WO2016166733A1

WO2016166733A1 - A process for preparing a pharmaceutical composition comprising rivaroxaban

Info

Publication number: WO2016166733A1
Application number: PCT/IB2016/052185
Authority: WO
Inventors: Pankaj Sharad MANDPE; Vikas Dinanath YANDE; Namrata Mandar BHOGAN; Vijaykumar Kashinath SHIVPUJE
Original assignee: Micro Labs Limited
Priority date: 2015-04-17
Filing date: 2016-04-16
Publication date: 2016-10-20

Abstract

The present invention relates to a process for preparing a pharmaceutical composition comprising Rivaroxaban in the form of a tablet or a capsule.

Description

A PROCESS FOR PREPARING A PHARMACEUTICAL COMPOSITION

COMPRISING RIVAROXABAN

Priority Document:

This patent application claims priority to Indian Provisional Patent Application number 1587/MUM/2015 (filed on 17th April 2015), the contents of which are incorporated by reference herein.

Technical field of the invention:

Background of the invention:

Atrial Fibrillation is a heart rhythm disorder. It is characterized by rapid and irregular beating. Non valvular atrial fibrillation is characterized by absence of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve repair. The main goals of treatment of atrial fibrillation are to prevent circulatory instability and stroke. Rate or rhythm control is used to prevent circulatory instability. Prevention of coagulation is used to decrease the risk of strokes.

Prevention of coagulation can be achieved by the use of anticoagulants like heparin, warfarin, dabigatran, rivaroxaban and apixaban. The method used depends on a number of issues, including: cost, risk of stroke, risk of falls, compliance, and speed of desired onset of anticoagulation.

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 oxazolidinone derivative optimized for inhibiting both free Factor Xa and Factor Xa bound in the prothrombinase complex which leads to thrombus formation. It is a highly selective direct Factor Xa inhibitor with oral bioavailability and rapid onset of action. Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. The chemical name of Rivaroxaban is (S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl] oxazolidin- 5-yl] methyl} thiophene-2-carboxamide. Its empirical formula is C19H18CIN3O5S and the molecular weight is 435.88. The chemical structure is:

RIVAROXABAN

Rivaroxaban is available as Xarelto® tablets (by Janssen Pharmaceuticals, Inc) in the US market which is licensed from Bayer HealthCare AG. It is a tablet containing 10mg, 15mg or 20mg of Rivaroxaban which is used as a treatment for deep vein thrombosis, pulmonary embolism, and for the reduction in the risk of recurrence of the same. Xarelto® tablet contains the following inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.

US7157456 discloses rivaroxaban specifically. US 7585860 claims Rivaroxaban and Rivaroxaban hydrate specifically.

US20140248349 discloses the process for producing rivaroxaban composition wherein Rivaroxaban is present in hydrophilized form with the steps of granulation using fluidized bed granulator.

US20130064888 discloses a pharmaceutical dosage form in the form of a tablet with a compressed inert core with a drug layer.

US20120231076 discloses a pharmaceutical composition prepared by melting a mixture of rivaroxaban in crystalline form along with suitable hydrophilic matrix former and a disintegrant.

US20130281457 discloses a process for producing a pharmaceutical composition by dry-compaction.

EP280801 1 A1 discloses a process for the preparation of a pharmaceutical composition by milling along with the use of at least one hydrophilic binder. WO/2015124995 discloses process for preparing solid dosage form of Rivaroxaban.

However, there still exists a need of alternative of pharmaceutical composition for poorly water soluble drug like Rivaroxaban which can be economical. The present inventors have developed a pharmaceutical composition comprising Rivaroxaban along with pharmaceutically acceptable excipients like microcrystalline cellulose, lactose, hydroxypropyl cellulose, croscarmellose sodium, sodium lauryl sulphate and magnesium stearate 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.

Summary of the invention:

The present invention provides a process for preparing a pharmaceutical composition comprising Rivaroxaban in the form of a tablet or a capsule.

In an embodiment, the present invention relates to a process for preparing an oral pharmaceutical composition of Rivaroxaban in non-hydrophilized form, wherein the process comprises the steps of:

a) mixing Rivaroxaban with pharmaceutically acceptable inert excipients to form a dry-mix;

b) granulating the dry mix in step (a) in high shear mixer granulator to form granules;

c) drying the granules formed in step (b) in fluidized bed dryer.

In an aspect of the embodiment, the weight ratio of Rivaroxaban to pharmaceutically acceptable inert excipients is 1 :0.1 to 1 :25.

In another aspect of the embodiment, the pharmaceutically acceptable inert excipients comprise diluents, disintegrants, binders and solubilizers, lubricants, glidants etc.

In yet another aspect of the embodiment, the granulation is non-aqueous granulation.

In a further aspect of the embodiment, Rivaroxaban is employed in crystalline form.

In yet another aspect of the embodiment, Rivaroxaban is in micronized form. In yet another aspect of the embodiment, 90% by volume of Rivaroxaban particles have a particle size less than 15 μιη.

In yet another aspect of the embodiment, the process comprises the steps of compressing into suitable dosage form and optionally coating the same.

Detailed description of the invention:

The terms used herein are defined as follows.

The term 'pharmaceutical composition' denotes a composition which shows immediate release.

The term "active ingredient" (used interchangeably with "active" or "active substance" or "drug") as used herein includes Rivaroxaban or its pharmaceutically acceptable salt and its different polymorphic forms (amorphous or crystalline).

The term "pharmaceutically acceptable inert excipients", denotes any of the components of a pharmaceutical composition other than the active and which are approved by regulatory authorities or are generally 'regarded as safe' for human or animal use.

c) drying the granules formed in step (b) in fluidized bed dryer.

Mixing and granulation of Rivaroxaban with pharmaceutically acceptable inert excipients is carried out in high shear mixer granulator (Saizoner mixer). The equipments used for granulation are high shear mixer granulator, planetary mixer, over head stirrer, mass mixer, ribbon blender, and like. The preferable equipment used for granulation is high shear mixer granulator.

Mixing, densification, and agglomeration of wetted material is achieved through shearing and compaction forces exerted by the impeller. The impeller rotates on the vertical shaft at a rotational speed corresponding to a radial blade tip speed of approximately 5-15 m/s. The chopper rotates at a similar tip speed which, because of its small diameter, corresponds to a very high rotation speed in revolutions per minute (rpm) (i.e. 1500-4000 rpm). The primary function of chopper is to cut lumps into smaller fragments and aids the bowl or sprayed onto the powder to achieve a more homogeneous liquid distribution.

The pharmaceutically acceptable excipients along with Rivaroxaban are placed in the high shear mixer granulator (Saizoner mixer) and mixing is carried out for 10 minutes. The binder is added to the dry mix in high shear mixer granulator (Saizoner mixer) with impeller at slow speed. The wet mass is raked and then kneaded with the impeller and chopper speeds at 'fast' for about 20- 40 seconds.

The use of high shear mixer granulator for granulation holds several advantages like efficient and homogenous mixing, rapid processing, and improving content uniformity.

The granules so obtained are transferred into suitable equipment to enable drying. Drying of granules can be carried out using Fluidized Bed Dryers, Tray Dryers, Belt Dryers, Vacuum Tray Dryers, Rotary Dryers and the like. The preferable equipment used for drying is Fluid Bed Dryer.

Fluid bed dryer is designed to introduce the hot air stream at the base of the product container which is filled with the material. Fluidization causes agitation of solid particles and since each particle gets surrounded by hot air, heat transfer is extremely high and hence uniformity of temperature is maintained. The product is dried fast without appreciable loss of heat. The equipment also has filter bags which prevents particles escaping from the dryer.

The granules are transferred to Fluidized Bed Dryer and are air dried for about 10 minutes. Product temperature and inlet temperature is set to 45°C +/- 5°C. Drying is continued till desired moisture loss is achieved (LOD 1 .5% to 3% w/w.)

The use of fluidized bed dryer offers several advantages, including rapid heat and mass transfer, large capacity, and relatively low capital cost. Also, due to the continuous movements of product during drying, lump formation, case hardening etc. are minimized.

The dried granules are transferred into a vibratory sifter for sizing using a 30 mesh screen. Milling is done if required through a multimill with a 1 .0m screen at 750 +/- 250 RPM speed with knives forward. Lubrication is carried out with Magnesium stearate in a bin blender for 5 minutes at slow speed.

Compression is carried out using suitable tooling followed by coating using Opadry suspension.

Examples of pharmaceutically acceptable inert excipients include, but are not limited to diluents, disintegrants, lubricants, binders, solubilizers, solvents and plasticizers. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.

Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch (maize starch); microcrystalline cellulose such as products known under the registered trademarks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose (HPMC), ethyl cellulose, sodium carboxymethylcellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinylpyrrolidone, poly-N- vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth and other materials known to one ordinarily skilled in the art and mixtures thereof.

Low viscosity grades of Hydroxypropyl methyl cellulose are used as binders in order to facilitate granulation. They can thicken, bind and suspend particulates to form stable granules. A 2% solution of Hydroxypropyl methyl cellulose in water at 20°C produces a solution of 4- 6 mPa.S. Hydroxypropyl methyl cellulose is odorless and tasteless, white or creamy-white fibrous or granular powder.

Diluents, which include, but are not limited to confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate and other materials known to one ordinarily skilled in the art and mixtures thereof.

Lactose is widely used as a filler and diluent in tablets and capsules. Fine size of lactose monohydrate is used in granulation for tablet preparation as it allows better mixing. Lactose occurs as white to off-white crystalline particles or powder in various polymorphic forms. Lactose is odorless and slightly sweet- tasting.

Microcrystalline cellulose is also used as a diluent. It is purified, partially depolymerized cellulose that occurs as a white, odorless, tasteless, crystalline powder composed of porous particles. Microcrystalline cellulose has a nominal mean particle size ranging from 20 to 200 μιη. Preferable nominal mean particle size is 50 μιη.

Solubilizers may be selected from sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate, sulphosuccinates such as sodium dioctyl sulphosuccinate, partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, partial fatty acid esters of sorbitan such as sorbitan monolaurate, partial fatty acid esters of polyhydroxyethylenesorbitan such as polyethylene glycol sorbitan monolaurate, monostearate or monooleate, polyhydroxyethylene fatty alcohol ethers, polyhydroxyethylene fatty acid esters, ethylene oxide-propylene oxide block copolymers (Pluronic®) or ethoxylated triglycerides.

Sodium lauryl sulfate is a mixture of sodium alkyl sulfates consisting chiefly of sodium lauryl sulfate. It consists of white or cream to pale yellow colored crystals, flakes, or powder having a smooth feel, a soapy, bitter taste, and a faint odor of fatty substances.

Lubricants may be selected from, but are not limited to, those conventionally known in the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, talc and other materials known to one ordinarily skilled in the art and mixtures thereof.

Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one ordinarily skilled in the art and mixtures thereof.

Solvents include, but are not limited to purified water, acetone, ethyl alcohol, isopropyl alcohol, dichloromethane and other materials known to one ordinarily skilled in the art and mixtures thereof.

Disintegrants include, but are not limited to maize starch, potato starch, pre- gelatinized and modified starches, microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polacrillin potassium, croscarmellose sodium, sodium starch glycolate, carboxymethyl cellulose calcium and other materials known to one ordinarily skilled in the art and mixtures thereof.

In an aspect of the embodiment, the weight ratio of Rivaroxaban to pharmaceutically acceptable inert excipients is 1 :0.1 to 1 :25. Specifically, the weight ratio of Rivaroxaban to pharmaceutically acceptable inert excipients is 1 :0.1 or 1 : 0.5 or 1 :1 or 1 :2 or 1 :4 or 1 :5 or 1 :7 or 1 :7.5 or 1 :9 or 1 :10 or 1 :15 or 1 :20 or 1 :25.

It should be appreciated that there is considerable overlap between the above- listed excipients in common usage, since a given excipient is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed excipients should be taken as merely exemplary, and not limiting, of the types of excipients that can be included in compositions of the present invention. One or more of these excipients can be selected and used by the skilled artisan having regard to the particular desired properties of the dosage form by routine experimentation without any undue burden.

The amount of each type of excipients employed may vary within ranges conventional in the art.

In yet another aspect of the embodiment the granulation is non-aqueous granulation. Although water is the most commonly used solvent for non aqueous granulation, the process of aqueous granulation takes a long time and is labor intensive. Hence, the use of non-aqueous solvents like alcohols, dichloromethane, dimethyl sulfoxide, glycerin, propylene glycol, polyethylene glycol 400, hydrocarbons or glyceryl esters can be employed. Preferably alcohols and/or dichloromethane are used. Most preferably Isopropyl Alcohol and dichloromethane are used.

In yet another aspect of the embodiment Rivaroxaban is employed in crystalline form. Various polymorphic forms of Rivaroxaban are disclosed in WO2007039132 like Form I, II, III crystalline forms. APO- A is also another known polymorphic form disclosed in WO2010075631 .

In yet another aspect of the embodiment Rivaroxaban is in micronized form. In yet another aspect of the embodiment 90% by volume of Rivaroxaban particles have a particle size less than 15 μιη.

Particle size can affect the solubility properties of a compound. Particle size reduction is one of the methods to overcome the solubility issue of poorly soluble APIs like Rivaroxaban. Particle size reduction can also improve the dissolution rate, and hence, its bioavailability. The enhanced dissolution rate is achieved with the increase in the surface area as a result of particle size reduction. Sometimes the rate of dissolution of a poorly soluble drug is the rate limiting factor in its rate of absorption in the body. However, these drugs may be more readily bioavailable if administered in a finely divided state. Particle size may affect the flowability of the API which has consequences in the production process.

Coating may be performed by applying the coating composition as a solution/suspension/blend using any conventional coating technique known in the art, such as spray coating in a conventional coating pan. The coating may be functional or non-functional.

The foregoing examples are illustrative embodiments and are merely exemplary. A person skilled in the art may make variations and modifications without deviating from the spirit and scope of the invention. All such modifications and variations are intended to be included within the scope of the claims.

Example 1 : Pharmaceutical composition comprising Rivaroxaban

Manufacturing Process:

1 ) Binder Preparation:

(a) Hypromellose was dissolved in solvent mixture of Isopropyl Alcohol and Dichloromethane added under continuous stirring to form a clear solution.

(b) Sodium Lauryl Sulfate was added to this solvent mixture. 2) Dry Mixing:

(a) Microcrystalline Cellulose, Lactose Monohydrate, Croscarmellose Sodium and Rivaroxaban were sifted through suitable sieves and loaded into high shear mixer Granulator.

(b) The material in step (a) was thoroughly mixed until required.

3) Granulation & drying:

(a) Solution prepared in step 1 (b) was sprayed on the materials loaded in high shear Mixer Granulator in step 2.

(b) The granules thus obtained were dried in a Fluid Bed Processor and screened and sifted as required.

4) Lubrication & Compression:

Granules obtained in step 3 were lubricated with magnesium stearate & the mixture was compressed.

5) Coating:

Tablets obtained in step 4 were coated using suitable Opadry.

Claims

We Claim:

1 . A process for preparing an oral pharmaceutical composition of Rivaroxaban in non-hydrophllized form, wherein the process comprises the steps of:

a) dry mixing Rivaroxaban with pharmaceutically acceptable inert excipients to form a dry-mix;

b) granulating the dry mix in step (a) in rapid mixer granulator to form granules;

c) drying the granules formed in step (b) in fluidized bed dryer.

2. The process according to claim 1 , wherein the weight ratio of Rivaroxaban to pharmaceutically acceptable inert excipients is 0.1 to 0.5.

3. The process according to claim 1 , wherein the pharmaceutically acceptable inert excipients comprise diluents, disintegrants, binders and solubilizers, lubricants.

4. The process according to claim 1 , wherein the granulation is non-aqueous granulation.

5. The process according to claim 1 , wherein Rivaroxaban is employed in crystalline form.

6. The process according to claim 1 , wherein Rivaroxaban is in micronized form.

7. The process according to claim 1 , wherein 90% by volume of Rivaroxaban particles have a particle size less than 15 μιη.

8. The process according to claim 1 , further comprising the steps of compressing into suitable dosage form and optionally coating the same.