Formulation comprising edoxaban and preparation thereof

Abstract

The invention relates to the tablet composition comprising edoxaban obtained by the direct compression process comprising the step of co-blending edoxaban and first portion of mannitol, wherein the weight ratio of edoxaban and first portion of mannitol is from 1:1 to 1:2.5.

Description

[0001] FORMULATION COMPRISING EDOXABAN AND PREPARATION

[0002] THEREOF

[0003] BACKGROUND OF THE PRESENT INVENTION

[0004] Edoxaban, chemically N-(5-chloropyridin-2-yl)-N'-[(lS,2R,4S)-4 (N,N-dimethyl- carbamoyl)- 2-(5-methyl-4,5,6,7-tetrahydro[l,3]thiazolo[5,4-c]pyridine-2-carboxamido) cyclohexyl]oxamide of formula (I), is a selective reversible inhibitor of the coagulation factor Xa (FXa) that is used in prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, as well as in treatment of deep-vein thrombosis and pulmonary embolism.

[0005] Edoxaban was first disclosed in W02003000680 by Daiichi. It is marketed in the form of tosylate monohydrate salt under the brand names Lixiana® and Roteas®. Both Lixiana® and Roteas® are available as film-coated, immediate release tablets with the strengths 15 mg, 30 mg and 60 mg.

[0006] Edoxaban is soluble in strongly acidic aqueous solutions, but its solubility is very low in neutral or alkaline aqueous media. It also exhibits low permeability making it classified as Biopharmaceutics Classification System (BCS) Class IV.

[0007] The commercial formulation of Lixiana® comprises 15% by weight of edoxaban tosylate monohydrate, relative to the weight of the whole tablet (equivalent to 15 mg, 30 mg, and 60 mg edoxaban free base), mannitol, pregelatinised starch, crospovidone, hydroxypropylcellulose and magnesium stearate. The composition of marketed edoxaban tablets was disclosed in WO2008128846. The document discloses edoxaban tablets comprising a sugar alcohol and a water-swelling additive that are prepared by wet granulation process (fluid bed). WO2011115067 further discloses that the composition according to W02008129846 produced under high moisturization water conditions shows high variation in dissolution when assessing single tablets. As a solution to the problem, it teaches a method of keeping the maximum water content of granules during granulation at 10% or less to improve dissolution properties.

[0008] W02010147169 discloses that dissolution properties can be improved when the amount of edoxaban in the composition is adjusted (i.e. lowered) to less than 15% by weight with respect to the total weight of the pharmaceutical composition. The tablets disclosed comprise the same excipients as present in Lixiana® and are also prepared by wet granulation method.

[0009] WO2016020080 (Sandoz) discloses compositions comprising edoxaban and two binders - water-soluble vinylpyrrolidone polymer and a cellulose ether. The tablets use lactose and calcium phosphate as diluents and are prepared by wet granulation method.

[0010] WO2020239986 (Tiefenbacher) discloses compositions comprising lactose as diluent, one binder and two disintegrants - crospovidone and sodium starch glycolate prepared by wet granulation. The document discloses that direct compression method is not suitable, because of blend flowability issues and punch sticking.

[0011] WO2021123192 (Biohorm) discloses tablet composition comprising lactose as first diluent and starch as second diluent. Tablets according to invention described are also prepared by wet granulation.

[0012] WO2022129535 (Krka) discloses tablets that are prepared by wet granulation, that comprise saccharides (glucose, fructose or dextrates) as diluents. Wet granulation manufacturing process has been proved effective in producing edoxaban formulations, but it has some disadvantages. In the most complex form, it consists of six steps: dry mixing, wet mixing, milling of the wetted mass, drying, milling of the dried mass and final blending. Wet granulation process, especially when fluidized bed granulator is used, often results in high porosity granules and therefore a low control of the drug substance release from the composition. Upon aging, the dissolution from the granules can be slower after tableting. The use of solvent can cause stability problems or variability in dissolution between single tablets. For these reasons, it would be desirable to have a tablet composition comprising edoxaban that is bioequivalent to Lixiana®, but is prepared by direct compression method. Therefore, the object of the invention is to provide a formulation comprising edoxaban tosylate monohydrate in the form of swallowable tablet that is prepared by direct compression.

[0013] BRIEF DESCRIPTION OF THE PRESENT INVENTION

[0014] The present invention relates to a direct compression process to prepare edoxaban tosylate monohydrate tablets. The process includes the step of co-sieving and blending edoxaban, a first portion of mannitol and an optional glidant, followed by the addition of a second portion of mannitol and one or more pharmaceutically acceptable excipients, and the compression of the obtained blend into tablets. The weight ratio of edoxaban and first portion of mannitol is from 1:1 to 1:2.5.

[0015] The invention further relates to the tablet composition comprising edoxaban obtained by the process comprising the step of co-blending edoxaban and first portion of mannitol, wherein the weight ratio of edoxaban and first portion of mannitol is from 1 : 1 to 1 :2.5. Tablet composition according to the invention comprises 10 - 30% by weight of edoxaban tosylate and 55 - 80% by weight of mannitol relative to the total weight of the tablet. The tablet formulation according to the invention has only few excipients and its preparation employs efficient and cost-effective process.

[0016] BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 shows the dissolution profile of the tablet prepared in example 1 compared to Lixiana® using USP II paddles, 50 rpm, 500 ml of 0.1 HC1 up to 30 minutes + 900 ml of phosphate buffer pH 6.8 up to 60 minutes phosphate buffer pH 6.8 at 37°C.

[0018] DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0019] Despite involving only a few process steps, product design in the direct compression method for tablets can be challenging because of the numerous reasons. Among several requirements, the compression blend has to exhibit good flowability, it has to compress and compact into robust tablets and the resulting tablets have to remain stable over time to maintain safety and efficacy. The properties of the API and direct compression excipients are responsible for the compressibility and flow properties of the powder. The most commonly used direct compression excipients are microcrystalline cellulose and lactose.

[0020] The use of mannitol in direct compression process can result in its fragmenting under compaction and obtained tablets can be mechanically weak and friable. On the other hand, mannitol constitutes an excellent excipient, in particular for its very great chemical inertness towards the active ingredients, and because of low hygroscopicity of its crystalline form. There are also no known human tolerance issues with mannitol, as there are for lactose.

[0021] The inventors have surprisingly found that a direct compression process can be used to prepare edoxaban tablet comprising mannitol as diluent, if the process comprises a step of coblending edoxaban and part of the mannitol in a weight ratio of edoxaban and mannitol is from 1:1 to 1:2.5. Tablets obtained by the process of the present invention have excellent processability properties and exhibit excellent long term stability. Moreover, they exhibit adequate dissolution and are bioequivalent to commercial Lixiana® tablets. Problems reported in prior art related to flowability and sticking during formulating edoxaban compositions using direct compression method are avoided.

[0022] Present invention relates to the process to prepare a pharmaceutical tablet composition comprising edoxaban tosylate, the process comprising a step of co-blending edoxaban, a first portion of mannitol, followed by the addition of a second portion of mannitol and one or more pharmaceutically acceptable excipients and the compression of the obtained blend into tablets, wherein the weight ratio of edoxaban and first portion of mannitol is from 1 : 1 to 1:2.5.

[0023] In one embodiment, edoxaban can be co-sieved with first portion of mannitol prior to blending. In another embodiment, edoxaban is added to a sieved first portion of mannitol followed by blending step.

[0024] In an embodiment, the blend of edoxaban, first portion of mannitol and optional glidant is sieved through a suitable sieve mesh before the addition of second portion of mannitol and one or more pharmaceutically acceptable excipients.

[0025] During a step of co-blending edoxaban and a first portion of mannitol, glidant can be added. The addition of glidant is especially beneficial if micronized edoxaban in used. Micronization is often used to improve solubility and dissolution rate of poorly soluble drugs like edoxaban. It is however known that micronized particles having the increased surface area can result in poor flow and cause electrostatic charge to build up. Micronized API granules have a tendency of agglomeration to each other due to their high surface energy. The process of the present invention can be used even if edoxaban is in the form of micronized material without encountering flowability or sticking issues. The glidant to be used in accordance with the present invention may be any glidant known to a person of ordinary skill in the art. Colloidal silicon dioxide is a particularly preferred glidant.

[0026] One or more pharmaceutically acceptable excipients are added together with second portion of mannitol. One or more pharmaceutically acceptable excipients to be used in accordance with the present invention are well-known and are those excipients which are conventionally used by the person skilled in the art in pharmaceutical compositions. The excipients are selected from one or more binders, disintegrants and lubricants.

[0027] In one embodiment, the process according to present invention comprises following steps: a) Co-sieving edoxaban tosylate, first portion of mannitol and optional glidant through a suitable sieve mesh and blending the components; b) Sieving second portion of mannitol and one or more pharmaceutically acceptable excipients and mixing with the blend obtained in step a); c) Adding lubricant and mixing it with the blend obtained in step c); d) Compression of the blend on a tablet press using the appropriate punches.

[0028] In another embodiment, the process comprises following steps: a) Sieving first portion of mannitol optionally with a glidant through a suitable sieve mesh; b) Adding edoxaban and blending the components; c) Sieving second portion of mannitol and one or more pharmaceutically acceptable excipients and mixing with the blend obtained in step b); d) Adding lubricant and mixing it with the blend obtained in step c); e) Compression of the blend on a tablet press using the appropriate punches. Tablets prepared by the process according to the invention can be further coated by a film-coat. The coating may be selected from amongst one or more of those suitable coating materials known in the art.

[0029] In one embodiment, the present invention relates to the tablets comprising edoxaban obtained by a process comprising a step of co-blending edoxaban, a first portion of mannitol and optionally a glidant, wherein the weight ratio of edoxaban and first portion of mannitol is from 1:1 to 1:2.5, followed by the addition of second portion of mannitol and one or more pharmaceutically acceptable excipients.

[0030] The weight ratio of edoxaban to first portion of mannitol is from 1 : 1 to 1 : 2.5, more preferably from 1:1.5 to 1:2.

[0031] Edoxaban is preferably in the form of tosylate monohydrate salt and is preferably present in the tablet composition in an amount ranging from 10 to 30%, more preferably from 15 to 25%, even more preferably from 17.5 to 22.5% by weight with respect to the total weight of the tablet composition.

[0032] The tablet according to the invention comprises mannitol as diluent. Preferably, mannitol is the only diluent in the tablet composition. Total amount of mannitol in the tablet composition, that is combined amount of first and second portion of mannitol, is in the range from 55 to 80%, more preferably from 60 to 75% by weight, even more preferably from 65 to 70% by weight with respect to the total weight of the tablet composition.

[0033] The glidant to be used in accordance with the present invention may be any glidant known to a person of ordinary skill in the art. Colloidal silicon dioxide is a particularly preferred glidant. Glidant is present in the tablet composition in an amount from 0 to 2%, more preferably from 0 to 1%, even more preferably 0.5% by weight with respect to the total weight of the tablet. The tablet composition according to the present invention further comprises one or more pharmaceutically acceptable excipients. One or more pharmaceutically acceptable excipients to be used in accordance with the present invention are well known and are those excipients, which are conventionally used by the person skilled in the art in pharmaceutical compositions. The excipients are selected from one or more binders, disintegrants and lubricants.

[0034] The binder to be used in accordance with the present invention may be any binder known to a person of ordinary skill in the art. Suitable binders are selected from the group comprising hydroxypropyl cellulose, starch, polyethylene glycol, sodium carboxymethylcellulose and polyvinyl pyrrolidone. Hydroxypropyl cellulose is a particularly preferred binder. The amount of binder in tablet composition is between 1 and 5% by weight based on the total weight of the tablet. Preferably, the amount of binder in the tablet is between 1 and 5% by weight based on the total weight of the tablet. More preferably, the amount of binder in the tablet is between 2 and 4% by weight, even more preferably between 2.5 and 3.5% by weight based on the total weight of the tablet.

[0035] The disintegrant to be used in accordance with the present invention may be any disintegrant known to a person of ordinary skill in the art. Suitable disintegrants to be used in accordance with the present invention are selected from the group comprising croscarmellose sodium, crospovidone and sodium starch glycolate. Crospovidone is a particularly preferred disintegrant. The amount of disintegrant in the tablet is between 2 and 12% by weight based on the total weight of the tablet. Preferably, the amount of disintegrant in the tablet is between 3 and 8 %, even more preferably between 4.5 and 7% by weight based on the total weight of the tablet.

[0036] The lubricant to be used in accordance with the present invention may be any lubricant known to a person of ordinary skill in the art. Magnesium stearate is a particularly preferred lubricant. The amount of lubricant in the tablet is between 2 and 5% by weight, more preferably between 2.5 and 4.5% by weight with respect to the total weight of the tablet.

[0037] The tablet composition according to the invention can be coated with film-coat comprising at least one coating agent selected from a group comprising hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, povidone, polyvinyl acetate, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer RS, ethyl aery late- methyl methacrylate copolymer, pea starch, polyethylene glycol-polyvinyl alcohol graft copolymer or polyvinyl alcohol-acrylic acid- methyl methacrylate copolymer. Polyethylene glycol-polyvinyl alcohol graft copolymer is particularly preferred coating agent to be used in the present invention.

[0038] In any embodiments, the swallowable tablet according to the present invention is prepared by direct compression.

[0039] The tablet composition in accordance with the present invention can be used as a medicament.

[0040] EXAMPLES

[0041] Example 1:

[0042] Tablets composition described in Table 1 were prepared according to the following process.

[0043] Edoxaban tosylate monohydrate, approximately 135 mg of mannitol and colloidal silicon dioxide were sieved through a suitable sieve mesh (e.g. 0.8 mm) and added to the blending container. The components were mixed in a diffusion mixer for 15 minutes. The obtained blend was sieved through 0.8 mm sieve mesh. The remaining amount of mannitol, hydroxypropyl cellulose and crospovidone were sieved through 0.8 mm sieve mesh, added to the blend in the mixer and blended together for 15 minutes. Magnesium stearate sieved through 0.5 mm sieve and mixed with the blend for 3 minutes. The final blend was compressed on a rotary tablet press using appropriate punches. The tablets were coated with a water suspension of Opadry KB comprising polyethylene glycol-polyvinyl alcohol graft copolymer coating agent until 5% weight gain.

[0044] Table 1

[0045] The stability of the tablets in different packaging has been evaluated in different conditions. The results are presented in table 2.

[0046] Table 2

Claims

CLAIMS1. A process to prepare a pharmaceutical tablet composition comprising edoxaban tosylate, the process comprising a step of co-blending edoxaban, a first portion of mannitol and an optional glidant, followed by the addition of a second portion of mannitol and one or more pharmaceutically acceptable excipients and the compression of the obtained blend into tablets, wherein the weight ratio of edoxaban and first portion of mannitol is from 1:1 to 1:2.5.

2. The process according to claim 1, wherein edoxaban, a first portion of mannitol and an optional glidant are co-sieved before blending step.

3. The process according to claim 1, wherein mannitol and optional glidant are sieved before the addition of edoxaban.

4. The process according to any of the preceding claims, wherein the blend of edoxaban, a first portion of mannitol and an optional glidant is co-sieved before the addition of a second portion of mannitol and one or more pharmaceutically acceptable excipients.

5. The process according to any of the preceding claims, wherein the process is a direct compression process.

6. The process according to any of the preceding claims, wherein the glidant is colloidal silicon dioxide.

7. The process according to any of the preceding claims, wherein one or more pharmaceutically acceptable excipients are selected from disintegrants, binders and lubricants.

8. The process according to any of the preceding claims comprising: a) Co-sieving edoxaban tosylate, first portion of mannitol and glidant through a suitable sieve mesh and blending the components;b) Sieving second portion of mannitol and one or more pharmaceutically acceptable excipients and mixing with the blend obtained in step a) in a diffusion mixer; c) Adding lubricant and mixing it with the blend obtained in step c) in a diffusion mixer; d) Compression of the blend on a tablet press using the appropriate punches. The process according to any of the preceding claims comprising: a) Co-sieving first portion of mannitol and glidant through a suitable sieve mesh; b) Adding edoxaban and blending the components; c) Sieving second portion of mannitol and one or more pharmaceutically acceptable excipients and mixing with the blend obtained in step b); d) Adding lubricant and mixing it with the blend obtained in step c); e) Compression of the blend on a tablet press using the appropriate punches. The process according to any preceding claims further comprising coating the obtained tablets. A tablet composition prepared by the process according to any of the preceding claims. A tablet composition comprising edoxaban tosylate obtained by a process comprising a step of co-blending edoxaban, a first portion of mannitol and optionally a glidant, wherein the weight ratio of edoxaban and first portion of mannitol is from 1 : 1 to 1 : 2.5, followed by the addition of second portion of mannitol and one or more pharmaceutically acceptable excipients. Tablet composition according to claim 12, wherein the process is a direct compression process.Tablet composition according to claim 12 or 13, wherein one or more pharmaceutically acceptable excipients are selected from disintegrants, binders and lubricants. Tablet composition according to any of any of the claims 12 to 14, comprising 10 - 30% by weight of edoxaban tosylate, 55 - 80% by weight of mannitol relative to the total weight of the tablet.

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