Solid pharmaceutical compositions comprising edoxaban

Abstract

The present invention provides a solid pharmaceutical composition in the form of tablet, comprising edoxaban particles having specific particle size distribution with D90 value less than 20 µm, having specific disintegrants to obtain desired dissolution profile, stability and in-vitro results.

Description

[0001] SOLID PHARMACEUTICAL COMPOSITIONS COMPRISING EDOXABAN

[0002] Field of invention

[0003] The present invention provides a solid pharmaceutical composition in the form of tablet, comprising edoxaban particles having specific particle size distribution with D90 value less than 20 pm, having specific disintegrants to obtain desired dissolution profile, stability and in-vitro results.

[0004] Background of the invention

[0005] Edoxaban is described as N'-(5-chloropyridin-2-yl)-N-[(lS,2R,4S)-4-(dimethylcarbamoyl)-2- [(5-methyl-6,7-dihydro-4H-[l,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino] cyclohexyl] oxamide and its chemical structure is shown in the Figure I. Edoxaban has molecular weight of 548.1 g / mol, is white to pale yellowish-white crystalline powder.

[0006] Figure 1

[0007] Edoxaban is an anticoagulant medication and a direct factor Xa inhibitor. It was developed by Daiichi Sankyo. The brand name of edoxaban is Lixiana. It is indicated for preventing blood clots in people with nonvalvular atrial fibrillation who also have at least one risk factor, such as having had a previous stroke, high blood pressure (hypertension), diabetes mellitus, congestive heart failure.

[0008] Brief Description of the invention

[0009] The present invention relates to a pharmaceutical composition comprising edoxaban or pharmaceutically acceptable salts thereof having a particle size distribution with dw less than 20 pm, characterized in that the weight ratio of crospovidone to croscarmellose sodium used as disintegrants is from 1.0 to 3.0. The present invention relates to a pharmaceutical composition comprising edoxaban tosylate monohydrate and one or more pharmaceutically acceptable excipients.

[0010] The present invention relates to a process for manufacturing a pharmaceutical composition according to any one of the previous claims, wherein the process comprising the steps of; a. Mixing edoxaban, filler, croscarmellose sodium, crospovidone, binder and lubricant, b. Compressing tablet, c. Film coating to step b.

[0011] Detailed description of the invention

[0012] Aspects of the present invention relate to particle size distribution of pharmaceutical formulation comprising edoxaban or pharmaceutically acceptable salts thereof.

[0013] The present invention relates to the preparation of pharmaceutical compositions comprising edoxaban particles having a specific particle size distribution range with relevant excipients.

[0014] The present invention relates to the preparation of pharmaceutical compositions comprising edoxaban particles having a specific particle size distribution range with relevant excipients.

[0015] The present invention relates to the preparation of pharmaceutical compositions comprising edoxaban or pharmaceutically acceptable salts thereof as active ingredient, at least one disintegrant and other excipients.

[0016] The present invention relates to the preparation of pharmaceutical compositions comprising edoxaban particles having a specific particle size distribution range, croscarmellose sodium to crospovidone as disintegrants and other excipients.

[0017] The present invention relates to the preparation of pharmaceutical compositions comprising edoxaban particles having a specific particle size distribution range, with a spesific weight ratio for croscarmellose sodium and crospovidone as disintegrants and other excipients.

[0018] The present invention relates to the preparation of pharmaceutical compositions comprising edoxaban particles having a particle size distribution with d90 less than 20 pm, with a spesific weight ratio for crospovidone and croscarmellose sodium as disintegrants and other excipients.

[0019] The present invention relates to the preparation of pharmaceutical compositions comprising edoxaban particles having a specific particle size distribution range, with the weight ratio of crospovidone to croscarmellose sodium used as disintegrants is from 1.0 to 3.0 and other excipients.

[0020] The present invention relates to a pharmaceutical composition comprising edoxaban or pharmaceutically acceptable salts thereof having a particle size distribution with d90 less than 20 pm, characterized in that the weight ratio of crospovidone to croscarmellose sodium used as disintegrants is from 1.0 to 3.0.

[0021] The present invention relates to the preparation of pharmaceutical compositions comprising edoxaban or pharmaceutically acceptable salts thereof having a particle size distribution with d90 less than 20 pm with relevant excipients.

[0022] The present invention relates to the preparation of pharmaceutical compositions comprising edoxaban tosylate monohydrate having a particle size distribution with d90 less than 20 pm with relevant excipients.

[0023] The term "particle size" as used herein refers to the volume diameter of valsartan particles, as determined by laser light scattering using a Malvern-Mastersizer Apparatus MS 2000.

[0024] Methods of determining the size of particles are well known in the art. For example, Laser Diffraction, Dynamic Light Scattering, Image Particle Analysis, Acoustic Spectroscopy etc.

[0025] The dxvalue indicates that a certain percentage X of the particles has a size below a certain limit, dw means that 90% of particles (V / V) have a higher volume diameter than the indicated value.

[0026] A dw value of less than 20 pm means that 90 % by volume of the particles have a diameter below 20 pm.

[0027] A dgo value of larger than 10 pm means that 90 % by volume of the particles have a diameter above 10 pm.

[0028] The term " edoxaban particle" means a particle that contains edoxaban, preferably, a particle that essentially or completely consists of edoxaban.

[0029] In the present invention the pharmaceutical compositions of edoxaban have a edoxaban particle size such that dgo is 18 pm. In the present invention the pharmaceutical compositions of edoxaban have a edoxaban particle size such that dw is 15 pm.

[0030] In the present invention the pharmaceutical compositions of edoxaban have a edoxaban particle size such that dgo is 12 pm.

[0031] In the present invention the pharmaceutical compositions of edoxaban have a edoxaban particle size such that dgo is 10 pm.

[0032] In the present invention the pharmaceutical compositions of edoxaban have a edoxaban particle size such that dgo is 8 pm.

[0033] In the present invention the pharmaceutical compositions of edoxaban have a edoxaban particle size such that dgo is 5 pm.

[0034] In the present invention the pharmaceutical compositions of edoxaban have a edoxaban particle size such that dgo is 3 pm.

[0035] The present invention relates to the preparation of pharmaceutical compositions comprising edoxaban tosylate monohydrate as active ingredient, and relevant excipients.

[0036] In one embodiment pharmaceutical composition comprises edoxaban tosylate monohydrate in an amount of 5-30 % based on the total weight of the composition.

[0037] Suitable fillers according to the present invention include, but are not limited to, dibasic calcium phosphate, kaolin, microcrystalline cellulose, silicated microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, lactose such as example the anhydrous form or the hydrate form such as the monohydrate form, sugars such as dextrose, maltose, saccharose, glucose, fructose or maltodextrine, sugar alcohols such as mannitol, maltitol, sorbitol, xylitol, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate and starch. The preferred filler is mannitol.

[0038] The fillers can be comprised in an amount in a range of about 50.0-90.0% based on the total weight of the composition.

[0039] Suitable binders according to the present invention include, but are not limited to, hydroxypropyl cellulose, hypromellose (hydroxypropyl methylcellulose, HPMC), HPMC E5, microcrystalline cellulose, acacia, alginic acid, carboxymethylcellulose, ethyl cellulose, methylcellulose, hydroxyethyl cellulose, ethylhydroxyethylcellulose, polyvinyl alcohol, polyacrylates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, ethyl cellulose, gelatin, liquid glucose, methylcellulose, polyvinylpyrrolidone (PVP) and pregelatinized starch. The preferred binder is hydroxypropyl cellulose.

[0040] The binders can be comprised in an amount in a range of about 0.5-4.0% based on the total weight of the composition.

[0041] Lubricants can also be used in the process. Lubricants are used for preventing adhesion of the tablet material to the surfaces of the die and punches. This helps to reduce the wear and tear on the tableting equipment and to prevent the formation of tablet defects, such as cracks or chips.

[0042] Suitable lubricants according to the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearyl fumarate, zinc stearate and polyethylene glycol. The preferred lubricant is magnesium stearate.

[0043] The lubricants can be comprised in an amount in a range of about 0.2-2.0% based on the total weight of the composition.

[0044] Suitable disintegrants for this inventive formulation can be selected from the group, but are not limited to, alginic acid, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, microcrystalline cellulose, methyl cellulose, sodium starch glycolate, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidones, polacrilin potassium, starch, pregelatinized starch, sodium alginate, hydroxypropyl starch and other materials known to one of ordinary skill in the art. The combination of above-mentioned disintegrants can also be used. The preferred disintegrants are croscarmellose sodium and crospovidone.

[0045] The disintegrants can be comprised in an amount in a range of about 0.5-5.0% based on the total weight of the composition.

[0046] Edoxaban molecule is in Class IV according to the Biopharmaceutical Classification System (BCS). BCS Class IV molecules have low solubility and low penetration properties.

[0047] Low solubility and low penetration properties have an impact on the bioavailability of the drug. This is a rate-limiting factor in terms of dissolution and absorption of the drug molecule. For this reason, it is very difficult to develop successful formulations in terms of in-vitro and in- vivo. The biggest obstacle to be overcome in the development of the oral pharmaceutical composition of the edoxaban molecule is to improve the solubility of the molecule and to ensure the desired penetration. However, the developed pharmaceutical composition must be able to be kept soluble and stable throughout the shelf life.

[0048] For molecules such as Edoxaban, which are in Class IV according to the Biopharmaceutical Classification (BCS) classification system, the dispersant and its percentage are very important. Within the scope of the invention, crospovidone and croscarmellose sodium were selected as disintegrant.

[0049] The dispersion performance of the edoxaban formulation and the resulting desired in-vitro and in-vivo performance were taken into consideration. As a result, the desired result was achieved in the formulation, where crospovidone and croscarmellose sodium were used together in specific ratios.

[0050] Advantages

[0051] In the pharmaceutical industry, particle characterization of powder materials such as edoxaban has become more critical in drug product development and also quality control of solid oral dosage forms.

[0052] The particle size distribution (PSD) for active ingredients and related excipients may have high- level effect on final drug product and also manufacturing properties such as stability, dissolution, content uniformity, bioavailability, flowability, blend uniformity, compactibility. It also effective on bioequivalence results. Particle size distribution can effect its product properties such as safety, efficacy, and quality.

[0053] In this invention, a pharmaceutical formulation containing edoxaban having specific particle size distribution range, it provides a product that has properties such as stability, desired dissolution and bioavailability values.

[0054] The contact surface of Edoxaban Tosylate Monohydrate with water was increased by selecting the active substance with D90 less than 20 microns. Thus, it was aimed to obtain faster solubility. As a result of faster solubility, the desired solubility, in-vitro and in-vivo performance was obtained.

[0055] According to dissolution results and PSD results mentioned above parts, inventive product comprising has stability, desired dissolution. Because of using specific particle size range with edoxaban, uniformity is provided for pharmaceutical composition comprising active ingredient, filler, disintegrant, binder and lubricant.

[0056] It is desired to optimize particle size distribution and manufacturing process of oral solid dosage form of ivermectin and the methods of its preparation on a commercial scale.

[0057] It is surprisingly found that manufacturability problems are solved at both developing stage and also commercial scale with determined particle size distribution. Also, it is optimized parameters for manufacturing process which affect critical particle size distribution.

[0058] The present invention provides pharmaceutical composition comprising edoxaban and relevant excipients, characterized by i) A simple and exclusive manufacturing process ii) Stable formulation.

[0059] The disintegrant ensures the distribution of the tablet in the gastro-intestinal tract after oral administration. It is very important for the bioavailability of the active substance Edoxaban that the disintegrant shows the desired performance in the gastro-intestinal tract with different pH values. As a result of successful bioavailability of the active substance, the active substance is delivered to the patient with the desired efficacy and safety.

[0060] Disintegrants are used in oral pharmaceutical compositions (capsules, tablets, granules, etc.). Its general use is between 0.5% and 5%. In our composition, apart from its general use, it is used above 5% and is specific.

[0061] Dissolution Tests

[0062] In this invention, dissolution studies were carried out in which crospovidone and croscarmellose sodium were used in different ratios as disintegrants for the pharmaceutical composition comprising edoxaban and relevant excipients.

[0063] The results obtained can be found below;

[0064] Formula 1 : Pharmaceutical composition comprising edoxaban and relevant excipients (Weight ratio of Crospovidon to Croscarmellose sodium is 0.5)

[0065] In this invention, the dissolution test has been performed for Edoxaban tablet in pH 6.0 phosphate media. It is shown in Table 1.

[0066] Evaluation: Since rapid dissolution is observed, it causes low bioavailability.

[0067] Table 1 : Summary of Dissolution Result of Edoxaban Tablet in pH 6.0 phosphate media (Formula 1)

[0068] Formula 2: Pharmaceutical composition comprising edoxaban and relevant excipients (Weight ratio of Crospovidon to Croscarmellose sodium is 4.0) In this invention, the dissolution test has been performed for Edoxaban tablet in pH 6.0 phosphate media. It is shown in Table 2.

[0069] Evaluation: Since low dissolution is observed, it causes low bioavailability.

[0070] Table 2: Summary of Dissolution Result of Edoxaban Tablet in pH 6.0 phosphate media (Formula 2)

[0071] Formula 3: Pharmaceutical composition comprising edoxaban and relevant excipients (Weight ratio of Crospovidon to Croscarmellose sodium is 2.0)

[0072] In this invention, the dissolution test has been performed for Edoxaban tablet in pH 6.0 phosphate media. It is shown in Table 3.

[0073] Evaluation: Ideal bioavailability is achieved within the desired efficacy and safety limits.

[0074] Table 3: Summary of Dissolution Result of Edoxaban Tablet in pH 6.0 phosphate media (Formula 3) Overall conclusion of Dissolution Results:

[0075] Compared to above three formulations, the results of formula 3 are favourable in terms of bioavailability. Stability data

[0076] Pharmaceutical products comprising bilastine prepared according to the invention were tested for stability in below storage conditions:

[0077] 25°C ± 2°C / %60 RH ± %5 RH

[0078] 30°C ± 2°C / %65 RH ± %5 RH 40°C ± 2°C / %75 RH ± %5 RH

[0079] Result of the stability study indicates that present edoxaban composition in accordance with the present invention exhibits excellent storage stability.

[0080] During the stability period, the product was found to comply with specifications.

[0081] Formula 4: Pharmaceutical composition comprising edoxaban and relevant excipients in tablet form

[0082] Formula 5: Pharmaceutical composition comprising edoxaban and relevant excipients in tablet form Procedure for composition of Example 1 comprising edoxaban tablet;

[0083] 1. Mixing edoxaban, filler, croscarmellose sodium, crospovidone, binder and lubricant,

[0084] 2. Compressing tablet,

[0085] 3. Film coating to step b.

Claims

CLAIMS1. A pharmaceutical composition comprising edoxaban or pharmaceutically acceptable salts thereof having a particle size distribution with dw less than 20 pm, characterized in that the weight ratio of crospovidone to croscarmellose sodium used as disintegrants is from 1.0 to 3.0.

2. The pharmaceutical composition according claim 1, characterized in that the weight ratio of crospovidone to croscarmellose sodium used as disintegrants is from 1.5 to 2.5.

3. The pharmaceutical composition according to claim 1, characterized in that t dw particle size distribution of edoxaban is from 5 to 15 pm.

4. The pharmaceutical composition according to claim 1, characterized in that edoxaban is edoxaban tosylate monohydrate.

5. A process for manufacturing a pharmaceutical composition according to any one of the previous claims, wherein the process comprising the steps of; a. Mixing edoxaban, filler, croscarmellose sodium, crospovidone, binder and lubricant, b. Compressing tablet, c. Film coating to step b.

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