) and c), respectively, described in details above. The qualitative and quantitative compositions are given in Table 15 and 16, respectively, below. Table 15, composition of the coating, process step b), the same for Compositions la and 2a entering process step b).

Table 16, composition of the active coating (process step c), the same for Compositions lb and 2b entering process step c).

Table 17. Relative standard deviation of the mass of pellets obtained for process step c), respectively for Composition 1c and 2c

Content of tartaric acid in the final dabigatran pellets

The composition according to Table 18 has been used to prepare pellets batches according to process step a) with varying content of fraction with size <0.4mm

Table 18

Table 19 wt.% of size-fractions in tartaric acid crystals batch entering the step a) of the process vs wt.% of fraction in size range 0,63 - 0,80 mm

Coated pellets obtained in step a) are obtained in preferable size range of 0,63 - 0,80 mm when < 20%, preferably < 15 wt.% of the tartaric acid crystals entering the step a) is in the size of not more than 0.4 mm, measured by Ph. Eur. sieve analysis method.

Stability studies

Stability studies of a capsules manufactured in a full production scale of the invention according to formulation comprising 150 mg of dabigatran etexilate methanesulfonate of Table 10 (DABI hard capsules )packed in PA-aluminium-PVC (laminate) and aluminium foil blister and carton box have been carried out at accelerated conditions (25C/60%RH, 30C/65%RH, 30C/75%RH and 40C/75% RH), the dissolution profiles of the active substances remained substantially unchanged and no changes were observed in the aged formulations. The results are presented in Tables below. The batch of the highest strengths is a subject of a bioequivalence test.

The requirements for the parameters tested during the stability study were established according to guidelines CPMP/ICH/367/96 (ICH Q6A), and CPMP/ICH/2738/99 (ICH Q3B (R2)). The inhouse chromatographic method for related substances is selective for degradation products for Dabigatran etexilate according to Pharmacopoeia. Impurities of Dabigatran etexilate are specified in Pharmacopoeia No 04/2016: 1368. Table 20. Stability under long term conditions (25°C, 60% RH) - composition of Table 10-

DABI 150

Table 21. Stability under long term conditions (25°C, 60% RH) - composition of Table 10 DABI

110 mg

Table 22. Stability under long term conditions (25°C, 60% RH) - composition of Table 10 DABI 75 mg

Table 23. Stability under intermediate conditions (30°C, 65% RH) - composition of Table 10-

DAB I 150 mg

Table 24. Stability under intermediate conditions (30°C, 65% RH) - example x - DABI 110 mg b.no. 12551082

Table 25. Stability under intermediate conditions (30°C, 65% RH) - composition of Table 10

DABI 75 mg

Table 26. Stability under enhanced conditions (40°C, 75% RH) composition of Table 10, DABI 150 mg

Table 27. Stability under enhanced conditions (40°C, 75% RH) composition of Table 10, DABI

110 mg

Table 28. Stability under enhanced conditions (40°C, 75% RH) composition of Table 10, DABI 75 mg

Dissolution studies

Dissolution tests The pharmaceutical compositions according to the present invention prepared in Formulation of Table 10 (DABI hard capsules) and the marketed prior art formulations of dabigatran etexilate methanesulfonate [Pradaxa 150mg] were subjected to dissolution tests carried out in accordance with the test methods described in Table 29, below: Table 29.

Table 30. Dissolution testing for capsules hard DABI 150 mg reference

The dabigatran etexilate dissolution profiles from the tested tablet according to the present invention and reference drug products (Pradaxa 150 mg) were assessed in 0.01 M HC1 solution at pH 1.2 on the basis of the Weibull statistical method according to “ Guideline on the Investigation of Bioequivalence" (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**). Dissolution profiles are similar when U-CR < max MSD (where U-CR is upper limit of the range of acceptance MSD and max MSD is limit of similarity MSD). Obtained results of statistical calculation presented in table below, confirmed similarity of compared dissolution profiles.

Table 31

To compare dissolution profiles of Dabigatran etexilate from bio-batch of developed drug product with another manufactured batches, the bootstrap f2 calculation was applied. Obtained results are presented in Table below.

Table 32 . Similarity of the Dabigatran etexilate dissolution profiles in 0.01 M HC1.

Bootstrap f2 calculated values clearly indicated, that dissolution profiles of Dabigatran etexilate from all strengths of tested product in 0.01 M HC1 are similar to dissolution profile of API from Dabigatran etexilate, capsules hard, 150 mg batch submitted for bioequivalence study.

Table 33

Bioequivalence studies

Bioequivalence studies (pivotal 1 and pivotal 2) were full replicate, single dose studies designed in accordance with European Medicines Agency (EMA) regulatory guidelines and the EMA dabigatran etexilate product-specific bioequivalence guidance (EMA/CHMP/805498/2016, May 31, 2018), with the aim of characterizing the bioavailability of free dabigatran in the two formulations (Test and Reference) in healthy subjects in fasting conditions. The Test composition was prepared according to Experimental section batch no: 11899744. Additionally impact of multiple day pre-treatment with a Proton pump inhibitor (pantoprazole) on Dabigatran bioavailability was evaluated per requirements of EU productspecific bioequivalence guideline.

PIVOTAL STUDY 1

Title: Randomized, Open-Label, Single Dose, Full Replicate, Four-Period, Crossover, Comparative Bioavailability Study Comparing Dabigatran Etexilate, Capsules Hard, 150 mg (DABI hard capsules, 150 mg according to Table 10) to Pradaxa® 150 mg Hard Capsules (Boehringer Ingelheim International GmbH) in Healthy Adult Subjects Under Fasting Conditions.

Study design: The study was a single centre, randomized, single dose, 2-treatment, 4-period, 2- sequence, crossover, full replicate design in 92 healthy male and female subjects. Blood samples were collected prior to and up to 48 hours after drug administration. To avoid any carry-over effect, a wash-out of 7 calendar days was planned between drug administrations.

Results:

87 subjects were included in the PK and statistical analysis.

Table 37 Summary of the Statistical Analysis of Free Dabigatran

^a units are ng/mL for C max and ng h/mL for AUCo-r^b n=170 for AUCO-T Conclusion:

The results presented herein show that the criteria used to assess bioequivalence between the Test and Reference formulations were all fulfilled. The Test to Reference ratio of geometric LSmeans and corresponding 90% CI for Cmax, and AUCO-T were all within the acceptance range of 80.00 to 125.00%.

PIVOTAL STUDY 2

Title: Randomized, Open-label, Single Dose, Four-period, Full Replicate Crossover Comparative Bioavailability Study Comparing Dabigatran Etexilate, Capsules Hard, 150 mg mg (DABI hard capsules, 150 mg according to Table 10), To Pradaxa® 150 mg Hard Capsules (Boehringer Ingelheim International GmbH) In Healthy Adult Subjects Under Fasting Conditions And Following A Multiple-Day Pre-Treatment With A Proton Pump Inhibitor. The Test composition was prepared according to Experimental section batch no: 11899744.

Study design: The study was a single centre, randomized, single dose, open-label, laboratory- blinded, 4-period, 2 sequence, full replicate crossover design in 92 healthy male and female subjects. The study consisted of Pre-Treatment Phase (Day 1 to Day 4, inclusively) in which 40 mg oral dose of pantoprazole, twice a day was administered to the eligible subjects. Thereafter, starting on Day 5, subjects entered a Treatment Phase consisting of 4 study periods, in which the investigational products (Test or Reference product ) were administered under fasting conditions. The oral pantoprazole BID regimen was continued throughout the Treatment phase. Blood samples were collected prior to and up to 48 hours after investigational product administration. The dabigatran etexilate administrations in each period of the Treatment Phase were separated by 5 calendar days.

Results: 91 subjects were included in the PK and statistical analysis.

Table 34 Summary of the Statistical Analysis of Free Dabigatran

^a units are ng/mL for Cmax and ng h/mL for AUCO-T Conclusion:

The PK results demonstrate that the Test to Reference ratio of geometric LSmeans of Cmax and AUCO-T of free dabigatran and the corresponding 90% Cis were included within the range of 80.00% to 125.00%. The results of this study indicate that bioequivalence criteria were met when the Test formulation and the Reference product were administered under fasted conditions following a multiple-day pre-treatment with a PPI.

Claims

1. A process for the preparation of solid oral pellets comprising dabigatran etexilate methanesulfonate, wherein:

(b) the coated core of step (a) is coated with an isolating layer, and

2. The process according to claim 1, wherein Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of 0.3 -0.7 mm± 5 wt.%, preferably 0.4- 0.6 mm ± 5 wt.%.

3. The process according to claim 2, wherein Particle Size Distribution (PSD) of the irregular tartaric acid crystal in step a) is in a range of 0.4- 0.6 mm ± 5 wt.% and < 20 wt.% of the tartaric acid crystals is in the size of not more than 0.4 mm

4. The process according to claim 3, wherein 25 - 60 wt.% of the tartaric acid crystals is in a range of 0.5 - 0.63 mm.

5. The process according to any of the claims 1 to 4, wherein the solution comprising tartaric acid and a binder and optionally further pharmaceutical excipients in step a) is a homogenous solution, without any undissolved particles. Preferably, the said solution is mixed by a low- shear equipment, preferably by a propeller and wherein said solution is subsequently filtered via filtration mesh of the size of 0.5 - 0.8 mm.

6. The process according to any of the claims 1 to 5, wherein the tartaric acid amount in the pellet is in a range of 40.0-45.0 wt.%, preferably 43.83 wt.%. calculated on the total mass of the pellet.

7. The process according to any of the claims 1 to 6, wherein the crystals in step a) are coated with the use of fluid bed coating method.

8. The process according to any of the claims 1 to 7, wherein the binder in step a) is acacia or Hypromellose, preferably spray-dried acacia or Hypromellose 2910 .

9. The process according to any of the claims 1 to 8, wherein the core in step b) is coated with an ethanolic HPMC-talk suspension.

10. The process according to claim 9, wherein the HPMC has molecular weight of approximately 20000 -60000 g/mol, and viscosity in a range of 12-18 mPa-s (2wt.% in water at 20°C), preferably 15 mPa-s (2wt.% in water at 20°C).

11. The process according to claim 10, wherein the amount of HPMC in the insulation coat of step b) is in a range of 1.3- 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet.

12. The process according to any of the claims 9 to 11, wherein the amount of talk in the insulation coat of step b) is in a range of 6.0- 8.0 wt.%, most preferably 7.5 wt.% calculated on the total mass of the pellet.

13. The process according to any of the claims 9 to 12, wherein the insulating coat further comprises dimethicone, preferably in the form of an 35% aqueous emulsion, preferably dimethicone is present in the insulation coat of step b) in a range of 0.01- 0.03 wt.%, most preferably 0.02 wt.% calculated on the total mass of the pellet.

14. The process according to any of the claims 9 to 13, wherein the insulating coat is coated as a suspension in a mixture of ethanol 96% v/v and water.

15. The process according to any of the claims 1 to 14, wherein the layer in step c) comprises dabigatran etexilate methanesulfonate in an amount in a range of 35-45%, most preferably 41.85 wt.%, calculated on the total mass of the pellet.

16. The process according to claim 15, wherein the layer in step c) is coated as a HPC-talk suspension in isopropanol.

17. The process according to claim 16, wherein the HPC in the layer in step c), has molecular weight of approximately 80 000 Da, and its 10% aqueous solution has viscosity of 300 - 600 mPa-s in 25 °C.

18. The process according to claim 16 or 17, wherein the amount of HPC in the layer of step c) is in a range of 3.7- 4.3 wt.%, preferably 4.0-4.2, most preferably 4.17 wt.% calculated on the total mass of the pellet.

19. The process according to any of the claims 16 to 18, wherein in the layer of step c) the weight ratio of HPC to the active substance is in a range of 2: 10 to 1 : 10, preferably 1 : 10.

20. The process according to any of the claims 16 to 19, wherein the layer comprising dabigatran etexilate in step c) comprises talk, preferably the amount of talk is in a range of 5.0 - 7.0 wt.%, most preferably 6.05 wt.% calculated on the total mass of the pellet.

21. The pharmaceutical composition in the form of pellets obtainable by the process according to any of the claims 1 to 20.

22. The pharmaceutical composition according to claim 21 with the following formula:

23. The pharmaceutical composition as defined in claims 21 -22 packed into a hard capsule, preferably a HPMC capsule.

24. The capsule as defined in claim 23 containing 75mg, llOmg, or 150mg of Dabigatran active substance, which corresponds to 86.48mg, 126.83mg, and 172.95mg, respectively, of Dabigatran etexilate methanesulfonate.