WO2019008605A1

WO2019008605A1 - Novel pharmaceutical co-crystal of dabigatran etexilate

Info

Publication number: WO2019008605A1
Application number: PCT/IN2018/050444
Authority: WO
Inventors: Anwar Siraj DAUD; Shankar Dadasaheb POL; Rajesh Bhaskar NAWALE; Prashant Keshao PURANIK; Vijay Bhagwanswarup MATHUR; Shamsuddin JAMALUDDIN; Vishal Vasant RAJKONDAWAR
Original assignee: Zim Laboratories Limited
Priority date: 2017-07-07
Filing date: 2018-07-07
Publication date: 2019-01-10

Abstract

The present invention discloses novel co-crystals of dabigatran etexilate or its pharmaceutically acceptable salts. The novel co-crystals of dabigatran etexilate or its pharmaceutically acceptable salts are prepared using an amino acid as a co-former, preferably, with leucine. The present invention also provides formulation comprising novel co-crystals of dabigatran etexilate or its pharmaceutically acceptable salts.

Description

NOVEL PHARMACEUTICAL CO-CRYSTAL OF DABIGATRAN

ETEXILATE

FIELD OF THE INVENTION

The present invention relates to novel pharmaceutical co-crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts with improved solubility and/or stability and hence the increased rate of dissolution and higher bioavailability. It also relates to novel pharmaceutical formulations of co-crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION

Dabigatran Etexilate is a low-molecular-weight prodrug that exhibits no pharmacological activity. After oral administration, Dabigatran Etexilate is converted to its active form, Dabigatran, a potent, competitive, and reversible direct inhibitor of the active site of thrombin, the final effector in blood coagulation. Dabigatran is an oral anticoagulant from the class of the direct thrombin inhibitors. Dabigatran Etexilate Mesylate is an orally available mesylate salt form of the Etexilate prodrug of Dabigatran, direct thrombin inhibitor with anticoagulant activity.

The chemical name for Dabigatran Etexilate Mesylate, a direct thrombin inhibitor, is β- Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl] -amino]methyl]- l-methyl-lH-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate. The molecular weight of Dabigatran Etexilate Mesylate is about 723.86 and its molecular formula is C₃₄H₄₁N₇O₅ · CH₄O₃S. Dabigatran Etexilate Mesylate is represented by compound of

Formula I Dabigatran Etexilate or its salts are described in U.S. Patent No. 6087380.

The proprietary name of Dabigatran Etexilate Mesylate oral capsule is "PRADAXA" which is marketed by Boehringer Ingelheim in USA.

Dabigatran Etexilate is available in capsule form in 75 mg, 110 mg, and 150 mg strengths for oral administration. Each capsule contains Dabigatran Etexilate Mesylate as the active ingredient: 172.95 mg Dabigatran Etexilate Mesylate (equivalent to 150 mg Dabigatran Etexilate), 126.83 mg Dabigatran Etexilate Mesylate (equivalent to 110 mg Dabigatran Etexilate), or 86.48 mg (equivalent to 75 mg Dabigatran Etexilate) which is approved on October 19, 2010 (75 mg & 150 mg) and on November 20, 2015 (110 mg) to Boehringer Ingelheim in USA.

Dabigatran Etexilate Mesylate is indicated to a) reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation, b) for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days and c) to reduce the risk of recurrence of DVT and PE in patients who have been previously treated.

Dabigatran Etexilate mesylate has pH-dependent solubility hence its absorption is also pH- dependent. It is also reported that Dabigatran Etexilate mesylate have solubility as well as stability problems.

US 2017/0165247 relates to new crystalline compounds of dabigatran etexilate mesylate, namely to crystalline compounds comprising mixtures of dabigatran etexilate mesylate and an acid, selected from gallic acid, orotic acid, p-coumaric acid, hippuric acid, ferulic acid and Vanillic acid.

Efforts have been made to provide more soluble and stable forms of dabigatran etexilate mesylate. However, there is still a need to provide a form which is effectively stable and provides better dissolution formulations. Also, there is a need to provide suitable processes for preparation of such desirable forms of dabigatran etexilate mesylate. The applicant of the present invention has overcome problems related to solubility and/or stability by co-crystallization and providing suitable formulations.

The inventor of present invention found unique and surprising results related to improved solubility and/or stability of novel pharmaceutical co-crystal of Dabigatran Etexilate or its salts and associated formulations.

SUMMARY OF THE INVENTION

A first aspect of the present invention is to provide novel pharmaceutical co-crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts.

A second aspect of the present invention is to provide novel pharmaceutical co-crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts with improved stability.

A third aspect of the present invention is to provide novel pharmaceutical co-crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts with improved stability by using an amino acid as co-former.

Another aspect of the present invention is to provide novel pharmaceutical co-crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts with improved stability by using leucine as co-former.

In a preferred embodiment, the pharmaceutically acceptable salt of dabigatran etexialte in the co-crystal of dabigatran etexilate is dabigatran etexilate mesylate. In a most preferred embodiment, the co-crystal of the present invention has an impurity level of less than 0.55 after a period of 1 month, with stability study conducted at 40°C / 75 % RH using nitrogen purging packaging.

Another aspect of the present invention is to provide a process of preparing novel pharmaceutical co-crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts with improved stability by using leucine as co-former. In one embodiment, the present invention provides a process for preparing co-crystals of dabigatran etexilate or its pharmaceutically acceptable salts and leucine, wherein the process comprises, providing stoichiometric amounts of dabigatran etexilate or its pharmaceutically acceptable salts and leucine, and grinding them to obtain the co-crystals. In a preferred aspect, the process of grinding is carried in a ball miller. In a most preferred embodiment, the grinding process is carried out for about 30 minutes.

Another aspect of the present invention is to provide novel pharmaceutical co-crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts indicated a) to reduce the risk of stroke and systemic embolism in patients with non- valvular atrial fibrillation, b) for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days and c) to reduce the risk of recurrence of DVT and PE in patients who have been previously treated.

Yet another aspect of the present invention is to provide a formulation comprising novel pharmaceutical co-crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts.

Another aspect of the present invention is to provide a pharmaceutical formulation comprising novel pharmaceutical co-crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts with improved stability by using an amino acid. In preferred aspect, the present invention provides a pharmaceutical formulation comprising novel pharmaceutical co-crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts using leucine as co-former.

In a preferred embodiment, the formulation of the present invention comprises co-crystals of dabigatran etexilate or its pharmaceutically acceptable salts and leucine, comprising:

(a) a supporting core comprising an organic acid, and

(b) a layer of co-crystals of dabigatran etexilate or its pharmaceutically acceptable salts and leucine;

wherein the supporting core and the layer of co-crystals of dabigatran etexilate or its pharmaceutically acceptable salts and leucine is separated by a sugar coating layer and/or a barrier coating layer, and the sugar coating layer is adjacent to the supporting core and the barrier coating layer is adjacent to the co-crystals layer. In a preferred embodiment, the organic acid in the supporting core is selected from tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid or a combination thereof. In a further preferred embodiment, the barrier layer comprises a water-soluble and/or water-insoluble, pharmaceutically acceptable polymer.

Yet another aspect of the present invention provides a process for preparing formulation comprising novel pharmaceutical co-crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts. In a preferred aspect, the present invention provides a process for preparing a pharmaceutical formulation comprising novel pharmaceutical co- crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts by using leucine as co-former, with improved solubility and stability.

Another aspect of the present invention provides a pharmaceutical formulation of novel pharmaceutical co-crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts according to the present invention, for use in reducing risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation, treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days and/or reducing the risk of recurrence of DVT and PE in patients who have been previously treated.

DETAILED DESCRIPTION OF THE INVENTION

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

The solubility of the dabigatran etexilate mesylate in water is only 1.8 mg/ml, i.e. it is partly soluble. Also, studies have revealed the issues related to stability of dabigatran etexilate mesylate, whereby some toxic degradation products are formed during shelf life. Hence, there is also a need to provide stable forms of dabigatran etexilate mesylate. In view of the existing problems, an objective of the present invention is to provide novel pharmaceutical co-crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts. Although co-crystallisation has been known, but there is still no certainty to predict whether a drug would form a suitable co-crystal with a substance. A few co-crystals of dabigatran etexilate mesylate have been known, but they have been made with different objective.

In view of the existing problems, an objective of the present invention is to provide novel pharmaceutical co-crystal of Dabigatran Etexilate or its pharmaceutically acceptable salts with leucine as co-former. Hence, co-crystal of dabigatran etexilate mesylate with leucine has been provided, which provides increased stability.

In another aspect, the present invention provides a process for preparation of co-crystal of dabigatran etexilate mesylate and leucine. A skilled person would know how to prepare co-crystals of dabigatran etexilate mesylate with leucine, to obtain stable co-crystals, and are covered within the scope of this invention. In a preferred embodiment, the co-crystals of dabigatran etexilate mesylate and leucine are prepared by grinding method. The process involves dry grinding or solid state grinding. The dabigatran etexilate mesylate and leucine are provided in stoichiometric quantities and grinded together to obtain stable co-crystals of dabigatran etexilate mesylate and leucine. For grinding suitable methods may be employed. In the present invention, the grinding is carried out using a suitable Ball mill. Other suitable methods of preparing the co-crystals may also be used, provided the process results into stable co-crystals of dabigatran etexilate mesylate and leucine.

In another aspect, the present invention also provides a suitable formulation of co-crystals of dabigatran etexilate mesylate and leucine, for enhanced dissolution and stability. In a preferred aspect, the formulation comprises co-crystals of dabigatran etexilate mesylate and leucine, along with a suitable organic acid, wherein the co-crystals and the organic acid are separated from each other. The organic acid is preferably selected from tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid or a combination thereof, including the hydrates and acid salts thereof. In a most preferred embodiment, the acid is tartaric acid. In a preferred embodiment, the formulation comprises a core of tartaric acid, also referred to as supporting core, which is coated with a sugar coating layer. The acid core is a pellet, spherical or ellipsoid or bead shaped. Said acid core is coated with sugar by powder coating technology to form a sugar coating layer on the acid core. Said sugar coated layer is further coated with a barrier or insulating layer. The said barrier layer is followed by a layer of the co-crystals of dabigatran etexilate mesylate and leucine. The layer of the co- crystals of dabigatran etexilate mesylate and leucine is a powder coated layer. Said powder coated layer of the co-crystals of dabigatran etexilate mesylate and leucine is optionally coated with a coating for providing abrasion resistance.

The said formulation of co-crystals of dabigatran etexilate mesylate and leucine provides enhanced dissolution and stability. The acid core of the formulation provides the necessary microenvironment for enhancing the dissolution of co-crystals of dabigatran etexilate mesylate and leucine. The sugar coating and/or barrier coating provide a spatial separation between the acid and the co-crystals to provide enhanced stability.

In another aspect, the present invention also provides a process for preparing the formulation of the present invention. In a preferred embodiment, the pellets of tartaric acid are provided. Said pellets are prepared by known methods, or such pellets of tartaric acid are also available commercially. The content of the tartaric acid is usually between 30 and 100% in the core material, corresponding to an amount of between 20 and 90%, preferably between 20 and 80% in the finished formulation. The size of the pellets is preferably in the range of 500 to 2000 micrometer. Said tartaric acid pellet is coated with sugar to provide a sugar coating layer on the pellet. Once the pellets with sugar coating are prepared, a barrier coating layer is provided by coating the sugar coated pellets with a water-soluble and/or water-insoluble, pharmaceutically acceptable polymer. Suitable water-soluble polymers are selected from among the hydroxypropyl-celluloses, hydroxypropylmethylcelluloses, methylcelluloses, hydroxyl ethylcelluloses, carboxymethylcelluloses, polyvinylpyrrolidone, the copolymers of N-vinylpyrrollidone and vinyl acetate, or combinations of these polymers. If desired, the coating with the water-soluble, pharmaceutically acceptable polymer may be carried out with the addition of suitable plasticisers, separating agents and pigments, such as for example triethylcitrate, tributylcitrate, triacetin, polyethyleneglycols (plasticisers), talc, silicic acid (separating agents), titanium dioxide or iron oxide pigments (pigments). Any suitable pharmaceutically acceptable water-insoluble polymer may be used. In a preferred embodiment, water-insoluble polymers are selected from polyethylene, polypropylene, polytetrafluoroethylene, carnauba wax, castor wax, polyamide wax, and combinations thereof. After providing the barrier layer, the pellets are coated with the co-crystals of the present invention. The coating of co-crystals of dabigatran etexilate mesylate and leucine are done by powder coating method, to provide the final formulation of the present invention. Said formulation may optionally be coated with an outermost layer, usually to provide abrasion resistance. Said outermost layer consists of pharmaceutically acceptable film-forming agents, plasticisers and optionally pigments. Suitable film-forming agents are selected from hydroxypropyl-cellulose, hydroxypropylmethyl cellulose, methylcellulose, polymers and copolymers of acrylic and methacrylic acid and the esters thereof, or combinations of these polymers. Suitable plasticisers include inter alia triethylcitrate, tributylcitrate, triacetin or polyethyleneglycols. The pigments used may be e.g. titanium dioxide or iron oxide pigments. Preferably, the outer coating consists of hydroxypropylmethylcellulose and/or methylcellulose, optionally with the addition of polyethyleneglycols as plasticisers.

EXAMPLES

It is understood that the foregoing examples are merely illustrative of the present invention. Certain modifications of the articles and/or methods employed may be made and still achieve the objectives of the invention. Such modifications are contemplated as within the scope of the claimed invention.

Example 1

Preparation of co-crystal of dabigatran etexilate mesylate and leucine:

1 kg of dabigatran etexilate mesylate (DEM) and 181.15 gm of leucine were provided. DEM and leucine were mixed and grinded together in a Ball Mill for about 30 minutes to obtain the co-crystals of DEM and leucine.

Example 2 (Comparative)

Preparation of co-crystal of DEM with a few other amino acids: 1 kg of DEM, 123.05 gm of alanine, 201.9 gm of lysine and 201.85 gm of glutamine were provided. DEM and alanine was mixed and grinded to obtain co-crystals of DEM and alanine. DEM and lysine was mixed and grinded to obtain co-crystals of DEM and lysine. DEM and glutamine was mixed and grinded to obtain co-crystals of DEM and glutamine. The grinding was done as disclosed in Example 1.

Example 3

Stability study of co-crystals of DEM with leucine, alanine, lysine and glutamine:

The co-crystals of DEM prepared according to Examples 1 and 2 were subjected to stability study and the impurity levels were checked after the preparation, and at intervals of 15 days and 1 month. The results are provided in Table 1 below:

Table 1

Stability study conducted at 40°C/75 % RH using nitrogen purging packaging. The above table shows that the co-crystals of dabigatran etexilate mesylate with leucine are more stable than co-crystals of dabigatran etexilate mesylate with alanine, lysine and glutamine.

Example 4

Formulation of co-crystals of DEM and leucine:

Method of preparation of Formulation of Example 4:

Pellets of tartaric acid having average size of 500 to 2000 micrometer were provided. A sugar coating was provided on tartaric acid pellets, until the desired amount of coating is applied. Said sugar coated pellets were dried below 35°C temperature. Said dried sugar coated pellets were coated with HPC to provide barrier layer on the sugar coated pellets and dried below 35°C temperature. Co-crystals of DEM and leucine were powder coated on the above obtained barrier layer coated pellets and dried below 30°C temperature.

Optionally, for outermost coating layer, HPMC was provided and coated to obtain the formulation.

Claims

CLAIMS:

1. Co-crystal of dabigatran etexilate or its pharmaceutically acceptable salts and amino acids, preferably leucine.

2. The co-crystal as claimed in claim 1, wherein the pharmaceutically acceptable salt of dabigatran etexialte is dabigatran etexilate mesylate.

3. The co-crystal as claimed in claim 1, wherein the co-crystals have an impurity level of less than 1.6 after a period of 1 month.

4. A process for preparing co-crystals of dabigatran etexilate or its pharmaceutically acceptable salts and leucine, the process comprising, providing stoichiometric amounts of dabigatran etexilate or its pharmaceutically acceptable salts and leucine, and grinding to obtain the co-crystals.

5. The process as claimed in claim 4, wherein the grinding is carried in a ball mill.

6. The process as claimed in claim 4 or 5, wherein the grinding is carried out for about 30 minutes.

7. A formulation comprising co-crystals of dabigatran etexilate or its pharmaceutically acceptable salts and leucine, the formulation comprising:

(a) a supporting core comprising an organic acid, and

wherein the supporting core and the layer of co-crystals of dabigatran etexilate or its pharmaceutically acceptable salts and leucine is separated by a sugar coating layer and/or a barrier coating layer, and

the sugar coating layer is adjacent to the supporting core and the barrier coating layer is adjacent to the co-crystals layer.

8. The formulation as claimed in claim 7, wherein the pharmaceutically acceptable salt of dabigatran etexialte is dabigatran etexilate mesylate.

9. The formulation as claimed in claim 7 or 8, wherein the organic acid is selected from tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid or a combination thereof.

10. The formulation as claimed in any of the preceding claims 7 to 9, wherein the barrier layer comprises a water-soluble, pharmaceutically acceptable polymer.