WO2015124995A1 - Solid dosage forms of rivaroxaban - Google Patents

Solid dosage forms of rivaroxaban Download PDF

Info

Publication number
WO2015124995A1
WO2015124995A1 PCT/IB2015/000196 IB2015000196W WO2015124995A1 WO 2015124995 A1 WO2015124995 A1 WO 2015124995A1 IB 2015000196 W IB2015000196 W IB 2015000196W WO 2015124995 A1 WO2015124995 A1 WO 2015124995A1
Authority
WO
WIPO (PCT)
Prior art keywords
rivaroxaban
dosage form
solution
granules
iii
Prior art date
Application number
PCT/IB2015/000196
Other languages
French (fr)
Inventor
Saravanan Kannusamy
Venkata Vijaya Narasimha Kishan JAYANTHY
Taqiuddin Aman MOHAMMED
Jayant KARAJGI
Sivakumaran Meenakshisunderam
Original Assignee
Aurobindo Pharma Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aurobindo Pharma Ltd filed Critical Aurobindo Pharma Ltd
Publication of WO2015124995A1 publication Critical patent/WO2015124995A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a process for preparing solid dosage form of oxazolidinone derivative compound. More particularly, the present invention relates to a process for preparing solid dosage form of rivaroxaban.
  • Oral solid composition of oxazolidinone derivative compound are used for the prophylaxis, secondary prophylaxis and/or treating thromboembolic disorders.
  • Rivaroxaban is a oxazolidinone derivative compound, chemically known as 5-Chloro-N-( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]- l ,3- oxazo-lidin-5-yl ⁇ methyl)-2-thiophenecarboxamide and is disclosed in US 7, 157,456, US 7,585,860 and US 7,592,339.
  • Rivaroxaban is soluble in organic solvents (e.g., acetone, polyethylene glycol
  • XARELTO ® tablets are available coated tablets containing rivaroxaban as active ingredients and lactose monohydrate, croscarmellose sodium, hypromellose, microcrystalline cellulose, magnesium stearate, sodium lauryl sulfate, polyethylene glycol, titanium dioxide, ferric oxide red, polyvinyl alcohol and talc as inactive ingredients.
  • the pharmaceutical industry employs various methods for compounding pharmaceutical agents in tablet formulations. In particular granulation is one of the most prevalent methods.
  • Granulation is a process whereby granules are formed from a bulk drug substance with or without excipients to improve the properties of the bulk drug or formulation.
  • Granules are preparations consisting of solid, dry agglomerates of powder particles sufficiently robust to withstand handling.
  • Wet granulation is distinguished from dry granulation in that a granulating liquid, such as water, organic liquids or mixtures thereof, are used in wet granulation to produce granules.
  • the advantages of wet granulation include improvement of the cohesiveness and compatibility of powders, increase in density and good distribution providing uniform content of micronized or finely milled low-dosage drugs, reduction of dust and airborne contamination, and prevention of segregation of components.
  • US 7, 767,702 discloses combination comprising rivaroxaban and platelet aggregation inhibitor such as, for example, aspirin, ticlopidin (Ticlid), clopidogrel (Plavix); fibrinogen receptor antagonists.
  • platelet aggregation inhibitor such as, for example, aspirin, ticlopidin (Ticlid), clopidogrel (Plavix); fibrinogen receptor antagonists.
  • US 8,586,082 discloses solid pharmaceutical dosage forms of rivaroxaban in multiparticulate form, which can be prepared by melting the active agent with one or more excipients.
  • US 2008/0026057 disclose process for the preparation of a solid, orally administrable pharmaceutical composition comprising rivaroxaban in hydrophilized form, in which (a) first granules comprising the active compound (1) in hydrophilized form are prepared by moist granulation (b) and the granules are then converted into the pharmaceutical composition, if appropriate with addition of pharmaceutically suitable additives.
  • US 201 1/0189279 discloses composition comprising rivaroxaban, solubilizer, pseudo-emulsifier (natural gum), non-erodible polymer and pore-forming substance. US '279 further discloses modified release composition comprising pellet core coating with solution or suspension onto the pellet core and optionally blending the pellets with further excipients, compressing the resulting mixture into tablets. US 2012/0231076 discloses process of preaparing immediate release composition comprising rivaroxaban prepared by melt-granulation. The process for producing tablets comprising rivaroxaban and excipients, melting the mixture the mixture, granulating the melted mixture and compressing the mixture into tablets.
  • US 2013/0064888 discloses a pharmaceutical dosage form in the form of a tablet comprising: (a) a compressed inert core (b) an optional subcoat over the compressed inert core (c) a drug layer over the compressed core (a) or optional subcoat (b) comprising a drug having a water solubility at 25 °C of about 100 mg/1 or less, a coating polymer and optionally a surfactant, and (d) optionally one or more layers coating the drug layer.
  • US 2013/0281457 discloses pharmaceutical compositions of rivaroxaban comprising a solubilizer and a pseudo-emulsifier as excipients.
  • the solubilizer can be a surfactant
  • the pseudo-emulsifier is a natural product, such as a natural gum.
  • US '457 further discloses that the compositions can be prepared by dry granulation, by pellet layering to form a multiparticulate, by melting followed by grinding, or by co- precipitation with an antisolvent. These processes are said to form primary pharmaceutical compositions in the form of granules which are then further processed into a dosage form by mixing with further excipients and compressing to provide tablets.
  • WO 2010/146179 discloses solid pharmaceutical compositions of rivaroxaban, prepared by dry mixing or dry granulation of the rivaroxaban with at least one excipient, co-milling rivaroxaban with the excipients, hot melt granulation with a molten excipient, or hot melt extrusion with an excipient.
  • the mixture may then be agglomerated, granulated with a granulation liquid, or milled before compressing to form a tablet.
  • melt processing is not a particularly desirable procedure as it restricts the excipients that can be used and further entails operation at suitably high temperatures to enable the production of a melt.
  • This increases the risk of drug decomposition and polymorphic changes, as well as drug-excipient reactions, potentially leading to the presence of decomposition products in the final dosage form.
  • the above prior art references discloses different process for the preparation of solid oral dosage form of rivaroxaban.
  • the inventors of the present invention have endeavored to develop simple, cost effective alternate process which is more advantageous by means of comparable dissolution and bioavailability with respect to the marketed formulation of Xarelto® tablets.
  • the main objective of the present invention is to provide oral solid dosage form of rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.
  • Yet another, objective of the present invention is to provide oral solid dosage form of rivaroxaban in such a way that the dosage forms will comply with the reference product in terms of in terms of in vivo parameters like C max , T max and AUC and in vitro parameters like content uniformity, dissolution, disintegration and etc.
  • One embodiment of the present invention relates to oral solid composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, wherein the ratio of rivaroxaban to excipient is in the range of 1 :2 to 1 :8.
  • another embodiment of the present invention relates to oral solid composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, binder and one or more pharmaceutically acceptable excipients, wherein the percentage of binder is less than 1.0% by weight.
  • oral solid composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, binder and one or more pharmaceutically acceptable excipients, wherein the percentage of binder is more than 15.0% by weight.
  • step (iii) granulating the blend of step (i) with the solution of step (ii).
  • the present invention provides a process for preparing oral solid dosage form of rivaroxaban comprising the steps of:
  • step (iii) spraying the solution or suspension of step (ii) onto the compressed core of step (i).
  • One embodiment of the present . invention relates to oral solid composition
  • rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients wherein the ratio of rivaroxaban to excipient is in the range of 1 :2 to 1 :8.
  • the composition according to the invention comprises rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts thereof, as active ingredient.
  • rivaroxaban can be used in any crystalline, partly crystalline, amorphous form or modification form.
  • the active ingredient (a) of the pharmaceutical composition of the present invention has a volume mean particle size (D50) of 0.1 to 10 ⁇ , more preferably of 0.5 to 5 ⁇ , still more preferably of 1.0 to 4 ⁇ .
  • the D90 value of the volume mean particle size distribution is from 1 to 15 ⁇ , preferably from 2 to 10 ⁇ , more preferably from 3 to 8 ⁇ .
  • the D10 value of the volume mean particle size distribution is from 0.01 to 5 ⁇ , preferably from 0.1 to 2.0 ⁇ , more preferably from 0.5 to 1.0 ⁇ .
  • pharmaceutically acceptable excipient refers to additives useful for converting pharmacologically active compounds into pharmaceutical dosage forms which are suitable for administration to patients. Suitable excipients include diluents, binders, disintegrants , surfactants, lubricants, glidants and coloring agents. Other pharmaceutically acceptable excipients can also be included. In another embodiment the solid matrix may contain one or more excipients selected from diluents, binders, surfactant, disintegrants, lubricants and pH adjusting agent.
  • Suitable "diluents" used according to the present invention are selected from water soluble or water insoluble or combination thereof.
  • Suitable water soluble diluents include sucrose, dextrose, lactose, mannitol, sorbitol and the like and water insoluble diluents include starch, microcrystalline cellulose, silicified microcrystalline cellulose, calcium silicate and the like or combination thereof.
  • the amount of diluent may range from about 20% to 95% by weight.
  • Suitable binders used according to the present invention are selected from the group comprising of hydroxypropylmethylcellulose, maize starch, povidone, hydroxypropylcellulose, pregelatinized starch and the like or combination thereof.
  • the amount of binder may range from about 0% to 22% by weight. In one embodiment the percentage of binder is less than 1% or greater than 17% by weight of the composition.
  • Suitable surfactants are selected from Tyloxapol , Triton X- 100 , polysorbates, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearates, sorbitan monolaureates, sodium lauryl sulphate, polyethylene-propylene glycol copolymer (poloxamer), cremophor-40, propylene glycol and mixtures thereof.
  • the amount of surfactant may range from about 0.00 to 10.0% by weight.
  • Suitable disintegrants used according to the present invention are selected from starch, crospovidone, sodium starch glycolate, croscarmellose sodium and the like or combination thereof.
  • the amount of disintegrant may range from about 1 % to 10% by weight.
  • Suitable lubricants used according to the present invention are selected from magnesium stearate, hydrogenated castor oil, calcium stearate, sodium stearyl fumarate, talc, vegetable oils, stearic acid, fumaric acid and the like.
  • Suitable film coating polymers used according to the present invention are selected from povidone, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol and the like or mixtures thereof.
  • the amount of polymer may range from about 0.001 to 5.0 w/v%.
  • Suitable anti-sticking agents used according to the present invention are selected from talc, magnesium stearate and the like or a mixture thereof.
  • the amount of polymer may range from about 0.001 to 3.0 w/v%.
  • the composition is prepared either by moist granulation or direct compression.
  • oral solid composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, binder selected from hydroxypropylmethylcellulose, maize starch, povidone, hydroxypropylcellulose, pregelatinized starch and one or more pharmaceutically acceptable excipients, wherein the percentage of binder is less than 1.0% by weight.
  • oral solid composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, binder selected from hydroxypropylmethylcellulose, maize starch, povidone, hydroxypropylcellulose, pregelatinized starch and one or more pharmaceutically acceptable excipients, wherein the percentage of binder is more than 15.0% by weight.
  • the present invention provides a process for preparing oral solid dosage form of rivaroxaban comprising the steps of:
  • step (iii) granulating the blend of step (i) with the solution of step (ii),
  • step (iv) blending the granules of step (iii) with one or more extragranular excipients
  • step (v) formulating the blend obtained in step (iv) into solid dosage form.
  • the present invention also provides a process for preparing oral solid dosage form of rivaroxaban comprising the steps of:
  • step (iii) granulating the blend of step (i) with the solution of step (ii),
  • step (iv) blending the granules of step (iii) with one or more extragranular excipients selected from diluent, disintegrant and lubricant.
  • step (v) formulating the blend obtained in step (iv) into solid dosage form.
  • the present invention provides a process for preparing oral solid dosage form of rivaroxaban comprising the steps of:
  • excipients comprising about 20% to about 95% of diluents selected from sucrose, dextrose, lactose, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, calcium silicate; about 1 % to about 10% of disintegrant selected from croscarmellose sodium, sodium starch glycolate, crospovidone in rapid mixer granulator and optionally rivaroxaban,
  • step (iii) granulating the blend of step (i) with the solution of step (ii), (iv) blending the granules of step (iii) with one or more extragranular excipients comprising about 20% to about 95% of diluent, about 0.01% to 10% of disintegrant, and about 0.001% to 5% of lubricant,
  • step (v) formulating the blend obtained in step (iv) into solid dosage form.
  • the present invention provides a process for preparing oral solid dosage form of rivaroxaban comprising the steps of:
  • step (iii) spraying the solution or suspension of step (ii) onto the compressed core of step (i).
  • the present invention provides preparing oral solid dosage form of rivaroxaban comprising the steps of:
  • a compressed core comprising rivoroxaban and one or more pharmaceutically acceptable excipients comprising about 20% to about 95% of diluent, about 0% to about
  • step (iii) spraying the solution or suspension of step (ii) onto the compressed core of step (i).
  • the present invention provides preparing oral solid dosage form of rivaroxaban comprising the steps of:
  • step-iii prepare separate solution of 0.20% to about 2.00% hypromellose with purified water, add this solution to step-ii) and homogenized.
  • step-iv formulating the granules of step-i) blend using the solution of step-iii) and the wet mass was dried in fluidized bed drier, mill the oversized granules and sifted, (v) the granules of step-iv were then lubricated with 0.10% to about 2.50% magnesium stearate and compressed into tablets.
  • the present invention provides a process for producing a pharmaceutical composition, comprising the steps of
  • a compressed core comprising rivaroxaban and one or more pharmaceutically acceptable excipients comprising about 20% to about 95% of diluent selected from one or more of sucrose, dextrose, lactose, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, calcium silicate, about 0% to about 10% of binder selected from hydroxypropylmethylcellulose, maize starch, povidone, hydroxypropylcellulose, pregelatinized starch; about 0.01% to about 10% of disintegrant selected from starch, crospovidone, sodium starch glycolate, croscarmellose sodium; about 0.001 % to about 5% of lubricant selected from magnesium stearate, hydrogenated castor oil, calcium stearate, sodium stearyl fumarate, talc and 0% to about 10% of surfactant selected from Tyloxapol ® , Triton X-100 ® , polysorbates, polyoxyl 35
  • step (iii) spraying the solution or suspension of step (ii) onto the compressed core of step (i).
  • the compressed core is prepared either by direct compression or by granulation.
  • the solvents used according to present invention may be selected from isopropyl alcohol, methanol, ethanol, water, acetone, methylene chloride and the like or mixtures thereof.
  • the solid dosage forms include tablets and capsules.
  • the tablets may be uncoated or optionally coated.
  • film coating composition comprises a solution / suspension of film coating polymers and one or more excipients such as lactose, titanium dioxide, solubilizing agent and antisticking agent.
  • Suitable film coating polymers used according to the present invention are selected from ethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose and the like or mixtures thereof.
  • Suitable anti-sticking agents used according to the present invention are selected from talc, magnesium stearate and the like or a mixture thereof.
  • solvent may be water or organic solvent.
  • solvent may be water or organic solvent.
  • step (iii) the blend of step (a) was granulated using the solution of step (b) and the wet mass was dried, milled and sifted, (iv) granules of step (iii) were blended with microcrystalline cellulose/ lactose, and croscarmellose sodium,
  • step (v) the granules of step (iv) was then lubricated with magnesium stearate and was compressed into tablets,
  • solvent may be water or organic solvent
  • lactose, microcrystalline cellulose and croscarmellose sodium were sifted and blended in rapid mixer granulator, (ii) hydroxypropylcellulose/ hydroxypropylmethyl cellulose/povidone, sodium lauryl sulfate, lactose/ mannitol were dissolved in a solvent,
  • step (iii) the blend of step (a) was granulated using the solution of step (b) and the wet mass was dried, milled and sifted,
  • step (iv) granules of step (iii) were blended with microcrystalline cellulose/ lactose, and croscarmellose sodium,
  • step (v) the blend of step (iv) was then lubricated with magnesium stearate and was compressed into tablets,
  • solvent may be water or organic solvent
  • step (iii) the blend of step (i) was granulated using the solution of step (ii) and the wet mass was dried, milled and sifted,
  • step (iv) granules of step (iii) were blended with microcrystalline cellulose/ lactose, and croscarmellose sodium,
  • step (v) the granules of step (iv) was then lubricated with magnesium stearate and was compressed into tablets,
  • step (vi) the compressed tablets obtained in step (v) were then coated with coating dispersion.
  • step (iii) blend of step (i) and step (ii) were mixed in geometrical proportions
  • step (iv) blend of step (iii) was then lubricated with magnesium stearate and compressed to tablet,
  • step (vi) the tablets of step (iv) was coated using the solution of step (v) and then dried,
  • step (iii) the blend of step (a) was granulated using the solution of step (b) and the wet mass was dried, milled and sifted,
  • step (iv) granules of step (iii) were blended with microcrystalline cellulose/ lactose, and croscarmellose sodium,
  • step (v) the granules of step (iv) was then lubricated with magnesium stearate and was compressed into tablets,
  • step (vii) the tablets of step (v) was coated using the solution of step (vi) and then dried,
  • step-iii granulate the step-i blend using the solution of step-iii and the wet mass was dried in fluidized bed drier, mill the oversized granules and sifted,
  • Example-7 the granules of step-iv was then lubricated with magnesium stearate and was compressed into tablets.
  • step-iv granulate the step-i blend using the solution of step-iii and the wet mass was dried in fluidized bed drier, mill the oversized granules and sifted, (v) the granules of step-iv was then lubricated with magnesium stearate and was compressed into tablets.
  • Example-8 Example-8, Example-8a, Example-8b, Example-8c, Example-8d & Example-8e
  • step-iii granulate the step-i blend using the solution of step-iii and the wet mass was dried in fluidized bed drier, mill the oversized granules and sifted,
  • step-iv the granules of step-iv was then lubricated with magnesium stearate and was compressed into tablets.

Abstract

Process for preparing solid dosage form of oxazolidinone derivative compound is provided. More particularly, the present invention relates to a process for preparing solid dosage form of rivaroxaban.

Description

SOLID DOSAGE FORMS OF RIVAROXABAN
FIELD OF THE INVENTION
The present invention relates to a process for preparing solid dosage form of oxazolidinone derivative compound. More particularly, the present invention relates to a process for preparing solid dosage form of rivaroxaban.
BACKGROUND OF THE INVENTION
Oral solid composition of oxazolidinone derivative compound are used for the prophylaxis, secondary prophylaxis and/or treating thromboembolic disorders.
Oral solid composition of oxazolidinone derivative compound, rivaroxaban, was approved under the trade name XARELTO® in the United States for the treatment of thromboembolic disorders. Rivaroxaban is a oxazolidinone derivative compound, chemically known as 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]- l ,3- oxazo-lidin-5-yl}methyl)-2-thiophenecarboxamide and is disclosed in US 7, 157,456, US 7,585,860 and US 7,592,339.
Rivaroxaban is soluble in organic solvents (e.g., acetone, polyethylene glycol
400) and is practically insoluble in water and aqueous media. Commercially XARELTO® tablets are available coated tablets containing rivaroxaban as active ingredients and lactose monohydrate, croscarmellose sodium, hypromellose, microcrystalline cellulose, magnesium stearate, sodium lauryl sulfate, polyethylene glycol, titanium dioxide, ferric oxide red, polyvinyl alcohol and talc as inactive ingredients. The pharmaceutical industry employs various methods for compounding pharmaceutical agents in tablet formulations. In particular granulation is one of the most prevalent methods.
Granulation is a process whereby granules are formed from a bulk drug substance with or without excipients to improve the properties of the bulk drug or formulation. Granules are preparations consisting of solid, dry agglomerates of powder particles sufficiently robust to withstand handling. Wet granulation is distinguished from dry granulation in that a granulating liquid, such as water, organic liquids or mixtures thereof, are used in wet granulation to produce granules. The advantages of wet granulation include improvement of the cohesiveness and compatibility of powders, increase in density and good distribution providing uniform content of micronized or finely milled low-dosage drugs, reduction of dust and airborne contamination, and prevention of segregation of components. US 7, 767,702 discloses combination comprising rivaroxaban and platelet aggregation inhibitor such as, for example, aspirin, ticlopidin (Ticlid), clopidogrel (Plavix); fibrinogen receptor antagonists. US 8,586,082 discloses solid pharmaceutical dosage forms of rivaroxaban in multiparticulate form, which can be prepared by melting the active agent with one or more excipients.
US 2008/0026057 disclose process for the preparation of a solid, orally administrable pharmaceutical composition comprising rivaroxaban in hydrophilized form, in which (a) first granules comprising the active compound (1) in hydrophilized form are prepared by moist granulation (b) and the granules are then converted into the pharmaceutical composition, if appropriate with addition of pharmaceutically suitable additives. US Ό57 further discloses the moist granulation in process step (a) can be carried out in a mixer (=mixer granulation) or in a fluidized bed (=fluidized bed granulation); fluidized bed granulation is preferred. During the prosecution of the said application, the applicant had stated that the tablet produced by a fluidized bed granulation process showed superior bioavailability as compared to a tablet produced by direct tableting, while tablets produced via mixer granulation showed no significant difference in bioavailability as compared to a tablet produced by direct tableting.
US 201 1/0189279 discloses composition comprising rivaroxaban, solubilizer, pseudo-emulsifier (natural gum), non-erodible polymer and pore-forming substance. US '279 further discloses modified release composition comprising pellet core coating with solution or suspension onto the pellet core and optionally blending the pellets with further excipients, compressing the resulting mixture into tablets. US 2012/0231076 discloses process of preaparing immediate release composition comprising rivaroxaban prepared by melt-granulation. The process for producing tablets comprising rivaroxaban and excipients, melting the mixture the mixture, granulating the melted mixture and compressing the mixture into tablets. US 2013/0064888 discloses a pharmaceutical dosage form in the form of a tablet comprising: (a) a compressed inert core (b) an optional subcoat over the compressed inert core (c) a drug layer over the compressed core (a) or optional subcoat (b) comprising a drug having a water solubility at 25 °C of about 100 mg/1 or less, a coating polymer and optionally a surfactant, and (d) optionally one or more layers coating the drug layer. US 2013/0281457 discloses pharmaceutical compositions of rivaroxaban comprising a solubilizer and a pseudo-emulsifier as excipients. The solubilizer can be a surfactant, and the pseudo-emulsifier is a natural product, such as a natural gum. US '457 further discloses that the compositions can be prepared by dry granulation, by pellet layering to form a multiparticulate, by melting followed by grinding, or by co- precipitation with an antisolvent. These processes are said to form primary pharmaceutical compositions in the form of granules which are then further processed into a dosage form by mixing with further excipients and compressing to provide tablets.
WO 2010/146179 discloses solid pharmaceutical compositions of rivaroxaban, prepared by dry mixing or dry granulation of the rivaroxaban with at least one excipient, co-milling rivaroxaban with the excipients, hot melt granulation with a molten excipient, or hot melt extrusion with an excipient. The mixture may then be agglomerated, granulated with a granulation liquid, or milled before compressing to form a tablet.
However, melt processing is not a particularly desirable procedure as it restricts the excipients that can be used and further entails operation at suitably high temperatures to enable the production of a melt. This increases the risk of drug decomposition and polymorphic changes, as well as drug-excipient reactions, potentially leading to the presence of decomposition products in the final dosage form. The above prior art references discloses different process for the preparation of solid oral dosage form of rivaroxaban. However, the inventors of the present invention have endeavored to develop simple, cost effective alternate process which is more advantageous by means of comparable dissolution and bioavailability with respect to the marketed formulation of Xarelto® tablets.
OBJECTIVE OF THE INVENTION
Accordingly, the main objective of the present invention is to provide oral solid dosage form of rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.
Yet another, objective of the present invention is to provide oral solid dosage form of rivaroxaban in such a way that the dosage forms will comply with the reference product in terms of in terms of in vivo parameters like Cmax, Tmax and AUC and in vitro parameters like content uniformity, dissolution, disintegration and etc. SUMMARY OF THE INVENTION
One embodiment of the present invention relates to oral solid composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, wherein the ratio of rivaroxaban to excipient is in the range of 1 :2 to 1 :8. in another embodiment of the present invention relates to oral solid composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, binder and one or more pharmaceutically acceptable excipients, wherein the percentage of binder is less than 1.0% by weight.
In another embodiment of the present invention relates to oral solid composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, binder and one or more pharmaceutically acceptable excipients, wherein the percentage of binder is more than 15.0% by weight.
In another embodiment of the present invention provides a process for preparing oral solid dosage form of rivaroxaban comprising the steps of:
(i) blending one or more excipients , in rapid mixing granulator and optionally active agent,
(ii) preparing a solution comprising solvent, binder, surfactant and optionally active agent,
(iii) granulating the blend of step (i) with the solution of step (ii).
In another embodiment, the present invention provides a process for preparing oral solid dosage form of rivaroxaban comprising the steps of:
(i) a compressed core comprising rivoroxaban and one or more pharmaceutically acceptable excipients,
(ii) providing a solution or suspension comprising rivaroxaban and one or more pharmaceutically acceptable excipients,
(iii) spraying the solution or suspension of step (ii) onto the compressed core of step (i).
DETAILED DESCRIPTION OF THE INVENTION
One embodiment of the present . invention relates to oral solid composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, wherein the ratio of rivaroxaban to excipient is in the range of 1 :2 to 1 :8. In another embodiment the composition according to the invention comprises rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts thereof, as active ingredient. Generally, rivaroxaban can be used in any crystalline, partly crystalline, amorphous form or modification form.
In another embodiment rivaroxaban as the active ingredient (a) is employed in a micronized form. That means, the active ingredient (a) of the pharmaceutical composition of the present invention has a volume mean particle size (D50) of 0.1 to 10 μιη, more preferably of 0.5 to 5 μιτι, still more preferably of 1.0 to 4 μπι. Furthermore, the D90 value of the volume mean particle size distribution is from 1 to 15 μπι, preferably from 2 to 10 μηι, more preferably from 3 to 8 μιη. Furthermore, the D10 value of the volume mean particle size distribution is from 0.01 to 5 μιη, preferably from 0.1 to 2.0 μιη, more preferably from 0.5 to 1.0 μηι.
The term "pharmaceutical acceptable excipient" as used herein refers to additives useful for converting pharmacologically active compounds into pharmaceutical dosage forms which are suitable for administration to patients. Suitable excipients include diluents, binders, disintegrants , surfactants, lubricants, glidants and coloring agents. Other pharmaceutically acceptable excipients can also be included. In another embodiment the solid matrix may contain one or more excipients selected from diluents, binders, surfactant, disintegrants, lubricants and pH adjusting agent.
Suitable "diluents" used according to the present invention are selected from water soluble or water insoluble or combination thereof. Suitable water soluble diluents include sucrose, dextrose, lactose, mannitol, sorbitol and the like and water insoluble diluents include starch, microcrystalline cellulose, silicified microcrystalline cellulose, calcium silicate and the like or combination thereof. The amount of diluent may range from about 20% to 95% by weight. Suitable binders used according to the present invention are selected from the group comprising of hydroxypropylmethylcellulose, maize starch, povidone, hydroxypropylcellulose, pregelatinized starch and the like or combination thereof. The amount of binder may range from about 0% to 22% by weight. In one embodiment the percentage of binder is less than 1% or greater than 17% by weight of the composition. Suitable surfactants are selected from Tyloxapol , Triton X- 100 , polysorbates, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearates, sorbitan monolaureates, sodium lauryl sulphate, polyethylene-propylene glycol copolymer (poloxamer), cremophor-40, propylene glycol and mixtures thereof. The amount of surfactant may range from about 0.00 to 10.0% by weight.
Suitable disintegrants used according to the present invention are selected from starch, crospovidone, sodium starch glycolate, croscarmellose sodium and the like or combination thereof. The amount of disintegrant may range from about 1 % to 10% by weight. Suitable lubricants used according to the present invention are selected from magnesium stearate, hydrogenated castor oil, calcium stearate, sodium stearyl fumarate, talc, vegetable oils, stearic acid, fumaric acid and the like.
Suitable film coating polymers used according to the present invention are selected from povidone, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol and the like or mixtures thereof. The amount of polymer may range from about 0.001 to 5.0 w/v%.
Suitable anti-sticking agents used according to the present invention are selected from talc, magnesium stearate and the like or a mixture thereof. The amount of polymer may range from about 0.001 to 3.0 w/v%. In another embodiment, the composition is prepared either by moist granulation or direct compression.
In another embodiment of the present invention relates to oral solid composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, binder selected from hydroxypropylmethylcellulose, maize starch, povidone, hydroxypropylcellulose, pregelatinized starch and one or more pharmaceutically acceptable excipients, wherein the percentage of binder is less than 1.0% by weight.
In another embodiment of the present invention relates to oral solid composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, binder selected from hydroxypropylmethylcellulose, maize starch, povidone, hydroxypropylcellulose, pregelatinized starch and one or more pharmaceutically acceptable excipients, wherein the percentage of binder is more than 15.0% by weight.
In another embodiment, the present invention provides a process for preparing oral solid dosage form of rivaroxaban comprising the steps of:
(i) mixing one or more excipients in rapid mixer granulator and optionally rivaroxaban, (ii) preparing a solution comprising solvent, binder, surfactant and optionally rivaroxaban,
(iii) granulating the blend of step (i) with the solution of step (ii),
(iv) blending the granules of step (iii) with one or more extragranular excipients,
(v) formulating the blend obtained in step (iv) into solid dosage form.
In another embodiment, the present invention also provides a process for preparing oral solid dosage form of rivaroxaban comprising the steps of:
(i) mixing one or more excipients comprising about 20% to about 95% of diluents, about 1 % to about 10% of disintegrant, in rapid mixer granulator and optionally rivaroxaban, (ii) preparing a solution comprising solvent, about 0% to 22% of binder, about 0.00 to 10.0% of surfactant and optionally rivaroxaban,
(iii) granulating the blend of step (i) with the solution of step (ii),
(iv) blending the granules of step (iii) with one or more extragranular excipients selected from diluent, disintegrant and lubricant.
(v) formulating the blend obtained in step (iv) into solid dosage form.
In another embodiment, the present invention provides a process for preparing oral solid dosage form of rivaroxaban comprising the steps of:
(i) mixing one or more excipients comprising about 20% to about 95% of diluents selected from sucrose, dextrose, lactose, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, calcium silicate; about 1 % to about 10% of disintegrant selected from croscarmellose sodium, sodium starch glycolate, crospovidone in rapid mixer granulator and optionally rivaroxaban,
(ii) preparing a solution comprising solvent, 0% to about 22% of binder selected from hydroxypropylmethylcellulose, maize starch, povidone, hydroxypropylcellulose, pregelatinized starch, 0% to about 10% of surfactant selected from Tyloxapol®, Triton X- 100®, polysorbates, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearates, sorbitan monolaureates, sodium lauryl sulphate, polyethylene-propylene glycol copolymer (poloxamer), cremophor-40, propylene glycol and optionally rivaroxaban,
(iii) granulating the blend of step (i) with the solution of step (ii), (iv) blending the granules of step (iii) with one or more extragranular excipients comprising about 20% to about 95% of diluent, about 0.01% to 10% of disintegrant, and about 0.001% to 5% of lubricant,
(v) formulating the blend obtained in step (iv) into solid dosage form.
In another embodiment, the present invention provides a process for preparing oral solid dosage form of rivaroxaban comprising the steps of:
(i) a compressed core comprising rivoroxaban and one or more pharmaceutically acceptable excipients,
(ii) providing a solution or suspension comprising rivaroxaban and one or more pharmaceutically acceptable excipients,
(iii) spraying the solution or suspension of step (ii) onto the compressed core of step (i).
In another embodiment, the present invention provides preparing oral solid dosage form of rivaroxaban comprising the steps of:
(i) a compressed core comprising rivoroxaban and one or more pharmaceutically acceptable excipients comprising about 20% to about 95% of diluent, about 0% to about
10% of binder, about 0.01% to about 10% of disintegrant, about 0.001% to about 5% of lubricant and about 0% to about 10% of surfactant,
(ii) providing a solution or suspension comprising rivaroxaban and one or more pharmaceutically acceptable excipients comprising about 0.001% to about 5% of anti- sticking agents, about 0.001 % to about 5.00% of binder,
(iii) spraying the solution or suspension of step (ii) onto the compressed core of step (i).
In another embodiment, the present invention provides preparing oral solid dosage form of rivaroxaban comprising the steps of:
(i) blending 20.00% to about 40.00% w/w lactose, 33.50% to about 57.50% microcrystalline cellulose, 0.75% to about 3.00% croscarmellose sodium and 2.00% to about 7.00% hypromellose in rapid mixer granulator,
(ii) prepare binder solution using purified water, 0.02% to about 2.22% sodium lauryl sulfate and 0.00% to about 25.00% rivaroxaban stirred till dissolve completely,
(iii) prepare separate solution of 0.20% to about 2.00% hypromellose with purified water, add this solution to step-ii) and homogenized.
(iv) formulating the granules of step-i) blend using the solution of step-iii) and the wet mass was dried in fluidized bed drier, mill the oversized granules and sifted, (v) the granules of step-iv were then lubricated with 0.10% to about 2.50% magnesium stearate and compressed into tablets.
In another embodiment, the present invention provides a process for producing a pharmaceutical composition, comprising the steps of
(i) a compressed core comprising rivaroxaban and one or more pharmaceutically acceptable excipients comprising about 20% to about 95% of diluent selected from one or more of sucrose, dextrose, lactose, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, calcium silicate, about 0% to about 10% of binder selected from hydroxypropylmethylcellulose, maize starch, povidone, hydroxypropylcellulose, pregelatinized starch; about 0.01% to about 10% of disintegrant selected from starch, crospovidone, sodium starch glycolate, croscarmellose sodium; about 0.001 % to about 5% of lubricant selected from magnesium stearate, hydrogenated castor oil, calcium stearate, sodium stearyl fumarate, talc and 0% to about 10% of surfactant selected from Tyloxapol®, Triton X-100®, polysorbates, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearates, sorbitan monolaureates, sodium lauryl sulphate, polyethylene-propylene glycol copolymer (poloxamer), cremophor-40, propylene glycol,
(ii) providing a solution or suspension comprising rivaroxaban and one or more pharmaceutically acceptable excipients comprising about 0.001 % to about 5% of polyethylene glycol, about 0.001% to about 5% of anti-sticking agents selected from talc, magnesium stearate, about 0.001% to 5.00% of binder selected from hydroxypropylmethylcellulose, maize starch, povidone, hydroxypropylcellulose, pregelatinized starch,
(iii) spraying the solution or suspension of step (ii) onto the compressed core of step (i).
In another embodiment, the compressed core is prepared either by direct compression or by granulation.
In an embodiment of the present invention, the solvents used according to present invention may be selected from isopropyl alcohol, methanol, ethanol, water, acetone, methylene chloride and the like or mixtures thereof.
In another embodiment of the present invention, the solid dosage forms include tablets and capsules. The tablets may be uncoated or optionally coated. In yet another embodiment of the present invention, film coating composition comprises a solution / suspension of film coating polymers and one or more excipients such as lactose, titanium dioxide, solubilizing agent and antisticking agent.
Suitable film coating polymers used according to the present invention are selected from ethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose and the like or mixtures thereof.
Suitable anti-sticking agents used according to the present invention are selected from talc, magnesium stearate and the like or a mixture thereof.
The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.
Example-l(a)
Figure imgf000011_0001
* solvent may be water or organic solvent.
Example-l(b)
Figure imgf000012_0001
solvent may be water or organic solvent.
The processing steps involved in manufacturing of oral solid dosage form of rivaroxaban given in example 1 (a) & example 1 (b) are given below:
(i) rivaroxaban, lactose, microcrystalline cellulose and croscarmellose sodium were sifted and blended in rapid mixer granulator,
(ii) hydroxypropyl cellulose/ Hydroxypropylmethylcellulose and sodium lauryl were dissolved in a solvent, .
(iii) the blend of step (a) was granulated using the solution of step (b) and the wet mass was dried, milled and sifted, (iv) granules of step (iii) were blended with microcrystalline cellulose/ lactose, and croscarmellose sodium,
(v) the granules of step (iv) was then lubricated with magnesium stearate and was compressed into tablets,
(vi) the compressed tablets obtained in step (v) were then coated with coating dispersion. Example-2
Figure imgf000013_0001
* solvent may be water or organic solvent
The processing steps involved in manufacturing of oral solid dosage form of rivaroxaban given in example 2 are given below:
(i) lactose, microcrystalline cellulose and croscarmellose sodium were sifted and blended in rapid mixer granulator, (ii) hydroxypropylcellulose/ hydroxypropylmethyl cellulose/povidone, sodium lauryl sulfate, lactose/ mannitol were dissolved in a solvent,
(iii) the blend of step (a) was granulated using the solution of step (b) and the wet mass was dried, milled and sifted,
(iv) granules of step (iii) were blended with microcrystalline cellulose/ lactose, and croscarmellose sodium,
(v) the blend of step (iv) was then lubricated with magnesium stearate and was compressed into tablets,
(vi) the compressed tablets obtained in step (v) were then coated with coating dispersion. Example-3
Figure imgf000014_0001
* solvent may be water or organic solvent
The processing steps involved in manufacturing of oral solid dosage form of rivaroxaban given in example 3 are given below:
(i) rivaroxaban, lactose, microcrystalline cellulose and croscarmellose sodium were mixed in rapid mixer granulator,
(ii) hydroxypropylcellulose/ hydroxypropylmethyl cellulose/povidone, sodium lauryl sulfate, lactose/ mannitol and rivaroxaban were dissolved in a solvent,
(iii) the blend of step (i) was granulated using the solution of step (ii) and the wet mass was dried, milled and sifted,
(iv) granules of step (iii) were blended with microcrystalline cellulose/ lactose, and croscarmellose sodium,
(v) the granules of step (iv) was then lubricated with magnesium stearate and was compressed into tablets,
(vi) the compressed tablets obtained in step (v) were then coated with coating dispersion.
Exam lc-4
Figure imgf000015_0001
16 Talc 0.001 2.50
17 Titanium dioxide 0.001 2.50
18 Purified water QS QS
Coated Total weight 204.00 204.00
The processing steps involved in manufacturing of oral solid dosage form of rivaroxaban given in example 4 are given below:
(i) rivaroxaban and sodium lauryl sulfate were sifted and blended,
(ii) lactose, microcrystalline cellulose, croscarmellose sodium and Hydroxypropylcellulose/Hydroxypropylmethylcellulose were sifted ,
(iii) blend of step (i) and step (ii) were mixed in geometrical proportions,
(iv) blend of step (iii) was then lubricated with magnesium stearate and compressed to tablet,
(v) a solution of rivaroxaban, polyethylene glycol, Hydroxypropylcellulose/ Hydroxypropylmethylcellulose, sodium lauryl sulfate and talc in water was prepared,
(vi) the tablets of step (iv) was coated using the solution of step (v) and then dried,
(vii) coated tablets of step (vi) were then coated using the coating solution/dispersion. Example-5
Figure imgf000016_0001
cellulose
12 Hydroxypropylmethyl NA 5.00 5.00 0.001
cellulose
13 Polyethylene glycol 5.00 5.00 5.00 0.001
14 Talc 5.00 5.00 5.00. 0.001
Drug layered tablet weight 113.00 117.75 73.75 55.005
Film Coating
15 Polyvinyl alcohol 5.00 NA ■ NA NA
(partially hydrolyzed)
16 Hydroxypropyl methyl NA 5.00 5.00 0.001
cellulose
17 Polyethylene glycol 3.00 3.00 3.00 0.001
3350
18 Ferric oxide red 0.50 0.50 0.50 0.001
19 Talc 2.50 2.50 2.50 0.001
20 Titanium dioxide 2.50 2.50 2.50 0.001
21 Purified water QS QS QS QS
Coated Total weight 115.26 121.75 75.75 57.00
The processing steps involved in manufacturing of oral solid dosage form of rivaroxaban given in example 5 are given below:
(i) rivaroxaban, lactose, microcrystalline cellulose and croscarmellose sodium were sifted and blended in rapid mixer granulator,
(ii) hydroxypropyl cellulose/ hydroxypropylmethylcellulose and sodium lauryl were dissolved in a solvent,
(iii) the blend of step (a) was granulated using the solution of step (b) and the wet mass was dried, milled and sifted,
(iv) granules of step (iii) were blended with microcrystalline cellulose/ lactose, and croscarmellose sodium,
(v) the granules of step (iv) was then lubricated with magnesium stearate and was compressed into tablets,
(vi) a solution of rivaroxaban, polyethylene glycol, Hydroxypropylcellulose/Hydroxypropylmethylcellulose, sodium lauryl sulfate and talc in water was prepared,
(vii) the tablets of step (v) was coated using the solution of step (vi) and then dried,
(viii) coated tablets of step (vii) were then coated using the coating solution/dispersion. Example-6
Figure imgf000018_0001
The processing steps involved in manufacturing of oral solid dosage form of rivaroxaban given in example 6 are given below:
(i) lactose, microcrystalline cellulose, croscarmellose sodium and hypromellose were blended in rapid mixer granulator,
(ii) prepare binder solution using purified water, sodium lauryl sulfate and rivaroxaban stirred till dissolve completely.
(iii) prepare separate solution of hypromellose with purified water, add this solution to step-ii and homogenized.
(iv) granulate the step-i blend using the solution of step-iii and the wet mass was dried in fluidized bed drier, mill the oversized granules and sifted,
(v) the granules of step-iv was then lubricated with magnesium stearate and was compressed into tablets. Example-7, Example-7a, Example-7b, Example-7c, Example-7d & Example-7e
Figure imgf000019_0001
The processing steps involved in manufacturing of oral solid dosage form of rivaroxaban given in examples 7, 7a, 7b, 7c, 7d & 7e are given below:
(i) lactose, microcrystalline cellulose, croscarmellose sodium and hypromellose were blended in rapid mixer granulator,
(ii) prepare binder solution using purified water, sodium lauryl sulfate and rivaroxaban stirred till dissolve completely.
(iii) prepare separate solution of hypromellose with purified water, add this solution to step-ii and homogenized.
(iv) granulate the step-i blend using the solution of step-iii and the wet mass was dried in fluidized bed drier, mill the oversized granules and sifted, (v) the granules of step-iv was then lubricated with magnesium stearate and was compressed into tablets.
Example-8, Example-8a, Example-8b, Example-8c, Example-8d & Example-8e
Figure imgf000020_0001
The processing steps involved in manufacturing of oral solid dosage form of rivaroxaban given in example 8 are given below:
(i) lactose, microcrystalline cellulose, croscarmellose sodium and pregelatinized starch were blended in rapid mixer granulator,
(ii) prepare binder solution using purified water, sodium lauryl sulfate and rivaroxaban stirred till dissolve completely.
(iii) prepare separate solution of pregelatinized starch with purified water, add this solution to step-ii and homogenized.
(iv) granulate the step-i blend using the solution of step-iii and the wet mass was dried in fluidized bed drier, mill the oversized granules and sifted,
(v) the granules of step-iv was then lubricated with magnesium stearate and was compressed into tablets.

Claims

Claims
1. An oral solid dosage form comprising rivaroxaban and one or more pharmaceutically acceptable excipients, prepared by a process, comprising the steps of:
i) blending one or more pharmaceutically acceptable excipients,
ii) granulating the blend of step (i) using solvent, binder and rivaroxaban,
iii) the granules of step (ii) dried in drier and milled,
iv) blending the dried granules of step (iii) with one or more pharmaceutically acceptable excipients, and
v) formulating the blend obtained in step (iii) into solid dosage form.
2. The dosage form according to claim 1 , wherein one or more pharmaceutically acceptable excipients are selected from diluents, binders, disintegrants, glidants, lubricants, surfactants and combinations thereof.
3. The dosage form according to claim 2, wherein the diluent is selected from the group comprising of lactose, sucrose, dextrose, mannitol, sorbitol, xylitol, lactitol, starch, modified starches, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and combination thereof.
4. The dosage form according to claim 2, wherein the disintegrant is selected from the group comprising of low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, cross- linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose; sodium starch glycolate; ion- exchange resins; starch and modified starches including pregelatinized starch; formalin- casein; alginates, gums and combination thereof.
5. The dosage form according to claim 2, wherein the binder is selected from the group comprising of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose; starch and its derivatives, hydrocolloids; sugars; polyvinyl pyrrolidone, copovidone, methacrylic acid copolymers and combination thereof.
6. The dosage form according to claim 2, wherein the glidant is selected from the group comprising of talc, silicon dioxide, silicic acid, cornstarch, calcium silicate, magnesium carbonate, magnesium oxide, magnesium silicate, colloidal silicon dioxide, starch, castor wax and combination thereof.
7. The dosage form according to claim 2, wherein the lubricant is selected from the group comprising of calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric acid, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate, castor wax and combination thereof.
8. The dosage form according to claim 1 , wherein the solid dosage form is selected from tablet, film coated tablet or capsule.
9. An oral solid dosage form comprising rivaroxaban and one or more pharmaceutically acceptable excipients, prepared by a process according to claim 1 , comprising the steps of:
(i) blending lactose, microcrystalline cellulose, croscarmellose sodium and hypromellose in rapid mixer granulator,
(ii) prepare binder solution using purified water, sodium lauryl sulfate and rivaroxaban stirred till dissolve completely, wherein the percentage of binder is less than 1.0% by weight,
(iii) prepare separate solution of hypromellose with purified water, add this solution to step-ii and homogenized,
(iv) formulating the granules of step-i blend using the solution of step-iii and the wet mass was dried in fluidized bed drier, mill the oversized granules and sifted,
(v) the granules of step-iv was then lubricated with magnesium stearate and was compressed into tablets,
iv) compressed solid dosage form optionally coated with coating materials.
10. An oral solid dosage form comprising rivaroxaban and one or more pharmaceutically acceptable excipients, prepared by a process according to claim 9, comprising the steps of:
(i) blending 20.00% to about 40.00% w/w lactose, 33.50% to about 57.50% microcrystalline cellulose, 0.75% to about 3.00% croscarmellose sodium and 2.00% to about 7.00% hypromellose in rapid mixer granulator,
(ii) prepare binder solution using purified water, 0.02% to about 2.22% sodium lauryl sulfate and 0.00% to about 25.00% rivaroxaban stirred till dissolve completely, (iii) prepare separate solution of 0.20% to about 2.00% hypromellose with purified water, add this solution to step-ii and homogenized.
(iv) formulating the granules of step-i) blend using the solution of step-iii) and the wet mass was dried in fluidized bed drier, mill the oversized granules and sifted,
(v) the granules of step-iv were then lubricated with 0.10% to about 2.50% magnesium stearate and was compressed into tablets.
PCT/IB2015/000196 2014-02-19 2015-02-17 Solid dosage forms of rivaroxaban WO2015124995A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN785/CHE/2014 2014-02-19
IN785CH2014 2014-02-19

Publications (1)

Publication Number Publication Date
WO2015124995A1 true WO2015124995A1 (en) 2015-08-27

Family

ID=52808074

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2015/000196 WO2015124995A1 (en) 2014-02-19 2015-02-17 Solid dosage forms of rivaroxaban

Country Status (1)

Country Link
WO (1) WO2015124995A1 (en)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105267169A (en) * 2015-12-07 2016-01-27 石家庄康贺威药业有限公司 Rivaroxaban tablet and preparation method thereof
WO2017146709A1 (en) * 2016-02-25 2017-08-31 Mylan Inc. A unique high-shear granulation process for improved bioavailability of rivaroxaban
CN109157517A (en) * 2018-10-15 2019-01-08 吉林省中晟制药有限公司 A kind of razaxaban granule and preparation method
GR1009619B (en) * 2018-05-09 2019-10-23 Φαρμαζακ Α.Φ.Ε.Β.Ε. Pharmaceutical composition containing rivaroxaban and method for the preparation thereof
CN112451531A (en) * 2020-12-09 2021-03-09 乐普药业股份有限公司 Aspirin and rivaroxaban compound preparation and preparation method thereof
US20210267908A1 (en) * 2020-03-02 2021-09-02 Mankind Pharma Ltd. Pharmaceutical compositions of rivaroxaban
CN113425729A (en) * 2021-06-24 2021-09-24 上海奥全生物医药科技有限公司 Rivaroxaban-containing pharmaceutical composition and application thereof
WO2022049602A1 (en) * 2020-09-05 2022-03-10 Inventia Healthcare Limited Rivaroxaban compositions
CN114767647A (en) * 2022-03-22 2022-07-22 新发药业有限公司 Preparation method of rivaroxaban oral solid preparation
CN114886867A (en) * 2022-06-16 2022-08-12 北京四环制药有限公司 Rivaroxaban pharmaceutical composition with high stability and preparation method thereof
WO2022259118A1 (en) * 2021-06-10 2022-12-15 Shilpa Medicare Limited Fast dissolving oral film preparation comprising rivaroxaban
CN114767647B (en) * 2022-03-22 2024-04-16 新发药业有限公司 Preparation method of rivaroxaban oral solid preparation

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7157456B2 (en) 1999-12-24 2007-01-02 Bayer Healthcare Ag Substituted oxazolidinones and their use in the field of blood coagulation
US20070026065A1 (en) * 2004-12-24 2007-02-01 Bayer Healthcare Ag Solid, modified-release pharmaceutical dosage forms which can be administered orally
US20080026057A1 (en) 2003-11-27 2008-01-31 Bayer Healthcare Ag Process for the Preparation of a Solid, Orally Administrable Pharmaceutical Composition
US7767702B2 (en) 2001-06-20 2010-08-03 Bayer Schering Pharma Aktiengesellschaft Substituted oxazolidinones for combinational therapy
WO2010146179A2 (en) 2009-06-18 2010-12-23 Krka, Tovarna Zdravil, D.D., Novo Mesto Solid pharmaceutical composition comprising rivaroxaban
US20110189279A1 (en) 2008-08-11 2011-08-04 Ratiopharm Gmbh Pharmaceutical compositions with modified release properties comprising 5-chloro-n-(-methyl)-2-thiophencarboxamid
US20120231076A1 (en) 2009-10-06 2012-09-13 Ratiopharm Gmbh Pharmaceutical compositions comprising rivaroxaban
US20130064888A1 (en) 2011-08-08 2013-03-14 Roey Solomonovich Pharmaceutical formulations
US20130281457A1 (en) 2008-07-08 2013-10-24 Ratiopharm Gmbh Pharmaceutical compositions comprising 5-chloro-n-(-methyl)-2-thiophencarboxamid
US8586082B2 (en) 2005-10-04 2013-11-19 Bayer Intellectual Property Gmbh Solid orally administerable pharmaceutical dosage forms with rapid active principle release

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7157456B2 (en) 1999-12-24 2007-01-02 Bayer Healthcare Ag Substituted oxazolidinones and their use in the field of blood coagulation
US7585860B2 (en) 1999-12-24 2009-09-08 Bayer Schering Pharma Aktiengesellschaft Substituted oxazolidinones and their use in the field of blood coagulation
US7592339B2 (en) 1999-12-24 2009-09-22 Bayer Schering Pharma Aktiengesellschaft Substituted oxazolidinones and their use in the field of blood coagulation
US7767702B2 (en) 2001-06-20 2010-08-03 Bayer Schering Pharma Aktiengesellschaft Substituted oxazolidinones for combinational therapy
US20080026057A1 (en) 2003-11-27 2008-01-31 Bayer Healthcare Ag Process for the Preparation of a Solid, Orally Administrable Pharmaceutical Composition
US20070026065A1 (en) * 2004-12-24 2007-02-01 Bayer Healthcare Ag Solid, modified-release pharmaceutical dosage forms which can be administered orally
US8586082B2 (en) 2005-10-04 2013-11-19 Bayer Intellectual Property Gmbh Solid orally administerable pharmaceutical dosage forms with rapid active principle release
US20130281457A1 (en) 2008-07-08 2013-10-24 Ratiopharm Gmbh Pharmaceutical compositions comprising 5-chloro-n-(-methyl)-2-thiophencarboxamid
US20110189279A1 (en) 2008-08-11 2011-08-04 Ratiopharm Gmbh Pharmaceutical compositions with modified release properties comprising 5-chloro-n-(-methyl)-2-thiophencarboxamid
WO2010146179A2 (en) 2009-06-18 2010-12-23 Krka, Tovarna Zdravil, D.D., Novo Mesto Solid pharmaceutical composition comprising rivaroxaban
US20120231076A1 (en) 2009-10-06 2012-09-13 Ratiopharm Gmbh Pharmaceutical compositions comprising rivaroxaban
US20130064888A1 (en) 2011-08-08 2013-03-14 Roey Solomonovich Pharmaceutical formulations

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105267169A (en) * 2015-12-07 2016-01-27 石家庄康贺威药业有限公司 Rivaroxaban tablet and preparation method thereof
WO2017146709A1 (en) * 2016-02-25 2017-08-31 Mylan Inc. A unique high-shear granulation process for improved bioavailability of rivaroxaban
GR1009619B (en) * 2018-05-09 2019-10-23 Φαρμαζακ Α.Φ.Ε.Β.Ε. Pharmaceutical composition containing rivaroxaban and method for the preparation thereof
CN109157517A (en) * 2018-10-15 2019-01-08 吉林省中晟制药有限公司 A kind of razaxaban granule and preparation method
US20210267908A1 (en) * 2020-03-02 2021-09-02 Mankind Pharma Ltd. Pharmaceutical compositions of rivaroxaban
WO2022049602A1 (en) * 2020-09-05 2022-03-10 Inventia Healthcare Limited Rivaroxaban compositions
CN112451531A (en) * 2020-12-09 2021-03-09 乐普药业股份有限公司 Aspirin and rivaroxaban compound preparation and preparation method thereof
WO2022259118A1 (en) * 2021-06-10 2022-12-15 Shilpa Medicare Limited Fast dissolving oral film preparation comprising rivaroxaban
CN113425729A (en) * 2021-06-24 2021-09-24 上海奥全生物医药科技有限公司 Rivaroxaban-containing pharmaceutical composition and application thereof
CN114767647A (en) * 2022-03-22 2022-07-22 新发药业有限公司 Preparation method of rivaroxaban oral solid preparation
CN114767647B (en) * 2022-03-22 2024-04-16 新发药业有限公司 Preparation method of rivaroxaban oral solid preparation
CN114886867A (en) * 2022-06-16 2022-08-12 北京四环制药有限公司 Rivaroxaban pharmaceutical composition with high stability and preparation method thereof

Similar Documents

Publication Publication Date Title
WO2015124995A1 (en) Solid dosage forms of rivaroxaban
KR101156916B1 (en) Pharmaceutical compositions comprising imatinib and a release retardant
JP5833037B2 (en) Bilayer tablet containing telmisartan and diuretic
CA2940984A1 (en) Solid pharmaceutical compositions of androgen receptor antagonists
WO2017170858A1 (en) Oral preparation having exceptional elutability
CN106232144B (en) Solid dispersion
WO2011042156A1 (en) Pharmaceutical compositions comprising rivaroxaban
US20140319720A1 (en) Pharmaceutical compositions comprising rivaroxaban
US20150246053A1 (en) Solid oral compositions of tolvaptan
AU2013366512B2 (en) Solid unit with high fexofenadine content and process for the preparation thereof
EP2701689B1 (en) Pharmaceutical compositions of raltegravir, methods of preparation and use thereof
EP2440191A2 (en) A thrombin receptor antagonist and clopidogrel fixed dose tablet
US11260055B2 (en) Oral pharmaceutical composition of lurasidone and preparation thereof
EP2672959A1 (en) Granulated composition comprising tadalafil and a disintegrant
US20200171025A1 (en) Pharmaceutical composition comprising brexpiprazole and process for preparation thereof
US20120121700A1 (en) Pharmaceutical formulations comprising valganciclovir
JP6199922B2 (en) Irbesartan-containing tablets with improved chemical stability
US9775832B2 (en) Pharmaceutical composition for oral administration
US11452722B2 (en) Stable pharmaceutical compositions comprising lenalidomide
EP4279075A1 (en) A pharmaceutical composition comprising elagolix
JP6233911B2 (en) Irbesartan-containing tablets with improved chemical stability
JP6506810B2 (en) Solid dispersion of fenofibrate
WO2022138549A1 (en) Solid dispersion
WO2022153330A1 (en) Pharmaceutical compositions comprising acalabrutinib
JP2022547307A (en) Pharmaceutical formulations of indoleamine 2,3-dioxygenase inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15714010

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15714010

Country of ref document: EP

Kind code of ref document: A1