GRANULES

FIELD OF INVENTION

The present invention relates to a pharmaceutical composition, comprising non-hydrophilized rivaroxaban or a pharmaceutically acceptable salt thereof, wherein the composition is in an oral solid dosage form with good flowability and drug release profile.

STATE OF ART

Rivaroxaban (5-chloro-N-{[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]ox azolidin-5- yl] methyl }thiophene-2-carboxamide) is a low molecular weight, orally administrable anticoagulant drug. Rivaroxaban is an anticoagulant and the first orally active direct factor Xa inhibitor. The pharmaceutical directly inhibits the active form of serine protease Factor Xa (FXa). Rivaroxaban can be used for the prevention and treatment of various thromboembolic diseases, in particular of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infract, angina pectoris, re-occlusions and recurrence of stenosis after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, and peripheral arterial occlusive diseases.

Rivaroxaban was first disclosed in WO0147919, has the systematic name 5-chloro-N-({(5S)-2- oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-l ,3-oxazolidin-5-yl}methyl) thiophene-2-carboxamide and the following chemical structure:

Formula Three different polymorphic forms of rivaroxaban have been described in W007039132.

US2007/0149522 relates to a synthesis method of 5-chloro-N-({5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)-phenyl]-l,3-oxazolidin-5-yl}-methyl)-2-thiophen e carboxamide using from 5- chlorothiophene-2-carbonyl chloride and (2S)-3-amino-propane-l,2-diol and 4-(4-aminophenyl)- 3-morpholinone as starting materials.

W02009023233 relates to novel compounds that are substituted oxazolidinones derivatives and pharmaceutically acceptable salts thereof. More specifically, this invention relates to novel oxazolidinone compounds that are derivatives of Rivaroxaban. The invention also provides pyrogen-free compositions comprising one or more compounds of the invention and a carrier, along with the use of the disclosed compounds and compositions in methods of treating diseases and condition that are beneficially treated by administering a selective inhibitor of factor Xa, such as Rivaroxaban.

WO2015155307 relates to a novel pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt thereof in combination with a proton pump inhibitor for use in the anticoagulant treatment with preventing or reducing the risk of a gastrointestinal disorder.

WO2015169957 relates to a novel pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt thereof in combination with a proton pump inhibitor for use in the anticoagulant treatment with preventing or reducing the risk of a gastrointestinal disorder.

WO2016131896 relates to a pharmaceutical combination comprising dronedarone or a pharmaceutically acceptable salt thereof in combination with rivaroxaban and at least one pharmaceutically acceptable excipient.

W007039122 relates to rivaroxaban formulations comprising rivaroxaban in amorphous form or thermodynamically metastable crystal modification.

W009049820 relates to rivaroxaban formulations comprising at least one solid substance at room temperature, the thermodynamically preferred crystalline form of rivaroxaban, cellulose and/or cellulose derivatives, as well as optionally a surface-active substance, wherein more than 50% of rivaroxaban in the formulation is in amorphous mixed phase as determined by X-ray diffractometer.

EP3505160 relates to a manufacturing process of a tablet comprising rivaroxaban wherein it comprises of preparing a powder mixture comprising rivaroxaban, surfactant and pharmaceutically acceptable excipients and subjecting the powder mixture obtained previous to compress tablet by direct compression method.

TR2017/13325 and TR2017/13326 disclose a process for manufacturing a formulation comprising the step of granulating the solid mixture comprising the active ingredient rivaroxaban, at least one water-soluble binder and at least one water-soluble filler with a suitable granulation solution.

WO2017146709 relates to the rivaroxaban containing granules wherein process steps are; dry mixing rivaroxaban and a pharmaceutically acceptable excipient in a high-shear mixer to form a dry mix blend, adding a binder solution to the dry mix blend to form a granulating mixture and finally mixing, drying and milling the rivaroxaban-containing granules. The final granulating mixture has water content of less than 30% and the high shear granulation time is carried out between three to five minutes.

WO20 15124995 relates to an oral solid dosage form comprising rivaroxaban and one or more pharmaceutically acceptable excipients manufactured by a wet granulation process wherein the ratio of rivaroxaban to excipient is in the range of 1:2 to 1:8 and obtaining solid dosage form.

WO20 18007945 relates to an oral pharmaceutical composition comprising rivaroxaban, its solvates, hydrates and/or pharmaceutically acceptable salts prepared by non-aqueous granulation and hydroalcoholic granulation.

W02005060940 relates to a method for production of a solid, orally administrable pharmaceutical composition comprising rivaroxaban in hydrophilized form. The wet granulation manufacturing method is disclosed by using fluidized-bed granulation. In the manufacturing method, first rivaroxaban is introduced into the wet granulation suspended in the granulation liquid. In the description part of the patent document it is discussed that since rivaroxaban is a poor-water soluble drug, it should be dissolved in a suitable solvent for further processing and get a dosage form with good pharmaceutical properties.

WO2016166733 related to a process for preparing an oral pharmaceutical composition of Rivaroxaban in non-hydrophilized form, wherein rivaroxaban is incorporated in a dry mix with other pharmaceutically acceptable excipients which is granulated with non-aqueous solvents using high shear mixer granulator and dried using fluidized bed dryer.

WO20 17021482 relates to an immediate release tablet comprising; rivaroxaban, a non-ionic surfactant and optionally one or more pharmaceutically acceptable excipients obtainable by using a dry process wherein the particle size is not reduced during the process of manufacturing the tablets.

W02006072367 relates a process comprising hot melt extrusion of rivaroxaban and an excipient, performed a temperature exceeding 150°C, wherein 80% of rivaroxaban is released in a period of from 4 to 20 hours by using the USP release method with apparatus 2.

W010146179 or W011042156 disclose hot melt rivaroxaban formulations. The use of hot melt process, coated granules, milling with excipients or microspheres formulations imply complex, lengthy and costly processes; therefore, they are not desirable.

Rivaroxaban is a pharmaceutical agent that is used to reduce stroke risk in nonvalvular atrial fibrillation. It helps reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It is also indicated for treating deep vein thrombosis and pulmonary embolism. It also reduces in the risk of recurrence of the same. Specifically, rivaroxaban is used for the prophylaxis of deep vein thrombosis after knee or hip replacement surgery which may lead to pulmonary embolism.

Rivaroxaban is an orally active factor Xa inhibitor marketed for the treatment or prevention of atherothrombotic events, prevention of venous thromboembolism, prevention of stroke and systemic embolism, treatment and prevention of deep vein thrombosis or treatment and prevention of pulmonary embolism. Rivaroxaban is marketed in 2.5, 10, 15 and 20 mg strengths immediate release tablets. Rivaroxaban has poor water solubility (7 mg/L) and is thus difficult to incorporate into oral dosage forms that provide sufficient bioavailability of rivaroxaban following oral administration. There is thus a need to provide an improved process for the preparation of dosage forms of rivaroxaban with improved bioavailability of the rivaroxaban active ingredient.

Based on the information about the solubility of rivaroxaban wet granulation method is the preferred manufacturing method to achieve a solid dosage form with good pharmaceutical characteristics.

One process in wet granulation method is performed with high-shear granulator. A high-shear granulator consists of a cylindrical or conical mixing bowl, a three bladed impeller, a chopper, an auxiliary chopper, a motor to drive the blades and a discharge pot. By either circulating hot or cool liquid or steam through the jacket, the mixing bowl is jacketed for heating or cooling the contents of the bowl as the case may be.

The present invention is an oral dosage form comprising non-hydrophilized rivaroxaban with improved physicochemical and pharmaceutical characteristics manufactured by using high-shear granulation process as a part of wet granulation method.

SUMMARY OF THE INVENTION

The present invention relates to an immediate release solid oral composition comprising rivaroxaban and one or more acceptable excipients manufactured by using conventional manufacturing methods with characteristic process parameters.

Another object of the invention is the oral dosage form of the present invention for the treatment or prevention of atherothrombotic events, prevention of venous thromboembolism, prevention of stroke and systemic embolism, treatment and prevention of deep vein thrombosis or treatment and prevention of pulmonary embolism.

Another object of the invention is to develop an oral dosage form with improved physicochemical properties. However, since the water-solubility of rivaroxaban is very low it is difficult to have an oral dosage form with improved dissolution profile and flowability properties. Thus, critical manufacturing processes are improved. Another object of the invention is the oral dosage form comprising rivaroxaban in non- hydrophilized form mixed with convenient pharmaceutically acceptable excipients prior to introduce solvent and continue manufacturing by using high-shear technique which is one of the wet granulation processes.

An advantage of high-shear granulation is that the process is completed within a short period of time. It does, however, need to be carefully controlled as the formulation can quickly progress from under- to over-granulated.

The properties of the granules, such as porosity, hygroscopicity, hardness, size, shape, texture, surface area, density, elasticity, and plasticity, can be controlled through manipulation of several processing parameters and material attributes. It is of paramount significance to understand how material attributes and process parameters/conditions influence the quality attributes of granules.

Another object of the invention is to obtain a rivaroxaban containing granules with good flowability and dissolution profile. Thus, process parameters of water content in granulation solution and the time to give the solvent to the powder blend before granulation process should be characterized. The purpose is to obtain homogeneous granules to improve the flow, content uniformity, compression characteristics, and drug release profile; and to reduce the potential for segregation and dusting. Granules that possess ideal properties result in efficient processing and high throughput of solid dose units with desired critical quality attributes (CQAs).

It is surprisingly found that solid oral dosage forms comprising non-hydrophilized rivaroxaban manufactured by using high-shear granulation process has improved pharmaceutical properties through a specified time to give the solvent and mix before granulation step.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of granules of rivaroxaban together with one or more pharmaceutically acceptable excipients. The rivaroxaban- containing particles of the present invention may be incorporated into pharmaceutical dosage forms for oral administration to patients in need thereof. The present invention provides a solid oral dosage form comprising non-hydrophilized rivaroxaban and pharmaceutically acceptable excipients manufactured by using a high-shear granulation process with a specified time to give the solvent and mix before granulation step. The rivaroxaban-containing particles of the present invention is easily incorporated into pharmaceutical dosage forms for oral administration to patients in need thereof.

In one embodiment of the present invention, the granules are prepared using a high-moisture, high-shear granulation process with a minimized mixing time. This process minimizes segregation, dust and improves flowability.

These properties may result in enhanced granule consistency, improved workability of the final blend prior to tablet formation, and may also enhance the dissolution of the final dosage form. Surprisingly, when incorporated into oral dosage forms, these granules provide good flowability and dissolution profile when compared to tablets formulated with granules prepared using conventional, prior-art high-shear granulation techniques.

When liquid binder is introduced to the dry powder mix to promote granule growth, the liquid spray initially contacts the powder blend. Granule uniformity is therefore influenced by the composition of the powder blend, where ideally an even distribution of all excipients and active substance should be incorporated into the granule.

In an embodiment to improve granule characteristics, rivaroxaban is considered to be mixed with pharmaceutically acceptable excipients without a solvent which means it is in non-hydrophilized form.

A formulation and manufacturing method design is set considering rivaroxaban chemical structure and the most convenient pharmaceutically acceptable excipients to be used with. The amounts of pharmaceutically acceptable excipients are determined based on Handbook of Pharmaceutical Excipients. Formulation Design: Manufacturing process:

1. Sodium lauryl sulphate and a specified amount of HPMC are dissolved in water and mixed to obtain uniform solution (granulation solution).

2. Specified amount of rivaroxaban, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and the remaining part of HPMC are stirred in a separate bowl. 3. The granulation solution prepared in step 1 is added on the intragranular phase obtained in step

2 and granulation process is performed by using high-shear granulator.

4. Wet granules are dried to a specified moisture value and shifted through a proper sieve.

5. Pharmaceutically acceptable amount of magnesium stearate is added on the granules obtained in step 4 and stirred to obtain a uniform final blend. 6. Granules are used to get a pharmaceutically acceptable solid oral dosage forms.

According to the present invention, the water content of granulation solution in step 1 and the process of giving granulation solution at a specified duration to powder blend (intragranular phase) in step 3 are the critical parameters for the formulation design and manufacturing process stated above. Many experiments were performed to optimize key parameters of manufacturing process by using high-shear granulation techniques. The water content of granulation solution used to granulate the intragranular phase comprising non-hydrophilized rivaroxaban and pharmaceutically acceptable excipients is investigated.

Different water contents of granulation solutions were used in granulation of intragranular phase in step 3. It directly affects granule uniformity which is important in pharmaceutical manufacturing, as the tablet must contain a uniform distribution of active substance and excipients in the product to ensure product efficacy. Increasing the water content of granulation solution more than 55% w/w decreased the binder properties of the binder solution. It is due to hygroscopicity of a powder refers to its ability to absorb moisture from its surroundings. For granules to form, a critical amount of liquid must be available at the surface of the particles to form the required liquid bridges between the particles. Optimized amount of binder is therefore required to ensure a critical amount at the surface for the liquid bridges and granule formation. The binder is added to the intragranular phase in a certain duration range via granulation solution. This step is repeated a certain number of times usually taking the powder from the dry state to a suspension.

When the water content of granulation solution is under or equal to 20% w/w, granulation process is not achieved because the granules obtained were very fine like powder, not granule and also the granule formation is very bad. No further process was able to be performed.

When the water content of granulation solution is 30% w/w, obtained granule represents the same characteristics with 20% w/w level experiment.

When the water content of granulation solution is 40% w/w, it was observed that the flowability was improved but not enough. Thus, the experiments were performed for further levels of solvent.

When the water content of granulation solution is 45% w/w, it was observed that flowability of granule was good for the next step.

Optimization processes were performed to set out the upper limit water content of granulation solution for workability. It was found that higher water content of granulation solution than 55% w/w, it was observed that flowability of granule was good for the next step.

It was found that higher water content of granulation solution than 60% w/w, obtained granule was not able to be compressed into tablets. The physical appearance of the granule seems like a slurry.

The physico-chemical properties of granule were changed when different water contents of granulation solutions were used.

As a result, the workability range of water content of granulation solution is determined as 45- 55% w/w. The particle size of granule was used as a tool for initial characterization of the powder binder couple by carrying out the multiple binder addition test.

Optimization processes conducted due to different water contents of granulation solution were analyzed. Granule properties, such as particle size, Carr index (compressibility index) should be specified. Thereby, flowability properties will be optimized. Analysis were performed on the granules obtained.

Particle Size Distribution (PSD) analysis were performed using light-scattering method, in particular Malvern Mastersizer.

Carr index is one of the most popular method of predicting powder flow characteristics. The compressibility index has been proposed as an indirect measure of bulk density, size and shape, surface area, moisture content and cohesiveness of materials because all of these can influence the observed compressibility index. These calculations were done according United States Pharmacopeia <1174> Powder Flow test.

Calculated results of analysis are presented in the table below.

The second variation to be optimized with a constant water content of granulation solution between 45-55% w/w is the duration to give the granulation solution on intragranular phase. The granulation solution comprising binder and surfactant was given to intragranular phase by strring. Binders or “granulating agents” are a critical formulation component in wet granulation, ensuring appropriate surface wetting ability to ensure adhesion and cohesion between inter-particulate surfaces in the wet state, as well as excellent plasticity, compactibility and binding ability. Binder effect has a strong impact on granule formation and granule size.

The granule size affects disintegration and dissolution profile of the product directly. The duration for mixing during the meeting of intragranular phase with granulation solution was investigated through performing many experiments.

Different durations to give granulation solution were investigated: from 30 seconds to 3 minutes. Between these range, 1 ^st minute, 1.5 ^th minute, 2 ^nd minute and 3 ^rd minute intervals were applied.

According to the present invention, the granules may then be dried and milled.

Within the context of the present, the drying step may be achieved by well-known methods, for example, by oven tray drying, or by fluid bed drying. Milling may also be carried out by methods well known in the art, for example, by using a Fitzmill or a Comil.

According to the present invention, a binder solution is added to the intragranular phase of rivaroxaban and one or more pharmaceutically acceptable excipients, resulting in a granulation blend. In particularly advantageous embodiments of the present invention, the granulation solution at defined concentration range is added to the powder with a certain duration range to give granulation solution by using high shear granulation.

Within the context of the present invention, the binder may be, for example, hypromellose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. The binder is dissolved in a solvent, for instance, water, an alcohol, or mixtures thereof. In particularly advantageous embodiments of the present invention, the binder solution is hypromellose dissolved in water.

In a preferred embodiment of the invention the filler is selected from the group consisting of lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and / or tribasic), calcium sulphate trihydrate or dihydrate, calcium carbonate, kaolin, cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, glucose, mannitol, maltitol, sorbitol, xylitol, titanium dioxide (Ti02) or the mixture thereof.

In a preferred embodiment of the invention the disintegrant is selected from the group consisting of calcium phosphate (dibasic and/or tribasic), sodium starch glycolate, crospovidone, croscarmellose sodium and the mixture thereof.

In a preferred embodiment of the invention the surfactant is selected from the group consisting of alkylbenzene sulfonates, sodium lauryl sulphate, dialkyl sulfosuccinate, polyethylene glycol, sorbitan monoester, glycerol diester and the mixture thereof.

In a preferred embodiment of the invention the lubricant is selected from the group consisting of magnesium stearate, stearic acid, polyethylene glycol, sodium stearyl fumarate and the mixture thereof.

The critical steps in the process of the present invention are the step 1 and step 3, preparing granulation solution with defined concentration range and granulating the intragranular phase with a specified duration to give this granulation solution. Step 1 is optimized above with a specification range of 45-55% w/w. Furthermore, the duration time to give granulation solution in step 3 is investigated by performing in-vitro dissolution test.

Table 3: Results of In-vitro Analysis obtained with duration interval range to give granulation solution which is at certain range of 45-55 %

Most proper dissolution results are obtained with a duration range to give granulation solution from 30 seconds to 2 minutes.

Furthermore, formulation obtained with optimized duration time to give granulation solution in which the water content level lies between 45-55% is subjected to bioequivalence study.

According to “Guideline on the Investigation on Bioequivalence” published by EMA, to establish bioequivalence of the test product with that of reference product, 90% Confidence Interval (Cl) for the ratio (Test/Reference) of Least Square Means of the Ln transformed PK parameters (AUC _t and C _max ) must fall between 80.00% to 125.00%.

10 Table 4: In-vivo Bioequivalence study results

PK parameters (AUC _t and C _max ) are in line with the specifications based on Guideline on the Investigation on Bioequivalence.

Both in-vitro and in-vivo release profile of the drug comprising non-hydrophilized rivaroxaban and manufactured by wet granulation method in which high-shear granulator is used.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.